Clinical trial NCT02505269
Conditions: Hodgkin Lymphoma
Keywords: limited stage Hodgkin's disease non-bulky
Sponsor: Massachusetts General Hospital
Start date: 2015-08-07; Completion date: 2019-06-01
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Limited stage Hodgkin lymphoma is a highly curable disease, but standard treatment with ABVD chemotherapy and radiation can lead to late risks of secondary cancers, lung injury, heart injury, and others. This trial eliminates radiation therapy and reduces intensity of chemotherapy by incorporating the highly active FDA-approved targeted therapy brentuximab vedotin, an antibody-drug conjugate specifically against the lymphoma cells, combined with the standard chemotherapy drugs Adriamycin and Dacarbazine (AD).

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. It also means that the FDA (the U.S. Food and Drug Administration) has not yet approved brentuximab vedotin (brentuximab) as part of the initial treatment of Hodgkin lymphoma. Currently, brentuximab is FDA-approved for treatment of relapsed Hodgkin lymphoma.

* Brentuximab works by binding specifically to Hodgkin lymphoma cells, entering the cells, and then releasing the drug to destroy the cell.
* The chemotherapy drugs Adriamycin and Dacarbazine (AD) which which participants will receive in this research study are approved for use in people with Hodgkin Lymphoma.
* Patients will not receive planned radiation therapy, or the drugs bleomycin or vinblastine.

Arms: arm 1: The following procedures will take place during study visits beginning after the screening procedures:

\- Participants will receive combination therapy:

* Brentuximab Vedotin intravenously on predetermined days per cycle
* Adriamycin intravenously on predetermined days per cycle
* Dacarbazine intravenously on predetermined days per cycle
Interventions: intervention 1: Brentuximab Vedotin intervention 2: Adriamycin intervention 3: Dacarbazine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 




Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntial. D o n ot di scl ose or use e xce pt as a ut h orize d.  
 
T A B L E O F C O N T E N T S 
1.  
O B J E C TI V E S .................................................................................................................... ................................ 1 
1. 1  
St u dy De si g n .................................................................................................................................................... 1 
1. 2  
Pri m ary O bjective ............................................................................................................. .............................. 1 
1. 3  
Sec o n d ary O b jective ........................................................................................................... ............................. 1 
1. 4  
E n d p oi nts ..................................................................................................................... .................................... 1 
2.  
B A C K G R O U N D .................................................................................................................... ............................ 1 
2. 1  
St u dy A ge nt(s) ................................................................................................................ ................................. 1 
2. 2  
H o d gki n Ly m p h o m a .............................................................................................................. .......................... 3 
2. 3  
R ati o n ale ..................................................................................................................... .................................... 4 
3.  
P A R TI CI P A N T S E L E C TI O N ......................................................................................................... ................. 4 
3. 1  
I ncl usi o n Criteri a ............................................................................................................ ................................ 5 
3. 2  
Excl usi o n Cr iteri a ........................................................................................................................................... 5 
3. 3  
I ncl usi o n of W o me n, Mi n orities a n d Other U n derre prese nte d P o p ul ati o ns ................................................... 6  
4.  
R E GI S T R A TI O N P R O C E D U R E S ....................................................................................................... ........... 6 
4. 1  
Ge ner al G ui deli nes f or D F/ H C C a n d D F/ P C C I n stit uti ons ......................................................................... .. 6 
4. 2  
Re gistr ati o n Pr ocess f or D F/ H C C a n d D F/ P C C I n stit uti o ns ..................................................................... 6 
4. 3  
Ge ner al G ui deli nes f or Ot her P artici p ati n g I nstit uti o ns ................................................................................. 6 
4. 4  
Re gistr ati o n Pr ocess f or Ot her P artici p ati n g I nstit uti o ns ............................................................................... 6 
5.  
T R E A T M E N T P L A N ................................................................................................................ ........................ 7 
5. 1  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p ortive C are G ui deli nes ............................................................... 8  
5. 2  
D ur ati o n of T her a py ........................................................................................................... ............................. 8 
5. 3  
D ur ati o n of F oll o w U p ......................................................................................................... ........................... 8 
5. 4  
Criteri a f or Re m ov a l fr o m St u dy ..................................................................................................................... 8 
6.  
E X P E C T E D T O XI CI TI E S A N D 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 ...................................... 9 
6. 1  
A ntici p ate d T oxicities f or Bre nt uxi m a b, A d ri a myci n, Vi n bl asti ne, D ac ar b azi ne ............................................ 9  
6. 2  
T oxicity M a n a ge me nt a n d D o se M o dific ati ons/ Del ays ............................................................................. .... 1 1 
7.  
D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N ................................................................................. 1 4  
7. 1  
Bre nt uxi m a b ................................................................................................................... ............................... 1 4 
7. 2  
A dri a m yci n .................................................................................................................... ................................ 1 8 
7. 3  
D ac ar b azi ne ................................................................................................................... ............................... 1 9 
8.  
S T U D Y C A L E N D A R ................................................................................................................ ...................... 2 0 
8. 1  
Pre- Tre at me nt Ev al u ati o ns: w it hi n 4 2 d ays of t he st art of pr ot oc ol t her a py ................................................ 2 0 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntial. D o n ot di scl ose or use e xce pt as a ut h orize d.  
8. 2  
Ev al u ati o n D uri n g Tre at me nt.  All tre at me nt visits are +/- 3 d ays: ............................................................ .. 2 1 
8. 3  
P ost- Tre at me nt  Ev al u ati o n ............................................................................................................................ 2 1 
9.  
M E A S U R E M E N T O F E F F E C T.......................................................................................................... ........... 2 5 
9. 1  
A ntit u m or E ffect ............................................................................................................................................ 2 5 
1 0.  
A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S ............................................................................... 2 5  
1 0. 1  
Defi niti o ns ................................................................................................................... ............................. 2 5 
1 0. 2  
Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p or ti n g ............................................................................ 2 7  
1 0. 3  
Re p orti n g Re q u ire me nts ........................................................................................................................... 2 7 
1 0. 4  
Re p orti n g t o t he St u dy S p o ns or ................................................................................................ ................ 2 7 
1 0. 5  
Re p orti n g t o t he I nstit uti o n al Revie w B o ar d (I R B) ................................................................................... 2 9 
1 0. 6  
Re p orti n g t o t he F o o d a n d Dr u g A d mi nistr ati o n ( F D A) .......................................................................... 2 9  
1 0. 7  
Re p orti n g t o Se attle Ge netics ................................................................................................. .................. 2 9 
1 0. 8  
Re p orti n g t o H os pit al  Risk M a n a ge me nt .................................................................................................. 3 0 
1 0. 9  
M o nit ori n g of A dverse Eve nts a n d Peri o d of O bserv a ti o n ....................................................................... 3 0  
1 1.  
D A T A A N D S A F E T Y M O NI T O RI N G .................................................................................................... ...... 3 0 
1 1. 1  
D at a Re p o rtin g ................................................................................................................ ......................... 3 0 
1 1. 2  
S afety Mee ti n gs ......................................................................................................................................... 3 1 
1 1. 3  
M o nit o ri n g ................................................................................................................................................ 3 1 
1 2.  
R E G U L A T O R Y C O N S I D E R A TI O N S .......................................................................................................... 3 2 
1 2. 1  
Pr ot oc ol Revie w a n d A me n d m e nts ................................................................................................ ........... 3 2 
1 2. 2  
I nf or me d C o nse nt ..................................................................................................................................... 3 2 
1 2. 3  
Et hics ........................................................................................................................ ................................ 3 2 
1 2. 4  
St u dy D oc u me nt ati o n ........................................................................................................... ..................... 3 3 
1 2. 5  
Rec or ds Re te nti o n ..................................................................................................................................... 3 3 
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S .................................................................................................... ........ 3 4 
1 3. 1  
St u dy Desi g n/ E n d p oi nts ........................................................................................................ .................... 3 4 
1 4.  
R E F E R E N C E S .................................................................................................................... ............................. 3 6 
1 5.  
A P P E N DI C E S ...................................................................................................... Err or! B o o k mar k n ot defi ne d.  
A p pe n dix A: O bjective Res p o nse Criteri a (see De a uville  criteri a o n next p a ge f or i nter pret ati o n of P E T 
p ositive/ ne g at ive) .................................................................................................................................................... 3 8 
A p pe n dix B: Perf or m a nce St at us Criteri a ....................................................................................... ....................... 4 0 
A p pe n dix C: Dr u g  i nter acti o ns ............................................................................................................................... 4 1 
A p pe n dix D: F A C T/ G O G Ne ur ot oxic ity Q uesti o n n aire, Versi o n 4. 0 1 9 .............................................................. .. 4 2 
A p pe n dix E: M ulti- Ce nter D at a a n d S afety M o n it ori n g Pl a n ................................... Err or! B o o k m ar k n ot defi ne d.  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 
1.  O B J E C TI V E S 
 
1. 1  St u d y Desi g n 
 
T his  is  a n  o pe n  la bel  si n gle ar m  p hase  II  st u d y  t o  assess  t h e  efficac y  a n d  safet y  of 
Bre nt u xi ma b Ve d oti n ( hereafter re ferre d t o as bre nt u xi ma b) i n c o m bi nati o n wit h A dria m yci n 
a n d Dacar bazi ne ( A D) i n patie nts wit h pre vi o usl y u ntreate d sta ge I a n d II n o n- b ul k y classical 
H o d g ki n l y m p h o ma (c H L). All patie nts will re cei ve c o m bi nati o n t hera p y wit h bre nt u xi ma b 
a n d A D wit h all a ge nts a d mi nistere d o n da ys 1 a n d 1 5 of eac h 2 8 da y c ycle.  Bre nt u xi ma b 
will be a d mi nistere d at 1. 2 m g / k g. A D will be a d mi nistere d at sta n dar d d oses ( A dria m yci n 
2 5 m g/ m 2, Dacar bazi ne 3 7 5 m g/ m2).  I nteri m resta gi n g P E T- C T will be perf or me d f oll o wi n g 
c ycle 2. Patie nts wit h pr o gressi ve  disease will be ta ke n off st u d y.  Patie nts i n C R will recei ve 
a t otal of 4 c ycles of t hera p y;  patie nts wit h sta ble disease or partial res p o nse will recei ve a 
t otal  of  6  c ycles.  T here  is  n o  pla n ne d  ra di ot hera p y  f or  patie nts  achie vi n g  a  c o m plete 
re missi o n at t he e n d of t hera p y. 
 
1. 2  Pri m ar y O bjecti ve 
1. 2. 1  T o i n vesti gate t he cli nical acti vit y of  Bre nt u xi ma b wit h A D i n u ntreate d n o n-
b ul k y sta ge I a n d II Classica l H o d g ki n L y m p h o ma (c H L)   
1. 3  
Sec o n d ar y O bjecti ve 
1. 3. 1  T o descri be t he safet y a n d t olera bilit y of Bre nt u xi ma b c o m bi ne d wit h A D i n 
pre vi o usl y u ntreate d n o n - b ul k y li mite d sta ge c H L 
1. 4  
E n d p oi nts 
1. 4. 1  Pri mar y: C o m plete res p o nse rate ( C R R) at e n d of treat me nt resta gi n g, b y t he 
re vise d I nter nati o nal W or ki n g Gr o u p Criteria (see a p pe n di x A) 1 
1. 4. 2  Sec o n dar y: 
 Rate of gra de III a n d I V a d verse e ve nts  or disc o nti n uati o n d ue t o t o xicit y 
 O verall res p o nse rate ( O R R) at  e n d of treat me nt resta gi n g 
1. 4. 3  E x pl orat or y: 
 Fail ure-free s ur vi val ( F F S) 
 O verall s ur vi val ( O S) 
 
2.  B A C K G R O U N D 
 
2. 1  St u d y A ge nt(s) 
 
2. 1. 1  Bre nt u xi ma b Ve d oti n ( S G N- 3 5, A dcetris) 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2  
Bre nt u xi ma b  ve d oti n  is  a n  a nti- C D 3 0  a nti b o d y - dr u g  c o nj u gate  ( A D C)  c o nsisti n g  of  a n 
I g G 1 a nti b o d y a gai nst C D 3 0 b o u n d t o t he a nti- micr ot u b ule a ge nt m o n o met h yl a uristati n 
E  ( M M A E).  T here  ha ve  bee n  t w o  p hase  II st u dies  of  si n gle  a ge nt  bre nt u xi ma b  i n 
rela pse d/refract or y c H L a n d rela pse d/refract ory s yste mic a na plastic lar ge cell l y m p h o ma 
( A L C L).2, 3  I n t he pi v otal p hase II st u d y of c H L 1 0 2 patie nts recei ve d bre nt u xi ma b at 1. 8 
m g/ k g e ver y 3 wee ks.  T his pa tie nt p o p ulati o n was hea vil y pre-treate d wit h a me dia n of 
3. 5  pri or  treat me nts.    Se ve nt y-fi ve  perce n t  of  patie nts  ha d  a n  o bjecti ve  res p o nse 
(c o m plete or partial re missi o n) wit h me dia n d urati o n of a p pr o xi matel y 9 m o nt hs.  T hirt y-
f o ur  perce nt  of  patie nts  ac hie ve d  a  c o m plete  res p o nse  ( C R).    I n  t he  p hase  II  st u d y  of 
rela pse d or refract or y A L C L 3 8 patie nts recei ve d bre nt u xi ma b als o at 1. 8 m g/ k g e ver y 3 
wee ks.    Se ve nt y-t w o  perce nt  of  patie nts  were  A L K  ne gati ve  ( w hic h   t y picall y  carries  a 
p o or  pr o g n osis)  a n d  patie nts  ha d  recei ve d  a  me dia n  of  2  pri or  s yste mic  t hera pies.    T he 
o bjecti ve  res p o nse  rate  ( O R R)  was  8 6 %  wit h   C R  o btai ne d  i n  5 3 %  of  patie nts  ( me dia n 
d urati o n  of  res p o nse  n ot  yet  reac he d).    Nearl y  all  patie nts  ( > 9 0 %)  i n  b ot h  st u dies 
e x perie nce d a re d ucti o n i n t u m or v ol u me.  A p hase I st u d y e val uate d t he c o m bi nati o n of 
bre nt u xi ma b ve d oti n wit h eit her A B V D or A V D ( wit h o ut ble o m yci n). 4 T he ble o m yci n-
c o ntai ni n g  ar m  was  f o u n d  t o i n d uce  e xcess  p ul m o nar y  t o xicit y,  b ut  bre nt u xi ma b  wit h 
A V D  was  f o u n d  t o  be  o verall  well t olerate d  wit h  e xcelle nt  efficac y  i n  patie nts  wit h 
a d va nce d sta ge disease. T he rec o m me n de d p hase II d ose f or bre nt u xi ma b c o m bi ne d wit h 
A V D is 1. 2 m g/ k g e ver y 2 wee ks.    
 
Bre nt u xi ma b  has  bee n  well  t olerate d  i n  cli n ical  trials  t o  date  (see  secti o n  6. 1).  
Treat me nt-ass ociate d a d verse e ve nts ( A Es) occ urri n g i n ≥ 2 0 % of patie nts i n t he p hase II 
st u dies  c o m bi ne d  i ncl u de  peri p heral  se ns ory  ne ur o pat h y  ( 4 4 %),  fati g ue  ( 4 2 %),  na usea 
( 4 1 %),  diarr hea  ( 3 4 %),  p yre xia  ( 3 1 %),  u p per  res pirat or y  tract  i nfecti o n  ( 2 8 %), 
ne utr o pe nia ( 2 1 %), a n d v o miti n g ( 2 0 %).  T hese e ve nts were pri maril y Gra de 1 or 2, wit h 
t he  e xce pti o n  of  ne utr o pe nia,  f or  w hic h  Gra de  3  a n d  gra de  4  e ve n ts  were  re p orte d  f or 
1 3 %  a n d  7 %  of  patie nts,  res pecti vel y.  I m p orta ntl y,  m ost  of  t he  peri p heral  se ns or y 
ne ur o pat h y e ve nts were re versi b le.  Als o, of n ote, si milar patter ns a n d i nci de nces of A Es 
were ge nerall y o bser ve d f or H L a n d A L C L patie nts.  
 
Bre nt u xi ma b  p har mac o ki netics  were  as  f oll o ws .    After  a n  i ntra ve n o us  (I V)  d ose  of  1. 8 
m g/ k g  e ver y  3  wee ks,  ma xi m u m  c o nce ntrati o ns   were  t y picall y  o bser ve d  at  t he  e n d  of 
i nf usi o n.  A  m ulti-e x p o ne ntial  decli ne  i n bre nt u xi ma b  a nti b o d y- dr u g  c o nj u gate  ( A D C) 
ser u m c o nce ntrati o ns was o bser ved wit h a ter mi nal half-life of  a p pr o xi matel y 4 t o 6 da ys. 
E x p os ures were a p pr o xi matel y d ose pr o p orti o na l.  Stea d y-state was ac hie ve d b y 2 1 da ys, 
c o nsiste nt wit h t he ter mi nal  half-life esti mate. Mi ni mal t o n o acc u m ulati o n was o bser ve d 
wit h m ulti ple d oses at t he q 3 w k (e ver y 3 wee ks) sc he d ule. T he pri mar y treat me nt-relate d 
effects of re peat- d ose bre nt u xi ma b a d mi nistrati o n t o rats a n d m o n ke ys were b o ne marr o w 
h y p ocell ularit y a n d l y m p h oi d de pleti o n.  T he n o- o bser ve d-a d verse-effect le vel ( N O A E L) 
f or re peat- d ose a d mi nistrati o n of bre nt u xima b was 0. 5 a n d 1 m g/ k g i n rat a n d m o n ke y, 
res pecti vel y. T he hi g hest n o nse verel y t o xic d ose ( H N S T D) f or re peat- d ose a d mi nistrati o n 
of bre nt u xi ma b was 5 a n d 3 m g/ k g i n rat a n d m o n ke y, res pecti vel y. I n u p t o o ne- m o nt h 
re peat- d ose t o xicit y st u dies of bre nt u xi ma b i n rats at d oses u p t o 1 5 m g/ k g, t he f oll o wi n g 
tar get  or ga ns  were  i de ntifie d:  b o ne  marr o w  ( h y p ocell ularit y),  t h y m us  (l y m p h oi d 
de pleti o n),  s plee n  (l y m p h oi d  de pleti o n),  li ver  (f ocal  c oa g ul ati ve  necr osis),  i ntesti ne 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3  
(si n gle  cell  necr osis),  testis  (se mi nifer o us  t u b ular  de generati o n),  a n d  l u n g  (al ve olar 
histi oc yt osis)  i n  rat  o nl y.  F oll o wi n g  a  4- wee k   rec o ver y  peri o d,  all  tar get  or ga n  t o xicit y 
was  re versi ble  e xce pt  f or  testic ular  t o xicit y.  Testic ular  t o xicit y  i n  rat  was  partiall y 
res ol ve d f oll o wi n g a 1 6- wee k off-treat me nt rec o ver y p hase. 
 
Base d o n t he a b o ve data, t he O nc ol o g y Dr u g A d vis or y C o m mittee v ote d u na ni m o usl y o n 
7/ 1 4/ 1 1  t o  rec o m me n d  bre nt u xi ma b  ve d oti n be  F D A-a p pr o ve d  f or  rela pse d  classical 
H o d g ki n L y m p h o ma a n d a na pla stic lar ge cell l y m p h o ma. 
 
We  c o n d ucte d  a  p hase  2  st u d y  of  3 4  patie nt s  wit h  n o n- b ul k y  li mite d  sta ge  classical 
H o d g ki n l y m p h o ma, w hic h c o m plete d accr ual  i n 2 0 1 4.  T h o u g h data are i m mat ure, t he 
treat me nt a p peare d hi g hl y effecti ve a n d o verall well t olerate d.  Preli mi naril y, all patie nts 
ac hie ve d  c o m plete  res p o nse  after  2  c ycles of  c o m bi natri o n  bre nt u xi ma b- A D  a n d  n o 
patie nts  re q uire d  m ore  t ha n  4  c ycles  of c o m bi nati o n  c he m ot hera p y.    O ne  patie nt  di d 
rela pse after ac hie vi n g re missi o n a n d was s uccessf ull y treate d wit h sec o n d-li ne t hera p y.  
O ne  a d diti o nal  patie nt  de vel o pe d  ne utr o pe nic  se psis  a n d  die d  i n  re missi o n  d uri n g 
t hera p y.  A n i nitiall y hi g h rate of ne utro pe nic fe ver was o bser ve d, pr o m pti n g a pr ot oc ol 
a me n d me nt re q uiri n g t he use of G C S F s u p p ort, af ter w hic h t he i nci de nce of i nfecti o n a n d 
ne utr o pe nic fe ver was m uc h l o wer. 
 
 
2. 2  H o d g ki n L y m p h o m a 
 
O ver  t he  last  4 0 +  years  a d va nces  i n  t he treat me nt  H o d g ki n  L y m p h o ma  ha ve  le d  t o  a 
re mar ka ble  i m pr o ve me nt  i n  t he  l o n g-ter m o utc o mes  of  w hat  was  o nce  c o nsi dere d  a n 
i nc ura ble disease. Classical H o d g ki n l y m p h o ma (c H L) n o w carries o ne of t he m ost fa v ora ble 
pr o g n oses  i n  o nc ol o g y  wit h  patie nts  wit h  li mite d  sta ge  diseas e  ac hie vi n g  c ure rates  greater 
t ha n 8 5 %.5- 8  C o m bi ne d m o dalit y t hera p y has l o n g bee n t he sta n dar d of care f or li mite d sta ge 
disease,  t h o u g h  treat me nt  para di g ms  c o nti n ue t o  e v ol ve  wit h  c urre nt  eff orts  f oc use d  o n 
preser vi n g  hi g h  rates  of  c ure  w hile  mi ni mizi n g  p ote ntiall y  de vastati n g  late  effects  of 
ra diati o n a n d c he m ot hera p y i ncl u di n g sec o n dar y mali g na ncies a n d e n d or ga n da ma ge s uc h as 
heart a n d p ul m o nar y disease.  
 
I n  t he  last  deca de  t here  ha ve  bee n  a  n u m ber  of  p u blicati o ns  descri bi n g  t he  l o n g-ter m 
o utc o mes  of  patie nts  treate d  wit h  c o m bi ne d   m o dalit y  t hera p y  (i.e.  c he m ot hera p y  pl us 
ra diati o n) a n d c he m ot hera p y al o ne, wit h si milarl y e xcelle nt res ults re p orte d i n patie nts wit h 
n o n- b ul k y  li mite d  sta ge  disease.    St u dies  of  ra diati o n-c o ntai ni n g  strate gies  de m o nstrate  a 
c o nti n ue d ris k of treat me nt-relate d m or bi dit y  a n d m ortalit y d ue t o sec o n d mali g na ncies a n d 
car di o vasc ular  disease  well  afte r  t he  ris k  of  H L  rela pse  has  pea ke d.    F or  e xa m ple,  i n 
a n a nal ysis of 1, 4 7 4 patie nts tr eate d at a ge less t ha n  4 1, a si g nifica nt i ncrease of m y ocar dial 
i nfarcti o n ( 3 5. 7 e xcess cases per 1 0, 0 0 0 pt/ y) a n d c o n gesti ve heart fail ure ( 2 5. 6 e xcess cases 
per 1 0, 0 0 0 pt/ y) were see n i n patie nts  treate d wit h me diasti nal ra diati o n.9  T hese ris ks were 
greatl y i ncrease d if ra diati o n was c o m bi ne d wit h a n a nt hrac ycli ne.  I n a retr os pecti ve re vie w 
of  1, 0 8 0  patie nts  wit h  sta ge  I A-II B  disease  treate d  bet wee n  1 9 6 9  a n d  1 9 9 7,  t here  was  a 
relati ve ris k of deat h fr o m sec o n dar y ca ncers of 1 0- 1 4. 5, a n d fr o m car diac ca uses of 2. 8 t o 
4. 5. 1 0   


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
4  
 
Gi ve n  t hese  a d verse  late  o utc o mes  t here  ha ve  b ee n  eff orts  t o  de-escalate  t hera p y  wit h  t he 
h o pe of re d uci n g t o xicit y  w hile mai ntai ni n g hi g h c ure rates.  A strate g y e m plo yi n g 4- 6 c ycles 
of A B V D ( A dria m yci n, Ble o m yci n, Vi n blasti ne a n d Dacar bazi ne) wit h or wit h o ut ra diati o n 
i n  li mite d  sta ge  disease  f o u n d  n o  differe nce  i n  o verall  s ur vi val  bet ween  t hese  gr o u ps  at  5 
years of f oll o w- u p. 7 A nal ysis of t his ra n d o mize d trial at 1 2 years, h o we ver, de m o nstrate d a n 
i m pr o ve d o verall s ur vi val i n patie nts treate d wit h 4- 6 c ycles of A B V D al o ne o ver c o m bi ne d 
m o dalit y  t hera p y  d ue  t o  i ncrease d  late  e ve nts  i n  patie nts  treate d  wit h  ra diati o n.  
C he m ot hera p y  al o ne  yiel de d  a  fa v ora ble 1 2  year  o verall  s ur vi val  of  9 4 %. 1 1   M ulti ple  ot her 
pr os pecti ve a n d retr os pecti ve a nal yses ha ve f urt her vali dat e d A B V D c he m ot hera p y al o ne i n 
n o n- b ul k y li mite d sta ge c H L 1 2- 1 5  
 
W hile  a  c he m ot hera p y  al o ne  a p pr oac h  is  a p peali n g,  t he  sta n dar d  A B V D  re gi me n  is  n ot 
wit h o ut t o xicit y. P ul m o nar y t o xicit y fr o m Ble o m yci n is t he maj or n o n- he mat ol o gic t o xicit y 
of A B V D wit h i nci de nce of p ne u m o nitis ra n gi n g  fr o m 8- 1 4 %, a n d ma y res ult i n treat me nt-
relate d m ortalit y. Ne utr o pe nia is als o c o m m o n, a n d ma y be w orse w he n bre nt u xi ma b ve d oti n 
is  a d de d  t o  A V D,  base d  o n  a  hi g h  rate  of  ne utr o pe nic  fe ver  o bser ve d i n  o ur  p hase  2  trial 
pr o m pti n g a d diti o n of r o uti ne gr o wt h fact or s u p p or t.  We als o o bser ve d a si g nifica nt rate of 
peri p heral  ne ur o pat h y,  li kel y relate d  t o  t he  c o m bi nati o n  of  vi n blasti ne  a n d  bre nt u xi ma b 
ve d oti n, b ot h of w hic h ca use ne ur o p at h y d ue t o acti vit y o n micr ot u b ules. 
 
T he  Ger ma n  H o d g ki n  St u d y  gr o u p  e x pl ore d w het her  Ble o m yci n  a n d  Dacar bazi ne  are 
re q uire d t o preser ve t he efficac y of t his c o m bi nati o n b y c o m pari n g A B V D, A V B, A V D, a n d 
A V. 1 6  I n t he fi nal a nal ysis, t he o missi o n of Dacar bazi ne res ulte d i n a si g nifica ntl y i nferi or 
o utc o me,  a n d  o missi o n  of  ble o m yci n  als o  res ult e d  i n  a  sli g htl y  i nfe ri or  P F S  c o m pare d  t o 
A V D a n d A B V D. A n ot her atte m pt t o eli mi nate b ot h ble o m yci n a n d dacar bazi ne i n a p hase II 
C A L G B trial of A V G ( A dria m yci n, Vi n blasti ne a n d Ge mcita bi ne) i n n o n- b ul k y li mite d sta ge 
patie nts, h o we ver, res ulte d i n disa p p oi nti n g efficac y wit h a C R rate of 7 2. 7 % a n d 3- year P F S 
of 7 7 %. 1 7  T hese e x pereic nes s u g gest t hat a m ore p ote nt a nti-l y m p h o ma t hera p y w o ul d nee d 
t o be a d de d i n or der t o o mit ble o m yci n wit h preser ve d efficac y. 
 
2. 3  
R ati o n ale 
T he cli nical efficac y of t he A B V D re gi me n is li kel y t o be preser ve d or i m pr o ve d b y a d di n g 
bre nt u xi ma b,  t he  si n gle  m ost  acti ve  a ge nt  e v er  i de ntifie d  i n  H o d g ki n  l y m p h o ma,  w hile 
eli mi nati n g  t he  Ble o m yci n  will  re m o ve  t he  p ot e ntiall y  de vastati n g  ris k  of  ble o m yci n  l u n g 
i nj ur y.  Gi ve n t he o verla p pi n g mec ha nis m of acti o n of vi n blasti ne a n d bre nt u xi ma b ve d oti n 
tar geti n g  micr ot u b ules,  we  h y p ot hesize  t hat s u bstit uti n g  bre nt u xi ma b  f or  vi n blasti ne  will 
preser ve  efficac y  w hile  i m pr o vi n g  t he  t o xicit y pr ofile  wit h  a  re d ucti o n  i n  ne utr o pe nia  a n d 
peri p heral  ne ur o pat h y.  We  are  t h eref ore  c o n d ucti n g  t his  p hase II  trial  of  bre nt u xi ma b  i n 
c o m bi nati o n wit h A D ( A dria m yci n a n d Dacar bazi ne) as i nitial t hera p y f or n o n- b ul k y li mite d 
sta ge c H L. 
 
 
3.  P A R TI CI P A N T S E L E C TI O N 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
5  
Eli gi bilit y tests f or s u bjects m ust be c o m plete d wit hi n 4 2 da ys pri or e nr o ll me nt, u nless ot her wise 
state d. 
 
3. 1  
I ncl usi o n Criteri a 
 
3. 1. 1  Pre vi o usl y u ntreate d sta ge I A, I B, II A,  or II B classical H o d g ki n L y m p h o ma   
3. 1. 2  N o n- b ul k y disease defi ne d as less t ha n 1 0 c m i n ma xi mal dia meter 
3. 1. 3  Meas ura ble disease ≥ 1. 5 c m as meas ure d o n P E T- C T 
3. 1. 4  A ge ≥ 1 8   
3. 1. 5  E C O G perf or ma nce stat us 0- 2 (see A p pe n di x B) 
3. 1. 6  Partici pa nts m ust ha ve i nitial or ga n a n d marr o w f u ncti o n as defi ne d bel o w: 
 A bs ol ute ne utr o p hil c o u nt >  1, 0 0 0/ mc L 
 Platelets >  1 0 0, 0 0 0/ mc L 
 T otal bilir u bi n ≤ 2, u nless d ue t o Gil bert’s disease 
 A S T ( S G O T)/ A L T ( S G P T) <  2. 5 X i nstit uti o nal u p per li mit of n or mal 
 Creati ni ne cleara nce ≥3 0 m L/ mi n 
3. 1. 7  L V E F b y ec h ocar di o gra m or M U G A wit hi n i nstit uti o nal n or mal li mits  
3. 1. 8  Partici pa nt  m ust  be  willi n g  t o  use  t w o effecti ve  f or ms  of  birt h  c o ntr ol  d uri n g 
pr ot oc ol  t hera p y.  Me n  a n d  w o me n  m ust  c o nti n ue  usi n g  t w o  effecti ve  f or ms  of 
birt h c o ntr ol f or 6 m o nt hs f oll o wi n g treat me nt.  
3. 1. 9  A bilit y t o u n dersta n d a n d t he willi n g ne ss t o si g n a writte n i nf or me d c o nse nt 
d oc u me nt  
 
3. 2  
E xcl usi o n Criteri a 
 
3. 2. 1  Partici pa nts w h o ha ve ha d pri or c H L- di recte d c he m ot hera p y or ra di ot hera p y  
3. 2. 2  Partici pa nts recei vi n g a n y ot her i n vesti gati o nal a ge nts 
3. 2. 3  Partici pa nts wit h k n o w n C N S i n v ol ve me nt of l y m p h o ma 
3. 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 A dria m yci n, Dacar bazi ne, or bre nt u xi ma b 
3. 2. 5  Pre-e xisti n g gra de 2 or  greater ne ur o pat h y  
3. 2. 6  U nc o ntr olle d  i nterc urre nt  ill ness  i n cl 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, s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac 
arr h yt h mia,  or  ps yc hiatric  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 
3. 2. 7  Pre g na nt w o me n are e xcl u de d fr o m t his st u d y beca use bre nt u xi ma b is a n a nti b o d y 
dr u g  c o nj u gate  wit h  a  li n ke d  p ote nt  a nti -t u b ule  a ge nt  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 
of  a d verse  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 
bre nt u xi ma b,  breastfee di n g  s h o ul d  be  disc o nt i n ue d  if  t he  m ot her  is  treate d  wit h 
bre nt u xi ma 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. 
3. 2. 8  Partici pa nts  wit h  a  hist or y  of  a  differe nt  mali g na nc y  are  i neli gi ble  u nless  t he y 
ha ve  bee n  disease  free  f or  1  year  a n d  c o nsi dere d  at  l o w  ris k  f or  rela pse,  e xce pt 
f or: cer vical ca ncer i n sit u, d uctal carci n o ma i n sit u, l ocalize d pr ostate ca ncer wit h 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
6  
n o detecta ble disease b y i ma gi n g st u dies,  a n d n o n- mela n o ma ca ncers of t he s ki n, 
w hic h are eli gi ble at a n y ti me.  
3. 2. 9  K n o w n HI V p ositi vit y 
3. 3  
I ncl usi o n of W o me n, Mi n orities a n d Ot her U n derre prese nte d P o p ul ati o ns 
T here  is  n o  e vi de nce  t o  s u g gest  t hat  t he  o utc o me  will  differ  b y  ge n der  or  et h nicit y.  
Gi ve n t he s mall size of o ur st u d y t here is i ns u fficie nt p o wer t o detect s mall effects i n 
t hese  gr o u ps.    T here  is  n o  pla n  t o  e xclu de  w o me n,  mi n orities or  u n derre prese nte d 
p o p ulati o ns a n d t he y will be a ble t o partici pate if eli g i bilit y criteria are met.  
 
4.  R E GI S T R A TI O N P R O C E D U R E S 
   
4. 1  
Ge ner al G ui deli nes f or D F / H C C a n d D F/ P C C I nstit uti o ns 
I nstit uti o ns  will  re gister  eli gi ble  partici pa nts  wit h  t he  Cli nical  Trials  Ma na ge me nt 
S yste m  ( C T M S)  O n C ore.    Re gistrati o n  m ust occ ur  pri or  t o  t he  i n itiati o n  of  pr ot oc ol 
t hera p y.  A n y  partici pa nt  n ot  re gistere d  t o  t he  pr ot oc ol  bef ore  pr ot oc ol  t hera p y  be gi ns 
will be c o nsi dere d i neli gi ble a n d re gistrati o n will be de nie d.  
 
A n  i n vesti gat or  will  c o nfir m eli gi bilit y  criteria  a n d  a  me m ber  of  t he  st u d y  tea m  will 
c o m plete t he pr ot oc ol-s pecific eli gi bilit y c hec klist. 
  
F oll o wi n g  re gistrati o n,  partici pa nts  ma y  be gi n  pr ot oc ol  t hera p y.  Iss ues  t hat  w o ul d 
ca use treat me nt dela ys s h o ul d be disc usse d wi t h t he O verall Pri nci pal I n vesti gat or ( PI). 
If  a  partici pa nt  d oes  n ot  recei ve  pr otoc ol  t hera p y  f oll o wi n g  re gistrati o n,  t he 
partici pa nt’s  re gistrati o n o n  t he  st u d y  m ust  be  ca ncele d.   Re gistrati o n  ca ncellati o ns 
m ust be ma de i n O n C ore as s o o n as p ossi ble.   
 
4. 2  
Re gistr ati o n Pr ocess f or D F/ H C C a n d D F/ P C C I nstit uti o ns 
 
D F/ H C C  Sta n dar d  O perati n g  Pr oce d ur e  f or  H u ma n  S u bject  Researc h  Title d S u bject 
Pr ot oc ol Re gistr ati o n ( S O P #: R E GI S T- 1 0 1) m ust be f oll o we d. 
 
 
4. 3  
Ge ner al G ui deli nes f or Ot her P artici p ati n g I nstit uti o ns 
Eli gi ble  partici pa nts  will  be  e ntere d  o n  st u d y  ce ntrall y  at  Massac h usetts  Ge neral 
H os pital b y t he C o or di nati n g Ce nter. All site s s h o ul d c o ntact t he C o or di nati n g Ce nter 
t o verif y treat me nt a vaila bilit y pri or t o c o nse nti n g a patie nt. 
 
F oll o wi n g  re gistrati o n,  partici pa nts  ma y  be gi n pr ot oc ol  treat me nt.  Iss ues  t hat  w o ul d 
ca use treat me nt dela ys s h o ul d be disc usse d wit h t he Pri nci pal I n vesti gat or/ S p o ns or. If a 
partici pa nt  d oes  n ot  recei ve  pr ot oc ol  t her a p y  f oll o wi n g  re gistrati o n,  t he  partici pa nt’s 
pr ot oc ol  stat us  m ust  be  c ha n ge d.  T he C o or di nati n g  Ce nter  s h o ul d  be  n otifie d  of 
partici pa nt stat us c ha n ge s as s o o n as p ossi ble. 
 
4. 4  
Re gistr ati o n Pr ocess f or Ot her P artici p ati n g I nstit uti o ns 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
7  
T o re gister a s u bject, t he f oll o wi n g d oc u me nts s h o ul d be c o m plete d b y t he partici pati n g 
i nstit uti o n a n d f or war de d t o t he C o or di nati n g Ce nter: 
 
 C o p y  of 
s o urce  d oc u me ntati o n  f or  all  i nclusi o n/e xcl usi o n  criteria  a n d 
scree ni n g  pr oce d ures ( See secti o n 3 – Partici pa nt Selecti o n  a n d  Secti o n  9  – 
St u d y Cale n dar), i ncl u di n g b ut n ot li mite d t o: 
o  Pat h ol o g y c o nfir mi n g hist ol o g y a n d sta ge  
o  Ec h o or M U G A  
o  La b orat ories  
o  P E T C T re p ort  
 De m o gra p hics i nf or mati o n 
 Si g ne d st u d y c o nse nt f or m 
 St u d y e ntr y n ote d oc u me nti n g t he i nf or me d c o nse nt pr ocess 
 HI P A A a ut h orizati o n f or m, if a p plica ble 
 Eli gi bilit y c hec klist 
T he  C o or di nati n g  Ce nter  will  re vie w  t he  a b o ve  d oc u me ntati o n  a n d  c o ntact  t he 
partici pati n g  site t o  c o nfir m  eli gi bilit y.  T o  c o m plete  t he re gistrati o n  pr ocess,  t he 
C o or di nati n g Ce nter will: 
    Re gister t he partici pa nt o n t he st u d y wit h Q A C T. 
 Fa x or e- mail t he partici pa nt st u d y n u m ber , a n d if a p plica ble t he d ose treat me nt 
le vel, t o t he partici pati n g site. 
    Call t he partici pati n g site a n d ver ball y c o nfir m re gistrati o n, if necessar y. 
 
5.  T R E A T M E N T P L A N   
 
T his  is  a  p hase  II  trial  of bre nt u xi ma b  pl us  A D  ( A dria m yci n  a n d  Dacar bazi ne)  f or  ne wl y 
dia g n ose d,  n o n- b ul k y,  sta ge  I  or   II  classical  H o d g ki n  L y m p h oma.    Treat me nt  will  be 
a d mi nistere d  o n  a n  o ut patie nt  basis.  E x pecte d t o xicities  a n d  p ote ntial  ris ks  as  well  as  d ose 
m o dificati o ns  f or  bre nt u xi ma b/ A D  are  descri be d  i n  Secti o n  6  ( E x pecte d  T o xicities  a n d 
D osi n g  Dela ys/ D ose  M o dificati o n) .  N o  i n vesti gati o nal  or  c o m mercial  a ge nts  or  t hera pies 
ot her  t ha n  t h ose  descri be d  bel o w  ma y  be  a d mi nistere d  wit h  t he  i nte nt  t o  treat  t he 
partici pa nt’s mali g na nc y. All pr ot oc ol-s pecifie d treat me nts are +/ - 3 da ys of t he pla n ne d date, 
u nless ot her wise s pecifie d. 
 
All  partici pa nts  will recei ve  bre nt u xi ma b/ A D  f or  2  c ycles  f oll o we d  b y  a n  i nteri m 
resta gi n g  P E T- C T  sca n.  Patie nts  i n  C R  will  recei ve  2  a d diti o nal  c ycles  of 
bre nt u xi ma b/ A D t o c o m plete a t otal of 4 c ycles of t hera p y; patie nts wit h sta ble disease or 
partial res p o nse will recei ve 4 a d diti o nal c ycles  t o c o m plete a t otal of 6 c ycles. Patie nts 
wit h pr o gressi ve disease will be ta ke n off st u d y.  Bre nt u xi ma b/ A D will be a d mi nistere d 
o n  da ys  1  a n d  1 5  of  eac h  2 8  da y  c ycle.    O n treat me nt  da ys,  partici pa nts  will  recei ve 
bre nt u xi ma b ( 1. 2 m g/ k g) f oll o we d b y A dria m yci n ( 2 5 m g/ m 2 I V) a n d Dacar bazi ne ( 3 7 5 
m g/ m 2 I V).   
Bre nt u xi ma b  ve d oti n  will  be  a d mi nistere d  pri or  t o  a dria m yci n  a n d  dacar bazi ne.  
A dria m yci n a n d dacar bazi ne will be a d mi nistere d via i nstit uti o nal sta n dar ds. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
8  
5. 1  
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes 
 
A B V D is r o uti nel y a d mi nistere d at f ull d ose i n t he setti n g of ne utr o pe nia (see secti o n 6 f or 
d osi n g g ui deli nes).  T his is i n rec o g niti o n t h at t h o u g h ne utr o pe nia is c o m m o n, t he d urati o n of 
ne utr o pe nia  is  s h ort  a n d  fe ver  a n d  i nfecti o us  c o m plicati o ns  are  u nc o m m o n.  F urt her, 
treat me nt  dela y  a n d  re d uce d  d ose  i nte nsit y  may  i m pair  treat me nt  o utc o me.    G- C S F  is  n ot 
r o uti nel y  i ncl u de d  i n  t he  care  of  t hese  patie nts  a n d  t h us  will  be  use d  at  t he  treati n g 
i n vesti gat or’s  discreti o n  i n  t he  setti n g  of  ne utr o pe nia,  a n d  ma y  be  use d  as  pr o p h yla xis  f or 
s u bse q ue nt c ycles if t here is a n e pis o de of fe brile ne utr o pe nia.  
 
5. 2  
D ur ati o n of T her a p y 
 
D urati o n  of  t hera p y  will  de pe n d  o n  i n di vi d ual res p o nse  a n d  t o xicit y.    I n  t he  a bse nce  of 
disease pr o gressi o n or u nacce pta ble t o xicit y, treat me nt will c o nti n ue f or 4 t o 6 t otal c ycles of 
bre nt u xi ma b/ A D,  de pe n di n g  o n  treat me nt  res p o ns e  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 urt her a d mi nistrati o n of treat me nt 
 U nacce pta ble a d verse e ve nt(s), i ncl u di n g Gra de 4 ne ur o pat h y or ot her Gra de 4 
e ve nts felt t o be relate d t o bre nt u xi ma b 
 A n y t o xicit y re q uiri n g d ose dela ys of greater t ha n 2 wee ks 
 Partici pa nt de m o nstrates a n i na bilit y or u n willi n g ness t o c o m pl y wit h t he re gi me n 
a n d/ or d oc u me ntati o n re q uire me nts 
 Partici pa nt deci des t o wi t h dra w fr o m t he st u d y 
 Ge neral or s pecific c ha n ges i n t he partici pa nt's c o n diti o n re n der t he partici pa nt 
u nacce pta ble f or f urt her treat me nt i n t h e o pi ni o n of t he treati n g i n vesti gat or  
 
5. 3  
Criteri a f or Re m o v al fr o m St u d y Tre at me nt 
Partici pa nts  will  be  re m o ve d  fr o m  st u d y  treat me nt  w he n  i nterc urre nt  ill ness,  t o xicit y, 
i na bilit y t o partici pate or a c ha n ge i n c o n diti o n occ urs.   T he reas o n f or treat me nt re m o val 
a n d  t he  date  t he  partici pa nt  was  re m o ve d  m ust   be  d oc u me nte d  i n  t he  st u d y-s pecific  case 
re p ort f or m ( C R F). Alter nati ve care o pti o ns will be disc usse d w it h t he partici pa nt. 
 
I n  t he  e ve nt  of  u n us ual  or  life-t hreate ni n g  c om plicati o ns,  partici pati n g  i n vesti gat ors  m ust 
i m me diatel y  n otif y  t he  Pri nci pal  I n vesti gat or/ S p o ns or,  Jere m y  A bra ms o n,  M D  at  6 1 7- 7 2 4-
4 0 0 0. 
 
5. 4  
D ur ati o n of F oll o w U p  
 
All partici pa nts will be f oll o we d f or ne xt li ne of t hera p y a n d o verall s ur vi val.  A d diti o nall y, 
partici pa nts  w h o  ha ve  bee n  re m o ve d  fr o m st u d y  treat me nt  f or  u nacce pta ble  a d verse  e ve nts 
will be f oll o we d u ntil res ol uti o n or sta b ilizati o n of t he a d verse e ve nt.   
 
 
5. 5  
Criteri a f or Re m o v al fr o m St u d y  
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
9  
Partici pa nts will be re m o ve d fr o m t he st u d y u p o n deat h or wit h dra wal of 
c o nse nt.  T he reas o n f or st u d y re m o va l a n d t he date t he partici pa nt was 
re m o ve d m ust be d oc u me nte d i n t he stu d y-s pecific case re p ort f or m ( C R F).  
6.  E X P E C T E D T O XI CI TI E S A N D 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  
 
D ose  dela ys  a n d  m o dificati o ns  will  be  ma de   usi n g  t he  f oll o wi n g  rec o m me n dati o ns.  T o xicit y 
assess me nts  will  be  d o ne  usi n g  t he  C T E P 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,  w hic h  is  i de nti fie d  a n d  l ocate d  o n  t he  C T E P  we bsite  at: 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o ni c a p plicati o ns/ctc. ht m.  
 
If p ossi ble, s y m pt o ms s h o ul d be ma na ge d s y m pt omaticall y. I n t he case of t o xicit y, a p pr o priate 
me dical treat me nt s h o ul d be use d (i ncl u di n g a nti-e metics, a nti- diarr heals, etc.). 
 
All a d verse e ve nts e x perie nce d b y partici pa nts will be c ollecte d fr o m t he ti me of t he first d ose of 
st u d y  treat me nt,  t hr o u g h  t he  st u d y  a n d  u ntil  t he  final  st u d y  visit.  Partici pa nts  c o nti n ui n g  t o 
e x perie nce  t o xicit y  at  t he  off  st u d y  visit  ma y  be  c o ntacte d  f or  a d diti o nal  assess me nts  u ntil  t he 
t o xicit y has res ol ve d or is dee me d irre versi ble. 
  
6. 1  
A ntici p ate d T o xicities f or Bre nt u xi m a b, A dri a m yci n, D ac ar b azi ne 
6. 1. 1  A ntici pate d T o xicities f or Bre nt u xi ma b 
 
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he a ge nts a d mi nistere d i n 
t his  st u d y  a p pear  bel o w.  M ost  t o xicities  relate d  t o  bre nt u xi ma b  i n  t he  p hase  I  a n d  II 
st u dies  were  Gra de  2  or  less.    A  ta ble  detaili n g  t he  Gra de  3  t o xicities  i n  t he  p hase  II 
st u dies is bel o w.  
 
Peri p heral ne ur o pat h y has bee n c o m m o nl y re p orte d i n t he p hase II wit h 4 4 % of patie nts 
ha vi n g  peri p heral  se ns or y  ne ur o pat h y,  a n d  9 %  peri p heral  m ot or  ne ur o pat h y.  Of  t hese 
o nl y  1 1 %  were  Gra de  3  a n d  t here  were n o  Gra de  4  e ve nts.    T he  ne ur o pat h y  was 
re versi ble i n nearl y all patie nts wit h me dia n res ol uti o n of 6. 6 wee ks.     
 
Ne utr o pe nia occ urre d i n 2 1 % of patie nts i n  t he p hase II st u dies wit h 2 0 % of patie nts ≥  
G ra de 3 ( 1 3 % Gra de 3 a n d 7 % Gra de 4). Ne utr o pe nia ≥ Gra de 3 te n de d t o de vel o p after a 
me dia n of 2 d oses a n d laste d a me dia n of a p pr o xi matel y 1 wee k. Of t he 7 % of patie nts 
wit h Gra de 4 ne utr o pe nia, o nl y 3 ha d ne utr o pe nia t hat laste d ≥ 7 da ys.  
 
 
 




Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 1  
 
N ursi n g/ Patie nt I m plicati o ns: 
1.  M o nit or C B C, platelet c o u nts. 
2.  Vesica nt  -  d o  n ot  e xtra vasate.  Refer  t o e xtra vasati o n  pr ot oc ol  if  i na d verte nt 
i nfiltrati o n occ urs. 
3.  A d vise patie nt of al o pecia. I nstr uct o n h o w t o o btai n wi g, hair piece, etc. Hair l oss 
ge nerall y occ urs 2- 4 wee ks after i n jecti o n a n d is us uall y c o m plete. 
4.  A d vise patie nt of re d disc ol orati o n of ur i ne f or 2 4 h o urs after a d mi nistrati o n of t he 
dr u g. 
5.  A d mi nister a ntie metics as i n dicate d. 
6.  Assess  f or  st o matitis  a n d  treat  s y m pt o maticall y.  Ge nerall y  occ urs  7- 1 0  da ys  after 
i njecti o n. 
7.  Be  a ware  of  " A dria"  flare  -  m ost  c o m m o n reacti o n  c o nsists  of  a n  er yt he mat o us 
strea k u p t he vei n. It is ass ociate d wit h urticaria a n d pr urit us. Occasi o nall y t he use 
of c ortic oster oi ds a n d/ or a n ti hista mi nes has bee n usef ul. 
8.  M o nit or  f or  si g ns  a n d  s y m pt o ms  of  car di o m y o pat h y.  Calc ulate  t otal  c u m ulati ve 
d ose wit h eac h a d mi nistrati o n. 
6. 1. 3  A ntici pate d T o xicities f or Dacar bazi ne 
 
Si de Effects f or Dacar bazi ne i ncl u de: 
1.  He mat ol o gic:  M yel os u p pressi o n;  na dir  of   W B C  a n d  platelet  de pressi o n  occ urs 
a p pr o xi matel y 2 1- 2 5 da ys after treat me nt. 
2.  Der mat ol o gic: Al o pecia; facial fl us hi n g; e x tra vasati o n ma y res ult i n se vere pai n b ut 
has n ot res ulte d i n ti ss ue da ma ge. Ra pi d I V p us h ma y res ult i n pai n al o n g i njecti o n 
site or t hr o m b o p hle bitis. 
3.  Gastr oi ntesti nal: Se vere na usea a n d v o miti n g w hic h c haracteristicall y lesse ns wit h 
eac h s u bse q ue nt dail y d ose. 
4.  He patic: I ncrease d A S T, A L T. 
5.  Re nal: I ncrease d ser u m creati ni ne, B U N. 
6.  Ne ur ol o gic: Facial  parest hesia. 
7.  Ot her: Fl u-li ke s y n dr o me ( wit h fe ver, malais e, m yal gia) rarel y occ urs a b o ut 7 da ys 
after treat me nt a n d lasts 1- 3 wee ks. Rarel y A na p h yla xis. 
 
N ursi n g/ Patie nt I m plicati o ns: 
1.  A d mi nister pr o p h ylactic a n d pr n a nti-e metics. 
2.  M o nit or C B C, platelet c o u nt. 
3.  Ma y  ca use  pai n,  b ur ni n g  of  t he  vei n  w it h  ra pi d  a d mi nistrati o n.  T his  ca n  be 
mi ni mize d b y decreasi n g t he rate of i nf usi o n   
 
 
6. 2  
T o xicit y M a n a ge me nt a n d D o se M o dific ati o ns/ Del a ys 
6. 2. 1  S u p p orti ve care: 
Partici pa nts s h o ul d recei ve f ull s u p p orti ve care per i nstit uti o nal r o uti ne i ncl u di n g bl o o d 
pr o d ucts, a nti bi otics, a ntie metic s, a n d b o wel re gi me n at t he discreti o n of t he pr o vi der.  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 2  
6. 2. 2  Ster oi ds:  
Treat me nt wit h ster oi ds f or pre-e xisti n g c o n di ti o ns, a dre nal i ns ufficie nc y or na usea is 
all o we d pr o vi de d o n a sta ble d ose .  
6. 2. 3  He mat ol o gic T o xicit y:  
Bl o o d  c o u nts  s h o ul d  be  c hec ke d  o n  t he  da y  of  or  da y  bef ore  treat me nt.  He mat ol o gic 
g ui deli nes  are  e xtra p olate d  fr o m  t he  acce pte d  sta n dar d  of  care  wit h  A B V D,  w hic h  is 
r o uti nel y a d mi nistere d at f ull d ose i n t he setti ng of ne utr o pe nia, i n t he a bse nce of fe ver.  
T his is i n rec o g niti o n t hat t h o u g h ne utr o pe nia is c o m m o n, t he d urati o n of ne utr o pe nia is 
s h ort  a n d  fe ver  a n d  i nfecti o us  c o m plicatio ns  are  u nc o m m o n.    G- C S F  is  n ot  r o uti nel y 
i ncl u de d  i n  t he  care  of  t hese  patie nts  o utsi de  of  t he  setti n g  of  fe brile  ne utr o pe nia  or 
i nfecti o ns.   
 
Bl o o d C o u nts 
A d mi nister % of F ull D ose  
A N C 
( ne utr o p hils + b a n ds) 
 
P L Ts  
Bre nt u xi m a b, A dri a m yci n, D ac ar b azi ne D osi n g  
≥5 0 0 
A n d 
≥5 0, 0 0 0 
 
1 0 0 % 
 
< 5 0 0 a n d  patie nt 
afe brile (te m p < 1 0 0. 5 F) 
A n d 
≥5 0, 0 0 0 
 
1 0 0 %. G- C S F s u p p ort ma y be i ncl u de d at discreti o n of 
treati n g i n vesti gat or.  
 
< 5 0 0 a n d  patie nt fe brile 
(te m p ≥1 0 0. 5 F) 
Or  
< 5 0, 0 0 0 
H ol d all c he m ot hera p y a n d rec hec k wit hi n o ne wee k. 
Treat me nt of ne utr o pe nic fe ver per i nstit uti o nal g ui deli nes. 
Restart at f ull d ose o n sc he d ule or wit hi n o ne wee k after 
c o u nts ha ve re b o u n de d t o A N C ≥5 0 0 a n d P L T ≥7 5, 0 0 0. G-
C S F s h o ul d be i ncl u de d f or f ut ure c ycles at treati n g 
p h ysicia n’s discreti o n.  Treat me nt ma y be hel d f or a 
ma xi m u m of 2 wee ks, after w hic h patie nts will be re m o ve d 
fr o m st u d y. 
6. 2. 4  He patic D ysf u ncti o n 
L F T’s s h o ul d be c hec ke d o n t he da y of or da y pri or t o treat me nt.  N o d ose m o dificati o n 
re q uire d f or t otal bilir u bi n less t ha n 1. 5 m g/ d L.  Partici pa nts w it h t otal bilir u bi n of 1. 5 t o 
2. 0 m g/ d L at st u d y e ntr y (a n d n ot d ue t o Gil bert’s dise ase) will be i nitia te d at a 5 0 % d ose 
re d ucti o n  of  A dria m yci n.  F or  t otal  biliru bi n  greater  t ha n  1. 5  m g/ d L  o n  da y  1  or  1 5, 
A dria m yci n will be a d mi nistere d as bel o w. Bre nt u xi ma b ve d oti n will be hel d f or ≥ gra de 
3 bilir u bi n ( > 3 m g/ d L) u ntil t o xicit y is ≤ gra de 2.  U p o n restarti n g, t he bre nt u xi ma b d ose 
will be re d uce d t o 0. 8 m g/ k g.  If a sec o n d d ose re d ucti o n is re q uire d, d ose will be re d uce d 
t o 0. 6 m g/ k g. T here are n o d ose re d ucti o ns f or dacar bazi ne base d o n bilir u bi n. 
 
T otal Bilir u bi n ( m g/ d L)  % Bre nt u xi ma b D ose  
% A dria m yci n D ose  
% Dacar bazi ne D ose
< 1. 5 
1 0 0 % 
1 0 0 % 
1 0 0 % 
1. 5 – 3. 0 
1 0 0 % 
5 0 % 
1 0 0 % 
> 3. 0- 5. 0 
0 % 
2 5 % 
1 0 0 % 
> 5. 0 
0 % 
0 % 
1 0 0 % 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 3  
6. 2. 5  Car diac t o xicit y 
If  a n y  of  t he  f oll o wi n g  car diac  t o xicities  occ ur,  partici pa nts  will  be  re m o ve d  fr o m 
pr ot oc ol: 
 U nc o ntr olle d arr h yt h mia 
 Gra de 3 or 4 C o n gesti ve heart fail ure 
6. 2. 6  Gastr oi ntesti nal t o xicit y 
 M uc ositis, d ys p ha gia a n d diarr hea: 
F or  Gra de 3 gastr oi ntesti nal t o xicities me nti o ne d a b o ve, treat me nt will be hel d 
u ntil t o xicit y decreases t o ≤ 1 or baseli ne, after w hic h treat me nt will be res u me d 
at  f ull  d ose.  Treat me nt  ma y  be  hel d  f o r  a  ma xi m u m  of  2  wee ks,  after  w hic h 
partici pa nts will be re m o ve d fr o m st u d y. 
 C o nsti pati o n: 
Start st o ol s ofte ners a n d mil d b o wel s ti m ula nts ( d oc usate s o di u m 1 0 0 m g p o ti d 
pl us  se n na  a n d/ or  ps ylli u m  a n d/ or  mil k   of  ma g nesia  a n d/ or  Mirala x).    I ncrease 
re gi me n a n d a d d a d diti o nal a ge nts as nee de d.   
6. 2. 7  Peri p heral ner v o us s yste m t o xicit y 
6. 2. 8  I nf usi o n  reacti o ns:  
I nf usi o n  reacti o ns  are  relati vel y  u nc o m m o n  ( 1 1 %  of  patie nts  i n  p hase  II  st u dies).    Pre-
treat me nt is n ot re q uire d, h o we ver, i n vesti gat ors will a d d s u p p orti ve me dicati o ns d uri n g a 
reacti o n  a n d  wit h  s u bse q ue nt  c ycles,  as  i n dicate d.    Patie nts  wit h  pr i or  h y perse nsiti vit y 
reacti o ns  m ust  be  pre- me dicate d  f or  h y perse nsiti vit y  i n  s u bse q ue nt  c ycles  as  per 
i nstit uti o nal r o uti ne f or m o n ocl o nal a nti b o d y t hera p y. 
 
6. 2. 9  Ot her Bre nt u xi ma b t o xicities: 
All  ot her  Gra de  3- 4  t o xicit y  c o nsi dere d  p os si bl y,  pr o ba bl y,  or  defi nitel y  relate d  t o 
bre nt u xi ma b  ( N ot  i ncl u di n g  he mat ol o gic,  car di ac,  he patic,  gastr oi ntesti nal,  peri p heral 
ner v o us s yste m, or al o pecia). 
S u bjects will be re m o ve d fr o m st u d y treat me nt if a sec o n d e pis o de of gra de 3- 4 t o xicit y 
occ urs des pite d ose re d ucti o n acc or di n g t o ta ble bel o w. 
P E RI P H E R A L N E R V O U S S Y S T E M T O XI CI T Y 
Gr a de 
Bre nt u xi m a b d ose 
C o m me nts 
Gra de 1 
1. 2 m g/ k g ( 1 0 0 %) 
 
Gra de 2  
Re d uce d ose t o 0. 8 m g/ k g.  
 
Gra de 3 
Wit h h ol d d ose u ntil t o xicit y is < 
Gra de 2 or has ret ur ne d t o 
baseli ne.   Res u me at a d ose of 
0. 8 m g/ k g.  If d ose has alrea d y 
bee n re d uce d t o 0. 8 m g/ k g, 
re d uce d ose t o 0. 6 m g/ k g. 
W hile bre nt u xi ma b is hel d, t he ot her a ge nts 
will c o nti n ue as descri be d, pr o vi de d treat me nt 
criteria are met.  T he d ose of bre nt u xi ma b will 
n ot be re-escalate d. 
Gra de 4 
------ 
Patie nt t o c o me off of st u d y 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 4  
 
O T H E R T O XI CI T Y
Gr a de  
Bre nt u xi m a b d ose
A D d oses
C o m me nts
Gra de 1  
1. 2 m g/ k g ( 1 0 0 %)
1 0 0 %
 
Gra de 2  
1. 2 m g/ k g ( 1 0 0 %)
1 0 0 %
 
Gra de 3  
Wit h h ol d d ose u ntil 
t o xicit y is ≤ Gra de 2 or 
has ret ur ne d t o baseli ne.  
Re d uce t he d ose t o 0. 8 
m g/ k g .  If a sec o n d 
d ose re d ucti o n is 
re q uire d, d ose will be 
re d uce d t o 0. 6 m g/ k g.
Wit h h ol d d ose u ntil 
t o xicit y is ≤ Gra de 2 or 
has ret ur ne d t o baseli ne, 
t he n res u me at f ull d ose.
T he d ose of 
bre nt u xi ma b will n ot be 
re-escalate d. 
Gra de 4  
Wit h h ol d d ose u ntil 
t o xicit y is Gra de ≤2 or 
has ret ur ne d t o baseli ne, 
t he n re d uce d ose t o 0. 8 
m g/ k g a n d res u me 
treat me nt, or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or. If a sec o n d 
d ose re d ucti o n is 
re q uire d, d ose will be 
re d uce d t o 0. 6 m g/ k g, or 
disc o nti n ue at t he 
discreti o n of t he 
i n vesti gat or. 
Wit h h ol d d ose u ntil 
t o xicit y is Gra de ≤2 or 
has ret ur ne d t o baseli ne, 
t he n res u me at f ull d ose. 
T he d ose of 
bre nt u xi ma b will n ot be 
re-escalate d. 
 
7.  D R U G F O R M U L A TI O N A N D A D MI NI S T R A TI O N   
  
7. 1  
Bre nt u xi m a b 
 
7. 1. 1  Descri pti o n  
Bre nt u xi ma b  is  a  C D 3 0- directe d  a nti b o d y- dr u g  c o nj u gate  ( A D C)  c o nsisti n g  of  t hree 
c o m p o ne nts: 1) t he c hi meric m o n ocl o nal a n ti b o d y c A C 1 0, s pecific f or h u ma n C D 3 0, 2) 
t he  hi g hl y  p ote nt  a nti micr ot u b ule  a ge nt  m o n o met h yl  a uristati n  E ( M M A E),  a n d  3)  a 
pr otease clea va ble li n ker t hat c o vale ntl y a ttac hes M M A E t o c A C 1 0 ( Fi g ure 1).  Bi n di n g 
of  t he  A D C  t o  C D 3 0  o n  t he  cell  s urface  i ni tiates  i nter nalizati on  of  t he  A D C- C D 3 0 
c o m ple x,  w hic h  t he n  traffics  t o  t he  l ys os o mal  c o m part me nt.  Wit hi n  t he  cell  M M A E  is 
release d via pr ote ol ytic clea va ge. Bi n di n g of M M A E t o t u b uli n disr u pts t he micr ot u b ule 
net w or k wit hi n t he cell, i n d uces cell c ycle arrest, a n d res ults i n  a p o pt otic deat h. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 5  
 
 
 
7. 1. 2  F or m  
Bre nt u xi ma b is a sterile, preser vati ve-free, w h ite t o off- w hite l y o p hilize d ca ke or p o w der, 
s u p plie d  i n  si n gle- use  vials.  Bre nt u xi ma b  dru g  pr o d uct  is  rec o nstit ute d  wit h  water  f or 
i njecti o n ( W FI), U S P. T he rec o nstit ute d bre nt u xi ma b dr u g pr o d uct is a clear t o sli g htl y 
o palesce nt,  c ol orless  s ol uti o n  wit h  n o  visi bl e  partic ulate  matter.  T he  vial  size  is  5 0 m g. 
T he  rec o nstit ute d  s ol uti o n  is  s u bse q ue ntl y  di l ute d  i n  sterile  0. 9 %  S o di u m  C hl ori de  f or 
I njecti o n,  U S P,  5 %  De xtr ose  I njecti o n  U S P,  or  Lactate d  Ri n ger’s  I njecti o n  U S P,  f or 
i ntra ve n o us (I V) a d mi nistrati o n  
 
Bre nt u xi ma b  ve d oti n  is  t he  U nite d  States a d o pte d  na me  ( U S A N)  a n d  t he  I nter nati o nal 
N o n pr o prietar y  Na me  (I N N)  assi g ne d  t o  S G N- 3 5.  A dcetris  is  t he  U n ite d  States  tra de 
na me.  Viale d  dr u g  pr o d uct  ma y  be  la bele d as  S G N- 3 5,  A dcetris  or  as  bre nt u xi ma b 
ve d oti n; t he 3 na mes ca n be  use d i nterc ha n gea bl y. 
 
 
 
 
7. 1. 3  St ora ge a n d Sta bilit y  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 6  
Eac h vial c o ntai ns bre nt u xi ma b, tre hal ose, s o di u m citrate, a n d p olys or bate 8 0. T he dr u g 
pr o d uct vial is rec o nstit ute d wit h t he a p pr o pr iate a m o u nt of Sterile Water f or I njecti o n. 
T he p H of r ec o nstit ute d pr o d uct is a p pr o xi matel y 6. 6.  
 
 
Vials c o ntai ni n g bre nt u xi ma b m ust be st ore d u n der refri gerati o n at 2- 8° C. C he mical a n d 
p h ysical  sta bilit y  of  t he  rec o nstit ute d  bre nt u xi ma b  dr u g  pr o d uct  ha s  bee n  de m o nstrate d 
f or 2 4 h o urs at 2- 8° C. H o we ver, bre nt u xi ma b d oes n ot c o ntai n preservati ves; t heref ore, 
fr o m  a  micr o bi ol o gical  sta n d p oi nt,  o pe ne d a n d  rec o nstit ute d  vials  s h o ul d  be  use d 
i m me diatel y.  If  n ot  use d  i m me diatel y,  t he  i n- use  st ora ge  s h o ul d  n ot  be  l o n ger  t ha n  2 4 
h o urs  u n der  refri gerati o n  at 2 – 8° C.  It  is  rec o m me n de d  t h at  bre nt u xi ma b  vials  a n d 
s ol uti o ns be pr otecte d fr o m direct s u nli g ht u ntil t he ti me of use.  
7. 1. 4  Ha n dli n g  
Rec o m me n de d  safet y  meas ures  f or  t he  ha n dl i n g  a n d  pre parati o n  of  bre nt u xi ma b  f or 
i njecti o n  i ncl u de  mas ks,  pr otecti ve  cl ot hi n g,  glo ves,  a n d  vertical  la mi nar  airfl o w  safet y 
ca bi nets. 
 
Q ualifie d  pers o n nel,  fa miliar  wit h  pr oce d ures  t hat  mi ni mize  u n d ue  e x p os ure  t o 
t he msel ves  a n d  t he  e n vir o n me nt,  s h o ul d  u n derta ke  t he  pre parati o n,  ha n dli n g,  a n d  safe 
dis p osal of t he c he m ot hera pe utic a ge nt i n a self-c o ntai ne d a n d pr otecti ve e n vir o n me nt. 
 
7. 1. 5  A vaila bilit y  
Bre nt u xi ma b is a n i n vesti gati o nal a ge nt a n d will be s u p plie d b y S eattle Ge netics, I nc. 
 
7. 1. 6  Pre parati o n 
7. 1. 6. 1  Rec o nstit uti o n 
1.  Rec o nstit ute  l y o p hilize d  bre nt u xi ma b  b y  a d di n g  1 0. 5  m L  Sterile  Water  f or 
I njecti o n, U S P t o t he 5 0 m g vial, directi n g t he strea m t o t he si de of t he vial. T he 
c o nce ntrati o n  of  rec o nstit u te d  bre nt u xi ma b  is  5  m g/ m L wit h  a  t otal  v ol u me  of 
1 1 m L. 
 
2.  Ge ntl y  s wirl  t he  vial  u ntil  c o nte nts  are  c o m pletel y  diss ol ve d. T he  vi al  m ust 
n ot be s h a ke n or vi g or o usl y s wirle d as e xcess a git ati o n m a y c a use a g gre g ate 
f or m ati o n.  Sli g ht  “ b u b bli n g”  of  t he  s ol uti o n  u p o n  rec o nstit uti o n  ma y  be 
o bser ve d. 
 
3. All o w t he rec o nstit ute d vial t o settle f o r a mi n ute t o all o w b u b bles t o dissi pate. 
T he  rec o nstit ute d  pr o d uct  s h o ul d  be  a  c ol orless,  clear  t o  sli g htl y  o palesce nt 
s ol uti o n wit h n o visi ble partic ulates. 
 
4.  T he  pre pare d  d osi n g  s ol uti o n  m ust  be   st ore d  i n  a n  i nf usi o n  ba g  at  t he 
refri gerate d  c o n diti o n  ( 2- 8oC)  a n d  m ust  be  use d  wit hi n  2 4  h o urs  of  vial 
rec o nstit uti o n. Pr otect i nf usio n ba g fr o m direct s u nli g ht u ntil ti me of use. 
7. 1. 6. 2  D ose Pre parati o n 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 7  
1. Tra nsfer t he re q uire d v ol u me of rec o nstit ute d pr o d uct t o a 1 5 0 m L t o 2 5 0 m L 
i nf usi o n  ba g.  T he  f oll o wi n g  ba g  t y pes  are  c o m pati ble  wit h  bre nt u xi ma b: 
p ol y vi n ylc hl ori de  ( P V C),  et h yle ne 
vi n yl  acetate  ( E V A),  p ol y olefi n,  or 
p ol yet h yle ne. A partici pa nt i n a l o wer d ose c o h ort ( 0. 8 or 1. 2 m g/ k g) w h o has a 
ver y l o w b o d y wei g ht ma y re q uire less t ha n 1 5 0 m L of dil ue nt i n or der t o ac hie ve 
a c o nce ntrati o n of 0. 4 t o 1. 8 m g/ m L (see ta ble bel o w). 
 
2.  Dil ute  rec o nstit ute d  pr o d uct  i n  eit her   0. 9 %  S o di u m  C hl ori de  I njecti o n,  U S P, 
Lactate d Ri n ger’s s ol uti o n, U S P, or de xtr ose 5 % i n water ( D 5 W), U S P. T he fi nal 
c o nce ntrati o n  of  bre nt u xi ma b  i n  i nf usi o n  ba g  s h o ul d  be  i n  t he  ra n ge  of  0. 4- 1. 8 
m g/ m L.  Fi nal  c o nce ntrati o n  =  t otal  d os e/t otal  v ol u me  of  i nf usi o n.  E xa m ple  of 
d ose pre parati o n calc ulati o ns: 
 
P T 
W EI G H T
C  
D O S E 
L E V E L 
T O T A L 
D O S E ( P T 
W EI G H T 
X D O S E 
L E V E L) 
V O L U M E O F 
R E C O N S TI T U T E D 
P R O D U C T 
R E Q UI R E D 
( T O T A L D O S E 
( M G) / 5 M G/ M L) 
V O L U M E 
O F 
DI L U E N T  b 
T O T A L 
V O L U M E 
O F 
I N F U SI O N 
C O N C E N T R A TI O N 
( T O T A L D O S E / 
T O T A L V O L U M E 
O F I N F U SI O N) 
4 5 k g 
1. 2 
m g/ k g 
5 4 m g 
1 0. 8 m L 
(re q uires 2 vialsa) 
1 0 0 m L  
1 1 0. 8 m L  
0. 4 9 m g/ m L 
a A p pr o xi matel y 1 0 m L ca n be wit h dra w n fr o m eac h vial. 
b Patie nts wit h a l o w b o d y wei g ht ma y re q uire less t ha n 1 5 0 m L of dil ue nt. 
c F or patie nts wei g hi n g m ore t ha n 1 0 0 k g, t ota l d ose will be calc ulate d usi n g 1 0 0 k g. 
 
3. Ge ntl y i n vert t he i nf usi o n ba g. D O N O T S H A K E – e xcess a gitati o n ma y ca use 
a g gre gate f or mati o n. 
 
4. Pri or t o a d mi nistrati o n, i ns pect t he pr e pare d d osi n g s ol uti o n  (i n  i nf usi o n  ba g) 
f or a n y partic ulate matter or disc ol orati o n. 
 
5. D o n ot pre pare a si n gle d ose of bre nt u xi ma b usi n g vials fr o m differe nt l ots. Use 
vials fr o m t he sa me l ot n u m ber f or a gi ve n d ose. 
 
6.  T he  pre pare d  d osi n g  s ol uti o n  m ust  be   st ore d  i n  a n  i nf usi o n  ba g  at  t he 
refri gerate d  c o n diti o n  ( 2- 8oC)  a n d  m ust  be  use d  wit hi n  2 4  h o urs  of  vial 
rec o nstit uti o n. Pr otect i nf usi o n ba g fr o m direct s u nli g ht u ntil ti me of use. 
 
7. 1. 7  A d mi nistrati o n  
D ose  a n d  fr e q ue nc y  will  be  a d mi nistere d  per  st u d y  pr ot oc ol.  D osi n g  s h o ul d  be 
base d o n t he partici pa nt’s pre- d ose wei g ht deter mi ne d at da y 1 visit of eac h c ycle. 
D ose ma y be re-calc ulate d base d o n wei g ht o n da y 1 5 if t hat is c o nsiste nt wit h t he 
i nstit uti o nal sta n dar d of care. Bre nt u xi ma b d ose s h o ul d be r o u n de d t o t he nearest 
w h ole n u m ber of milli gra ms.  I nf usi o n ti me f or bre nt u xi ma b is 3 0 mi n utes. T he 
dr u g ma y be gi ve n at sl o wer i nf usi o n at t he discreti o n of t he treat me nt tea m i n t he 
setti n g of pri or h y perse nsiti vit y reacti o ns, c o nsiste nt wit h i nstit uti o nal sta n dar ds. 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 8  
 
7. 1. 8  Or deri n g  
Bre nt u xi ma b ve d oti n will be s u p plie d b y Seattle Ge netics a n d s h o ul d be o btai ne d 
b y t he researc h p har mac y usi n g t he st u d y s p ecific dr u g or der f or m.  Bre nt u xi ma b 
ve d oti n will be s u p plie d free of c har ge a n d will be or dere d fr o m Seattle Ge netics. 
 
7. 1. 9  Acc o u nta bilit y  
T he  i n vesti gat or,  or  a  res p o nsi ble  part y  desi g nate d  b y  t he  i n vesti gat or,  m ust 
mai ntai n  a  caref ul  rec or d  of  t he  i n ve nt or y  a n d  dis p ositi o n  of  t he  a ge nt 
(i n vesti gati o nal or free of c har ge) usin g t he N CI Dr u g Acc o u nta bilit y Rec or d or 
a n ot her  c o m para ble  dr u g  acc o u nta bilit y  f or m.  ( See  t he  C T E P  we bsite  at 
htt p://cte p.ca ncer. g o v/ p r ot oc ol De vel o p me nt    f or  t he  “ P olic y  a n d  G ui deli nes  f or 
Acc o u nta bilit y a n d St ora ge of I n vesti gati o nal A ge nts” or t o o btai n a c o p y of t he 
dr u g acc o u nta bilit y f or m.) 
 
7. 1. 1 0  Destr ucti o n a n d Ret ur n 
At  t he  e n d  of  t he  st u d y,  u n use d  s u p plies  of  bre nt u xi ma b  s h o ul d  be  destr o ye d 
acc or di n g  t o  i nstit uti o nal  p olicies.  Dest r ucti o n  will  be  d oc u me nte d  i n  t he  Dr u g 
Acc o u nta bilit y Rec or d F or m. 
 
7. 2  
A dri a m yci n 
Ot her Na mes: D o x or u bici n 
 
Classificati o n: A nt hrac ycli ne a nti bi otic. 
 
M o de  of  Acti o n:  I ntercalat i o n  bet wee n  a dj oi ni n g  n ucle oti de  pairs  i n  t he  D N A  heli x 
ca uses i n hi biti o n of D N A a n d D N A- de pe n de nt R N A s y nt hesis. Free ra dical ge nerati o n 
is res p o nsi ble f or car diac t o xicit y. A dria m yci n als o i n hi bits t o p ois o merase II. 
 
St ora ge  a n d  Sta bilit y:  A dria m yci n  R D F  i ntact vials  are  sta ble  pr otecte d  fr o m  li g ht  at 
r o o m te m perat ure. A dria m yci n P F S vials m ust be refri gerate d. Rec o nstit ute d s ol uti o ns 
are  sta ble  f or  2 4  h o urs  at  r o o m  te m per at ure  a n d  4 8  h o urs  u n der  refri gerati o n.  T he 
A dria m yci n  R D F  1 5 0  m g  m ulti d ose  vial  is  sta b le  after  rec o nstit uti o n  f or  7  da ys  at 
r o o m te m perat ure or 1 5 da ys if refri gerate d a n d pr otecte d fr o m s u nli g ht. 
 
D ose S pecifics: A dria m yci n will be gi ve n i n tra ve n o usl y at a d ose of 2 5 m g/ m² o n da ys 
1 a n d 1 5 of eac h c ycle. A c ycle will be re p eate d e ver y 2 8 da ys. Use act ual wei g ht t o 
calc ulate b o d y s urface area a n d d oses. 
 
Pre parati o n: A d d 5, 1 0, 2 5, 5 0, or 7 5 ml of pr eser vati ve-free n or mal sali ne t o t he 1 0, 
2 0, 5 0, 1 0 0, or 1 5 0 m g vial t o pr o d uce a s ol uti o n c o ntai ni n g 2 m g/ ml. 
 
A d mi nistrati o n: I ntra ve n o us l y as a b ol us i njecti o n. 
 
I nc o m pati bilities:  P h ysicall y  i nc o m pati ble  wit h  he pari n,  fl u or o uracil,  a mi n o p h ylli ne, 
ce p hal ot hi n, de xa met has o ne, diaze pa m, h y dr oc ortis o ne, a n d f ur ose mi de. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
1 9  
 
C o m pati bilities: Sta ble wit h vi ncristi ne i n n or mal sali ne f or 5 da ys at r o o m te m perat ure 
pr otecte d fr o m li g ht. Als o c o m pati ble i n s ol uti o n wit h c ycl o p h os p ha mi de. 
 
A vaila bilit y:  C o m merciall y  a vaila ble as  p o w der  f or  i njecti o n  i n  1 0,  2 0,  5 0,  1 0 0,  1 5 0 
m g vials, a n d as 2 m g/ ml s ol uti o n f or i njecti o n i n 1 0, 2 0, 5 0, a n d 2 0 0 m g vials. 
 
A dria m yci n will be o btai ne d fr o m c o m mercial s u p pl y. 
 
See secti o n 6. 1. 2 f or si de effects. 
 
See secti o n 6. 1. 2 f or n ursi n g/ patie nt i m plicati o ns. 
7. 3  
D ac ar b azi ne 
Ot her Na mes: D TI C 
 
Classificati o n: Al k ylati n g a ge nt. 
M o de of Acti o n: Acti vit y ma y be t he res ult of  at least 3 mec ha nis ms: 1) al k ylati o n; 2) 
a nti meta b olite  acti vit y  as  a  p uri ne  prec urs or; a n d  3)  i nteracti o n  wit h  s ulf h y dr yl  ( S H) 
gr o u ps  i n  pr otei ns.  Dacar bazi ne  a p pears  t o be  m ore  acti ve  i n  G 2   p hase  b ut  is  n ot 
partic ularl y cell c ycle p hase s pecific. 
 
St ora ge  a n d  Sta bilit y:  St ore vials  u n der  refri gerati o n  a n d pr otecte d  fr o m  li g ht.  I n 
s ol uti o n, Dacar bazi ne is sta ble f or 9 6 h o urs if refri gerate d a n d pr otecte d fr o m li g ht, 2 4 
h o urs if n ot refri gerate d b ut pr otecte d fr o m li g ht. W he n f u rt her dil ute d i n 5 0 0 ml D 5 W 
or  N S,  it  is  sta ble  f or  2 4 h o urs  if  refri gerate d,  a n d  8  h o ur s  at  r o o m  te m perat ure  a n d 
pr otecte d fr o m li g ht. P h ot o de gra dati o n: T he ma n ufact urer of dacar bazi ne states t hat t he 
dr u g  d oes  n ot  dec o m p ose  w he n  left  at r o o m  te m perat ure  u n der  n or mal  li g hti n g 
c o n diti o ns  f or  ei g ht  h o urs.  N O T E:  A  c ha n ge  i n   c ol or  of  s ol uti o n  fr o m  pale  yell o w  t o 
pi n k is i n dicati ve of dec o m p ositi o n of t he dr u g. 
 
D ose S pecifics: Patie nts will recei ve Dacar bazi ne i ntra ve n o usl y at a d ose of 3 7 5 m g/ m² 
o n da ys 1 a n d 1 5 of eac h c ycle of c he m ot hera p y. C ycles will be re peate d e v er y 2 8 da ys. 
Use act ual wei g ht t o calc ulate  b o d y s urface area a n d d oses. 
 
Pre parati o n: Dil ute t he 1 0 0, 2 0 0, a n d 5 0 0 m g vials wit h 9. 9, 1 9. 7, a n d 4 9. 5 ml of sterile 
water,  res pecti vel y,  res ulti n g  i n  a  c o nce ntrati o n  of  1 0  m g/ ml.  Pr otect  t he  dr u g  fr o m 
direct li g ht. D o n ot fr eeze. Discar d if s ol uti o n t ur ns pi n k/re d. T he dr u g ca n be f urt her 
dil ute d i n 5 0- 5 0 0 ml of 5 % de xtr ose or n or mal sali ne. 
 
A d mi nistrati o n:  Us uall y  a d mi nistere d  b y i ntra ve n o us  i nf usi o n  o ver  3 0  mi n utes  or 
l o n ger; has als o bee n gi ve n I V p us h. 
 
I nc o m pati bilities:  Meta b olis m  of  dacar bazi ne  ma y  be  i n d uce d  b y  p he n yt oi n  or 
p he n o bar bital.  T o xicit y  ma y  be  e n ha nce d  if   gi ve n  c o nc o mita ntl y  wit h  all o p uri n ol, 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 0  
azat hi o pri ne,  or  merca pt o p uri ne.  Dacar bazi ne  is  p h ysicall y  i nc o m pati ble  wit h 
h y dr oc ortis o ne s o di u m s ucci nate a n d he pari n. 
 
A vaila bilit y: C o m merciall y a vaila ble i n vial s c o ntai ni n g 1 0 0 m g, 2 0 0 m g, or 5 0 0 m g of 
l y o p hilize d dr u g. 
 
Dacar bazi ne will be o btai ne d fr o m c o m mercial s u p pl y. 
 
See secti o n 6. 1. 4 f or si de effects. 
 
See secti o n 6. 1. 4 f or n ursi n g/ patie nt i m plicati o ns. 
 
8.  S T U D Y C A L E N D A R 
8. 1  
Pre- Tre at me nt  E v al u ati o ns: T o  be  c o m plete d  wit hi n  4 2  da ys  pri or  t o  e nr oll me nt 
u nless ot her wise s pecifie d:  
 S i g n e d  i n f o r m  c o n s e n t   
 V i t a l  s i g n s ,  i n c l u d i n g  t e m p e r a t u r e ,  b l o o d  p r e s s u r e ,  h e a r t  r a t e ,  a n d   
r e s p i r a t o r y  r a t e  
 C o m p l e t e  p h y s i c a l  e x a m i n a t i o n ,  i n c l u d i n g  h e i g h t  a n d  w e i g h t  
 M e d i c a l  h i s t o r y :  D e t a i l e d  d o c u m e n t a t i o n  o f  d i s e a s e  a n d  t r e a t m e n t  
h i s t o r y  w i t h  o u t c o m e s  
 E C O G  p e r f o r m a n c e  s t a t u s  
 C o n c u r r e n t  m e d i c a l  c o n d i t i o n s ,  i n c l u d i n g  p e r i p h e r a l  n e u r o p a t h y  
 C o n c u r r e n t  m e d i c a t i o n s   
 C B C  w i t h  d i f f e r e n t i a l   
 E r y t h r o c y t e  s e d i m e n t a t i o n  r a t e  ( E S R )    
 S e r u m  c h e m i s t r i e s :  E l e c t r o l y t e s  ( s o d i u m ,  p o t a s s i u m ,  c h l o r i d e ,  a n d  
C O 2) ,  c a l c i u m ,  m a g n e s i u m ,  p h o s p h a t e ,  b l o o d  u r e a  n i t r o g e n  ( B U N ) ,  
c r e a t i n i n e ,  g l u c o s e ,  a n d  l i v e r  f u n c t i o n  t e s t s  ( a s p a r t a t e  
a m i n o t r a n s f e r a s e  ( A S T )  a n d  a l a n i n e  a m i n o t r a n s f e r a s e  ( A L T ) ,  a l k a l i n e  
p h o s p h a t a s e  ( A L P ) ,  t o t a l  p r o t e i n ,  a l b u m i n ,  a n d  t o t a l  b i l i r u b i n  
 C o a g u l a t i o n  s t u d i e s  i n c l u d i n g  p r o t h r o m b i n  t i m e  ( P T ) ,  p a r t i a l  
t h r o m b o p l a s t i n  t i m e  ( P T T )  a n d  i n t e r n a t i o n a l  n o r m a l i z e d  r a t i o  ( I N R )  
 H e p a t i t i s  B  s e r o l o g y  t e s t i n g  ( H e p a t i t i s  B  c o r e  a n t i b o d y ,  H e p a t i t i s  
B  s u r f a c e  a n t i g e n ,  H e p a t i t i s  B  s u r f a c e  a n t i b o d y )  ( m a y  b e  p e r f o r m e d  
w i t h i n  6  m o n t h s  p r i o r  t o  s t a r t  o f  s t u d y  t r e a t m e n t )  
 B a s e l i n e  E K G  
 E c h o c a r d i o g r a m  o r  M U G A  t o  d e t e r m i n e  L V E F  
 F u l l - b o d y  P E T - C T  s c a n  ( n e c k ,  c h e s t ,  a b d o m e n / p e l v i s ) .  T u m o r  
m e a s u r e m e n t s  w i l l  b e  c e n t r a l l y  p e r f o r m e d  b y  t h e  D F / H C C  t u m o r  
i m a g i n g  m e t r i c  c o r e  ( T I M C )  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 1  
 A s s e s s m e n t  o f  E a r l y  F a v o r a b l e  o r  E a r l y  U n f a v o r a b l e  b a s e d  o n  G H S G  
c r i t e r i a  ( s e e  f o o t n o t e  l  i n  r e q u i r e d  d a t a  t a b l e )  
 S e r u m  p r e g n a n c y  t e s t  f o r  w o m e n  o f  c h i l d b e a r i n g  p o t e n t i a l  m u s t  b e  
p e r f o r m e d  w i t h i n  7  d a y s  
8. 2  
E v al u ati o n D uri n g Tre at me nt:   
T he f oll o wi n g will be perf or me d o n t he da ys of treat me nt (e. g. da ys 1 a n d 1 5) d uri n g 
eac h c ycle of t he pr ot oc ol ( +/- 3 da ys):   
 V i t a l  s i g n s  
 P h y s i c a l  e x a m i n a t i o n  
 I n t e r v a l  h i s t o r y  i n c l u d i n g  r e c o r d i n g  o f  a d v e r s e  e v e n t s ,  t o x i c i t y  
a s s e s s m e n t ,  c h a n g e s  i n  m e d i c a l  c o n d i t i o n s  o r  m e d i c a t i o n s  
 E C O G  p e r f o r m a n c e  s t a t u s  
 N e u r o p a t h y  a s s e s s m e n t  u s i n g  F A C T / G O G - N e u r o t o x i c i t y  Q u e s t i o n n a i r e  
( A p p e n d i x  D ) ,  d a y  1  o n l y  
 C B C  w i t h  d i f f e r e n t i a l  
 S e r u m  c h e m i s t r i e s :  E l e c t r o l y t e s  ( s o d i u m ,  p o t a s s i u m ,  c h l o r i d e ,  a n d  
C O 2) ,  c a l c i u m ,  b l o o d  u r e a  n i t r o g e n  ( B U N ) ,  c r e a t i n i n e ,  g l u c o s e ,  a n d  
l i v e r  f u n c t i o n  t e s t s  ( a s p a r t a t e  a m i n o t r a n s f e r a s e  ( A S T )  a n d  a l a n i n e  
a m i n o t r a n s f e r a s e  ( A L T ) ,  a l k a l i n e  p h o s p h a t a s e  ( A L P ) ,  t o t a l  p r o t e i n ,  
a l b u m i n ,  a n d  t o t a l  b i l i r u b i n .   L F T’s s h o ul d be c hec ke d o n t he da y of or 
da y pri or t o treat me nt.  
 
O bjecti ve disease assess me nt wit h P E T- C T sca n is t o be perf or me d: 
 C ycle 2 da ys 2 2- 2 8 
8. 3  
P ost- Tre at me nt E v al u ati o n 
T he f oll o wi n g cli nical assess me nts will be perf or me d at t he p ost-treat me nt e val uati o n 
( 6 wee ks +/- 3 da ys of t he c o m pleti o n of t he last d ose of t hera p y): 
 I n t e r v a l  h i s t o r y  i n c l u d i n g  r e c o r d i n g  o f  a d v e r s e  e v e n t s ,  t o x i c i t y  
a s s e s s m e n t ,  c h a n g e s  i n  m e d i c a l  c o n d i t i o n s  o r  m e d i c a t i o n s  
 F u l l  p h y s i c a l  e x a m i n a t i o n  
 W e i g h t  a n d  v i t a l  s i g n s  ( b l o o d  p r e s s u r e ,  p u l s e  r a t e ,  r e s p i r a t o r y  
r a t e ,  a n d  t e m p e r a t u r e )  
 E C O G  P e r f o r m a n c e  S t a t u s  
 N e u r o p a t h y  a s s e s s m e n t  u s i n g  F A C T / G O G - N e u r o t o x i c i t y  Q u e s t i o n n a i r e  
( A p p e n d i x  D )  
 R e c o r d i n g  o f  A E s  
 R e c o r d i n g  o f  c o n c o m i t a n t  m e d i c a t i o n s  
 La b orat or y testi n g: C B C  w i t h  d i f f e r e n t i a l ,  s e r u m  c h e m i s t r i e s  ( N a ,  K ,  
C l ,  C O 2,  g l u c o s e ,  b l o o d  u r e a  n i t r o g e n  ( B U N ) ,  c r e a t i n i n e ,  c a l c i u m ,  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 2  
t o t a l  b i l i r u b i n ,  A S T ,  A L T ,  a l k a l i n e  p h o s p h a t a s e ,  a l b u m i n ,  a n d  t o t a l  
p r o t e i n )  
 P E T - C T  s c a n   
 
P artici p a nts c o mi n g off of tre at me nt:  If a partici pa nt disc o nti n ues treat me nt f or a n y reas o n 
ot her  t ha n  c o m pleti n g  treat me nt  (e. g.,  t o xicit y ,  disease  pr o gressi o n,  wit h dra w  of  c o nse nt, 
etc.), e n d of st u d y assess me nts are t o be perf or me d 1 4 da ys ( +/- 3 da ys) fr o m t he last st u d y 
d ose.  If  a  pre vi o us  P E T/ C T  was  o btai ne d  wi t hi n  2 8  da ys  of  partici pa nt  st o p pi n g  st u d y 
treat me nt, P E T/ C T d oes n ot nee d t o be re peate d at p ost-treat me nt e val uati o n.  
 
If  a  partici pa nt  c o m pletes  all  sc he d ule d  treat me nt  per  pr ot oc ol  ( 4  c ycles  of  t hera p y  f or 
partici pa nts wit h C R, or 6 c ycl es f or partici pa nts wit h P R or S D), e n d of st u d y assess me nts 
are t o be perf or me d 6 wee ks ( +/- 3 da ys) fr o m t he last st u d y d ose. If t he partici pa nt is n ot 
a vaila ble, t he reas o n f or n ot c o m pleti n g t he e n d of st u d y assess me nts m ust be rec or de d i n t he 
partici pa nt’s s o urce d oc u me nts.  
 
L o n g  T e r m  F o l l o w - u p :
L o n g  T e r m  F o l l o w - u p :  P a r t i c i p a n t s  w i l l  b e  f o l l o w e d  f o r  s u r v i v a l  s t a t u s .      
 Years 1- 2: 
o  Hist or y a n d P h ysical E xa m, C B C wit h differe ntial a n d c o m plete meta b olic 
pa nel e ver y 3 m o nt hs ( +/- 1 4 da ys) after t he p ost-treat me nt e val uati o n 
visit. 
o  Disease assess me nts b y i ma gi n g after t he p ost-treat me nt e val uati o n visit:  
 C T sca ns of t he c hest, a b d o me n a n d pel vis will be perf or me d at 6 
m o nt hs, 1 year, 1 8 m o nt hs a n d 2 years after t he c o m pleti o n of 
t hera p y P E T- C T ( +/- 1 4 da ys) 
o  N e u r o p a t h y  a s s e s s m e n t  u s i n g  F A C T / G O G - N e u r o t o x i c i t y  
Q u e s t i o n n a i r e  ( A p p e n d i x  D )  s h o u l d  b e  c o m p l e t e d  e v e r y  3  
m o n t h s  ( + / -  2 1  d a y s )  u n t i l  r e s o l u t i o n  o f  p e r i p h e r a l  
n e u r o p a t h y .   
o  T o x i c i t i e s  r e l a t e d  t o  s t u d y  t r e a t m e n t  s h o u l d  b e  f o l l o w e d  
u n t i l  r e s o l u t i o n  
 Years 3- 5: 
o  Hist or y a n d P h ysical E xa m, C B C wit h differe ntial a n d c o m plete meta b olic 
pa nel e ver y 6 m o nt hs ( +/- 2 1 da ys) 
o  T o x i c i t i e s  r e l a t e d  t o  s t u d y  t r e a t m e n t  s h o u l d  b e  f o l l o w e d  
u n t i l  r e s o l u t i o n  
o  I m a g i n g  t o  b e  p e r f o r m e d  a t  t h e  d i s c r e t i o n  o f  t h e  t r e a t i n g  
i n v e s t i g a t o r  
 Years 5 +: 
o  S ur vi val o nl y 




Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 4  
a. 
C o nti n ue d treat me nt o n c y cles 5 a n d 6 will de pe n d o n P E T- C T res p o ns e (less t ha n C R b ut n ot P D will c o nti n ue wit h c ycles 5 a n d 6) 
b.  
Al b u mi n, al kali ne p h os p hatase , t otal bilir u bi n, B U N, calci u m, c hl ori de, C O2, creati ni ne, gl uc ose, p otassi u m, t otal pr otei n, A S T, A L T, s o diu m. Ma g nesi u m a n d p h os p h or o us are 
re q uire d o nl y wit h scree ni n g la bs. 
c. 
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 
d.    I nf or me d c o nse nt m ust be o btai ne d pri or t o all st u d y-relate d pr oce d ures. 
e. 
Ser u m pre g na nc y test is o nl y re q uire d i n  w o me n of c hil d beari n g p ote ntial wit hi n 7 da ys of be gi n ni n g pr ot oc ol t hera p y. 
f. 
P E T- C T is t o be perf or me d wit hi n t he last  7 da ys of t he treat me nt c y cle (e. g. da ys 2 2- 2 8); See f o ot n otes g a n d h f or t he e n d of treat me nt a n d f oll o w- u p i ma gi n g. 
g.  
T he p ost-treat me nt e val uati o n  will occ ur 6 wee ks ( +/- 3 da ys) fr o m t he last d ose of t hera p y f or partici pa nts t hat c o m plete all sc he d ule d treat me nt per pr ot oc ol. T he p ost-treat me nt 
e val uati o n will occ ur 1 4 da ys ( +/- 7 da ys) fr o m t he last d ose of t hera p y f or partici pa nts t hat disc o nti n ue treat me nt earl y (e. g., t o xicit y, disease pr o gressi o n, etc.). If a pre vi o us 
P E T/ C T o btai ne d wit hi n 2 8 da ys of partic i pa nt st o p pi n g st u d y treat me nt earl y, P E T/ C T d oes n ot nee d t o be re peate d at p ost-treatme nt e val uati o n.  I ma gi n g at or pri or t o t his visit 
will be b y P E T- C T.  S A Es re q uire re p orti n g u p t o 3 0 da ys after last d ose of t hera p y.  
h.  
F oll o w- u p:  partici pa nts will be f oll o we d f or s ur vi val stat us.   D uri n g years 1- 2 p h ysicia n visits s h o ul d be  e ver y 3 m o nt hs a n d C T sca ns of t he c hest/a b d o me n/ pel vis ( n o P E T u nless 
cli nicall y i n dicate d) at 6 m o nt hs, 1 years, 1 8 m o nt hs a n d 2 y ears after t he e n d- of tr eat me nt resta gi n g sca n +/- 2 1 da ys).  T he ne ur o pat h y assess me nt q uesti o n naire s h o ul d be 
c o m plete d u ntil res ol uti o n of ne ur ot o xicit y.  D uri n g y ears 3- 5 pr o v i der visits s h o ul d be e ver y 6 m o nt hs. Be y o n d 5 years, partic i pa nts will be f oll o we d f or s ur vi val o nl y. 
i. 
C oa g ulati o n t o i ncl u de P T, P T T a n d I N R.  
j. 
Hei g ht re q uire d at baseli ne p h ysical e xa m o nl y.  B S A will be calc ulate d wit h t he D u b ois f or m ula, or alter nate f or m ula per i nsti t uti o nal sta n dar d.   
k.  
T o xicities relate d t o st u d y tr eat me nt s h o ul d be assesse d at L T F U visits u ntil res ol uti o n.  
l. 
G H S G criteria:  Prese nce of a n y o ne of t hese ris k fact ors de n otes earl y u nfa v ora ble disease: Me diasti nal mass ≥1 0c m, E xtra n o dal disease, ≥3 n o dal re gi o ns, or Ele vate d E S R. 
A bse nce of all ris k fact ors is c o nsi dere d earl y fa v ora ble disease. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 5 
 
9.  M E A S U R E M E N T O F E F F E C T   
9. 1  
A ntit u m or Effect 
R e s p o n s e   a n d   p r o g r e s s i o n   w i l l   b e   e v a l u a t e d   i n   t h i s   s t u d y   u s i n g   t h e  
I n t e r n a t i o n a l   W o r k i n g   g r o u p   c r i t e r i a   ( L u g a n o   c r i t e r i a )   f o r   l y m p h o m a  
r e s p o n s e  ( s e e  a p p e n d i x  A ) . 1  P E T  i n t e r p r e t a t i o n  w i l l  b e  i n t e r p r e t e d  a s  
p o s i t i v e   o r   n e g a t i v e   p e r   t h e   c o n s e n s u s   D e a u v i l l e   c r i t e r i a . 1 8  T h e  
p a r t i c i p a n t s   w i l l   b e   a s s e s s e d   f o r   r e s p o n s e   u s i n g   P E T - C T   s c a n   b e t w e e n  
d a y s   2 2   a n d   2 8   o f   c y c l e   2   o f   b r e n t u x i m a b / A D   ( w h i c h   w i l l   b e   u s e d  t o  
d e t e r m i n e   d i s e a s e   p r o g r e s s i o n   a n d   t h e   n u m b e r   o f   s u b s e q u e n t   c y c l e s   o f  
c o m b i n a t i o n   b r e n t u x i m a b / A D ) ,   a n d   a t   E O T  6  wee ks   a f t e r   c o m p l e t i o n   o f  
c o m b i n a t i o n  t h e r a p y  ( + / -  3  d a y s ) .     
1 0.  A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S 
1 0. 1  Defi niti o ns 
1 0. 1. 1  A d verse E ve nt ( A E)  
A n a d verse e ve nt ( A E) is a n y u n desira bl e si g n, s y m pt o m or me dical c o n diti o n or 
e x perie nce  t hat  de vel o ps  or  w orse ns  i n se verit y  after  starti n g  t he  first  d ose  of 
st u d y treat me nt or a n y pr oce d ure s pecifie d i n t he pr ot oc ol, e ve n if t he e ve nt is n ot 
c o nsi dere d t o be relate d t o t he st u d y.  
 
1 0. 1. 2  Seri o us a d verse e ve nt ( S A E)  
A  seri o us  a d verse  e ve nt  ( S A E)  is  a n y  a d verse  e ve nt,  occ urri n g  at  a n y  d ose  a n d 
re gar dless of ca usalit y t hat:  
 Res ults i n deat h 
 Is  life-t hreate ni n g.  Life-t hreate ni n g  mea ns  t hat  t he  patie nt  was  at 
i m me diate  ris k  of  deat h  fr o m  t he  reacti o n  as  it  occ urre d,  i.e.,  it  d oes  n ot 
i ncl u de  a  reacti o n  w hic h  h y p ot heticall y mi g ht  ha ve  ca use d  deat h  ha d  it 
occ urre d i n a m ore se vere f or m. 
 Re q uires  or  pr ol o n gs  i n patie nt  h os pita lizati o n  (i.e.,  t he  e ve nt  re q uire d  at 
least  a  2 4- h o ur  h os pitalizati o n  or pr ol o n ge d  a  h os pita lizati o n  be y o n d  t he 
e x pecte d  le n gt h  of  sta y).  H os pita lizati o n  a d missi o ns a n d/ or  s ur gical 
o perati o ns sc he d ule d t o occ ur d uri n g t he st u d y peri o d, b ut pla n ne d pri or t o 
st u d y e ntr y are n ot c o nsi dere d S A Es if t he ill ness or disease e xiste d bef ore 
t he partici pa nt was e nr olle d i n t he trial, pr o vi de d t hat it di d n ot deteri orate 
i n  a n  u ne x pecte d  ma n ner  d uri n g  t he  trial  (e. g.,  s ur ger y  perf or me d  earlier 
t ha n pla n ne d). 
 Res ults  i n  persiste nt  or  si g nifica nt disa bilit y/i nca pacit y.  Disa bilit y  is 
defi ne d  as  a  s u bsta ntial  disr u pti o n  of   a  partici pa nt’s  a bilit y  t o  c o n d uct 
n or mal life f u ncti o ns. 
 Is a c o n ge nital a n o mal y or birt h defect; or 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 6  
 Is  a n  i m p orta nt  me dical  e ve nt  w he n,  base d  u p o n  a p pr o priate  me dical 
j u d g me nt, it ma y je o par dize t he partici pa nt a n d 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  a b o ve.  E xa m ples  of 
s uc h  me dical  e ve nts  i ncl u de  aller gic  br o nc h os pas m re q uiri n g  i nte nsi ve 
treat me nt  i n  a n  e mer ge nc y  r o o m or  at  h o me;  bl o o d  d yscrasias  or 
c o n v ulsi o ns  t hat  d o  n ot  res ult  i n i n patie nt  h os pitalizati o n,  or  t he 
de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. 
 
E ve nts n ot c o nsi dere d t o be seri o us a d verse e ve nts are h os pitalizati o ns f or: 
 R o uti ne  treat me nt  or  m o n it ori n g  of  t he  st u die d  i n dicati o n,  n ot  ass ociate d 
wit h a n y deteri orati o n i n c o n di ti o n, or f or electi ve pr oce d ures 
 Electi ve or pre- pla n ne d treat me nt f or a pre-e xisti n g c o n diti o n t hat di d n ot 
w orse n 
 E mer ge nc y  o ut patie nt  treat me nt  f or  a n  e ve nt  n ot  f ulfilli n g  t he  seri o us 
criteria o utli ne d a b o ve a n d n ot re s ulti n g i n i n patie nt a d missi o n 
 Res pite care 
 N o n-cli nicall y si g nifica n t la b orat or y a b n or malities 
1 0. 1. 3  E x pecte d ness 
A d verse e ve nts ca n be ' E x pecte d' or ' U ne x pecte d.'  
1 0. 1. 3. 1  
E x pecte d a d verse e ve nt  
E x pecte d a d verse e ve nts are t h ose t hat  ha ve bee n pre vi o usl y i de ntifie d as 
res ulti n g fr o m a d mi nistrati o n of t he a ge nt. F or t he p ur p oses of t his st u d y, 
a n  a d verse  e ve nt  is  c o nsi dere d  e x pecte d   w he n  it  a p pears  i n  t he  c urre nt 
a d verse  e ve nt  list,  t he  I n vesti gat or’s Br oc h ure,  t he  pac ka ge  i nsert  or  is 
i ncl u de d i n t he i nf or me d c o nse nt d oc u me nt as a p ote ntial ris k.   
 
Refer t o Secti o n 6. 1 f or a listi n g of e x pecte d a d verse e v e nts ass ociate d 
wit h t he st u d y a ge nt(s). 
1 0. 1. 3. 2  
U ne x pecte d a d verse e ve nt  
F or t he p ur p oses of t his st u d y, a n a d verse e ve nt is c o nsi dere d u ne x pecte d  
w he n  it  varies  i n  nat ure,  i nte nsit y  or  fre q ue nc y  fr o m  i nf or mati o n 
pr o vi de d  i n  t he  c urre nt  a d verse  e ve nt list,  t he  I n vesti gat or’s  Br oc h ure, 
t he  pac ka ge  i nsert  or  w he n  it  is  n ot  i ncl u de d  i n  t he  i nf or me d  c o nse nt 
d oc u me nt as a p ote ntial ris k.   
1 0. 1. 4  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 verse e ve nt or seri o us a d verse e ve nt 
a n d t he st u d y treat me nt. 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 treat me nt. 
 Pr o ba ble – T he A E is li kel y relate d  t o t he st u d y treat me nt. 
 P ossi ble – T he A E ma y be relate d  t o t he st u d y treat me nt.  
 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 treat me nt. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
2 7  
 U nrelate d - T he A E is clearl y N O T relate d  t o t he st u d y treat me nt. 
1 0. 2  Pr oce d ures f or A E a n d S A E Rec or di n g a n d Re p orti n g 
 
Partici pati n g i n vesti gat ors will assess t he o cc urre nce of A Es a n d S A Es at all partici pa nt 
e val uati o n ti me p oi nts d uri n g t he st u d y. A Es re late d t o st u d y treat me nt will be f oll o we d 
at L o n g Ter m F oll o w- u p visits. 
 
All A Es a n d S A Es w het her re p orte d b y t he pa rtici pa nt, disc o vere d d uri n g q uesti o ni n g, 
directl y o bser ve d, or detecte d  b y p h ysical e xa mi nati o n, la b orat or y test or ot her mea ns, 
will  be  rec or de d  i n  t he  partici pa nt’s  me dical  rec or d  a n d  o n  t he  a p pr o priate  st u d y-
s pecific case re p ort f or ms.  
 
T he  descri pti o ns  a n d  gra di n g  scales  f o u n d  i n  t he  re vise d  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 will be utilize d f or A E re p orti n g. All 
a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 4. 0. 
A c o p y of t he C T C A E versi o n 4. 0 ca n be d o w nl oa de d fr o m t he C T E P we bsite at: 
 
 htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o ni c _a p plicati o ns/ctc. ht m.  
1 0. 3  Re p orti n g Re q uire me nts 
 
F or  m ulti-site  trials  w here  a  D F/ H C C  i n vesti gat or  is  ser vi n g  as  t he  pri nci pal 
i n vesti gat or,  eac h  partici pati n g  i n vesti gator  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  D F/ H C C.  T he  st u d y m ust  be  c o n d ucte d  i n  c o m plia nce  wit h 
F D A re g ulati o ns, l ocal safet y re p orti n g re q uire me nts, a n d re p orti n g re q uire me nts of t he 
pri nci pal i n vesti gat or.  
 
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  partici pati n g  i n vesti gat or  t o 
re p ort seri o us a d verse e ve nts t o t he st u d y s p o ns or a n d/ or others as descri be d bel o w.  
1 0. 4  Re p orti n g t o t he St u d y S p o ns or 
1 0. 4. 1  D F/ H C C Re p orta ble A d verse E ve nt Re p orti n g 
 
I n  a d diti o n  t o  S A Es  t hat  meet  criteria  fr o m  secti o n  1 0. 1. 2,  t he  S p o ns or  re q uires 
a d diti o nal  e ve nts  t o  be  re p orte d  t o t he  C o or di nati n g  Ce nter.  All  D F/ H C C 
re p orta ble  a d verse  e ve nts t hat  occ ur  after t he  i nitial  d ose  of  st u d y  treat me nt, 
d uri n g treat me nt, or wit hi n 3 0 da ys of t he last d ose of treat me nt m ust be re p orte d 
t o t he C o or di nati n g Ce nter o n t he l ocal i nstit uti o nal S A E f or m. T his i ncl u des t he 
f oll o wi n g: 
 Gra de  2  ( m o derate)  a n d  Gra de  3  (se vere)  E ve nts  e ve nts  t hat  are 
u ne x pecte d  
a n d  
c o nsi dere d  
p ossi bl y,  
pr o ba bl y  
or  
defi nitel y 
relate d/ass ociate d wit h t he i nter ve nti o n. 
 






Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 0  
t he  seri o us  a d verse  e ve nt  i m me diatel y  (e. g., partici pa nt  s o u g ht  treat me nt  else w here), 
t he partici pati n g i n vesti gat or is t o re p ort t he e ve nt wit hi n 1 b usi ness da y after lear ni n g of 
it  a n d  d oc u me nt  t he  ti me  of  his  or  her  first  a ware ness  of  t he  a d verse  e ve nt.  Re p ort 
seri o us a d verse e ve nts b y facsi mile t o: 
 
C o or di nati n g Ce nter Fa x:      
 
   
T he C o or di nati n g Ce nter will be res p o nsi ble f or f or war di n g all seri o us a d verse e ve nts 
t o  Seattle  Ge netics  Dr u g  Safet y  De partme nt 
 wit hi n  3 0  da ys  of 
recei vi n g  t he  i nitial  fa x  n otificati o n  fr o m  partici pati n g  i n vesti gat ors.  E ve nts  meeti n g 
F D A re p orti n g criteria (see 1 1. 6) wi ll be re p orte d t o Seattle Ge netics Dr u g Safet y at t he 
sa me ti me t he F D A is n otifie d b y t he C o or di nati n g Ce nter. 
1 0. 8  Re p orti n g t o H os pit al  Ris k M a n a ge me nt 
Partici pati n g i n vesti gat ors will re p ort t o t h eir l ocal Ris k Ma na ge me nt office a n y s u bject 
safet y re p orts or se nti nel e ve nts t hat re q uire re p orti n g acc o r di n g t o i nstit uti o nal p olic y. 
1 0. 9  M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n 
All a d verse e ve nts, b ot h seri o us a n d n o n-seri o us, a n d deat hs t hat are e nc o u ntere d fr o m 
i nitiati o n  of  st u d y  i nter ve ntio n,  t hr o u g h o ut  t he  st u d y,  a n d  wit h i n  3 0  da ys  of  t he  last 
st u d y  i nter ve nti o n  s h o ul d  be  f oll o we d  t o  t heir  res ol uti o n,  or  u ntil  t he  partici pati n g 
i n vesti gat or  assesses  t he m  as  sta ble,  or  t he  partici pati n g  i n vesti gat or  deter mi nes  t he 
e ve nt  t o  be  irre versi ble,  or   t he  partici pa nt  is  l ost  t o  f oll o w- u p.  T he  prese nce  a n d 
res ol uti o n of A Es a n d S A Es ( wit h dates) s h o ul d be d oc u me nte d o n t he a p pr o priate case 
re p ort  f or m  a n d  rec or de d  i n  t he  partici pa nt’s  me dical  rec or d  t o  facilitate  s o urce  data 
verificati o n.  
 
F or  s o me  S A Es,  t he  Pri nci pal  I n vesti gat or/ S p o ns or  or  desi g nee  ma y  f oll o w- u p  b y 
tele p h o ne,  fa x,  a n d/ or  m o nit ori n g  visit  t o  o btai n  a d diti o nal  case  details  dee me d 
necessar y t o a p pr o pria tel y e val uate t he S A E re p ort (e. g., h os pital disc har ge s u m mar y, 
c o ns ulta nt re p ort, or  a ut o ps y re p ort).  
 
Partici pa nts  s h o ul d  be  i nstr ucte d  t o  re p or t  a n y  seri o us  p ost-st u d y  e ve nt(s)  t hat  mi g ht 
reas o na bl y  be  relate d  t o  partici pati o n  i n  t his  st u d y.  Partici pati n g  i n vesti gat ors  s h o ul d 
n otif y t he C o or di nati n g Ce nter a n d t heir res p ecti ve I R B of a n y u na ntici pate d deat h or 
a d verse  e ve nt  occ urri n g  after  a  partici p a nt  has  disc o nti n ue d  or  ter mi nate d  st u d y 
partici pati o n t hat ma y reas o na bl y be relate d t o t he st u d y.   
1 1.  D A T A A N D S A F E T Y M O NI T O RI N G 
1 1. 1  D at a Re p orti n g 
1 1. 1. 1  Met h o d  
T he  Q A C T  a n d  t he  C o or di nati n g  Ce nter   will  c ollect,  ma na ge,  a n d  perf or m 
q ualit y c hec ks o n t he data f or t his st u d y.    
 
1 1. 1. 2  Data  S u b missi o n  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 1  
T he  sc he d ule  f or  c o m pleti o n  a n d  s u b mi ssi o n  of  case  re p ort  f or ms  ( pa per  or 
electr o nic) t o t he Q A C T is as f oll o ws: 
 
F or m 
S u b missi o n Ti meli ne 
Eli gi bilit y C hec klist 
C o m plete pri or t o re gistrati o n wit h Q A C T 
O n St u d y F or m 
Wit hi n 1 4 da ys of re gistrati o n 
Baseli ne Assess me nt F or m  
Wit hi n  1 4 da ys of re gistrati o n 
Treat me nt F or m 
Wit hi n 1 0 da ys of t he last da y of t he c ycle 
A d verse E ve nt Re p ort F or m  
Wit hi n 1 0 da ys of t he last da y of t he c ycle 
Res p o nse Assess me nt F or m 
Wit hi n 1 0 da ys of t he c o m pleti o n of t he c ycle 
re q uire d f or res p o nse e val uati o n 
Off Treat me nt/ Off St u d y F or m 
Wit hi n 1 4 da ys of c o m pleti n g treat me nt or 
bei n g ta ke n off st u d y f or a n y reas o n 
F oll o w u p/ S ur vi val F or m 
Wit hi n 1 4 da ys of t he pr ot oc ol defi ne d f oll o w 
u p visit date or call 
 
1 1. 2  S afet y Meeti n gs 
T he D F/ H C C Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) will re vie w a n d m o nit or 
t o xicit y  a n d  accr ual  data  fr o m  t his  trial.  T he  c o m mittee  is  c o m p ose d  of  cli nical 
s pecialists  wit h  e x perie nce i n  o nc ol o g y  a n d  w h o  ha ve  n o  direct  relati o ns hi p  wit h  t he 
st u d y. I nf or mati o n t hat raises a n y q uesti o ns a bo ut partici pa nt safet y  will be a d dresse d 
wit h t he Pri nci pal I n vesti g at or/ S p o ns or a n d st u d y tea m. 
 
T he  D S M C  will  meet  q uarterl y  a n d/ or  m ore  ofte n  if  re q uire d  t o  re vie w  t o xicit y  a n d 
accr ual  data.    I nf or mati o n  t o  be  pr o vi de d  t o  t he  c o m mittee  ma y  i ncl u de:    u p-t o- date 
partici pa nt  accr ual;  c urre nt  d o se  le vel  i nf or mati o n;  D L T  i nf or mati o n;  all  gra de  2  or 
hi g her  u ne x pecte d  a d verse  e ve nts  t hat  ha ve   bee n  re p orte d;  s u m mar y  of  all  deat hs 
occ urri n g  wit hi n  3 0  da ys  f o r  P hase  I  or  II  pr ot oc ols;  f or  ge ne  tra nsfer  pr ot oc ols, 
s u m mar y  of  all  deat hs  w hile  bei n g  treate d a n d  d uri n g  acti ve  f oll o w- u p;  a n y  res p o nse 
i nf or mati o n;  a u dit  res ults,  a n d  a  s u m mar y  pr o vi de d  b y  t he  st u d y  tea m.  Ot her 
i nf or mati o n (e. g. sca ns, la b orat or y val ues) will be pr o vi de d u p o n re q uest.  
1 1. 3  M o nit ori n g  
I n v ol ve me nt  i n  t his  st u d y  as  a  partici pati n g  i n vesti gat or  i m plies  acce pta nce  of 
p ote ntial  a u dits  or  i ns pecti o ns,  i ncl u di n g  s o urce  data  veri ficati o n,  b y  re prese ntati ves 
desi g nate d b y t he Pri nci pal I n vesti gat or/ S p o ns or or C o ordi nati n g Ce nter. T he p ur p ose 
of t hese a u dits or i ns pecti o ns is t o e xa m i ne 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 data were rec or de d, a nal yze d, 
a n d acc uratel y re p orte d i n acc or da nce wit h t he pr ot oc ol, i nstit uti o nal p olic y, a n d a n y 
a p plica ble re g ulat or y re q uire me nts.   
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 2  
All data will be m o nit ore d f or ti meli ness of s u b missi o n, c o m plete ness, a n d a d here nce 
t o pr ot oc ol re q uire me nts. M o nit ori n g will begi n at t he ti me of partici pa nt re gistrati o n 
a n d will c o nti n ue d uri n g pr ot oc ol perf or ma nce a n d c o m pleti o n.  
1 2.  R E G U L A T O R Y C O N SI D E R A TI O N S 
1 2. 1  Pr ot oc ol Re vie w a n d A me n d me nts 
T his pr ot oc ol, t he pr o p ose d i nf or me d c o nse n t a n d all f or ms of partici pa nt i nf or mati o n 
relate d  t o  t he  st u d y  (e. g.,  a d vertise me nts  use d  t o  recr uit  partici pa nts)  a n d  a n y  ot her 
necessar y  d oc u me nts  m ust  be  s u b mitte d,  re vie we d  a n d  a p pr o ve d  b y  a  pr o perl y 
c o nstit ute d I R B g o ver ni n g eac h st u d y l ocati o n.  
A n y  c ha n ges  ma de  t o  t he  pr ot oc ol  m ust be  s u b mitte d  as  a me n d me nts  a n d  m ust  be 
a p pr o ve d b y t he I R B pri or t o i m ple me ntati o n. A n y c ha n ges i n st u d y c o n d uct m ust be 
re p orte d  t o  t he  I R B.  T he  Pri nci pal  I n vesti gat or/ S p o ns or  or  C o or di nati n g  Ce nter  will 
disse mi nate pr ot oc ol a me n d me nt i nf or mati o n t o all partici pati n g i n vesti gat ors.  
All decisi o ns of t he I R B c o ncer ni n g t he c o n d uc t of t he st u d y m ust be ma de i n writi n g. 
1 2. 2  I nf or me d C o nse nt 
 
All  partici pa nts  m ust  be  pr o vi de d  a  c o nse n t  f or m  descri bi n g  t his  st u d y  a n d  pr o vi di n g 
s ufficie nt  i nf or mati o n  f or  partici pa nts  t o  ma ke  a n  i nf or me d  decisi o n  a b o ut  t heir 
partici pati o n i n t his st u d y. T he f or mal c o nse nt of a partici pa nt, usi n g t he I R B a p pr o ve d 
c o nse nt f or m, m ust be o btai ne d bef ore t he pa rtici pa nt is i n v ol ve d i n a n y st u d y-relate d 
pr oce d ure.  T he  c o nse nt  f or m  m ust  be  si g ne d  a n d  date d  b y  t he  partici pa nt  or  t he 
partici pa nt’s le gall y a ut h orize d re prese ntati v e, a n d b y t he pers o n o btai ni n g t he c o nse nt. 
T he partici pa nt m ust be gi ve n a c o p y of t he si g ne d a n d date d c o nse nt d oc u me nt. T he 
ori gi nal si g ne d c o p y of t he c o nse nt d oc u me nt m ust be retai ne d i n t he me dical rec or d or 
researc h file.  
1 2. 3  Et hics 
T his  st u d y  is  t o  be  c o n d ucte d  acc or di n g  t o  t he  f oll o wi n g  c o nsi derati o ns,  w hic h 
re prese nt g o o d a n d s o u n d researc h practice: 
 
U S C o de of Fe deral Re g ulati o ns ( C F R ) g o ver ni n g cli nical st u d y c o n d uct a n d 
et hical pri nci ples t hat ha ve t heir or i gi n i n t he Declarati o n of Helsi n ki 
o  Title 2 1 Part 5 0 – Pr otecti o n of H u ma n S u bjects 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 5 0 _ 0 2. ht ml   
o  Title 2 1 Part 5 4 – Fi na ncial Discl os ure b y Cli nical I n vesti gat ors 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x 0 2/ 2 1cfr 5 4 0 2. ht ml   
o  Title 2 1 Part 5 6 – I nstit uti o nal Re vie w B oar ds 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 5 6 _ 0 2. ht ml   


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 3  
o  Title 2 1 Part 3 1 2 – I n vesti ga ti o nal Ne w Dr u g A p plicati o n 
w w w.access. g p o. g o v/ nara/cfr/ waisi d x _ 0 2/ 2 1cfr 3 1 2 _ 0 2. ht ml   
 
State la ws 
 
D F/ H C C researc h p olicies a n d pr oce d ures        
htt p:// w w w. df hcc. har var d.e d u/cli nical-resea rc h-s u p p ort/cli nical-researc h- u nit-
cr u/ p olicies-a n d- pr oce d ures/   
It  is  u n derst o o d  t hat  de viati o ns  fr o m  t he pr ot oc ol  s h o ul d  be a v oi de d,  e xce pt  w he n 
necessar y t o eli mi nate a n i m me diate hazar d t o a researc h partici pa nt.  I n s uc h case, t he 
de viati o n m ust be re p orte d t o t he I R B acc or di n g t o t he l ocal re p orti n g p olic y.  
 
1 2. 4  
M ultice nter G ui deli nes 
 
T his pr ot oc ol will a d here t o t he p olicies a n d re q uire me nts of t he D F/ H C C M ulti- Ce nter Data a n d 
Safet y M o nit ori n g Pla n.  T he s peci fic res p o nsi bilities of t he O verall PI, C o or di nati n g Ce nter, a n d 
Partici pati n g I nstit uti o ns a n d t he pr oce d ures f or a u diti n g are prese nte d i n A p pe n di x E. 
 
 T he Over all PI/ C o or di n ati n g Ce nter is res p o ns i ble f or distri b uti n g all I N D Acti o n Letters 
or S afety Re p orts t o a ll p artici p ati n g i nstit uti ons f or s u b missi o n t o t heir i n divi d u al I R Bs 
f or acti o n as re q uire d. 
 
 Mec h a nis ms will be i n pl ace t o e ns ure q u al ity ass ur a nce, pr ot oc ol c o m pli a nce, a n d 
a dverse eve nt re p orti n g at e ac h site. 
 
 Exce pt i n very u n us u al circ u mst a nces, e ac h p ar tici p ati n g i nstit uti o n will or der t he st u dy 
a ge nt(s) directly fr o m s u p plier.  A p artici p at i n g site m ay or der t he a ge nt(s) o nly after t he 
i niti al I R B a p pr ov al f or t he site h as bee n f or w ar de d t o t he C o or di n ati n g Ce nter. 
 
1 2. 5  St u d y D oc u me nt ati o n 
 
T he  i n vesti gat or  m ust  pre pare  a n d  mai nta i n  a de q uate  a n d  acc urate  case  hist ories 
desi g ne d  t o  rec or d  all  o bser vati o ns  a n d  ot her  data  pert i ne nt  t o  t he  st u d y  f or  eac h 
researc h partici pa nt. T his i nf or mati o n e na bles t he st u d y t o be f ull y d oc u me nte d a n d t he 
st u d y data t o be s u bse q ue ntl y verifie d. 
 
Ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he case re p ort f or ms i ncl u de b ut are 
n ot  li mite d  t o  h os pital  rec or ds,  cli nical c harts,  la b orat or y  a n d  p har mac y  rec or ds, 
rec or de d  data  fr o m  a ut o mate d  i nstr u me nts,  micr ofic hes,  p h ot o gra p hic  ne gati ves, 
micr ofil m or ma g netic me dia, a n d/ or x-ra ys.  
1 2. 6  Rec or ds Rete nti o n 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 4  
All  st u d y-relate d  d oc u me nts m ust  be  retai ne d  f or  t he ma xi m u m  peri o d  re q uire d  b y 
a p plica ble fe deral re g ulati o ns a n d g ui d eli nes or i nstit uti o nal p olicies.  
 
 
1 3.  S T A TI S TI C A L C O N SI D E R A TI O N S  
1 3. 1  St u d y Desi g n/ E n d p oi nts 
 
T his  is  a n  o pe n  la bel  si n gle ar m  p hase  II  st u d y  t o  assess  t h e  efficac y  a n d  safet y  of 
bre nt u xi ma b i n c o m bi nati o n wit h A dria m yci n a n d Dacar bazi ne ( A D) i n pre vi o usl y u ntreate d 
sta ge I a n d II n o n- b ul k y c H L. Bre nt u xi ma b a n d A D are a d mi nistere d a d mi nistere d o n da ys 1 
a n d 1 5 of eac h 2 8 da y c ycle.  I nteri m resta gi n g P E T- C T will be perf or me d f oll o wi n g c ycle 2. 
Patie nts wit h pr o gressi ve disease will be ta ke n off st u d y.  Patie nts i n C R will recei ve a t otal 
of 4 c ycles of t hera p y; patie nts wit h sta ble disease or  partial res p o nse will recei ve a t otal of 6 
c ycles.  
 
 
 
 
1 3. 1. 1  Pri mar y E n d p oi nt a n d Sa m ple Size  
T he pri mar y e n d p oi nt of t his st u d y is c o m plete res p o nse rate at E O T resta gi n g. A 
o ne-sta ge desi g n is use d.  A t otal of 3 4 pa rtici pa nts will be e ntere d o n t his st u d y.  
T he  e x pecte d  accr ual  is  1- 2  partici pa nts per  m o nt h.    If  at least  9 1 %  ( 3 1)  of 
e val ua ble  partici pa nts  ac hie ve  c o m plete  res p o nses,  t he  treat me nt  will  be 
c o nsi dere d  pr o misi n g  a n d  w ort h y  of  f u rt her  st u d y.  Patie nts  re m o ve d  fr o m  st u d y 
pri or  t o  i nitial  resta gi n g  f or  reas o ns ot her  t ha n  disease  pr o gressi o n  are  n ot 
c o nsi dere d e val ua ble f or res p o nse. T h e st u d y has 9 1 % p o wer a n d 0. 0 9 o ne-si de d 
t y pe  I  err or  t o  test  a  C R  rate  of  9 5 % vs.  a  C R  rate  of  8 1 %.  Wit h  3 4  eli gi ble 
patie nts  t he  9 0 %  c o nfi de nce  i n ter val  f or  t he  tr ue  res p o nse  rate  will  be  n o  wi der 
t ha n  3 0 %.  If  greater  t ha n  2  e val ua ble  partici pa nts  are  see n  n ot  t o  ha ve  disease 
res p o nse  ( C R  or  P R)  f oll o wi n g  bre nt u xi ma b- A D  t hera p y,  t he  st u d y  will  st o p. 
Ass u mi n g  t he  n ull  res p o nse  rate  of  8 1 % ,  t he  st u d y  will  st o p  earl y  wit h  a 
ma xi m u m pr o ba bilit y of 0. 9 7. U n der t he pr o m isi n g rate, t he st u d y will st o p earl y 
wit h a ma xi m u m pr o ba bilit y of 0. 2 4. 
1 3. 1. 2  Sec o n dar y a n d E x pl orat or y E n d p oi nts 
 
O verall S ur vi val ( O S) will be meas ure d fr o m date of st u d y e ntr y t o date of deat h 
a n d  c haracterize d  usi n g  t he  Ka pla n- Meier   met h o d.    Fail ure-free  S ur vi val  ( F F S) 
will be meas ure d fr o m date of st u d y e ntr y t o date of d oc u me ntati o n of treat me nt 
fail ure  a n d  calc ulate d  usi n g  t he  Ka pla n- Meier  met h o d.    Treat me nt  fail ure  is 
defi ne d as: pr o gressi ve disease, fail ure t o  ac hie ve a c o m plete re missi o n, or rela pse 
after  i nitial  res p o nse.    T his  st u d y  is  n ot  p o were d  f or F F S,  b ut  o ur  h y p ot hesis  is 
t hat  it  will  ac hie ve  a  2  year  F F S  of ≥8 7 %,  c o nsiste nt  wit h all  pri or  st u dies  of 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 5  
c he m ot hera p y al o ne i n n o n- b ul k y li mite d sta ge H L. 7, 1 1, 1 2, 1 9, 2 0 T w o year F F S less 
t ha n t his will n ot be c o nsi dere d w ort h y of f urt her i n vesti gati o n. 
 
All partici pa nts w h o recei ve treat me nt, re gar dless of eli gi bilit y, will be assesse d 
f or t o xicit y.   
1 3. 1. 3  E val uati o n of t o xicit y  
All partici pa nts will be e val ua ble f or t o xicit y  fr o m t he ti me of t heir first treat me nt.  
Partici pa nts will be assesse d f or t o xicit y wit h eac h treat me nt a n d partici pa nts wit h 
u nacce pta ble  t o xicit y  will  be  re m o ve d  fr o m  t he  st u d y.    All  partici pa nts  w h o 
recei ve treat me nt, re gar dless of eli gi bilit y, will be e val uated f or t o xicit y.   
1 3. 1. 4  E val uati o n of res p o nse   
All partici pa nts w h o reac h i n itial resta gi n g sca n will be e val ua ble f or res p o nse, as 
will s u bjects w h o are re m o ve d fr o m st u d y pri o r t o i nitial resta gi n g d ue t o cli nical 
disease  pr o gressi o n.  Patie nts  re m o ve d  fr o m   st u d y  pri or  t o  i nitial  resta gi n g  f or 
reas o ns ot her t ha n disease pr o gressi o n are n ot c o nsi dere d e val ua ble f or res p o nse. 
Eac h partici pa nt s h o ul d be assi g ne d o ne of t he f oll o wi n g cate g ories: 1) c o m plete 
res p o nse,  2)  partial  res p o nse,  3)  sta ble  disease,  4)  pr o gressi ve  disease,  5)  earl y 
deat h fr o m mali g na nt disease, 6) earl y de at h fr o m t o xicit y, 7) earl y deat h beca use 
of  ot her  ca use,  or  9)  u n k n o w n  ( n ot  assessa ble,  i ns uffi cie nt  data).  B y  ar bitrar y 
c o n ve nti o n,  cate g or y  9  us uall y  desi g nates t he  " u n k n o w n"  stat us  of  a n y  t y pe  of 
data i n a cli nical data base.  
S u bjects w h o are re m o ve d fr o m pr ot oc ol pr i or t o first resta gi n g f or reas o ns ot her 
t ha n t o xicit y or disease pr o gressi o n ma y be re place d. 
All c o ncl usi o ns s h o ul d be base d o n all eli g i ble partici pa nts. Su ba nal yses ma y t he n 
be perf or me d o n t he basis of a s u bset of partici pa nts, e xcl u di n g t h ose f or w h o m 
maj or  pr ot oc ol  de viati o ns  ha ve  bee n i de ntifie d  (e. g.,  earl y  disc o nti n uati o n  of 
treat me nt,  maj or  pr ot oc ol  vi olati o ns,  etc.).  H o we ver,  t hese  s u ba nal yses  ma y  n ot 
ser ve as t he basis f or dra wi n g c o ncl usi o ns c o ncer ni n g treat me nt efficac y, a n d t he 
reas o ns  f or  e xcl u di n g  partici pa nts  fr o m  t he  a nal ysis s h o ul d  be  clearl y  re p orte d. 
T he 9 0 % c o nfi de nce i nter vals s h o ul d als o be pr o vi de d. 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 6  
1 4.  R E F E R E N C E S  
 
1.  C hes o n B D, Fis her RI, Barri n gt o n S F, et al. Rec o m me n dati o ns f or I nitial E val uati o n, 
Sta gi n g, a n d Res p o nse Assess me nt of H o d g ki n a n d N o n- H o d g ki n L y m p h o ma: T he L u ga n o 
Classificati o n. J Cli n O nc ol 2 0 1 4. 
2.  Y o u nes A, G o pal A K, S mit h S E, et al. Res ult s of a pi v otal p hase II st u d y of bre nt u xi ma b 
ve d oti n f or patie nts wit h rela pse d or re fract or y H o d g ki n's l y m p h o ma. J Cli n O nc ol 
2 0 1 2; 3 0: 2 1 8 3- 9. 
3.  A d va ni R, S h ust o v R, Bri ce P, et al. Bre nt u xi ma b Ve d o ti n ( S G N- 3 5) i n Patie nts wit h 
Rela pse d or Refract or y S yste mic A na pla stic Lar ge Cell L y m p h o ma: A P hase 2 St u d y 
U p date. A S H A n n ual Meeti n g A bstracts 2 0 1 1; 1 1 8: 4 4 3-. 
4.  Y o u nes A, C o n n ors J M, Par k SI, et al. Bre n t u xi ma b ve d oti n c o m bi ne d wit h A B V D or A V D 
f or patie nts wit h ne wl y dia g n ose d H o d g ki n's l y m p h o ma: a p hase 1, o pe n-la bel, d ose-
escalati o n st u d y. T he la n cet o nc ol o g y 2 0 1 3; 1 4: 1 3 4 8- 5 6. 
5.  Fer me C, E g h bali H, Meer wal dt J H, et al. C h e m ot hera p y pl us i n v ol ve d-fiel d ra diati o n i n 
earl y-sta ge H o d g ki n's disease.  N E n gl J Me d 2 0 0 7; 3 5 7: 1 9 1 6- 2 7. 
6.  Ca nell os G P, A n ders o n J R, Pr o pert KJ, et al . C he m ot hera p y of a d va nce d H o d g ki n's disease 
wit h M O P P, A B V D, or M O P P alter nati n g wit h A B V D. N E n gl J Me d 1 9 9 2; 3 2 7: 1 4 7 8- 8 4. 
7.  Me yer R M, G os p o dar o wicz M K, C o n n ors J M, et al. Ra n d o mize d c o m paris o n of A B V D 
c he m ot hera p y wit h a strate g y t hat i ncl u des ra di ati o n t hera p y i n patie nts wit h li mite d-sta ge 
H o d g ki n's l y m p h o ma: Nati o nal Ca ncer I nstit ute of Ca na da Cli nical Trials Gr o u p a n d t he 
Easter n C o o perati ve O nc ol o g y Gr o u p. J Cli n O nc ol 2 0 0 5; 2 3: 4 6 3 4- 4 2. 
8.  Fe deric o M, L u mi nari S, Ia n nitt o E, et al . A B V D c o m pare d wit h B E A C O P P c o m pare d wit h 
C E C f or t he i nitial treat me nt of patie nts wit h a d va nce d H o d g ki n's l y m p h o ma: res ults fr o m 
t he H D 2 0 0 0 Gr u p p o Italia n o per l o St u di o dei Linf o mi Trial. J Cli n O nc ol 2 0 0 9; 2 7: 8 0 5- 1 1. 
9.  Ale ma n B M, va n de n Belt- D use b o ut A W, De Br ui n M L, et al. Late car di ot o xicit y after 
treat me nt f or H o d g ki n l ym p h o ma. Bl o o d 2 0 0 7; 1 0 9: 1 8 7 8- 8 6. 
1 0. N g A K, Ber nar d o M V, Weller E, et al. S ec o n d mali g na nc y after H o d g ki n disease treate d 
wit h ra diati o n t hera p y wit h or  wit h o ut c he m ot hera p y: l o n g-term ris ks a n d ris k fact ors. Bl o o d 
2 0 0 2; 1 0 0: 1 9 8 9- 9 6. 
1 1. Me yer R M, G os p o dar o wicz M K, C o n n ors J M, et  al. A B V D al o ne vers us ra diati o n- base d 
t hera p y i n li mite d-sta ge H o d g ki n's l ym p h o ma. N E n gl J Me d 2 0 1 2; 3 6 6: 3 9 9- 4 0 8. 
1 2. Stra us DJ, P ortl oc k C S, Qi n J, et al. Res ults  of a pr os pecti ve ra n d o mize d cli nical trial of 
d o x or u bici n, ble o m yci n, vi n blasti ne, a n d dacar ba zi ne ( A B V D) f oll o we d b y ra diati o n t hera p y 
( R T) vers us A B V D al o ne f or sta ges I, II, a n d III A n o n b ul k y H o d g ki n disease. Bl o o d 
2 0 0 4; 1 0 4: 3 4 8 3- 9. 
1 3. R ue da D o mi n g uez A, Mar q uez A, G u ma J, et  al. Treat me nt of sta ge I a n d II H o d g ki n's 
l y m p h o ma wit h A B V D c he m ot hera p y: res ults after 7 years of a pr os pecti ve st u d y. A n n 
O nc ol 2 0 0 4; 1 5: 1 7 9 8- 8 0 4. 
1 4. Bar nes J A, Lacasce A S, Z u k ot y ns ki K, et al. E n d- of-treat me nt b ut n ot i nteri m P E T sca n 
pre dicts o utc o me i n n o n b ul k y li mite d-st a ge H o d g ki n's l y m p h o ma. A n n O nc ol. 
1 5. Ca nell os G P, A bra ms o n J S, Fis her D C, La Cas ce A S. Treat me nt of fa v ora ble, li mite d-sta ge 
H o d g ki n's l y m p h o ma wit h c he m ot hera p y wit h o ut c o ns oli dati o n b y ra dia ti o n t hera p y. J Cli n 
O nc ol; 2 8: 1 6 1 1- 5. 
1 6. B orc h ma n n P, Die hl V, G or ge n H, L o hri A, Zijlstra J, T o p p M S. Dacar bazi ne Is A n Esse ntial 
C o m p o ne nt Of A b v d I n T he Treat me nt Of Earl y Fa v o ura ble H o d g ki n L y m p h o ma: Res ults Of T he 
Sec o n d I nteri m A nal ysis Of T he G hs g H d 1 3 Trial  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 7  
 Hae mat ol o gica 2 0 1 0. 
1 7. Stra us DJ, J o h ns o n J L, Lacasce A S, et al. D o x or u bici n, vi n blasti ne, a n d ge mcita bi ne 
( C A L G B 5 0 2 0 3) f or sta ge I/II n o n b ul k y H o d g ki n l y m p h o ma: pretreat me nt pr o g n ostic fact ors 
a n d i nteri m P E T. Bl o o d; 1 1 7: 5 3 1 4- 2 0. 
1 8. Mei g na n M, Galla mi ni A, Itti E, Barri n gt o n S, Hai o u n C, P olliac k A. Re p ort o n t he T hir d 
I nter nati o nal W or ks h o p o n I nteri m P ositr o n E missi o n T o m o gra p h y i n L y m p h o ma hel d i n 
Me nt o n, Fra nce, 2 6- 2 7 Se pte m ber 2 0 1 1 a n d Me nt o n 2 0 1 1 c o nse ns us. Le u k L y m p h o ma 2 0 1 2. 
1 9. Ca nell os G P, A bra ms o n J S, Fis her D C, La Cas ce A S. Treat me nt of fa v ora ble, li mite d-sta ge 
H o d g ki n's l y m p h o ma wit h c he m ot hera p y wit h o ut c o ns oli dati o n b y ra dia ti o n t hera p y. J Cli n 
O nc ol 2 0 1 0; 2 8: 1 6 1 1- 5. 
2 0. Ra df or d J, Illi d ge T, C o u nsell N, et al. Res ults  of a trial of P E T- directe d t hera p y f or earl y-
sta ge H o d g ki n's l y m p h o ma. N E n gl J Me d 2 0 1 5; 3 7 2: 1 5 9 8- 6 0 7. 
2 1. Cella D F, T uls k y D S, Gra y G, et al. T he F u ncti o nal Assess me nt of Ca ncer T hera p y scale: 
de vel o p me nt a n d vali dati o n of t he ge neral meas ure. J Cli n O nc ol 1 9 9 3; 1 1: 5 7 0- 9. 
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 8  
1 5.  A P P E N DI C E S  
A p pe n di x  A:  O bjecti ve  Res p o nse  Criteri a 
(see  Dea u ville  criteria  o n  ne xt  pa ge  f or 
i nter pretati o n of P E T p ositi ve/ ne gati ve) 
 
Re vise d criteri a f or res p o nse assess me nt 1 
 
 
P E T- C T- b ase d res p o nse  
 
C o m plete Met a b olic Res p o nse ( C M R) 
L y m p h n o des a n d 
e xtral y m p hatic 
sites 
Sc ore 1, 2, or 3 wit h or wit h o ut a resi d ual mass o n 5- p oi nt ( Dae u ville) 
scale (see bel o w) 
 
It is rec o g nize d t hat i n Wal de yer’s ri n g or e xtra n o dal sites wit h hi g h 
p h ysi ol o gical u pta ke or wit h acti vati o n wit hi n s plee n or marr o w, e. g. 
wit h c he m ot hera p y or m yel oi d c ol o n y  sti m ulati n g fact ors, u pta ke ma y 
be greater t ha n n or mal me diasti n u m a n d/ or li ver.  I n t his circ u msta nce, 
C M R ma y be i nferre d if u pta ke at s ites of i nitial i n v ol ve me nt is n o 
greater t ha n s urr o u n di n g n or mal tiss u e e ve n if t he tiss ue has hi g h 
p h ysi ol o gical u pta ke 
N o n- meas ure d 
lesi o n 
N ot a p plica ble 
Or ga n 
e nlar ge me nt 
N ot a p plica ble 
Ne w lesi o ns  
N o ne 
B o ne marr o w  
N o e vi de nce of F D G-a vi d disease i n marr o w 
 
 
 
P arti al Met a b olic Res p o nse ( P M R) 
L y m p h n o des a n d 
e xtral y m p hatic 
sites 
Sc ore 4, 5 wit h re d uce d u pta ke c o m pare d wit h baseli ne a n d resi d ual 
mass(es) of a n y size. 
At i nteri m  t hese fi n di n gs s u g gest res p o n di n g disease  
 
At e n d of tre at me nt  t hese fi n di n gs i n dicate resi d ual disease 
N o n- meas ure d 
lesi o ns 
N ot a p plica ble 
Or ga n 
e nlar ge me nt 
N ot a p plica ble 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
3 9  
De a u ville Criteri a f or P E T sc a n I nter pret ati o n i n L y m p h o m a 1 8  
Fi ve- p oi nt scale: 
1.  
N o U pta ke 
2.  
U pta ke ≤ me diasti n u m 
3.  
U pta ke > me diasti n u m b ut ≤ li ver 
4.  
U pta ke m o deratel y i ncrease d c o m pare d t o li ver at a n y site 
5.  
U pta ke mar ke dl y i ncrease d c o m pare d t o t h e li ver at a n y site or/a n d ne w sites of 
disease 
X.    Ne w u pta ke felt u nrelate d t o l y m p h o ma 
 
A sc ore of 1- 3 is P E T N E G A TI V E. 
A sc ore of 4- 5 is P E T P O SI TI V E. 
 
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 2, 5/ 1 3/ 1 5  
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 0 
A p pe n di x B: Perf or m a n ce St at us Criteri a 
 
 
E C O G Perf or m a nce St at us Sc ale 
 
 
K ar n ofs k y Perf or m a nce Sc ale 
Gra de 
Descri pti o n 
Perce nt 
Descri pti o n 
0 
N or mal acti vit y. F ull y acti ve, a ble t o 
carr y o n all pre- disease perf or ma nce 
wit h o ut restricti o n. 
1 0 0 
N or mal, n o c o m plai nts, n o 
e vi de nce of disease. 
9 0 
A ble t o carr y o n n or mal acti vit y; 
mi n or si g ns or s y m pt o ms of 
disease. 
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). 
8 0 
N or mal acti vit y wit h eff ort; s o me 
si g ns or s y m pt o ms of disease. 
7 0 
Cares f or self, u na ble t o carr y o n 
n or mal acti vit y or t o d o acti ve 
w or k. 
2 
I n be 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. 
6 0 
Re q uires occasi o nal assista nce, 
b ut is a ble t o care f or m ost of 
his/ her nee ds. 
5 0 
Re q uires c o nsi dera ble assista nce 
a n d fre q ue nt me dical care. 
3 
I n be 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 0 
Disa ble d, re q uires s pecial care 
a n d assista nce. 
3 0 
Se verel y disa ble d, h os pitalizati o n 
i n dicate d. Deat h n ot i m mi ne nt. 
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. 
2 0 
Ver y sic k, h os pitalizati o n 
i n dicate d. Deat h n ot i m mi ne nt. 
1 0 
M ori b u n d, fatal pr ocesses 
pr o gressi n g ra pi dl y.  
5  
Dea d. 
0  
Dea d. 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 1
A p pe n di x C: Dr u g i nter acti o ns 
 
I n h u ma ns, bre nt u xi ma b di d n ot affect t he P K of mi daz ola m, a se nsiti ve C Y P 3 A 4 s u bstrate, 
s u g gesti n g t hat bre nt u xi ma b a n d M M A E are neit her i n hi bit ors n or i n d ucers of C Y P 3 A 4. I n 
h u ma ns,  data  fr o m  c oa d mi nistrati o n  of  bre n t u xi ma b  wit h  rifa m pi n,  a  C Y P 3 A 4  a n d  P- g p 
i n d ucer,  or  ket oc o naz ole,  a  stro n g  C Y P 3 A 4  a n d  P- g p  i n hi bit or,  i n dicate  t hat  M M A E  is  a 
s u bstrate of C Y P 3 A 4. T his is co nsiste nt wit h res ults fr o m i n vitr o st u dies, w hic h s h o w t hat 
t he meta b olites of M M A E are pr o d uce d pri maril y t hr o u g h t he acti o n of C Y P 3 A 4. N o d ose 
a dj ust me nt  s h o ul d  be  necessar y  base d  o n  c oa d mi nistrati o n  of  a  C Y P 3 A 4  i n d ucer.  Patie nts 
recei vi n g  str o n g  C Y P 3 A 4  or  P- g p  i n hi bit ors  s h o ul d  be  cl osel y  m o nit ore d  f or  A Es  w he n 
c oa d mi nistere d wit h bre nt u xi ma b. 
 
E xa m ple str o n g i n hi bit ors of C Y P 3 A 4: s o me pr otease i n hi bit ors (ataza na vir, rit o na vir, 
i n di na vir, nelfi na vir, sa q ui na vir), clarit hr o m yci n, telit hr o m yci n, c hl ora m p he nic ol, 
ket oc o naz ole, i ntrac o naz ole, nefaz o d o ne, fl u v o xa mi ne 
 
E xa m ple i n hi bit ors of P- g p: a mi o dar o ne, clarit hr o m yci n, c ycl os p ori ne, diltiaze m, 
er yt hr o m yci n, i n di na vir, itrac o naz ole, ket oc o naz ole, nelfi na vir, ni car di pi ne, pr o pafe n o ne, 
q ui ni di ne, rit o na vir, sa q ui na vir, tacr oli m us, ta m o xife n, vera pa mil  
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 2
A p pe n di x D: Ne ur ot o xi cit y Q uesti o n n aire 
F A C T/ G O G- Ne ur ot o xicit y Q uesti o n naire, Versi o n 4. 0 2 1 
 
 
 
 
Patie nt Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    
Date C o m plete d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
Patie nt Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 3
 
 
 
 
 
 
 
 
 
D F CI I R B Pr ot oc ol #: 1 5- 1 9 6  
 
 
 
 
 
A P P E N DI X E  
 
D a n a- F ar ber/ H ar v ar d C a ncer Ce nter 
M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 4
T a ble of C o nte nts 
 
 
1. 0  I ntr o d ucti o n … … … … … … … … … … … … … … … … … … … … … … … …... … … …. … … 4 7 
1. 1  P ur p ose … … … … … … … … … … … … … … … … …. … … … … … … … … … … ….. 4 7 
1. 2  M ulti- Ce nter  
D at a  
a n d  
S afet y 
M o nit ori n g  
Pl a n  
Defi niti o ns 
… … … … … … ….. … … … … … 4 7 
2. 0  Ge ner al R oles a n d Res p o nsi bilities … … … … … … … ….................................................. 4 8 
 
2. 1  D F/ H C C 
S p o ns or  
… … … … … … … … …. … … … … … … … … … … … …. … … … ….. 4 8 
 
2. 2  C o or di n ati n g Ce nter … … … … … … ….. … … … … … … ….. … … … ….. … … … … 4 9 
 
2. 3  P artici p ati n g I nstit uti o n … … … … … … … … … … … … … … … … … …. … … …... 4 9 
 
 
 
 
3. 0  
  
  
D F/ H C C  
Re q uire me nts  
f o r  
M ulti- Ce nter  
Pr ot oc ols 
… … … … … … … … … … … … … … ….. … … … … …... … … … …. 5 1 
 
3. 1 Pr ot oc ol Distri b uti o n … … … … … … … … … … ….. … … … ….. … …. … … … … … 5 1 
 
3. 2 Pr ot oc ol Re visi o ns a n d Cl os ures … … … … … … … … … ….. … … … … … … … …. 5 1  
 
3. 3 I nf or me d C o nse nt Re q uire me nts … … … … … … … … … … … ….. ….. … … … …. 5 2 
 
3. 4 I R B D oc u me nt ati o n … … … … … … … … … … …. … … … … … … ….. … … … … … 5 2 
 
3. 5 I R B Re – A p pr o v als … … … … … … … … … … …. … … … … … … … ….. … … … … 5 2 
 
3. 6  
P artici p a nt  
C o nfi de nti alit y  
a n d  
A ut h oriz ati o n 
St ate me nt … … … … … ….. … …. … … … … 5 3  
 
3. 7  
D F/ H C C  
M ulti- Ce nter  
Pr ot oc ol   
  
Re gistr ati o n  
P olic y  
… … … … … … … …... … … … ….. 5 3 
 
3. 8 D F/ H C C Pr ot oc ol C ase N u m ber .................................................... 5 3  
 
3. 9 S afet y Assess me nts a n d T o xicit y M o nit ori n g ........................................... 5 3 
 
3. 1 0 D at a M a n a ge me nt … … … … … … … … …... … … …... … … … … … … 5 4 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 5
 
 
 
 
4. 0 Re q uisiti o ni n g I n vesti g ati o n al Dr u g … … … … … … … … … … …. ….. … … … … … … … 5 7 
 
 
5. 0 M o nit ori n g: Q u alit y C o ntr ol … … … … … … … … … … … … … …. … … … ….. … … … … 6 0 
 
5. 1 O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce … … … … … … … … ….. … … …... 6 0 
 
5. 2 M o nit ori n g Re p orts … … … …. … … … … … … 6 1 
5. 3  Accr u al M o nit ori n g............................................................................................... 6 1 
 
6. 0 A u diti n g: Q u alit y Ass ur a nce … … … … … … … … … … … … … … … … …..... … … … ….. 6 1 
 
 
6. 1  
A u dit  
Pl a n:  
D F/ H C C  
S p o ns ore d  
Tri als 
… … … … … … … … … … … … … … …... … … … … …. 6 1 
 
6. 3 A u dit N otific ati o n … … … … … … … … … … … … … … … … … … … … … … 6 1 
 
6. 4 A u dit Re p orts … … … … … … … … … … … … ….. … … …. … … … …. … ….. 6 2 
 
6. 5 
P artici p ati n g 
I nstit uti o n 
Perf or m a nce 
… … … … … … … … … … … ….. … …. … … … … … …. 6 2  
 
 
 
 
 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 6
1. 0  I N T R O D U C TI O N 
 
T he  Da na- Far ber/ Har var d  Ca ncer  Ce nter  M ulti- Ce nter  Data  a n d  Safet y  M o nit ori n g  Pla n 
( D F/ H C C D S M P) o utli nes t he pr oce d ures f or a D F/ H C C M ulti- Ce nter researc h pr ot oc ol. T he 
D F/ H C C  D S M P  s h o ul d  ser ve  as  a  refere nce  f or a n y  sites  e xter nal  t o  D F/ H C C  t hat  will  be 
partici pati n g i n t he researc h pr ot oc ol. 
 
1. 1  P ur p ose 
T o  esta blis h  sta n dar ds  t hat  will  e ns ure  t h at  a  Da na- Far ber/ Har var d  Ca ncer  Ce nter 
( D F/ H C C) M ulti-ce nter pr ot oc ol will c o m pl y wit h Fe deral re g ulati o ns, Healt h I ns ura nce 
P orta bilit y  a n d  Acc o u nta bilit y  Act  ( HI P A A)  re q uire me nts  a n d  a p plica ble  D F/ H C C 
Sta n dar d O perati n g Pr oce d ures.          
 
1. 2  M ulti- Ce nter D at a a n d S afet y M o nit ori n g Pl a n  Defi niti o ns   
 
D F/ H C C  M ulti-ce nter  Pr ot oc ol :    A  researc h  pr ot oc ol  i n w hic h  o ne  or  m ore  o utsi de 
i nstit uti o ns are c olla b orati n g wit h Da na- Far ber/ Har var d Ca ncer Ce nter w here a D F/ H C C 
i n vesti gat or  is  t he  s p o ns or.    D F/ H C C  i nclu des  Da na- Far ber/ Part ners  Ca ncer  Care 
( D F/ P C C) Net w or k Cli nical Trial Affilitates.   
Le a d I nstit uti o n:  O ne of t he  Da na- Far ber/ Har var d Ca ncer Ce nter c o ns orti u m me m bers 
( Da na- Far ber  Ca ncer  I nstit ute  ( D F CI),  Massac h usetts  Ge neral  H os pital  ( M G H),  Bet h 
Israel Deac o ness Me dical Ce nter ( BI D M C), B ost o n C hil dre n’s H os pital ( B C H), Bri g ha m 
a n d  W o me n’s  H os pital  ( B W H)  res p o nsi ble  f or  t he  c o or di nati o n,  de vel o p me nt, 
s u b missi o n,  a n d  a p pr o val  of  a  pr ot oc ol  as well  as  its  s u bse q ue nt  a me n d me nts  per  t he 
D F CI  I R B  a n d  a p plica ble  re g ulat or y  g ui de li nes  ( C T E P,  F D A,  O B A  etc.).    T he  Lea d 
I nstit uti o n is t he h o me of t he D F/ H C C S p o ns or.  T he Lea d I nstit uti o n als o t y picall ser ves 
as t he C o or di nati n g Ce nter f or t he D F/ H C C M ulti- Ce nter Pr ot oc ol.     
 
D F/ H C C  S p o ns or:     T he  pers o n  s p o ns ori n g  t he  s u b mitte d  M ulti- Ce nter  pr ot oc ol.  
Wit hi n D F/ H C C, t his pers o n is t he O verall Pr i nci pal I n vesti gat or wh o ta kes res p o nsi bilit y 
f or  i nitiati o n,  ma na ge me nt  a n d c o n d uct  of  t he  pr ot oc ol  at all  researc h  l ocati o ns.    I n 
a p plica ble  pr ot oc ols,  t he  D F/ H C C  S p o ns or will  ser ve  as  t he  si n gle  liais o n  wit h  a n y 
re g ulat or y a ge ncies.  T he D F/ HC C S p o ns or has ulti mate a ut h orit y o ver t he pr ot oc ol a n d 
is res p o nsi ble f or t he c o n d uct of t he st u d y at D F/ H C C a n d all Partici p ati n g I nstit uti o ns.  
I n m ost cases t he D F/ H C C S p o ns or is t he same pers o n as t he D F/ H C C O verall Pri nci pal 
I n vesti gat or; h o we ver, b ot h r oles ca n be fille d b y t w o differe nt pe o ple  
 
P artici p ati n g  I nstit uti o n:   A n  i nstit uti o n  t hat  is  o utsi de  t he  D F/ H C C  a n d  D F/ P C C 
c o ns orti u m  t hat  is  c olla b orati n g  wit h  D F/ H C C  o n  a  pr ot oc ol  w here  t he  s p o ns or  is  a 
D F/ H C C I n vesti gat or.  T he Partici pati n g I nstit uti o n ac k n o wle d ges t he D F/ H C C S p o ns or 
as ha vi n g t he ulti mate a ut h orit y a n d res p o nsi bilit y f or t he o verall co n d uct of t he st u d y.   
C o or di n ati n g  Ce nter:   T he  e ntit y  (i.e.  Lea d  I nstit uti o n,  Me dical  M o nit or,  C o ntract 
Researc h Or ga nizati o n ( C R O), etc) t hat pr o vi des a d mi nistrati ve s u p p ort t o t he D F/ H C C 
S p o ns or  i n  or der  t hat  he/s he  ma y  f ulfill  t h e  res p o nsi bilities  o utli ne d  i n  t he  pr ot oc ol 
d oc u me nt  a n d  D S M P  a n d  as  s pecifie d  i n  a p plica ble  re g ulat or y  g ui deli nes  (i.e.  C T E P 
M ulti- Ce nter G ui deli nes).  I n ge neral, t he L ea d I nstit uti o n is t he C o or di nati n g Ce nter f or 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 7
t he D F/ H C C M ulti- Ce nter Pr ot oc ol.   
 
 
D F/ H C C  Q u alit y  Ass ur a nce  Office  f or  Cli nic al  Tri als: A  gr o u p  wit hi n  D F/ H C C 
res p o nsi ble f or re gisteri n g h uma n s u bjects f or trials, e ns u ri n g hi g h- q ualit y sta n dar ds are 
use d f or data c ollecti o n a n d t he o n g oi n g ma na ge me nt of cli nical trials, a u diti n g, a n d data 
a n d safet y m o nit ori n g.  Q A C T als o c o or di nate s q ualit y ass ura nce eff orts relate d t o m ulti-
ce nter cli nical researc h.     
 
2. 0  G E N E R A L R O L E S A N D R E S P O N SI BI LI TI E S 
 
F or D F/ H C C M ulti- Ce nter Pr ot oc ols, t he D F/ H C C S p o ns or, t he C o or di na ti n g Ce nter, a n d t he 
Partici pati n g I nstit uti o ns are e x pecte d t o a d here t o t he f oll o wi n g ge neral res p o nsi bilities:  
 
2. 1  D F/ H C C S p o ns or  
 
T he D F/ H C C S p o ns or, Jere m y A bra ms o n, M D,  will acce pt res p o nsi bilit y f or all as pects 
of c o n d ucti n g a D F/ H C C M ulti- Ce nter pr ot oc ol  w hic h i ncl u des b ut is n ot li mite d t o:  
 O versee  t he  c o or di nati o n,  de vel o p me nt,  s u b missi o n,  a n d  a p pr o val  of  t he 
pr ot oc ol as well as s u bse q ue nt a me n d me nts.  
 E ns ure t hat t he i n vesti gat ors, st u d y tea m me m bers, a n d Partici pati n g I nstit uti o ns 
are q ualifie d a n d a p pr o priatel y res o ur ce d t o c o n d uct t he pr ot oc ol.   
 I ncl u de t he M ulti- Ce nter Data a n d Safet y M o nit ori n g Pla n as a n a p pe n di x t o t he 
pr ot oc ol. 
 E ns ure all Partici pati n g I nstit uti o ns are usi n g t he c orrect vers i o n of t he pr ot oc ol. 
 E ns ure  t hat  eac h  partici pati n g  i n vesti g at or  a n d  st u d y  tea m  me m ber  recei ves 
a de q uate  pr ot oc ol  trai ni n g a n d/ or  a  Site  I nitiati o n  Visit  pri or  t o  e nr olli n g 
partici pa nts a n d t hr o u g h o ut tr ial’s c o n d uct as nee de d.   
 E ns ure  t he  pr ot oc ol  will  be  pr o vi de d  t o   eac h  partici pati n g  site  i n  a  la n g ua ge 
u n dersta n da ble t o all a p pli ca ble site pers o n nel w he n E n glis h is n ot t he pri mar y 
la n g ua ge.   
 M o nit or  pr o gress  a n d  o verall  c o n d uct 
of  t he  st u d y  at  all  Partici pati n g 
I nstit uti o ns.  
 E ns ure  all  D F CI  I nstit uti o nal  Re vie w  B oar d  (I R B),  D F/ H C C  a n d  ot her 
a p plica ble (i.e. C T E P, F D A, O B A) re p orti n g re q uire me nts are met.  
 Re vie w data a n d mai ntai n ti mel y s u b m issi o n of data f or st u d y a nal ysis.  
 Act as t he si n gle liais o n wit h  t he F D A (i n vesti gat or- hel d I N D trials). 
 E ns ure  c o m plia nce  wit h  all  re q uire me nts as  set  f ort h  i n  t he  C o de  of  Fe deral 
Re g ulati o ns,  a p plica ble  D F/ H C C  re q uire me nts,  HI P A A  re q uire me nts,  a n d  t he 
a p pr o ve d pr ot oc ol. 
 C o m mit t o t he pr o visi o n t hat t he pr ot oc ol  will n ot be re writte n or m o difie d b y 
a n y o ne ot her t ha n t he D F/ H C C S p o ns or. 
 I de ntif y  a n d  q ualif y  Partici pati n g  I nstit uti o ns  a n d  o btai n  accr ual  c o m mit me nts 
pri or t o e xte n di n g t he pr ot oc ol t o t hat site. 
 M o nit or accr ual a n d a d dress Partici pati n g I nstit uti o ns t hat are n ot meeti n g t heir 
accr ual re q uire me nts. 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 8
 
2. 2  C o or di n ati n g Ce nter  
 
T he  ge neral  res p o nsi bilities of  t he  T he  C o or di nati n g  Ce nt er  ma y  i ncl u de  b ut  are  n ot 
li mite d t o: 
 Assist i n pr ot oc ol de vel o p me nt 
 Mai ntai n F D A c orres p o n de nce . 
 Re vie w  re gistrati o n  materials  f or  eli gi b ilit y  a n d  re gister  partici pa nts  fr o m 
Partici pati n g I nstit uti o ns  wit h D F/ H C C Q A C T.   
 Distri b ute  pr ot oc ol  a n d  i nf or me d  c o nse nt  d oc u me nt  u p dates  t o  Partici pati n g 
I nstit uti o ns  as  nee de d.    O versee  t he  data  c ollecti o n  pr ocess  fr o m  Partici pati n g 
I nstit uti o ns.   
 Mai ntai n  d oc u me ntati o n  of  Seri o u s  A d verse  E ve nt  ( S A E)  re p orts  a n d 
de viati o ns/ vi olati o n  s u b mitte d  b y  Partici pati n g  I nstit uti o ns  a n d  pr o vi de  t o 
D F/ H C C S p o ns or f or ti mel y re vie w.   
 Distri b ute  Seri o us  A d verse  E ve nts  re p or te d  t o  t he  D F/ H C C  S p o ns or  t hat  fall 
u n der  t he  D F CI  I R B  A d verse  E ve nt  Re p orti n g  P olic y  t o  all  Partici pati n g 
I nstit uti o ns.    Pr o vi de  Partici pati n g  I nstit uti o ns  wit h  i nf or mati o n  re gar di n g 
D F/ H C C  re q uire me nts  t hat  t he y  will  be  e x pecte d  t o  c o m pl y  wit h.    Carr y  o ut 
pla n t o m o nit or Partici pati n g I nstit uti o ns  w hic h i ncl u des b ut is n ot li mite d t o t he 
f oll o wi n g:  l ocal  I R B  a p pr o vals/ n otificati o ns  fr o m  all  Partici pati n g  I nstit uti o ns, 
c o nfir mati o n  of  Fe deral wi de  Ass ura nce  ( F W As)  f or  all  sites,  all  S A E 
s u b missi o ns, Scree ni n g L o gs f or all sites, I R B a p pr o ve d c o nse nts f or all sites.   
 C o n d uct re g ular c o m m u nicati o ns wit h all Partici pati n g I nstit uti o ns (c o nfere nce 
calls, e mailes, etc) a n d mai ntai n d oc u m e ntati o n of all rele va nt c o m m u nicati o ns. 
 
2. 3  P artici p ati n g I nstit uti o n 
 
 
Eac h Partici pati n g I nstit uti o n is e x pecte d t o c o m pl y wit h all a p plica ble fe deral re g ulati o ns 
a n d D F/ H C C re q uire me nts, t he pr ot oc ol a n d HI P A A re q uire me nts.  
 
T he  ge neral  res p o nsi bilities  f or  eac h  Partici p ati n g  I nstit uti o n  ma y  i ncl u de  b ut  are  n ot 
li mite d t o: 
 D oc u me nt t he dele gati o n of researc h s pecific acti vities t o st u d y pers o n nel. 
 C o m mit t o t he accr ual of partici pa nts t o t he pr ot oc ol. 
 S u b mit pr ot oc ol a n d/ or a me n d m e nts t o t heir l ocal I R B. 
 Mai ntai n re g ulat or y files as per s p o ns or re q uire me nts. 
 Pr o vi de t he C o or di nati n g Ce nter wit h re g ulat or y d oc u me nts or s o urce d oc u me nts 
as re q ueste d. 
 Partici pate  i n  pr ot oc ol  trai ni n g  pri or  t o  e nr oll i n g  partici pa nts a n d  t hr o u g h o ut  t he 
trial as re q uire d (i.e. telec o nfere nces). 
 U p date C o or di nati n g Ce nter wit h res earc h staff c ha n ges o n a ti mel y basis. 
 Re gister partici pa nts t hr o u g h t he C o or di na ti n g Ce nter pri or t o be gi n ni n g researc h 
relate d acti vities.  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
4 9
 S u b mit Seri o us A d verse E ve nt ( S A E) re p ort s t o l ocal I R B per l ocal re q uire me nts 
a n d t o t he C o or di nati n g Ce nter, i n acc or da nce wit h D F/ H C C re q uire me nts.   
 S u b mit pr ot oc ol de viati o ns a n d vi olati o ns t o l ocal I R B per l ocal re q uire me nts a n d 
t o t he D F/ H C C S p o ns or i n acc or da nce wit h D F/ H C C re q uire me nts. 
 Or der,  st ore  a n d  dis pe nse  i n vesti gati o na l  a ge nts  a n d/ or  ot her  pr ot oc ol  ma n date d 
dr u gs per fe deral g ui deli nes a n d pr ot oc ol re q uire me nts. 
 Ha ve  office  s pace,  office  e q ui p me nt,  a n d  i nter net  access  t hat  meet  HI P A A 
sta n dar ds. 
 Partici pate i n a n y q ualit y ass ura nce acti vitie s a n d meet wit h m o nit ors or a u dit ors at 
t he c o ncl usi o n of a visit t o re vie w fi n di n gs. 
 Pr o m ptl y  pr o vi de  f oll o w- u p  a n d/ or  c orre cti ve  acti o n  pla ns  f or  a n y  m o nit ori n g 
q ueries or a u dit fi n di n gs. 
 
 
3. 0  D F/ H C C re q uire me nts f or M ulti- Ce nter Pr ot oc ols  
T he  f oll o wi n g  secti o n  will  clarif y  D F/ H C C  Re q uire me nts  a n d  f urt her  detail  t he  e x pectati o ns 
f or partici pati n g i n a D F/ H C C M ulti- Ce nter pr ot oc ol. 
3. 1  Pr ot oc ol Distri b uti o n  
 
T he  C o or di nati n g  Ce nter  will distri b ute  t he  fi nal  D F CI  I R B  a p pr o ve d  pr ot oc ol  a n d  a n y 
s u bse q ue nt a me n de d pr ot oc ols t o all Partici pati n g I nstit uti o ns.    
 
 
 
 
3. 2  Pr ot oc ol Re visi o ns a n d Cl os ures  
  
T he  Partici pati n g  I nstit uti o ns  will  recei ve  n ot ificati o n  of  pr ot oc ol re visi o ns  a n d  cl os ures 
fr o m t he C o or di nati n g Ce nter.  It is t he i n di vi d ual Partici pati n g I nstit uti o n’s res p o nsi bilit y 
t o n otif y its I R B of t hese re visi o ns. 
 
 N o n  life-t hre ate ni n g  re visi o ns:   Partici pati n g  I nstit uti o ns  will  recei ve  writte n 
n otificati o n  of  pr ot oc ol  re visi o ns  re gar di n g  n o n  life-t h reate ni n g  e ve nts  fr o m  t he 
C o or di nati n g  Ce nter.  N o n-life-t hreate n i n g  pr ot oc ol  re visi o ns  m ust  be  I R B 
a p pr o ve d a n d i m ple me nte d wit hi n 9 0 da ys fr o m recei pt of t he n otificati o n. 
 
 Re visi o ns  f or  life-t hre ate ni n g  c a uses:   Partici pati n g  I nstit uti o ns  will  recei ve 
i m me diate n otificati o n fr o m t he C o or di nati n g Ce nter c o ncer ni n g pr ot oc ol re visi o ns 
re q uire d t o pr otect li ves wit h f oll o w- u p b y fa x, mail, e- mail, etc.  Life-t hreate ni n g 
pr ot oc ol re visi o ns will be i m ple me nte d i m me diatel y f oll o we d b y I R B re q uest f or 
a p pr o val. 
 
 Pr ot oc ol  cl os ures  a n d  te m p or ar y  h ol ds:   Partici pati n g  I nstit uti o ns  will  recei ve 
n otificati o n  of  pr ot oc ol cl os ures  a n d  te m p orar y  h ol ds  fr o m  t he  C o or di nati n g 
Ce nter.  Cl os ures  a n d  h ol ds   will  be  effecti ve  i m me diatel y.    I n  a d diti o n,  t he 
C o or di nati n g Ce nter, will u p date t he Par tici pati n g I nstit uti o ns o n a n o n g oi n g basis 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 0
a b o ut  pr ot oc ol  accr ual  data s o  t hat  t he y  will  be  a ware  of  i m mi ne nt  pr ot oc ol 
cl os ures. 
3. 3  
I nf or me d C o nse nt Re q uire me nts 
 
T he  D F/ H C C  a p pr o ve d  i nf or me d  c o nse nt  d oc u me nt  will  ser ve  as  a  te m plate  f or  t he 
i nf or me d c o nse nt f or Partici pati n g I nstit uti o ns. T he Partici pati n g I nstit uti o n c o nse nt f or m 
m ust f oll o w t he c o nse nt te m plate as cl osel y as  p ossi ble a n d s h o ul d a d here t o s pecificati o ns 
o utli ne d i n t he D F/ H C C G ui da nce D oc u me nt o n M o del C o nse nt La n g ua ge f or PI-I nitiate d 
M ulti- Ce nter Pr ot oc ols.  T his d oc u me nt will be  pr o vi de d se paratel y t o eac h Partici pati n g 
I nstit uti o n. 
 
Partici pati n g I nstit uti o ns are t o se n d t heir versi o n of t he i nf or me d c o nse nt d oc u me nt a n d 
HI P A A a ut h orizati o n, if a se parate d oc u me nt , t o t he C o or di nati n g Ce nter f or re vie w a n d 
a p pr o val pri or t o s u b missi o n t o t heir l ocal I R B. T he a p pr o ve d c o nse nt f or m m ust als o be 
s u b mitte d  t o  t he  C o or di nati n g  Ce nter  after a p pr o val  b y  t he  l ocal  I R B  f or  all  c o nse nt 
versi o ns. 
 
T he Pri nci pal I n vesti gat or ( PI)  at eac h Partici pati n g I nstituti o n will i de n tif y t he p h ysicia n 
me m bers of t he st u d y tea m w h o will be o btai ni n g c o nse nt a n d si g ni n g t he c o nse nt f or m 
f or t hera pe utic pr ot oc ols. Partici pati n g i nstit uti o ns m ust f oll o w t he D F/ H C C re q uire me nt 
t hat  o nl y  atte n di n g  p h ysicia ns  o btai n  i nf or me d  c o nse nt  a n d  re-c o nse nt  t o  i nter ve nti o nal 
trials (i.e. dr u g a n d/ or de vice trials).   
 
3. 4  I R B D oc u m e nt ati o n 
 
T he f oll o wi n g m ust be o n file wit h t he C o or di nati n g Ce nter: 
 I nitial a p pr o val letter of t he Partici pati n g I nstit uti o n's I R B.  
 C o p y of t he I nf or me d C o nse nt F or m(s) a p pr o ve d b y t he Partici pati n g I nstit uti o n’s 
I R B.  
 Partici pati n g I nstit uti o n’s I R B a p pr o val f or all a me n d me nts. 
 A n n ual a p pr o val letters b y t he Par tici pati n g I nstit uti o n's I R B. 
 
3. 5  I R B Re- A p pr o v al 
 
Verificati o n of I R B re-a p pr o val fr o m t he Partici p ati n g I nstit uti o ns is re q uire d i n or der t o 
c o nti n ue researc h acti vities.  T here is n o grace peri o d f or c o nti n ui n g a p pr o vals. 
 
T he C o or di nati n g Ce nter will n ot re gister partic i pa nts if a re-a p pr o val letter is n ot recei ve d 
fr o m  t he  Partici pati n g  I nstit uti o n  o n  or  bef ore  t he  a n ni versar y  of  t he  pre vi o us  a p pr o val 
date.   
3. 6  P artici p a nt C o nfi de nti alit y a n d A ut h oriz ati o n St ate me nt 
 
I n 1 9 9 6, c o n gress passe d t he first fe deral la w c o veri n g t he pri vac y of  healt h i nf or mati o n 
k n o w n  as  t he Healt h  I ns ura nce  P orta bilit y   a n d  Acc o u nta bilit y  Act  (HI P P A).  A n y 
i nf or mati o n,  relate d  t o  t he  p h ysical  or  me ntal healt h  of  a n  i n di vi d ual  is  calle d  Pr otecte d 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 1
Healt h I nf or mati o n ( P HI). HI P A A o utli nes h o w a n d u n der w hat circ u msta nces P HI ca n be 
use d or discl ose d.  
 
I n  or der  f or  c o vere d  e ntities  t o  use  or  discl ose  pr otecte d  healt h  i nf or mati o n  d uri n g  t he 
c o urse  of  a  st u d y,  t he  st u d y  partici pa nt  m ust si g n  a n  a ut h orizati o n  state me nt.    T his 
a ut h orizati o n state me nt ma y or ma y n ot be se parate fr o m t he i nf or me d c o nse nt d oc u me nt.  
T he  C o or di nati n g  Ce nter,  wit h  t he a p pr o val  fr o m  t he  D F CI  I R B  a n d if  a p plica ble 
N CI/ C T E P , will pr o vi de a c o nse nt te m plate, wit h i nf or mati o n re gar di n g a ut h orizati o n f or 
t he discl os ure of pr otecte d healt h i nf or mati o n.  
 
T he D F/ H C C S p o ns or will use all eff orts t o li mit its use of pr otecte d healt h i nf or mati o n i n 
its  trials.  H o we ver,  beca use  of  t he  nat ure of  t hese  trials,  certai n  pr otecte d  healt h 
i nf or mati o n  m ust  be  c ollecte d.  D F/ H C C  has  ch ose n  t o  use  a ut h orizati o ns,  si g ne d  b y  t he 
partici pa nt i n t he trial, rat her t ha n li m ite d data sets wit h data use a gree me nts. 
 
 
3. 6. 1  
D F/ H C C M ulti- Ce nter Pr ot oc ol C o nfi de nti alit y 
 
All d oc u me nts, i n vesti gati ve re p orts, or i nf or m ati o n relati n g t o t he partici pa nt are strictl y 
c o nfi de ntial. W he ne ver reas o na bl y feasi ble, a n y partici pa nt s pecific re p orts (i.e. Pat h ol o g y 
Re p orts,  M RI  Re p orts,  O perati ve  Re p orts,  et c.)  s u b mitte d  t o  t he  C o or di nati n g  Ce nter 
s h o ul d be de-i de ntifie d. It is rec o m me n de d t hat t he assi g ne d D F/ H C C Q A C T case n u m ber 
(as  descri be d  bel o w)  be  use d  f or  all  partici pa nt  s pecific  d oc u me nts.  Partici pa nt  i nitials 
ma y be i ncl u de d or retai ne d f or cr oss verificati o n of  i de ntificati o n.  
 
3. 7  D F/ H C C M ulti- Ce nter Pr ot oc ol Re gistr ati o n P olic y 
Ple ase see Secti o n 4. 4 of t he Pr ot oc ol  
 
3. 7. 2  
I niti ati o n of T her a p y 
 
Partici pa nts  m ust  be  re gistere d  wit h  t he  D F/ H C C  Q A C T  bef ore   recei vi n g  treat me nt.  
Treat me nt ma y n ot be i nitiate d u ntil t he Partici pati n g I nstit u ti o n recei ves c o nfir mati o n of 
t he  partici pa nt’s  re gistrati o n  fr o m  t he  Co or di nati n g  Ce nter.  T he  D F/ H C C  S p o ns or  a n d 
D F CI I R B m ust be n otifie d of a n y vi olati o ns t o t his p olic y. 
 
3. 7. 3  
Eli gi bilit y E xce pti o ns 
 
T he D F/ H C C Q A C T will ma ke n o e xce pti o ns t o t he eli gi bilit y re q uire me nts f or a pr ot oc ol 
wit h o ut  D F CI  I R B  a p pr o val.  T he  D F/ H C C Q A C T  re q uires  eac h  i nstit uti o n  t o  f ull y 
c o m pl y wit h t his re q uire me nt. 
 
3. 8  
  
D F/ H C C Pr ot oc ol C ase N u m ber 
 
At  t he  ti me  of  re gistrati o n,  Q A C T  re q uires  t h e  f oll o wi n g  i de ntifiers  f or  all  s u bjects: 
i nitials, date of birt h, ge n der, race a n d et h nicit y. O nce eli gi bilit y has bee n esta blis he d a n d 
t he  partici pa nt  s uccessf ull y  re gistere d,  t he  partici pa nt  is  assi g ne d  a  u ni q ue  pr ot oc ol  case 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 2
n u m ber.    Partici pati n g  I nstit uti o ns  s h o ul d  s u b mit  all  de-i de ntifie d  s u bse q ue nt 
c o m m u nicati o n  a n d  d oc u me nts  t o  t he  C o or di nati n g  Ce nter,  usi n g  t his  case  n u m ber  t o 
i de ntif y t he s u bject.   
 
3. 8. 1  
Pr ot oc ol De vi ati o ns, E xce pti o ns a n d Vi ol ati o ns 
 
Fe deral Re g ulati o ns re q uire a n I R B t o re vie w pr o p ose d c ha n ges i n a researc h acti vit y t o 
e ns ure t hat researc hers d o n ot i nitiate c ha n ges i n a p pr o ve d researc h wit h o ut I R B re vie w 
a n d  a p pr o val,  e xce pt  w he n  necessar y  t o  el i mi nate  a p pare nt  i m me diate  hazar ds  t o  t he 
partici pa nt. D F/ H C C re q uires all de part ures fr o m t he defi ne d pr oce d ures set f ort h i n t he 
I R B a p pr o ve d pr ot oc ol t o be re p orte d t o t he D F/ H C C S p o ns or, w h o i n t ur n is res p o nsi ble 
f or re p orti n g t o t he D F CI I R B. 
 
 
F or re p orti n g p ur p oses, D F/ H C C uses t he ter ms “ vi olati o n”, “ de viati o n” a n d “e xce pti o n” 
t o descri be de part ures fr o m a pr ot oc ol. All Partici pati n g I nst it uti o ns m ust a d here t o t hese 
re q uire me nts  f or  re p orti n g  t o  t he  D F/ H C C  S po ns or  a n d  will  f oll o w  t heir  i nstit uti o nal 
p olic y f or re p orti n g t o t heir l ocal I R B. 
 
 
3. 8. 2  
Defi niti o ns 
 
Pr ot oc ol  De viati o n :  A n y  de part ure  fr o m  t he  defi ne d pr oce d ures  set  f ort h  i n  t he  I R B-
a p pr o ve d pr ot oc ol w hic h is pr os pectively a p pr ove d  pri or t o its i m ple me ntati o n. 
 
Pr ot oc ol E xce pti o n :  A n y pr ot oc ol de viati o n t hat relates t o t he eli gi bilit y criteria, e. g. 
e nr oll me nt of a partici pa nt w h o d oes n ot meet all i ncl usi o n/e xcl usi o n criteria. 
   
 
Pr ot oc ol  Vi olati o n :  A n y  pr ot oc ol  de viati o n  t hat  was  n ot pr os pectively  a p pr ove d   b y  t he 
I R B pri or t o its i nitiati o n or i m ple me ntati o n. 
 
3. 8. 3  
Re p orti n g Pr oce d ures 
 
D F/ H C C S p o ns or:  is res p o nsi ble f or e ns uri n g t hat clear d oc u me ntati o n is a vaila ble i n t he 
me dical rec or d a n d/ or re g ulat or y d oc u me nts t o descri be all pr ot oc ol e xce pti o ns, de viati o ns 
a n d  vi olati o ns.  T he  D F/ H C C  S p o ns or  will  al s o  be  res p o nsi ble  f or  e ns uri n g  t hat  all 
pr ot oc ol vi olati o ns/ de viati o ns are pr o m ptl y re p orte d per D F CI I R B g ui deli nes.  
 
Partici pati n g I nstit uti o ns : Pr ot oc ol de viati o ns re q uire pros pecti ve a p pr o val fr o m t he D F CI 
I R B.  T he  Partici pati n g  I nstit uti o n  m ust  s u b mit  t he  de viati o n  re q uest  t o  t he  C o or di nati n g 
Ce nter  w h o  will  t he n  s u b mit  t he  de viati o n re q uest  t o  t he  D F CI I R B.  U p o n  D F CI  I R B 
a p pr o val  t he  de viati o n  is  s u b mitte d  t o  t he  Par tici pati n g  I nstit uti o n  I R B,  per  i nstit uti o nal 
p olic y.  A  c o p y  of  t he  Partici pati n g  I nstit ut i o n’s  I R B  re p ort  a n d  deter mi nati o n  will  be 
f or war de d  t o  t he  C o or di nati n g  Ce nter  wit hi n  1 0  b usi ness  da ys after  t he  ori gi nal 
s u b missi o n.  
 
All pr ot oc ol vi olati o ns m ust be se nt t o t he C o or di nati n g Ce nter i n a ti mel y ma n ner.  


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 3
 
C o or di nati n g Ce nter:   U p o n recei pt of t he vi olati o n/ de viati o n re p ort fr o m t he Partici pati n g 
I nstit uti o n,  t he  C o or di nati n g  Ce nter  will  su b mit  t he  re p ort  t o  t he  D F/ H C C  S p o ns or  f or 
re vie w. S u bse q ue ntl y, t he Partici pati n g I nstit uti o n’s I R B vi olati o n/ de viati o n re p ort will be 
s u b mitte d t o t he D F CI I R B f or re vie w per D F CI I R B re p orti n g g ui deli nes. D F/ H C C will 
f or war d all vi olati o n re p orts t o C T E P via a n i nter nal D F/ H C C pr ocess, as a p plica ble. 
 
 
3. 9  
S afet y Assess me nts a n d T o xicit y M o nit ori n g 
 
T he  st u d y  tea ms  at  all  partici p ati n g  i nstit uti o ns  ar e  res p o nsi ble  f or  pr otecti n g  t he  safet y, 
ri g hts a n d well- bei n g of st u d y partici pa nts. Rec or di n g a n d re p orti n g of a d verse e ve nts t hat 
occ ur d uri n g t he c o urse of a st u d y hel p e ns ure t he c o nti n ui n g safet y of st u d y partici pa nts.  
 
All partici pa nts recei vi n g i n vesti gati o nal a ge n ts a n d/ or ot her pr ot ocol ma n date d treat me nt 
will be e val uate d f or safet y. T he safet y para meters i ncl u de all la b orat or y tests a n d 
he mat ol o gical a b n or malities, p h ysical e xa mi n ati o n fi n di n gs, a n d s p o nt a ne o us re p orts of 
a d verse e ve nts re p orte d b y partici pa nts.  A ll t o xicities e nc o u ntere d d uri n g t he st u d y will 
be e val uate d acc or di n g t o t he N CI criteria s p ecifie d i n t he pr ot oc ol. Life-t hreate ni n g 
t o xicities m ust be re p orte d i m me diatel y t o t he D F/ H C C S p o ns or via t he C o or di nati n g 
Ce nter.  
 
A d diti o nal safet y assess me nts a n d t o xicit y m o nit ori n g will be o utli ne d i n t he pr ot oc ol. 
 
 
3. 9. 1  
G ui deli nes f or Re p orti n g Seri o us A d verse E ve nts  
 
G ui deli nes  f or  re p orti n g  A d verse  E ve nts  ( A Es)  a n d  Seri o us  A d verse  E ve nts  ( S A Es)  are 
detaile d i n pr ot oc ol secti o n 1 0 . 
 
 
 
 
 
Partici pati n g  I nstit uti o ns  m ust  re p ort t he  S A Es  t o  t he  D F/ H C C  S p o ns or  a n d  t he 
C o or di nati n g Ce nter f oll o wi n g t he D F CI I R B A d verse E ve nt Re p orti n g P olic y .  
 
T he  C o or di nati n g  Ce nter  will  mai ntai n  d oc u me ntati o n  of  all  Partici pati n g  I nstit uti o n 
A d verse  E ve nt  re p orts  a n d  be  res p o nsi ble   f or  c o m m u nicati n g  t o  all  partici pati n g 
i n vesti gat ors,  a n y  o bser vati o ns  re p orta ble u n der  t he  D F CI  I R B  Re p or ti n g  Re q uire me nts.  
Partici pati n g  I nstit uti o ns  will  re vie w  a n d  s u b mit  t o  t heir  I R B  acc or di n g  t o  t heir 
i nstit uti o nal p olicies a n d pr oce d ures. 
 
3. 9. 2  
G ui deli nes f or Pr ocessi n g I N D S afet y Re p orts  
 
T he D F/ H C C S p o ns or will re vie w all I N D Safet y  Re p orts a n d e ns ure t hat all I N D Safet y 
Re p orts are distri b ute d t o t he Partici pati n g I nstit uti o ns. Partici pati n g I nstit uti o ns will 
re vie w a n d s u b mit t o t heir I R B acc or di n g t o t heir i nstit uti o nal p olicies a n d pr oce d ures. 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 4
3. 1 0   D at a M a n a ge me nt 
T he D F/ H C C Q A C T de vel o ps case re p ort f or ms ( C R F/e C R Fs), f or use wit h t he pr ot oc ol.  
T hese f or ms are desi g ne d t o c ollect data  f or eac h st u d y. T he D F/ H C C Q A C T pr o vi des a 
we b base d trai ni n g f or e C R F users. 
 
3. 1 0. 1  
D at a F or ms Re vie w 
 
Data  s u b missi o ns  are  m o nit ore d  f or  ti me li ness  a n d  c o m plete ness  of  s u b missi o n. 
Partici pati n g I nstit uti o ns are n otifie d of t heir data s u b mi ssi o n deli n q ue ncies i n acc or da nce 
wit h t he f oll o wi n g: 
 
I nc o m plete or Q uesti o na ble Data 
If  st u d y  f or ms  are  recei ve d  wit h  missi n g  or q uesti o na ble  data,  t he s u b mitti n g  i nstit uti o n 
will  recei ve  a  writte n  or  electr o nic  q uer y   fr o m  t he  D F/ H C C  Q A C T  Data  A nal yst, 
C o or di nati n g  Ce nter  or  desi g nee.    Res p o nses  t o   all  q ueries  s h o ul d  be  c o m plete d  a n d 
s u b mitte d wit hi n 1 4 cale n dar da ys.  Res p o nses may be ret ur ne d o n t he writte n q uer y or o n 
a n  a me n de d  pa per  case  re p ort  f or m,  or  i n  t h e  case  of  electr o nic  q ueries,  wit hi n  t he 
electr o nic data ca pt ure (e D C) s yste m. I n t he ca se of a writte n q uer y f or data s u b mitte d o n 
a  pa per  case  re p ort  f or m,  t he  q uer y  m ust  be attac he d  t o  t he  s pecific  data  bei n g  re-
s u b mitte d i n res p o nse.   
 
Missi n g F or ms  
If  st u d y  f or ms  are  n ot  s u b mitte d  o n  sc he d ule,  t he  Partici pati n g  I nstit uti o n  will  recei ve  a 
Missi n g  F or m  Re p ort  fr o m  t he  C o or di nati n g  Ce nter  n oti n g  t he  missi n g  f or ms.    T hese 
re p orts are c o m pile d b y t he D F/ H C C Q A C T an d distri b ute d o n a m o nt hl y basis.  
 
4  
R E Q UI SI TI O NI N G I N V E S TI G A TI O N A L D R U G 
T he or deri n g of i n vesti gati o nal a ge nt is s pecifie d i n t he pr ot oc ol secti o n 
 
5  
M O NI T O RI N G: Q U A LI T Y C O N T R O L 
 
T he q ualit y c o ntr ol pr ocess f or a cli nical trial re q uires verificati o n of pr ot oc ol c o m plia nce 
a n d data acc urac y. T he C o or di nati n g Ce nter, wit h t he ai d of t he Q A C T pr o vi des q ualit y 
c o ntr ol o versi g ht f or t he pr ot oc ol. 
 
5. 1 O n g oi n g M o nit ori n g of Pr ot oc ol C o m pli a nce 
 
T he Partici pati n g I nstit uti o ns ma y be re q uire d t o s u b mit partici pa nt s o urce d oc u me nts t o 
t he  C o or di nati n g  Ce nter  f or  m o nit ori n g.  Partici pati n g  I nstit uti o n  ma y  als o  be  s u bject  t o 
o n-site m o nit ori n g c o n d ucte d b y t he C o or di nati n g Ce nter.  
 
T he  C o or di nati n g  Ce nter  will  i m ple me nt  o n g oi n g  m o nit ori n g  acti vities  t o  e ns ure  t hat 
Partici pati n g  I nstit uti o ns  are  c o m pl yi n g  wit h  re g ulat or y  a n d  pr ot oc ol  re q uire me nts,  data 
q ualit y,  a n d  partici pa nt  safet y.  A n  o n-site  m o nit ori n g  visit  will  be  c o n d ucte d  wit hi n  3 
m o nt hs  of  t he  first  s u bject 
e nr olle d  at  eac h  partici pa ti n g  I nstit uti o n.    S u bse q ue nt 
m o nit ori n g  visits  will  be  c o n d ucte d  e ver y  f o ur  m o nt hs  via a  c o m bi nati o n  of  re m ote  a n d 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 5
o n-site m o nit ori n g wit h at least o ne o n-site m o nit ori n g visit e ver y 2 4 m o nt hs.  M o nit ori n g 
will  occ ur  bef ore  t he  cli nical  p hase  of  t he  pr ot oc ol  be gi ns,  c o nti n ue  d uri n g  pr ot oc ol 
perf or ma nce a n d t hr o u g h st u d y c o m pleti o n. A d diti o nal m o nit ori n g practices ma y i ncl u de 
b ut are n ot li mite d t o; s o urce ve rificati o n, re vie w a n d a nal ysis of t he f oll o wi n g: eli gi bilit y 
re q uire me nts  of  all  partici pa nts,  i nf or me d c o nse nt  pr oce d ures,  a d verse  e ve nts  a n d  all 
ass ociate d  d oc u me ntati o n,  st u d y  dr u g  a d mi nistra ti o n/treat me nt,  re g ulat or y  files,  pr ot oc ol 
de part ures, p har mac y rec or ds, res p o nse assess me nts, a n d data ma na ge me nt.  
 
Partici pati n g  i nstit uti o ns  will  be  re q uire d  t o   partici pate  i n  m o nt hl y  C o or di nati n g  Ce nter 
i nitiate d telec o nfere nces d urin g t he scree ni n g/e nr oll me nt p ha se t hr o u g h acti ve treat me nt.  
 
Re m ote  M o nit ori n g  will  i n v ol ve  t he Partici pati n g  I nstit uti o n  t o  f or war d  de-i de ntifie d 
c o pies of partici pa nts’ me dica l rec or d a n d s o urce d oc u me nts t o t he C o or di nati n g Ce nter t o 
ai d i n s o urce data verificati o n  
 
a n d/ or 
 
O n- Site  M o nit ori n g  will  i n v ol ve 
s o urce  d oc u me ntati o n  verificati o n  ( S D V)  will  be 
c o n d ucte d  b y  ha vi n g  access  t o  partici pa nts’ c o m plete  me dical  rec or d  a n d  s o urce 
d oc u me nts. 
 
5. 2    M o nit ori n g Re p orts 
 
T he  D F/ H C C  S p o ns or  will  re vie w  all  m o nit ori n g  re p orts  f or  o n-site  a n d  re m ote 
m o nit ori n g  of  Partici pati n g  I nstit uti o ns  t o e ns ure  pr ot oc ol  c o m plia nce.  T he  D F/ H C C 
S p o ns or ma y i ncrease t he m o nit ori n g acti vities at  Partici pati n g I nstit uti o ns t hat are u na ble 
t o  c o m pl y  wit h  t he  pr ot oc ol,  D F/ H C C  Sp o ns or  re q uire me nts  or  fe deral  a n d  l ocal 
re g ulati o ns. Partici pati n g I nstit uti o ns ma y als o be s u bject t o a n a u dit as deter mi ne d b y t he 
D F/ H C C S p o ns or. 
 
5. 3  Accr u al M o nit ori n g 
 
Pri or t o e xte n di n g a pr ot oc ol t o a n e xter nal  site, t he D F/ H C C S p o ns or will esta blis h 
accr ual re q uire me nts f or eac h partici pati n g i nst it uti o n. Accr ual will be m o nit ore d f or eac h 
partici pati n g i nstit uti o n b y t he D F/ H C C S p o ns or  or desi g nee. Sites t hat are n ot meeti n g 
t heir accr ual e x pectati o ns ma y be s u bject t o ter mi nati o n. 
 
Accr ual f or t his st u d y are 3 per site a n n uall y 
 
6  A U DI TI N G: Q U A LI T Y A S S U R A N C E 
 
A u diti n g is a met h o d of Q ualit y Ass ura nce. Its mai n f oc us is t o meas ure w het her sta n dar ds 
a n d pr oce d ures were f oll o we d. A u diti n g is t he s yste matic a n d i n de pe n de nt e xa mi nati o n of 
all  trial  relate d  acti vities  a n d  d oc u me nts.    A u dits  deter mi ne  if  e val uate d  acti vities  were 
a p pr o priatel y  c o n d ucte d  a n d  w het her  data  wa s  ge nerate d,  rec or de d  a n d  a nal yze d,  a n d 
acc uratel y re p orte d per t he pr ot oc ol, Sta n dar d O perati n g Pr oce d ures ( S O Ps), a n d t he C o de 
of Fe deral Re g ulati o ns ( C F R). 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 6
 
6. 1  A u dit Pl a n: D F/ H C C S p o ns ore d Tri als 
O ne  o n-site  a u dit  will  be  sc he d ule d  b y  t he  Q A C T,  ass u mi n g  at   least  t hree  partici pa nts 
ha ve bee n treate d o n pr ot oc ol at t he site. A p pr o xi matel y 3- 4 partici p a nts w o ul d be a u dite d 
at  t he  site  o ver  a  2  da y  peri o d.     If  vi olati o ns  w hic h  i m pact  partici pa nt  safet y  or  t he 
i nte grit y of t he st u d y are f o u n d, m ore partici pa nt rec or ds ma y be a u dite d.  
 
6. 2  A u dit N otific ati o n 
 
It  is  t he  Partici pati n g  I nstit uti o n’s  res p o nsi bilit y  t o  n otif y  t he  C o or di nati n g  Ce nter  of  all 
sc he d ule d  a u dit  dates  (i nter nal  or  N CI)  a n d  re-a u dit  dates  (if  a p plica ble),  w hic h  i n v ol ve 
t his pr ot oc ol. All i nstit uti o ns will f or war d a co p y of fi nal a u dit a n d/ or re-a u dit re p orts a n d 
c orrecti ve  acti o n  pla ns  (if  a p plica ble)  t o  t h e  C o or di nati n g  Ce nter, wit hi n  1 2  wee ks  after 
t he a u dit date.  
 
 
6. 3   A u dit Re p orts  
 
T he  D F/ H C C  S p o ns or  will  re vie w   all  fi nal  a u dit  re p orts  a n d c orrecti ve  acti o n  pla ns  if 
a p plica ble.  T he  C o or di nati n g  Ce nter,  m ust f or war d  t hese  re p orts  t o  t he  D F/ H C C  Q A C T 
per  D F/ H C C  p olic y  f or  re vie w  b y  t he  D F/ H C C  A u dit  C o m mittee.  Base d  u p o n  t he  a u dit 
assess me nts t he D F/ H C C A u dit C o m mittee c o ul d acce pt or c o n diti o nall y acce pt t he a u dit 
rati n g  a n d  fi nal  re p ort.  C o n diti o nal  a p pr o val  c o ul d  re q uire  t he  D F/ H C C  S p o ns or  t o 
i m ple me nt  rec o m me n dati o ns  or  re q uire  f urther  f oll o w- u p.    F or  u nacce pta ble  a u dits,  t he 
D F/ H C C A u dit C o m mittee w o ul d f or war d t he fi na l a u dit re p ort a n d c orrecti ve acti o n pla n 
t o t he D F CI I R B as a p plica ble. 
 
6. 4  P artici p ati n g I nstit uti o n Perf or m a nce 
 
T he  D F/ H C C  S p o ns or,  D F CI  I R B  a n d  t he N CI  f or  C T E P  trials ,  is  c har ge d  wit h 
c o nsi deri n g  t he  t otalit y  of  a n  i nstit uti o n’s  perf or ma nce  i n  c o nsi deri n g  i nstit uti o nal 
partici pati o n i n t he pr ot oc ol. 
 
6. 5. 1  
C orrecti ve Acti o ns 
 
Partici pati n g I nstit uti o ns t hat fail t o meet t he perf or ma nce g oals of accr ual, s u b missi o n of 
ti mel y a n d acc urate data, a d here nce t o pr ot ocol re q uire me nts, a n d c o m plia nce wit h state 
a n d  fe deral  re g ulati o ns,  ma y be  rec o m me n de d  f or  a  si x- m o nt h  pr o bati o n  peri o d.  S uc h 
i nstit uti o ns  m ust  res p o n d  wit h  a  c orrecti ve acti o n  pla n  a n d  m ust de m o nstrate  d uri n g  t he 
pr o bati o n  peri o d  t hat  deficie n cies  ha ve  bee n  c orrecte d,  as  e vi de nce d  b y  t he  i m pr o ve d 
perf or ma nce  meas ures.  Partici p ati n g  I nstit uti o ns  t hat  fail  t o  de m o nstrate  si g nifica nt 
i m pr o ve me nt will be c o nsi dere d b y t he D F/ H C C S p o ns or f or re v ocati o n of partici pati o n. 
A  D F/ H C C  S p o ns or  a n d/ or  t he D F CI  I R B  ma y  ter mi nate  a  site’s  partici pati o n  if  it  is 
deter mi ne d t hat a site is n ot f ulfilli n g its res p o nsi bilities as descri be d a b o ve. 
 
 


Bre nt u xi m a b pl us A D i n N o n- b ul k y  Li mite d St a ge H o d g ki n L y m p h o m a 
Versi o n 2. 7, 6/ 2 3/ 1 6 
 
 
C O N FI D E N TI A L 
T his d oc u me nt is c o nfi de ntia l. D o n ot discl ose or use e xce pt as a ut h orize d. 
 
5 7
 
 
 


1 
 
HI G H LI G H T S O F P R E S C R I BI N G I N F O R M A TI O N 
T h e s e hi g hli g ht s d o n ot i n cl u d e all t h e i nf or m ati o n n e e d e d t o u s e 
A D C E T RI S s af el y a n d eff e cti v el y .  S e e f ull pr e s cri bi n g i nf or m ati o n f or 
A D C E T RI S.  
A D C E T RI S ®  ( br e nt u xi m a b v e d oti n) f or inj e cti o n , f or i ntr a v e n o u s u s e 
I niti al U. S. a p pr o v al: 2 0 1 1  
 
 
 R E C E N T M A J O R C H A N G E S  
 
D o s a g e a n d A d mi ni str ati o n (2. 1 )  
1 1 / 2 0 1 4 
W ar ni n g s a n d Pr e c a uti o n s (5. 6 , 5 . 7, 5. 8 , 5. 1 1 ) 
1 1 / 2 0 1 4 
W ar ni n g s a n d Pr e c a uti o n s (5. 1 0 ) 
0 2/ 2 0 1 5  
 ---------------------------------- I N DI C A TI O N S A N D U S A GE --------------------------- 
A D C E T RI S i s a C D 3 0 -dir e ct e d a nti b o d y -dr u g c o nj u g at e i n di c at e d f or  
tr e at m e nt of p ati e nt s wit h: 
• 
H o d g ki n l y m p h o m a  aft er f ail ur e of a ut ol o g o u s st e m c ell tr a n s pl a nt  
( A S C T) or aft er f ail ur e of at l e a st t w o pri or m ulti-a g e nt c h e m ot h er a p y 
r e gi m e n s i n p ati e nt s w h o ar e n ot A S C T c a n di d at e s  (1. 1 ). 
•  
Sy st e mi c a n a pl a sti c l ar g e c ell l y m p h o m a  aft er f ail ur e of at l e a st o n e 
pri or m ulti -a g e nt c h e m ot h er a p y r e gi m e n  (1. 2 ). 
A c c el er at e d a p pr o v al w a s gr a nt e d f or t h e a b o v e i n di c ati o n s b a s e d o n 
o v er all re s p o n s e rat e .  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or 
s ur vi v al h a s n ot b e e n e st a bli s h e d .  C o nti n u e d a p pr o v al f or  t h e s e i n di c ati o ns 
m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d d e s cri pti o n of cli ni c al b e n efit i n 
c o nfir m at or y tri al s.  
   
 D O S A G E A N D A D MI NI S T R A TI O N  
 
• 
A d mi ni st er o nl y a s a n i ntr a v e n o u s i nf u si o n o v er 3 0 mi n ut e s e v er y 
3 w e e k s.  
• 
T h e r e c o m m e n d e d d o s e i s 1. 8 m g/ k g (2 ). 
• 
R e d u c e d o s e i n p ati e nt s wit h mil d h e p ati c i m p air m e nt  (2 ). 
• 
C o nti n u e tr e at m e nt u ntil di s e a s e pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y.  
 --------------------------- D O S A G E F O R M S A N D S T R E N G T H S  -------------------- 
F or i nj e cti o n: 5 0 m g l y o p hili z e d p o w d er i n a si n gl e -u s e vi al (3 ). 
 
 C O N T R AI N DI C A TI O N S  
  
C o n c o mit a nt u s e wit h bl e o m y ci n d u e t o p ul m o n ar y t o xi cit y (4 ). 
 
 
 ------------------------- W A R NI N G S A N D P R E C A U T I O N S ---------------------  
• 
P eri p h er al n e ur o p at h y : M o nit or p ati e nt s f or n e ur o p at h y a n d i n stit ut e 
d o s e m o difi c ati o n s a c c or di n gl y (5. 1 ). 
• 
A n a p h yl a xi s a n d i nf u si o n r e a cti o n s: If a n i nf u si o n r e a cti o n o c c ur s, 
i nt err u pt t h e i nf u si o n.  If a n a p h yl a xi s o c c ur s, i m m e di at el y 
di s c o nti n u e t h e i nf u si o n (5. 2 ). 
• 
H e m at ol o gi c to xi citi e s : M o nit or c o m pl et e bl o o d c o u nt s pri or t o e a c h 
d o s e of A D C E T RI S .  Cl o s el y m o nit or p ati e nt s f or f e v er .  If Gr a d e 3 
or 4 n e utr o p e ni a d e v el o p s, c o n si d er d o s e d el a y s , r e d u cti o n s, 
di s c o nti n u ati o n , or G -C S F pr o p h yl a xi s wit h s u b s e q u e nt d o s e s  (5. 3 ). 
• 
S eri o u s i nf e cti o n s a n d o p p ort u ni sti c i nf e cti o n s : Cl o s el y m o nit or  
p ati e nt s  f or t h e e m er g e n c e of b a ct eri al, f u n g al or vir al i nf e cti o n s 
(5. 4 ). 
• 
T u m or ly si s s y n dr o m e : Cl o s el y m o nit or p ati e nt s wit h r a pi d l y 
pr olif er ati n g t u m or or hi g h t u m or b ur d e n (5. 5 ). 
• 
H e p at ot o xi cit y : M o nit or li v er e n z y m e s a n d bilir u bi n (5. 8 ). 
• 
P ul m o n ar y T o xi cit y : E v al u at e n e w or w or s e ni n g p ul m o n ar y 
s y m pt o m s (5. 1 0 ). 
• 
S eri o u s d er m at ol o gi c r e a cti o n s: Di s c o nti n u e if S t e v e n s-J o h n s o n 
s y n dr o m e or t o xi c e pi d er m al n e cr ol y si s o c c ur s  (5. 1 1 ). 
• 
E m br y o -f et al t o xi cit y: F et al h ar m c a n o c c ur.  A d vi s e p r e g n a nt 
w o m e n of t h e p ot e nti al h a z ar d t o t h e f et u s  (5. 1 2 ). 
 
 A D V E R S E R E A C TI O N S  
  
T h e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 0 %) ar e n e utr o p e ni a, 
p eri p h er al s e n s or y n e ur o p at h y, f ati g u e, n a u s e a, a n e mi a, u p p er 
r e s pir at or y tr a ct i nf e cti o n, di arr h e a, p yr e xi a, r a s h, t hr o m b o c yt o p e ni a, 
c o u g h , a n d v o miti n g (6. 1 ). 
T o r e p ort S U S P E C T E D A D V E R S E R E A C TI O N S, c o nt a ct S e attl e 
G e n eti c s, I n c . at 1 -8 5 5 -4 7 3 -2 4 3 6  or F D A at 1 -8 0 0 -F D A -1 0 8 8 or 
w w w.f d a. g o v/ m e d w at c h.  
 --------------------------------- D R U G I N T E R A C TI O N S  -----------------------------  
C o n c o mit a nt u s e of str o n g C Y P 3 A 4 i n hi bit or s or i n d u c er s, or P -g p 
i n h bit or s, h a s t h e p ot e nti al t o aff e ct t h e e x p o s ur e t o m o n o m et h yl 
a uri st ati n E ( M M A E ) (7. 1 ). 
 ------------------------- U S E I N S P E CI FI C P O P U L A TI O N S  ---------------------  
M o d er at e or s e v er e h e p ati c i m p air m e nt or s e v er e r e n al i m p air m e nt: 
M M A E e x p o s ur e a n d a d v er s e r e a cti o n s ar e i n cr e a s e d .  A v oi d u s e  (5. 6 , 
5. 7 , 8. 6 , 8. 7 ). 
S e e  1 7  f or P A TI E N T C O U N S E LI N G I N F O R M A TI O N . 
 
R e vi s e d : 0 2/ 2 0 1 5   
W A R NI N G: P R O G R E S SI V E  M U L TI F O C A L 
L E U K O E N C E P H A L O P A T H Y ( P M L) 
S e e f ull pr e s cri bi n g i nf or m ati o n f or c o m pl et e  b o x e d w ar ni n g . 
 
J C vir u s i nf e cti o n r e s ulti n g i n P M L a n d d e at h c a n o c c ur i n p ati e nt s 
r e c ei vi n g A D C E T RI S (5. 9 , 6. 2 ). 


1 
 
HI G H LI G H T S O F P R E S C R I BI N G I N F O R M A TI O N 
T h e s e hi g hli g ht s d o n ot i n cl u d e all t h e i nf or m ati o n n e e d e d t o u s e 
A D C E T RI S s af el y a n d eff e cti v el y .  S e e f ull pr e s cri bi n g i nf or m ati o n f or 
A D C E T RI S.  
A D C E T RI S ®  ( br e nt u xi m a b v e d oti n) f or inj e cti o n , f or i ntr a v e n o u s u s e 
I niti al U. S. a p pr o v al: 2 0 1 1  
 
 
 R E C E N T M A J O R C H A N G E S  
 
D o s a g e a n d A d mi ni str ati o n (2. 1 )  
1 1 / 2 0 1 4 
W ar ni n g s a n d Pr e c a uti o n s (5. 6 , 5 . 7, 5. 8 , 5. 1 1 ) 
1 1 / 2 0 1 4 
W ar ni n g s a n d Pr e c a uti o n s (5. 1 0 ) 
0 2/ 2 0 1 5  
 ---------------------------------- I N DI C A TI O N S A N D U S A GE --------------------------- 
A D C E T RI S i s a C D 3 0 -dir e ct e d a nti b o d y -dr u g c o nj u g at e i n di c at e d f or  
tr e at m e nt of p ati e nt s wit h: 
• 
H o d g ki n l y m p h o m a  aft er f ail ur e of a ut ol o g o u s st e m c ell tr a n s pl a nt  
( A S C T) or aft er f ail ur e of at l e a st t w o pri or m ulti-a g e nt c h e m ot h er a p y 
r e gi m e n s i n p ati e nt s w h o ar e n ot A S C T c a n di d at e s  (1. 1 ). 
•  
Sy st e mi c a n a pl a sti c l ar g e c ell l y m p h o m a  aft er f ail ur e of at l e a st o n e 
pri or m ulti -a g e nt c h e m ot h er a p y r e gi m e n  (1. 2 ). 
A c c el er at e d a p pr o v al w a s gr a nt e d f or t h e a b o v e i n di c ati o n s b a s e d o n 
o v er all re s p o n s e rat e .  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or 
s ur vi v al h a s n ot b e e n e st a bli s h e d .  C o nti n u e d a p pr o v al f or  t h e s e i n di c ati o ns 
m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d d e s cri pti o n of cli ni c al b e n efit i n 
c o nfir m at or y tri al s.  
   
 D O S A G E A N D A D MI NI S T R A TI O N  
 
• 
A d mi ni st er o nl y a s a n i ntr a v e n o u s i nf u si o n o v er 3 0 mi n ut e s e v er y 
3 w e e k s.  
• 
T h e r e c o m m e n d e d d o s e i s 1. 8 m g/ k g (2 ). 
• 
R e d u c e d o s e i n p ati e nt s wit h mil d h e p ati c i m p air m e nt  (2 ). 
• 
C o nti n u e tr e at m e nt u ntil di s e a s e pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y.  
 --------------------------- D O S A G E F O R M S A N D S T R E N G T H S  -------------------- 
F or i nj e cti o n: 5 0 m g l y o p hili z e d p o w d er i n a si n gl e -u s e vi al (3 ). 
 
 C O N T R AI N DI C A TI O N S  
  
C o n c o mit a nt u s e wit h bl e o m y ci n d u e t o p ul m o n ar y t o xi cit y (4 ). 
 
 
 ------------------------- W A R NI N G S A N D P R E C A U T I O N S ---------------------  
• 
P eri p h er al n e ur o p at h y : M o nit or p ati e nt s f or n e ur o p at h y a n d i n stit ut e 
d o s e m o difi c ati o n s a c c or di n gl y (5. 1 ). 
• 
A n a p h yl a xi s a n d i nf u si o n r e a cti o n s: If a n i nf u si o n r e a cti o n o c c ur s, 
i nt err u pt t h e i nf u si o n.  If a n a p h yl a xi s o c c ur s, i m m e di at el y 
di s c o nti n u e t h e i nf u si o n (5. 2 ). 
• 
H e m at ol o gi c to xi citi e s : M o nit or c o m pl et e bl o o d c o u nt s pri or t o e a c h 
d o s e of A D C E T RI S .  Cl o s el y m o nit or p ati e nt s f or f e v er .  If Gr a d e 3 
or 4 n e utr o p e ni a d e v el o p s, c o n si d er d o s e d el a y s , r e d u cti o n s, 
di s c o nti n u ati o n , or G -C S F pr o p h yl a xi s wit h s u b s e q u e nt d o s e s  (5. 3 ). 
• 
S eri o u s i nf e cti o n s a n d o p p ort u ni sti c i nf e cti o n s : Cl o s el y m o nit or  
p ati e nt s  f or t h e e m er g e n c e of b a ct eri al, f u n g al or vir al i nf e cti o n s 
(5. 4 ). 
• 
T u m or ly si s s y n dr o m e : Cl o s el y m o nit or p ati e nt s wit h r a pi d l y 
pr olif er ati n g t u m or or hi g h t u m or b ur d e n (5. 5 ). 
• 
H e p at ot o xi cit y : M o nit or li v er e n z y m e s a n d bilir u bi n (5. 8 ). 
• 
P ul m o n ar y T o xi cit y : E v al u at e n e w or w or s e ni n g p ul m o n ar y 
s y m pt o m s (5. 1 0 ). 
• 
S eri o u s d er m at ol o gi c r e a cti o n s: Di s c o nti n u e if S t e v e n s-J o h n s o n 
s y n dr o m e or t o xi c e pi d er m al n e cr ol y si s o c c ur s  (5. 1 1 ). 
• 
E m br y o -f et al t o xi cit y: F et al h ar m c a n o c c ur.  A d vi s e p r e g n a nt 
w o m e n of t h e p ot e nti al h a z ar d t o t h e f et u s  (5. 1 2 ). 
 
 A D V E R S E R E A C TI O N S  
  
T h e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 0 %) ar e n e utr o p e ni a, 
p eri p h er al s e n s or y n e ur o p at h y, f ati g u e, n a u s e a, a n e mi a, u p p er 
r e s pir at or y tr a ct i nf e cti o n, di arr h e a, p yr e xi a, r a s h, t hr o m b o c yt o p e ni a, 
c o u g h , a n d v o miti n g (6. 1 ). 
T o r e p ort S U S P E C T E D A D V E R S E R E A C TI O N S, c o nt a ct S e attl e 
G e n eti c s, I n c . at 1 -8 5 5 -4 7 3 -2 4 3 6  or F D A at 1 -8 0 0 -F D A -1 0 8 8 or 
w w w.f d a. g o v/ m e d w at c h.  
 --------------------------------- D R U G I N T E R A C TI O N S  -----------------------------  
C o n c o mit a nt u s e of str o n g C Y P 3 A 4 i n hi bit or s or i n d u c er s, or P -g p 
i n h bit or s, h a s t h e p ot e nti al t o aff e ct t h e e x p o s ur e t o m o n o m et h yl 
a uri st ati n E ( M M A E ) (7. 1 ). 
 ------------------------- U S E I N S P E CI FI C P O P U L A TI O N S  ---------------------  
M o d er at e or s e v er e h e p ati c i m p air m e nt or s e v er e r e n al i m p air m e nt: 
M M A E e x p o s ur e a n d a d v er s e r e a cti o n s ar e i n cr e a s e d .  A v oi d u s e  (5. 6 , 
5. 7 , 8. 6 , 8. 7 ). 
S e e  1 7  f or P A TI E N T C O U N S E LI N G I N F O R M A TI O N . 
 
R e vi s e d : 0 2/ 2 0 1 5   
W A R NI N G: P R O G R E S SI V E  M U L TI F O C A L 
L E U K O E N C E P H A L O P A T H Y ( P M L) 
S e e f ull pr e s cri bi n g i nf or m ati o n f or c o m pl et e b o x e d w ar ni n g .
 
J C vir u s i nf e cti o n r e s ulti n g i n P M L a n d d e at h c a n o c c ur i n p ati e nt s 
r e c ei vi n g A D C E T RI S (5. 9 , 6. 2 ).


2 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N: C O N T E N T S * 
W A R NI N G: P R O G R E S SI V E  M U L TI F O C A L 
L E U K O E N C E P H A L O P A T H Y ( P M L) 
1  
I N DI C A TI O N S A N D U S A GE  
1. 1  
H o d g ki n L y m p h o m a  
1. 2  
S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
2  
D O S A G E A N D A D MI NI S T R A TI O N  
2. 1  
D o s a g e R e c o m m e n d ati o n s  
2. 2  
D o s e M o difi c ati o n  
2. 3  
I n str u cti o n s f or Pr e p ar ati o n a n d A d mi ni str ati o n 
3  
D O S A G E F O R M S A N D S T R E N G T H S  
4  
C O N T R AI N DI C A TI O N S  
5  
W A R NI N G S A N D P R E C A U T I O N S 
5. 1  
P eri p h er al N e ur o p at h y  
5. 2  
A n a p h yl a xi s a n d  I nf u si o n R e a cti o n s 
5. 3  
H e m at ol o gi c T o xi citi e s  
5. 4  
S eri o u s I nf e cti o n s a n d O p p ort u ni sti c I nf e cti o n s  
5. 5  
T u m or L y si s S y n dr o m e  
5. 6  
I n cr e a s e d T o xi cit y i n t h e Pr e s e n c e of S e v er e R e n al 
I m p air m e nt 
5. 7  
I n cr e a s e d T o xi cit y i n t h e Pr e s e n c e of M o d er at e or 
S e v er e H e p ati c I m p air m e nt  
5. 8  
H e p at ot o xi cit y  
5. 9  
Pr o gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y  
5. 1 0  
P ul m o n ar y T o xi cit y  
5. 1 1  
S eri o u s D er m at ol o gi c R e a cti o n s  
5. 1 2  
E m br y o -F et al T o xi cit y 
6  
A D V E R S E R E A C TI O N S  
6. 1  
Cli ni c al Tri al E x p eri e n c e  
6. 2  
P o st M ar k eti n g E x p eri e n c e  
6. 3  
I m m u n o g e ni cit y 
7  
D R U G I N T E R A C TI O N S  
7. 1  
Eff e ct of Ot h er Dr u g s o n A D C E T RI S  
7. 2  
Eff e ct of A D C E T RI S o n Ot h er Dr u g s  
8  
U S E I N S P E CI FI C P O P U L A TI O N S  
8. 1  
Pr e g n a n c y  
8. 3  
N ur si n g M ot h er s  
8. 4  
P e di atri c U s e  
8. 5  
G eri atri c U s e  
8. 6  
R e n al I m p air m e nt  
8. 7  
H e p ati c I m p air m e nt  
1 0  
O V E R D O S A G E  
1 1  
D E S C RI P TI O N  
1 2  
C LI NI C A L P H A R M A C O L O G Y  
1 2. 1  
M e c h a ni s m  of A cti o n  
1 2. 2  
P h ar m a c o d y n a mi c s  
1 2. 3  
P h ar m a c o ki n eti c s  
1 3  
N O N C LI NI C A L T O XI C O L O G Y  
1 3. 1  
C ar ci n o g e n e si s, M ut a g e n e si s, I m p air m e n t of F ertilit y 
1 4  
C LI NI C A L S T U DI E S  
1 4. 1  
H o d g ki n L y m p h o m a  
1 4. 2  
S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
1 5  
R E F E R E N C E S  
1 6  
H O W S U P P LI E D/ S T O R A G E  A N D H A N D LI N G  
1 6. 1  
H o w S u p pli e d  
1 6. 2  
St or a g e  
1 6. 3  
S p e ci al H a n dli n g  
1 7  
P A TI E N T C O U N S E LI N G I N F O R M A TI O N  
 
* S e cti o n s or s u b s e cti o n s o mitt e d fr o m t h e f ull pr e s cri bi n g i nf or m ati o n ar e n ot 
li st e d. 
 
 
 


3 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N  
 
1 
I N DI C A TI O N S A N D U S A GE 
1. 1  
H o d g ki n L y m p h o m a  
A D C E T RI S  ( br e nt u xi m a b v e d oti n) i s i n di c at e d f or tr e at m e nt of p ati e nt s wit h H o d g ki n l y m p h o m a 
( H L) aft er f ail ur e of a ut ol o g o u s st e m c ell tr a n s pl a nt ( A S C T) or  aft er  f ail ur e of at l e a st t w o pri or 
m ulti -a g e nt c h e m ot h er a p y r e gi m e n s  i n p ati e nt s w h o ar e n ot A S C T c a n di d at e s. 
T hi s i n di c ati o n i s a p pr o v e d u n d er a c c el er at e d a p pr o v al b a s e d o n o v er all r e s p o n s e r at e  [ s e e 
Cli ni c al St u di e s ( 1 4. 1 )].  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or s ur vi v al h a s n ot b e e n 
e st a bli s h e d .  C o nti n u e d a p pr o v al f or t hi s i n di c a ti o n m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d 
d e s cri pti o n of cli ni c al b e n efit i n c o nfir m at or y tri al s.  
1. 2  
S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
A D C E T RI S  i s i n di c at e d f or tr e at m e nt of p ati e nt s wit h s y st e mi c a n a pl a sti c l ar g e c ell l y m p h o m a  
( sA L C L)  aft er f ail ur e of at l e a st o n e pri or m ulti -a g e nt c h e m ot h er a p y r e gi m e n . 
T hi s i n di c ati o n i s a p pr o v e d u n d er a c c el er at e d a p pr o v al b a s e d o n o v er all r e s p o n s e r at e  [ s e e 
Cli ni c al St u di e s ( 1 4. 2 )].  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or s ur vi v al h a s n ot b e e n 
e st a bli s h e d .  C o nti n u e d a p pr o v al f or t hi s i n di c ati o n m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d 
d e s cri pti o n of cli ni c al b e n efit i n c o nfir m at or y tri al s.  
2 
D O S A G E A N D A D MI NI S T R A TI O N  
2. 1  
D o s a g e R e c o m m e n d ati o n s  
A d mi ni st er A D C E T RI S  a s a n i ntr a v e n o u s i nf u si o n o v er 3 0  mi n ut e s e v er y 3 w e e k s  u ntil di s e a s e 
pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y .  S e e T a bl e  1 f or t h e r e c o m m e n d e d st arti n g d o s a g e. 
T a bl e  1: 
R e c o m m e n d e d A D C E T RI S D o s a g e  
 
R e c o m m e n d e d St arti n g D o s a g e  
N or m al r e n al a n d h e p ati c f u n cti o n  
1. 8 m g/ k g u p t o 1 8 0 m g  
R e n al i m p air m e nt  
Mil d ( cr e ati ni n e cl e ar a n c e > 5 0 – 8 0 m L/ mi n) or 
m o d er at e ( cr e ati ni n e cl e ar a n c e  3 0 – 5 0 m L/ mi n ) 
1. 8 m g/ k g u p t o 1 8 0 m g  
S e v er e ( c r e ati ni n e c l e ar a n c e l e s s t h a n 3 0 m L/ mi n ) 
A v oi d u s e  
[ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 6 )] 
H e p ati c i m p air m e nt  
Mil d ( C hil d -P u g h A)  
1. 2 m g/ k g u p t o 1 2 0 m g  
M o d er at e ( C hil d -P u g h B) or s e v er e ( C hil d -P u g h C)  
A v oi d u s e  
[ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 7 )] 
W A R NI N G: P R O G R E S SI V E  M U L TI F O C A L L E U K O E N C E P H A L O P A T H Y ( P M L) 
 
J C vir u s i nf e cti o n r e s ulti n g i n P M L a n d d e at h c a n o c c ur i n p ati e nt s r e c ei vi n g 
A D C E T RI S [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 9 ), A d v er s e R e a cti o n s ( 6. 1 )]. 


4 
 
2. 2  
D o s e M o difi c ati o n  
P eri p h er al N e ur o p at h y:   F or n e w or w or s e ni n g Gr a d e 2 or 3 n e ur o p at h y, d o si n g s h o ul d b e 
h el d u ntil n e ur o p at h y i m pr o v e s t o Gr a d e 1 or b a s eli n e a n d t h e n r e st art e d at 1. 2  m g/ k g .  F or 
Gr a d e 4 p eri p h er al n e ur o p at h y, A D C E T RI S s h o ul d b e di s c o nti n u e d.  
N e utr o p e ni a:  T h e d o s e of A D C E T RI S s h o ul d b e h el d f or Gr a d e 3 or 4 n e utr o p e ni a u ntil 
r e s ol uti o n t o b a s eli n e or Gr a d e 2 or l o w er .  C o n si d er G- C S F  pr o p h yl a xi s f or s u b s e q u e nt c y cl e s 
i n pati e nt s w h o e x p eri e n c e G r a d e 3 or 4 n e utr o p e ni a i n t h e pr e vi o u s c y cl e.  I n p ati e nt s wit h 
r e c urr e nt Gr a d e 4 n e utr o p e ni a d e s pit e t h e u s e of G- C S F  pr o p h yl a xi s , c o n si d er di s c o nti n u ati o n 
or d o s e r e d u cti o n of A D C E T RI S t o  1. 2 m g/ k g.  
2. 3  
I n str u cti o n s f or Pr e p ar ati o n a n d A d mi ni str ati o n  
A d mi ni str ati o n  
•  
A d mi ni st er  A D C E T RI S a s a n i ntr a v e n o u s i nf u si o n o nl y . 
•  
D o n ot mi x A D C E T RI S wit h, or a d mi ni st er a s a n i nf u si o n wit h, ot h er m e di ci n al 
pr o d u ct s.  
R e c o n stit uti o n  
•  
F oll o w p r o c e d ur e s f or pr o p er h a n dli n g a n d di s p o s al of a nti c a n c er dru g s  [ s e e R ef er e n c e s 
(1 5 )]. 
•  
U s e a p pr o pri at e a s e pti c t e c h ni q u e f or r e c o n stit uti o n a n d pr e p ar ati o n of d o si n g s ol uti o n s.  
•  
D et er mi n e t h e n u m b er of 5 0 m g vi al s n e e d e d b a s e d o n t h e p ati e nt’ s w ei g ht  a n d t h e 
pr e s cri b e d d o s e [ s e e D o s a g e a n d A d mi ni str ati o n (2. 1 )]. 
•  
R e c o n stit ut e e a c h 5 0 m g vi al of A D C E T RI S  wit h 1 0. 5 m L of St eril e W at er f or I nj e cti o n, 
U S P, t o yi el d a si n gl e -u s e s ol uti o n c o nt ai ni n g 5 m g/ m L br e nt u xi m a b v e d oti n . 
•   
Dir e ct t h e str e a m t o w ar d t h e w all of vi al a n d n ot dir e ctl y at t h e c a k e  or p o w d er . 
•  
G e ntl y  s wirl t h e vi al t o ai d di s s ol uti o n .  D O N O T S H A K E . 
•  
I n s p e ct t h e r e c o n stit ut e d s ol uti o n f or p arti c ul at e s a n d di s c ol or ati o n.  T h e r e c o n stit ut e d 
s ol uti o n s h o ul d b e cl e ar t o sli g htl y o p al e s c e nt, c ol orl e s s, a n d fr e e of vi si bl e p arti c ul at e s . 
•  
F oll o wi n g r e c o n stit uti o n, dil ut e i m m e di at el y i nt o a n i nf u si o n b a g .  If n ot dil ut e d 
i m m e di at el y, st or e t h e s ol uti o n at 2– 8° C ( 3 6 – 4 6 °F) a n d u s e wit hi n  2 4 h o ur s  of 
r e c o n stit uti o n.  D O N O T F R E E Z E . 
•  
Di s c ar d a n y u n u s e d p orti o n l eft i n t h e vi al.  
Dil uti o n  
•  
C al c ul at e t h e r e q uir e d v ol u m e of 5 m g/ m L r e c o n stit ut e d A D C E T RI S  s ol uti o n n e e d e d . 


5 
 
•   
Wit h dr a w t hi s a m o u nt fr o m t h e vi al a n d i m m e di at el y a d d it t o a n i nf u si o n b a g c o nt ai ni n g 
a mi ni m u m v ol u m e of 1 0 0 m L of 0. 9 % S o di u m C hl ori d e I nj e cti o n , 5 % D e xtr o s e I nj e cti o n 
or L a ct at e d Ri n g er' s I nj e cti o n  t o a c hi e v e a fi n al c o n c e ntr ati o n of 0. 4 m g/ m L t o 1. 8 m g/ m L 
br e nt u xi m a b v e d oti n . 
•  
G e ntl y i n v ert t h e b a g t o mi x t h e s ol uti o n . 
•  
F oll o wi n g dil uti o n, i nf u s e t h e A D C E T RI S  s ol uti o n i m m e di at el y .  If n ot u s e d i m m e di at el y, 
st or e t h e s ol uti o n  at 2 – 8° C ( 3 6 – 4 6° F) a n d u s e wit hi n 2 4 h o ur s  of r e c o n stit uti o n .  D O 
N O T F R E E Z E.  
3 
D O S A G E F O R M S A N D S T R E N G T H S  
F or inj e cti o n : 5 0  m g of br e nt u xi m a b v e d oti n a s a st eril e, w hit e t o off -w hit e l y o p hili z e d , 
pr e s er v ati v e -fr e e c a k e or p o w d er  i n a si n gl e-u s e vi al f or r e c o n stit uti o n . 
4 
C O N T R AI N DI C A TI O N S  
A D C E T RI S i s c o ntr ai n di c at e d wit h c o n c o mit a nt bl e o m y ci n d u e t o p ul m o n ar y t o xi cit y 
( e. g., i nter stiti al i nfiltr ati o n a n d/ or i nfl a m m ati o n)  [ s e e A d v er s e R e a cti o n s  (6. 1 )]. 
5  
W A R NI N G S A N D P R E C A U TI O N S  
5. 1  
P eri p h er al N e ur o p at h y  
A D C E T RI S tr e at m e nt c a u s e s a p eri p h er al n e ur o p at h y t h at i s pr e d o mi n a ntl y s e n s or y .  C a s e s of 
p eri p h er al m ot or n e ur o p at h y h a v e al s o b e e n r e p ort e d .  A D C E T RI S -i nd u c e d p eri p h er al 
n e ur o p at h y i s  c u m ul ati v e .  I n t h e H L a n d s A L C L cli ni c al tri al s, 5 4 % of p ati e nt s e x p eri e n c e d a n y 
gr a d e of n e ur o p at h y .  Of t h e s e p ati e nt s, 4 9 % h a d c o m pl et e r e s ol uti o n, 3 1 % h a d p arti al 
i m pr o v e m e nt, a n d 2 0 % h a d n o i m pr o v e m e nt.  Of t h e p ati e nt s w h o r e p ort e d n e ur o p at h y, 5 1 % 
h a d r e si d u al n e ur o p at h y at t h e ti m e of t h eir l a st e v al u ati o n .  M o nit or p ati e nt s  f or s y m pt o m s of 
n e ur o p at h y, s u c h a s h y p o e st h e si a, h y p er e st h e si a, p ar e st h e si a, di s c o mf ort, a b ur ni n g s e n s ati o n, 
n e ur o p at hi c p ai n , or w e a k n e s s .  P ati e nt s e x p eri e n ci n g n e w or w or s e ni n g p eri p h er al n e ur o p at h y 
m a y r e q uir e a d el a y, c h a n g e i n d o s e, or di s c o nti n u ati o n  of A D C E T RI S  [ s e e D o s e M o difi c ati o n 
(2. 2 )]. 
5. 2  
A n a p h yl a xi s a n d I nf u si o n R e a cti o n s 
I nf u si o n-r el at e d r e a cti o n s, i n cl u di n g a n a p h yl a xi s, h a v e  o c c urr e d  wit h A D C E T RI S .  M o nit or 
p ati e nt s d uri n g i nf u si o n .  If a n a p h yl a xi s o c c ur s, i m m e di at el y a n d p er m a n e ntl y di s c o nti n u e 
a d mi ni str ati o n of A D C E T RI S a n d a d mi ni st er a p pr o pri at e m e di c al t h er a p y .  If a n i nf u si o n-r el at e d 
r e a cti o n o c c ur s, t h e i nf u si o n s h o ul d b e i nt err u pt e d a n d a p pr o pri at e m e di c al m a n a g e m e nt 
i n stit ut e d.  P ati e nt s w h o h a v e e x p eri e n c e d a pri or i nf u si o n -r el at e d r e a cti o n s h o ul d b e 
pr e m e di c at e d f or s u b s e q u e nt i nf u si o n s .  Pr e m e di c ati o n m a y i n cl u d e a c et a mi n o p h e n, a n 
a nti hi st a mi n e , a n d a c orti c o st er oi d.  
5. 3  
H e m at ol o gi c T o xi citi e s  
P r ol o n g e d ( ≥1 w e e k) s e v er e n e utr o p e ni a a n d  Gr a d e 3 or Gr a d e 4 t hr o m b o c yt o p e ni a  or a n e mi a  
c a n o c c ur wit h A D C E T RI S .  F e bril e n e utr o p e ni a h a s b e e n r e p ort e d wit h tr e at m e nt wit h 
A D C E T RI S .  C o m pl et e bl o o d c o u nt s s h o ul d b e m o nit or e d  pri or t o e a c h d o s e of A D C E T RI S  a n d 


6 
 
m or e  fr e q u e nt m o nit ori n g s h o ul d b e c o n si d er e d f or p ati e nt s wit h Gr a d e 3 or 4 n e utr o p e ni a .  
M o nit or p ati e nt s f or f e v er.  If Gr a d e 3 or 4 n e utr o p e ni a d e v el o p s, c o n si d er  d o s e d el a y s , 
r e d u cti o n s, di s c o nti n u ati o n, or G-C S F pr o p h yl a xi s wit h s u b s e q u e nt A D C E T RI S d o s e s  [ s e e 
D o s e M o difi c ati o n ( 2. 2 )]. 
5. 4  
S eri o u s  I nf e cti o n s a n d O p p ort u ni sti c I nf e cti o n s  
S eri o u s i nf e cti o n s a n d o p p ort u ni sti c i nf e cti o n s s u c h a s p n e u m o ni a, b a ct er e mi a, a n d s e p si s  or 
s e pti c s h o c k (i n cl u di n g f at al o ut c o m e s) h a v e b e e n r e p ort e d i n p ati e nt s tr e at e d wit h A D C E T RI S .  
P ati e nt s s h o ul d b e  cl o s el y  m o nit or e d  d uri n g tr e at m e nt f or t h e e m er g e n c e of p o s si bl e b a ct eri al, 
f u n g al, or vir al i nf e cti o n s.  
5. 5  
T u m or L y si s S y n dr o m e  
P ati e nt s wit h r a pi dl y pr olif er ati n g t u m or a n d hi g h t u m or b ur d e n m a y b e  at i n cr e a s e d ri s k of 
t u m or l y si s s y n dr o m e.  M o nit or  cl o s el y a n d t a k e a p pr o pri at e m e a s ur e s.  
5. 6  
I n cr e a s e d T o xi cit y i n t h e Pr e s e n c e of S e v er e R e n al I m p air m e nt  
T h e fre q u e n c y of ≥Gr a d e 3 a d v er s e r e a cti o n s  a n d  d eat h s w a s  gre a ter  i n p atie nt s  wit h s e v er e 
r e n al i m p air m e nt c o m p ar e d t o p ati e nt s wit h n or m al r e n al f u n cti o n.  D u e t o hi g h er M M A E 
e x p o s ur e, ≥Gr a d e 3 a d v er s e r e a cti o n s m a y b e m or e fr e q u e nt i n p ati e nt s wit h s e v er e r e n al 
i m p air m e nt c o m p ar e d t o p ati e nt s wit h n or m al r e n al f u n cti o n.  A v oi d t h e u s e of A D C E T RI S i n 
p ati e nt s wit h s e v er e r e n al i m p air m e nt [ cr e ati ni n e cl e ar a n c e ( C L cr) < 3 0 m L/ mi n] [ se e U s e i n 
S p e cifi c P o p ul ati o n s (8. 6 )]. 
5. 7  
I n cr e a s e d T o xi cit y i n t h e Pr e s e n c e of M o d er at e or S e v er e H e p ati c I m p air m e nt  
T h e  fre q u e n c y of ≥Gr a d e 3 a d v er s e r e a cti o n s  a n d  d eat h s w a s  gre a ter  i n p atie nt s  wit h  m o d er at e 
a n d s e v er e h e p ati c i m p air m e nt c o m p ar e d t o p ati e nt s wit h n or m al h e p ati c f u n cti o n .  A v oi d t h e u s e of 
A D C E T RI S i n p ati e nt s wit h m o d er at e ( C hil d -P u g h B) or  s e v er e ( C hil d -P u g h C) h e p ati c 
i m p air m e nt [ se e U s e i n S p e cifi c P o p ul ati o n s (8. 7 )]. 
5. 8  
H e p at ot o xi cit y  
S eri o u s c a s e s of h e p at ot o xi cit y,  i n cl u di n g f at al o ut c o m e s, h a v e o c c urr e d i n p ati e nt s r e c ei vi n g 
A D C E T RI S.  C a s e s w er e  c o n si st e nt wit h h e p at o c ell ul ar i nj ur y, i n cl u di n g el e v ati o n s of 
tr a n s a mi n a s e s a n d/ or bilir u bi n.  C a s e s h a v e o c c urr e d aft er t h e fir st d o s e of A D C E T RI S or aft er 
A D C E T RI S r e c h all e n g e .  Pr e e xi sti n g li v er di s e a s e, el e v at e d b a s eli n e li v er e n z y m e s, a n d 
c o n c o mi t a nt m e di c ati o n s m a y al s o i n cr e a s e t h e ri s k.  M o nit or li v er e n z y m e s a n d bilir u bi n .  
P ati e nt s e x p eri e n ci n g n e w, w or s e ni n g, or r e c urr e nt h e p at ot o xi cit y m a y r e q uir e a d el a y, c h a n g e 
i n d o s e, or di s c o nti n u ati o n of A D C E T RI S. 
5. 9  
Pr o gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y  
J C vir u s i nf e cti o n r e s ulti n g i n P M L a n d d e at h h a s b e e n r e p ort e d  i n A D C E T RI S-tr e at e d p ati e nt s.  
I n a d diti o n t o A D C E T RI S t h er a p y, ot h er p o s si bl e c o ntri b ut or y f a ct or s i n cl u d e pri or t h er a pi e s a n d 
u n d erl yi n g di s e a s e t h at m a y c a u s e i m m u n o s u p p r e s si o n.  C o n si d er t h e di a g n o si s of P M L i n a n y 
p ati e nt pr e s e nti n g wit h n e w -o n s et si g n s a n d s y m pt o m s of c e ntr al n er v o u s s y st e m a b n or m aliti e s .  


7 
 
H ol d A D C E T RI S d o si n g f or a n y s u s p e ct e d c a s e of P M L a n d di s c o nti n u e A D C E T RI S d o si n g if a 
di a g n o si s of P M L i s c o nfir m e d.  
5. 1 0  
P ul m o n ar y T o xi cit y  
P ul m o n ar y t o xi cit y h a s b e e n r e p ort e d i n p ati e nt s r e c ei vi n g A D C E T RI S.  A c a u s al a s s o ci ati o n 
wit h si n gl e -a g e nt A D C E T RI S h a s n ot b e e n e st a bli s h e d. I n t h e e v e nt of n e w or w or s e ni n g 
p ul m o n ar y s y m pt o m s ( e. g., c o u g h, d y s p n e a), p erf or m a pr o m pt di a g n o sti c e v al u ati o n a n d 
i n stit ut e a p pr o pri at e m e di c al t h er a p y. 
5. 1 1  
S eri o u s D er m at ol o gi c R e a cti o n s  
St e v e n s -J o h n s o n s y n dr o m e ( S J S) a n d t o xi c e pi d er m al n e cr ol y si s ( T E N), i n cl u di n g f at al 
o ut c o m e s, h a v e  b e e n r e p ort e d wit h A D C E T RI S .  If S J S or T E N o c c ur s, d i s c o nti n u e A D C E T RI S  
a n d a d mi ni st er a p pr o pri at e m e di c al t h er a p y.  
5. 1 2  
E m br y o -F et al T o xi cit y  
T h er e ar e n o a d e q u at e a n d w ell -c o ntr oll e d st u di e s of A D C E T RI S  i n pr e g n a nt w o m e n.  H o w e v er, 
b a s e d o n it s m e c h a ni s m of a cti o n a n d fi n di n g s i n a ni m al s, A D C E T RI S c a n c a u s e f et al h ar m 
w h e n a d mi ni st er e d t o a pr e g n a nt w o m a n .  Br e nt u xi m a b v e d oti n c a u s e d e m br y o -f et al t o xi citi e s, 
i n cl u di n g si g nifi c a ntl y d e cr e a s e d e m br y o  vi a bilit y  a n d f et al m alf or m ati o n s, i n a ni m al s at m at er n al 
e x p o s ur e s t h at w er e si mil ar t o h u m a n e x p o s ur e s at t h e r e c o m m e n d e d d o s e s f or p ati e nt s wit h 
H L a n d s A L C L .  If t hi s dr u g i s u s e d d uri n g pr e g n a n c y, or if t h e p ati e nt b e c o m e s pr e g n a nt w hil e 
r e c ei vi n g t he dr u g, t h e p ati e nt s h o ul d b e a p pri s e d of t h e p ot e nti al h a z ar d t o t h e f et u s  [ s e e U s e 
i n S p e cifi c P o p ul ati o n s (8. 1 )]. 
6 
A D V E R S E R E A C TI O N S  
T h e f oll o wi n g s eri o u s a d v er s e r e a cti o n s ar e di s c u s s e d i n gr e at er d et ail i n ot h er s e cti o n s of t h e 
pr e s cri bi n g i nf or m ati o n:  
•  
P eri p h er al N e ur o p at h y  [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 1 )] 
•  
A n a p h yl a xi s a n d I nf u si o n R e a cti o n s [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 2 )] 
•  
H e m at ol o gi c T o xi citi e s [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 3 )] 
•  
S eri o u s I nf e cti o n s a n d O p p ort u ni sti c I nf e cti o n s [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 4 )] 
•  
T u m or L y si s  S y n dr o m e [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 5 )] 
•   In cr e a s e d T o xi cit y i n t h e Pr e s e n c e of S e v er e R e n al I m p air m e n t [ se e W ar ni n g s a n d 
Pr e c a uti o n s ( 5. 6 )] 
•  
I n cr e a s e d T o xi cit y i n t h e Pr e s e n c e of M o d er at e or S e v er e H e p a ti c I m p air m e nt [ s e e 
W ar ni n g s  a n d Pr e c a uti o n s ( 5. 7 )] 
•  
H e p at ot o xi cit y [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 8 )] 
•  
Pr o gr e s si v e M ultif o c al L e u k o e n c e p h al o p at h y [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 9 )] 


8 
 
•  
P ul m o n ar y T o xi cit y [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 1 0 )] 
•  
S eri o u s D er m at ol o gi c R e a cti o n s [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 1 1 )] 
•  
E m br y o -F et al T o xi cit y [ se e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1 2 )] 
6. 1  
Cli ni c al Tri al E x p eri e n c e  
B e c a u s e cli ni c al tri al s ar e c o n d u ct e d u n d er wi d el y v ar yi n g c o n diti o n s, a d v er s e r e a cti o n r at e s 
o b s er v e d i n cli ni c al tri al s of a dr u g c a n n ot b e dir e ctl y c o m p ar e d t o r at e s i n t h e cli ni c al tri al s of 
a n ot h er dr u g a n d m a y n ot r efl e ct t h e r at e s o b s er v e d i n pr a cti c e.  
A D C E T RI S  w a s st u di e d a s m o n ot h er a p y i n 1 6 0 p ati e nt s i n t w o p h a s e 2 tri al s.  A cr o s s b ot h 
tri al s, th e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 0 %), r e g ar dl e s s of c a u s alit y, w e r e n e utr o p e ni a, 
p eri p h er al s e n s or y n e ur o p at h y, f ati g u e, n a u s e a, a n e mi a, u p p er r e s pir at or y tr a ct i nf e cti o n, 
di arr h e a, p yr e xi a, ra s h, t hr o m b o c yt o p e ni a, c o u g h , a n d v o miti n g .  T h e m o st c o m m o n a d v er s e 
r e a cti o n s o c c urri n g i n at l e a st 1 0 % of p ati e nt s i n eit h er tri al, r e g ar dl e s s of c a u s alit y, u si n g t h e 
N CI C o m m o n T o xi cit y Crit eri a V er si o n 3. 0, ar e s h o w n i n T a bl e  2. 
E x p eri e n c e  i n Ho d g ki n L y m p h o m a  
A D C E T RI S  w a s st u di e d i n 1 0 2  p ati e nt s wit h H L i n a si n gl e ar m  cli ni c al tri al  i n w hi c h t h e 
r e c o m m e n d e d st arti n g d o s e a n d s c h e d ul e w a s  1. 8 m g/ k g i ntr a v e n o u sl y e v er y 3 w e e k s .  M e di a n 
d ur ati o n of tr e at m e nt w a s  2 7 w e e k s  (r a n g e, 3 t o 5 6 w e e k s) [ s e e Cli ni c al St u di e s  (1 4. 1 )]. 
T h e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 0 %), r e g ar dl e s s of c a u s alit y, w er e n e utr o p e ni a, 
p eri p h er al s e n s or y n e ur o p at h y, f ati g u e, u p p er r e s pir at or y tr a ct i nf e cti o n , n a u s e a, di arr h e a, 
a n e mi a, p yr e xi a, t hr o m b o c yt o p e ni a , r a s h, a b d o mi n al p ai n, c o u g h , a n d v o miti n g. 
P ul m o n ar y T o xi cit y  
I n an ot h er  cli ni c al tri al  i n p ati e nt s wit h H L  t h at st u di e d A D C E T RI S wit h bl e o m y ci n a s p art of a 
c o m bi n ati o n r e gi m e n , t h e r at e of n o n-i nf e cti o u s p ul m o n ar y t o xi cit y w a s hi g h er t h a n t h e hi st ori c al 
i n ci d e n c e r e p ort e d wit h A B V D ( a dri a m y ci n, bl e o m y ci n, vi n bl a sti n e, d a c ar b a zi n e).  P ati e nt s 
t y pi c all y r e p orte d  c o u g h a n d d y s p n e a .  I nt er stiti al i nfiltr ati o n a n d/ or i nfl a m m ati o n w er e o b s er v e d 
o n r a di o gr a p h s a n d c o m p ut e d t o m o gr a p hi c i m a gi n g of t h e c h e st .  M o st p ati e nt s r e s p o n d e d t o 
c orti c o st er oi d s .  T h e c o n c o mit a nt u s e of A D C E T RI S wit h bl e o m y ci n i s c o ntr ai n di c at e d [s e e 
C o ntr ai n di c ati o n s  (4 )]. 
E x p eri e n c e i n S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
A D C E T RI S  w a s st u di e d i n 5 8 p ati e nt s wit h s A L C L i n a si n gl e ar m cli ni c al tri al i n w hi c h t h e 
r e c o m m e n d e d st arti n g d o s e a n d s c h e d ul e w a s 1. 8 m g/ k g i ntr a v e n o u sl y e v er y 3 w e e k s .  M e di a n 
d ur ati o n of tr e at m e nt  w a s  2 4 w e e k s  (r a n g e, 3 t o 56 w e e k s ) [ s e e Cli ni c al St u di e s  (1 4. 2 )]. 
T h e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 0 %), r e g ar dl e s s of c a u s alit y, w er e n e utr o p e ni a, 
a n e mi a, p eri p h er al s e n s or y n e ur o p at h y, f ati g u e, n a u s e a, p yr e xi a, r a s h, di arr h e a , a n d p ai n . 


9 
 
C o m bi n e d E x p eri e n c e  
T a bl e  2: 
M o st C o m m o nl y R e p ort e d ( ≥1 0 %) A d v er s e R e a cti o n s 
  
H L  
s A L C L  
T ot al N = 1 0 2  
% of p ati e nt s  
T ot al N = 5 8  
% of p ati e nt s  
A d v er s e R e a cti o n  
A n y 
Gr a d e  
Gr a d e 
3 
Gr a d e 
4 
A n y 
Gr a d e  
Gr a d e 
3 
Gr a d e 
4 
Bl o o d a n d l y m p h ati c s y st e m 
di s or d er s  
  
  
  
  
  
  
  N e utr o p e ni a*  
5 4  
1 5  
6  
5 5  
1 2  
9  
  A n e mi a*  
3 3  
8  
2  
5 2  
2  
- 
  T hr o m b o c yt o p e ni a*  
2 8  
7  
2  
1 6  
5  
5  
  L y m p h a d e n o p at h y  
1 1  
- 
- 
1 0  
- 
- 
N er v o u s s y st e m di s or d er s  
  
  
  
  
  
  
  P eri p h er al s e n s or y  n e ur o p at h y  
5 2  
8  
- 
5 3  
1 0  
- 
  P eri p h er al  m ot or  n e ur o p at h y  
1 6  
4  
- 
7  
3  
- 
  H e a d a c h e  
1 9  
- 
- 
1 6  
2  
- 
  Di z zi n e s s  
1 1  
- 
- 
1 6  
- 
- 
G e n er al di s or d er s a n d 
a d mi ni str ati o n sit e c o n diti o n s  
  
  
  
  
  
  
   F ati g u e  
4 9  
3  
- 
4 1  
2  
2  
   P yr e xi a  
2 9  
2  
- 
3 8  
2  
- 
   C hill s  
1 3  
- 
- 
1 2  
- 
- 
   P ai n  
7  
- 
- 
2 8  
- 
5  
   E d e m a p eri p h er al  
4  
- 
- 
1 6  
- 
- 
I nf e cti o n s a n d i nf e st ati o n s 
  
  
  
  
  
  
   U p p er r e s pir at or y tr a ct  i nf e cti o n 
4 7  
- 
- 
1 2  
- 
- 
G a str oi nt e sti n al di s or d er s  
  
  
  
  
  
  
   N a u s e a  
4 2  
- 
- 
3 8  
2  
- 
   Di arr h e a  
3 6  
1  
- 
2 9  
3  
- 
   A b d o mi n al p ai n  
2 5  
2  
1  
9  
2  
- 
   V o miti n g  
2 2  
- 
- 
1 7  
3  
- 
   C o n sti p ati o n  
1 6  
- 
- 
1 9  
2  
- 
S ki n a n d s u b c ut a n e o u s ti s s u e 
di s or d er s  
  
  
  
  
  
  
  R a s h  
2 7  
- 
- 
3 1  
- 
- 
  Pr urit u s  
1 7  
- 
- 
1 9  
- 
- 
  Al o p e ci a  
1 3  
- 
- 
1 4  
- 
- 
  Ni g ht s w e at s  
1 2  
- 
- 
9  
- 
- 
  Dr y s ki n  
4  
- 
- 
1 0  
- 
- 
R e s pir at or y, t h or a ci c a n d 
m e di a sti n al di s or d er s  
  
  
  
  
  
  


1 0  
 
  
H L  
s A L C L  
T ot al N = 1 0 2  
% of p ati e nt s  
T ot al N = 5 8  
% of p ati e nt s  
A d v er s e R e a cti o n  
A n y 
Gr a d e  
Gr a d e 
3 
Gr a d e 
4 
A n y 
Gr a d e  
Gr a d e 
3 
Gr a d e 
4 
  C o u g h  
2 5  
- 
- 
1 7  
- 
- 
  D y s p n e a  
1 3  
1  
- 
1 9  
2  
- 
  Or o p h ar y n g e al p ai n  
1 1  
- 
- 
9  
- 
- 
M u s c ul o s k el et al a n d c o n n e cti v e 
ti s s u e di s or d er s 
  
  
  
  
  
  
  Art hr al gi a  
1 9  
- 
- 
9  
- 
- 
  M y al gi a  
1 7  
- 
- 
1 6  
2  
- 
  B a c k p ai n  
1 4  
- 
- 
1 0  
2  
- 
  P ai n i n e xtr e mit y  
1 0  
- 
- 
1 0  
2  
2  
  M u s cl e s p a s m s  
9  
- 
- 
1 0  
2  
- 
P s y c hi atri c di s or d er s  
  
  
  
  
  
  
  I n s o m ni a 
1 4  
- 
- 
1 6  
- 
- 
  A n xi et y  
1 1  
2  
- 
7  
- 
- 
M et a b oli s m a n d n utriti o n di s or d er s  
  
  
  
  
  
  
  D e cr e a s e d a p p etit e  
1 1  
- 
- 
1 6  
2 
- 
I n v e sti g ati o n s 
  
  
  
  
  
  
  W ei g ht d e cr e a s e d  
6  
- 
- 
1 2  
3  
- 
* D eri v e d fr o m l a b or at or y v al u e s a n d a d v er s e r e a cti o n d at a 
 
I nf u si o n r e a cti o n s 
T w o c a s e s of a n a p h yl a xi s w er e r e p ort e d i n p h a s e 1 tri al s .  T h er e w er e n o Gr a d e 3 or 4 i nf u si o n -
r el at e d r e a cti o n s r e p ort e d i n t h e p h a s e 2 tri al s, h o w e v er, Gr a d e 1 or 2 i nf u si o n-r el at e d r e a cti o n s 
w er e r e p ort e d f or 1 9 p ati e nt s ( 1 2 %) .  T h e m o st c o m m o n a d v er s e r e a cti o n s ( ≥2 %) a s s o ci at e d 
wit h i nf u si o n -r el at e d r e a cti o n s w er e c hill s ( 4 %), n a u s e a ( 3 %), d y s p n e a ( 3 %), pr urit u s ( 3 %), 
p yr e xi a ( 2 %),  a n d c o u g h ( 2 %).  
S eri o u s a d v er s e r e a cti o n s 
I n t h e ph a s e 2 tri al s, s eri o u s a d v er s e r e a cti o n s, r e g ar dl e s s of c a u s alit y, w er e r e p ort e d i n 3 1 % of 
p ati e nt s r e c ei vi n g A D C E T RI S .  T h e m o st c o m m o n s eri o u s a d v er s e r e a cti o n s e x p eri e n c e d b y  
p ati e nt s wit h H L i n cl u d e p eri p h er al m ot or n e ur o p at h y ( 4 %), a b d o mi n al p ai n ( 3 %),  p ul m o n ar y 
e m b oli s m  ( 2 %), p n e u m o niti s ( 2 %), p n e u m ot h or a x ( 2 %), p y el o n e p hriti s ( 2 %), a n d p yr e xi a ( 2 %).  
T h e m o st c o m m o n s eri o u s a d v er s e r e a cti o n s  e x p eri e n c e d b y p ati e nt s wit h s A L C L w er e s e pti c 
s h o c k  ( 3 %), s u pr a v e ntri c ul ar arr h yt h mi a ( 3 %) , p ai n i n e xtr e mit y ( 3 %), a n d uri n ar y tr a ct i nf e cti o n 
(3 % ).  Ot h er i m p ort a nt s eri o u s a d v er s e r e a cti o n s  r e p ort e d i n cl u de P M L , St e v e n s -J o h n s o n 
s y n dr o m e , a n d  t u m or l y si s s y n dr o m e. 


1 1  
 
D o s e m o difi c ati o n s  
A d v er s e r e a cti o n s t h at l e d t o d o s e d el a y s i n m or e t h a n 5 % of p ati e nt s w er e n e utr o p e ni a ( 1 4 %) 
a n d p eri p h er al s e n s or y n e ur o p at h y ( 1 1 %)  [ s e e D o s a g e a n d A d mi ni str ati o n  (2. 2 )]. 
Di s c o nti n u ati o n s  
A d v er s e r e a cti o n s l e d t o tr e at m e nt di s c o nti n u ati o n i n 2 1 % of p ati e nt s .  A d v er s e r e a cti o n s t h at 
l e d t o tr e at m e nt di s c o nti n u ati o n i n 2 or m or e p ati e nt s wit h H L or s A L C L  w er e p eri p h er al s e n s or y 
n e ur o p at h y ( 8 %)  a n d  p eri p h er al m ot or n e ur o p at h y ( 3 %).  
6. 2  
P o st M ar k eti n g E x p eri e n c e  
T h e f oll o wi n g a d v er s e r e a cti o n s h a v e b e e n i d e ntifi e d d uri n g p o st -a p pr o v al u s e of A D C E T RI S .  
B e c a u s e t h e s e r e a cti o n s ar e r e p ort e d v ol u nt aril y fr o m a p o p ul ati o n of u n c ert ai n si z e, it i s n ot 
al w a y s p o s si bl e t o r eli a bl y e sti m at e t h eir fr e q u e n c y or e st a bli s h a c a u s al r el ati o n s hi p t o dr u g 
e x p o s ur e .   
Bl o o d a n d l y m p h ati c s y st e m  di s or d er s : fe bril e n e utr o p e ni a [ s e e W ar ni n g s a n d Pr e c a uti o n s 
(5. 3 )]. 
H e p at o bili ar y di s or d er s : h e p at ot o xi cit y [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 8 )]. 
I nf e cti o ns : P M L  [ s e e B o x e d W ar ni n g , W ar ni n g s a n d Pr e c a uti o n s (5. 9 )], s eri o u s  i nf e cti o n s a n d 
o p p ort u ni sti c i nf e cti o n s  [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 4 )]. 
M et a b oli s m a n d n utriti o n  di s or d er s : h y p er gl y c e mi a. 
G a str oi nt e sti n al  di s or d er s : P a n cr e atiti s (i n cl u di n g f at al o ut c o m e s) .  C o n si d er t h e di a g n o si s of 
p a n cr e atiti s f or p ati e nt s pr e s e nti n g wit h  s e v er e a b d o mi n al p ai n.  
R e s pir at or y, t h or a ci c a n d m e di a sti n al di s or d er s : p ul m o n ar y t o xi cit y [ s e e W ar ni n g s a n d 
Pr e c a uti o n s ( 5. 1 0 )]. 
S ki n a n d s u b c ut a n e o u s ti s s u e di s or d er s : T o xi c e pi d er m al n e cr ol y si s, i n cl u di n g f at al o ut c o m e s 
[s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1 1 )]. 
6. 3  
I m m u n o g e ni cit y 
P ati e nt s wit h H L a n d s A L C L i n t h e ph a s e 2 tri al s [ s e e Cli ni c al St u di e s ( 1 4 )] w er e t e st e d f or 
a nti b o di e s t o br e nt u xi m a b v e d oti n e v er y 3 w e e k s u si n g a s e n siti v e el e ctr o c h e mil u mi n e s c e nt 
i m m u n o a s s a y.  A p pr o xi m at el y 7 % of p ati e nt s i n t h e s e tri al s d e v el o p e d p er si st e ntl y p o siti v e 
a nti b o di e s  (p o siti v e t e st at m or e t h a n 2 ti m e p oi nt s) a n d 3 0 % d e v el o p e d tr a n si e ntl y p o siti v e 
a nti b o di e s ( p o siti v e i n 1 or 2 p o st -b a s eli n e ti m e p oi nt s) .  T h e a nti -br e nt u xi m a b a nti b o di e s w er e 
dir e ct e d a g ai n st t h e a nti b o d y c o m p o n e nt of br e nt u xi m a b v e d oti n i n all p ati e nt s wit h tr a n si e ntl y 
or p er si st e ntl y p o siti v e a nti b o di e s .  T w o of t h e p ati e nt s ( 1 %) wit h p er si st e ntl y  p o siti v e a nti b o di e s 
e x p eri e n c e d a d v er s e r e a cti o n s c o n si st e nt wit h i nf u si o n r e a cti o n s t h at l e d t o di s c o nti n u ati o n of 
tr e at m e nt.  O v er all, a hi g h er i n ci d e n c e of i nf u si o n r el at e d r e a cti o n s w a s o b s er v e d i n p ati e nt s 
w h o  d e v el o p e d p er si st e ntl y p o siti v e a nti b o di e s.  


1 2  
 
A t ot al of 5 8 p ati e nt s a m pl e s t h at w er e eit h er tr a n si e ntl y or p er si st e ntl y p o siti v e f or a nti -
br e nt u xi m a b v e d oti n a nti b o di e s w er e t e st e d f or t h e pr e s e n c e of n e utr ali zi n g a nti b o di e s .  Si xt y -
t w o p er c e nt of t h e s e p ati e nt s h a d at l e a st o n e s a m pl e t h at w a s p o siti v e f or t h e pr e s e n c e of 
n e utr ali zi n g a nti b o di e s .  T h e eff e ct of a nti -br e nt u xi m a b v e d oti n a nti b o di e s  o n s af et y a n d effi c a c y 
i s n ot k n o w n. 
I m m u n o g e ni cit y a s s a y r e s ult s ar e hi g hl y d e p e n d e nt o n s e v er al f a ct or s i n cl u di n g a s s a y 
s e n siti vit y a n d s p e cifi cit y, a s s a y m et h o d ol o g y, s a m pl e h a n dli n g, ti mi n g of s a m pl e c oll e cti o n, 
c o n c o mit a nt m e di c ati o n s, a n d u n d erl yi n g di s e a s e .  F or t h e s e r e a s o n s, c o m p ari s o n of i n ci d e n c e 
of a nti b o di e s t o A D C E T RI S  wit h t h e i n ci d e n c e of a nti b o di e s t o ot h er pr o d u ct s m a y b e 
mi sl e a di n g.  
7 
D R U G I N T E R A C TI O N S  
I n vitr o d at a i n di c at e t h at m o n o m et h yl a uri st ati n E ( M M A E ) i s a s u b str at e a n d a n i n hi bit or of 
C Y P 3 A 4/ 5 .  I n vitr o d at a i n di c at e t h at M M A E i s al s o a s u b str at e of t h e effl u x tr a n s p ort er 
P- gl y c o pr ot ei n ( P -g p).  
7. 1  
Eff e ct of Ot h er Dr u g s o n A D C E T RI S  
C Y P 3 A 4 I n hi bit or s /I n d u c er s: M M A E i s pri m aril y m et a b oli z e d b y C Y P 3 A  [ s e e Cli ni c al 
P h ar m a c ol o g y (1 2. 3 )].  C o -a d mi ni str ati o n of A D C E T RI S  wit h k et o c o n a z ol e, a p ot e nt C Y P 3 A 4 
i n hi bit or, i n cr e a s e d e x p o s ur e t o M M A E b y a p pr o xi m at el y 3 4 % .  P ati e nt s w h o ar e r e c ei vi n g 
str o n g C Y P 3 A 4 i n hi bit or s c o n c o mit a ntl y wit h A D C E T RI S s h o ul d b e cl o s el y m o nit or e d f or 
a d v er s e r e a cti o n s .  C o -a d mi ni str ati o n of A D C E T RI S  wit h rif a m pi n, a p ot e nt C Y P 3 A 4 i n d u c er, 
r e d u c e d e x p o s ur e t o M M A E b y a p pr o xi m at el y 4 6%. 
P- g p I n hi bit or s:  C o -a d mi ni str ati o n of A D C E T RI S wit h P -g p i n hi bit or s m a y i n cr e a s e e x p o s ur e t o 
M M A E .  P ati e nt s w h o ar e r e c ei vi n g P -g p i n hi bit or s c o n c o mit a ntl y wit h A D C E T RI S s h o ul d b e 
cl o s el y m o nit or e d f or a d v er s e r e a cti o n s.  
7. 2  
Eff e ct of A D C E T RI S  o n Ot h er Dr u g s  
C o -a d mi ni str ati o n of A D C E T RI S  di d n ot aff e ct e x p o s ur e t o mi d a z ol a m, a C Y P 3 A 4 s u b str at e .  
M M A E  do e s n ot i n hi bit ot h er C Y P e n z y m e s at r el e v a nt cli ni c al c o n c e ntr ati o n s  [ s e e Cli ni c al 
P h ar m a c ol o g y (1 2. 3 )].  A D C E T RI S  i s n ot e x p e ct e d t o alt er t h e e x p o s ur e t o dr u g s t h at ar e 
m et a b oli z e d b y C Y P 3 A 4 e n z y m e s.  
8 
U S E I N S P E CI FI C P O P U L A TI O N S  
8. 1  
Pr e g n a n c y  
Pr e g n a n c y C at e g or y D [s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1 2 )]. 
Ri s k S u m m ar y  
T h er e ar e n o a d e q u at e a n d w ell -c o ntr oll e d st u di e s wit h A D C E T RI S i n pr e g n a nt w o m e n .  
H o w e v er, b a s e d o n it s m e c h a ni s m of a cti o n  a n d fi n di n g s  i n a ni m al s, A D C E T RI S  c a n  c a u s e f et al 
h ar m w h e n a d mi ni st er e d t o a pr e g n a nt w o m a n .  Br e nt u xi m a b v e d oti n c a u s e d e m br y o -f et al 
t o xi citi e s i n a ni m al s at m at er n al e x p o s ur e s t h at w er e si mil ar t o h u m a n e x p o s ur e s at t h e 


1 3  
 
r e c o m m e n d e d d o s e s f or p ati e nt s wit h H L a n d s A L C L .  If t hi s dr u g i s u s e d d uri n g pr e g n a n c y, or 
if t h e p ati e nt b e c o m e s pr e g n a nt w hil e r e c ei vi n g t hi s dr u g, t h e p ati e nt s h o ul d b e a p pris e d of t h e 
p ot e nti al h a z ar d t o t h e f et u s.  
A ni m al D at a  
I n a n e m br y o -f et al d e v el o p m e nt al  st u d y, pr e g n a nt r at s  r e c ei v e d 2 i ntr a v e n o u s d o s e s of 0. 3, 1, 3, 
or  1 0  m g/ k g br e nt u xi m a b v e d oti n d uri n g t h e p eri o d of or g a n o g e n e si s ( o n c e e a c h o n Pr e g n a n c y 
D a y s 6 a n d 1 3) .  Dr u g -i n d u c e d e m br y o-f et al t o xi citi e s w er e s e e n m ai nl y i n a ni m al s tr e at e d wit h 
3 a n d 1 0 m g/ k g of t h e dr u g a n d i n cl u d e d i n cr e a s e d e arl y r e s or pti o n ( ≥9 9 %), p o st -i m pl a nt ati o n 
l o s s ( ≥9 9 %), d e cr e a s e d n u m b er s of li v e f et u s e s, a n d e xt er n al m alf or m ati o n s (i. e., u m bili c al 
h er ni a s a n d m alr ot at e d hi n dli m b s) .  S y st e mi c  e x p o s ur e i n a ni m al s at t h e br e nt u xi m a b v e d oti n 
d o s e of 3  m g/ k g i s a p pr o xi m at el y t h e s a m e e x p o s ur e i n p ati e nt s wit h H L or  s A L C L w h o r e c ei v e d 
t h e r e c o m m e n d e d d o s e of 1. 8 m g/ k g e v e r y t hr e e w e e k s. 
8. 3  
N ur si n g M ot h er s  
It i s n ot k n o w n w h et h er br e nt u xi m a b v e d oti n i s e x cr et e d i n h u m a n mil k .  B e c a u s e m a n y dr u g s 
ar e e x cr et e d i n h u m a n mil k a n d b e c a u s e of t h e p ot e nti al f or s eri o u s a d v er s e r e a cti o n s i n 
n ur si n g i nf a nt s fr o m  A D C E T RI S  a d e ci si o n s h o ul d b e m a d e w h et h er t o di s c o nti n u e n ur si n g or t o 
di s c o nti n u e t h e dr u g, t a ki n g i nt o a c c o u nt t h e i m p ort a n c e of t h e dr u g t o t h e m ot h er. 
8. 4  
P e di atri c U s e  
T h e s af et y a n d eff e cti v e n e s s of A D C E T RI S h a v e n ot b e e n e st a bli s h e d i n t h e p e di atri c 
p o p ul ati o n .  Cli ni c al tri al s  of  A D C E T RI S  i n cl u d ed o nl y 9 p e di atri c p ati e nt s a n d t hi s n u m b er i s n ot 
s uffi ci e nt t o d et er mi n e w h et h er t h e y r e s p o n d diff er e ntl y t h a n a d ult p ati e nt s. 
8. 5  
G eri atri c U s e  
Cli ni c al tri al s of  A D C E T RI S  di d n ot i n cl u d e s uffi ci e nt n u m b er s of p ati e nt s a g e d 6 5 a n d o v er t o 
d et er mi n e w h et h er t h e y r e s p o n d diff er e ntl y fr o m y o u n g er p ati e nt s .  S af et y a n d effi c a c y h a v e n ot 
b e e n e st a bli s h e d . 
8. 6  
R e n al I m p air m e nt  
A v oi d t h e u s e of A D C E T RI S  i n p ati e nt s wit h s e v er e r e n al i m p air m e nt ( C L cr < 3 0 m L/ mi n) [ S e e 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 6 )]. 
T h e ki d n e y i s a r o ut e of e x cr eti o n f or m o n o m et h yl a uri st ati n E ( M M A E ).  T h e p h ar m a c o ki n eti c s 
a n d s af et y of br e nt u xi m a b v e d oti n a n d M M A E w er e e v al u at e d aft er t h e a d mi ni str ati o n of 
1. 2  m g/ k g  of A D C E T RI S t o p ati e nt s wit h mil d ( C L cr > 5 0 – 8 0 m L/ mi n; n = 4 ), m o d er at e  
(C L cr 3 0 – 5 0  m L/ mi n; n = 3 ) a n d s e v er e (C L cr < 3 0 m L/ mi n; n = 3) r e n al i m p air m e nt .  I n p ati e nt s 
wit h s e v er e r e n al i m p air m e nt, t h e r at e of Gr a d e 3 or w or s e a d v er s e e v e nt s w a s 3/ 3 ( 1 0 0 %) 
c o m p ar e d t o 3/ 8  ( 3 8 %) i n p ati e nt s wit h n or m al r e n al f u n cti o n.  A d diti o n all y, t h e A U C of M M A E 
( c o m p o n e nt of A D C E T RI S ) w a s a p pr o xi m at el y 2- f ol d hi g h er i n p ati e nt s wit h s e v er e r e n al 
i m p air m e nt c o m p ar e d t o p ati e nt s wit h n or m al r e n al f u n cti o n .  D u e t o hi g h er M M A E e x p o s ur e, 
≥Gr a d e 3 a d v er s e r e a cti o n s m a y b e m or e fr e q u e nt i n p ati e nt s wit h s e v er e r e n al i m p air m e nt 
c o m p ar e d t o p ati e nt s wit h n or m al r e n al f u n cti o n . 


1 4  
 
8. 7  
H e p ati c I m p air m e nt  
A v oi d t h e u s e of A D C E T RI S i n p ati e nt s wit h m o d er at e or  s e v er e h e p ati c  i m p air m e nt [S e e 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 7 )]. 
T h e li v er i s a r o ut e of cl e ar a n c e  f or M M A E.  T h e p h ar m a c o ki n eti c s a n d s af et y of br e nt u xi m a b 
v e d oti n a n d M M A E w er e e v al u at e d aft er t h e a d mi ni str ati o n of 1. 2 m g/ k g of A D C E T RI S t o 
p ati e nt s wit h mil d ( C hil d -P u g h A; n = 1), m o d er at e ( C hil d -P u g h B; n = 5) a n d s e v er e ( C hil d -P u g h 
C; n = 1) h e p ati c i m p air m e nt .  I n p ati e nt s wit h m o d er at e a n d  s e v er e h e p ati c i m p air m e nt, t h e r at e 
of ≥Gr a d e 3 a d v er s e r e a cti o n s w a s 6 / 6 ( 1 0 0 %) c o m p ar e d t o 3/ 8 ( 3 8 %) i n p atie nt s wit h n or m al 
h e p ati c f u n cti o n . A d diti o n all y, t h e A U C of  M M A E w a s a p pr o xi m at el y 2. 2- f ol d hi g h er  i n p ati e nt s 
wit h h e p ati c i m p air m e nt  c o m p ar e d t o p ati e nt s wit h n or m al h e p ati c f u n cti o n .   
1 0  O V E R D O S A G E  
T h er e i s n o k n o w n a nti d ot e f or o v er d o s a g e of A D C E T RI S .  I n c a s e of o v er d o s a g e, t h e p ati e nt 
s h o ul d b e cl o s el y m o nit or e d f or a d v er s e r e a cti o n s, p arti c ul arl y n e utr o p e ni a, an d  s u p p orti v e 
tr e at m e nt s h o ul d b e a d mi ni st er e d . 
1 1  D E S C RI P TI O N  
A D C E T RI S  ( br e nt u xi m a b v e d oti n) i s a C D 3 0 -dir e ct e d  a nti b o d y -dr u g c o nj u g at e  ( A D C) c o n si sti n g 
of t hr e e c o m p o n e nt s: 1) t h e c hi m eri c I g G 1  a nti b o d y c A C 1 0, s p e cifi c f or h u m a n C D 3 0, 2) t h e 
mi cr ot u b ul e di sr u pti n g a g e nt M M A E, a n d 3) a pr ot e a s e -cl e a v a bl e li n k er t h at c o v al e ntl y att a c h e s 
M M A E t o c A C 1 0.  
 
Br e nt u xi m a b v e d oti n h a s a n a p pr o xi m at e m ol e c ul ar w ei g ht of 1 5 3 k D a .  A p pr o xi m at el y 
4 m ol e c ul e s of M M A E ar e att a c h e d t o e a c h a nti b o d y m ol e c ul e .  Br e nt u xi m a b v e d oti n  i s 
pr o d u c e d b y c h e mi c al c o nj u g ati o n of t h e a nti b o d y a n d s m all m ol e c ul e c o m p o n e nt s .  T h e 
a nti b o d y i s pr o d u c e d b y m a m m ali a n ( C hi n e s e h a m st er o v ar y) c ell s, a n d t h e s m all m ol e c ul e 
c o m p o n e nt s ar e pr o d u c e d b y  c h e mi c al s y nt h e si s.  
A D C E T RI S  ( br e nt u xi m a b v e d oti n) f or I nj e cti o n i s s u p pli e d a s a st eril e, w hit e  t o off -w hit e , 
pr e s er v ati v e -fr e e l y o p hili z e d c a k e or p o w d er i n si n gl e-u s e vi al s .  F oll o wi n g r e c o n stit uti o n wit h 
1 0. 5 m L St eril e W at er f or I nj e cti o n, U S P, a s ol uti o n c o nt ai ni n g 5 m g/ m L br e nt u xi m a b v e d oti n i s 
pr o d u c e d .  T h e r e c o n stit ut e d pr o d u ct c o nt ai n s  7 0 m g/ m L tr e h al o s e di h y dr at e, 5. 6 m g/ m L 
s o di u m citr at e di h y dr at e, 0. 2 1 m g/ m L citri c a ci d m o n o h y dr at e, a n d 0. 2 0 m g/ m L p ol y s or b at e 8 0  
a n d w at er f or inj e cti o n .  T h e p H i s a p pr o xi m at el y 6. 6.  


1 5  
 
1 2  C LI NI C A L P H A R M A C O L O G Y 
1 2. 1  
M e c h a ni s m of  Acti o n  
Br e nt u xi m a b v e d oti n i s a n A D C.  T h e a nti b o d y i s a  c hi m eri c  I g G 1 dir e ct e d a g ai n st C D3 0 .  T h e 
s m all m ol e c ul e , MM A E, i s a mi cr ot u b ul e di sr u pti n g a g e nt .  M M A E i s c o v al e ntl y att a c h e d t o t h e 
a n ti b o d y vi a a li n k er.  N o n cli ni c al d at a s u g g e st t h at t h e a nti c a n c er a cti vit y of A D C E T RI S i s d u e 
t o t h e bi n di n g of t h e A D C t o C D 3 0 -e x pr e s si n g c ell s, f oll o w e d b y i nt er n ali z ati o n of t h e 
A D C -C D 3 0 c o m pl e x, a n d t h e r el e a s e of M M A E vi a pr ot e ol yti c cl e a v a g e .  Bi n di n g of M M A E  t o 
t u b uli n di sr u pt s t h e mi cr ot u b ul e n et w or k wit hi n t h e c ell, s u b s e q u e ntl y i n d u ci n g c ell c y cl e arr e st 
a n d a p o pt oti c d e at h of t h e c ell s.  
1 2. 2  
P h ar m a c o d y n a mi c s  
Q T/ Q T c Pr ol o n g ati o n P ot e nti al  
T h e eff e ct of br e nt u xi m a b v e d oti n ( 1. 8 m g/ k g) o n t h e Q T c i nt er v al w a s e v al u at e d i n a n  o p e n -
l a b el, si n gl e-ar m st u d y i n 4 6 e v al u a bl e p ati e nt s wit h C D 3 0 -e x pr e s si n g h e m at ol o gi c 
m ali g n a n ci e s .  A d mi ni str ati o n of br e nt u xi m a b v e d oti n d i d n ot pr ol o n g t h e m e a n Q T c i nt er v al 
> 1 0  m s fr o m b a s eli n e .  S m all i n cr e a s e s i n t h e m e a n Q T c i nt er v al ( < 1 0 m s) c a n n ot b e e x cl u d e d 
b e c a u s e t hi s st u d y di d n ot i n cl u d e a pl a c e b o ar m a n d a p o siti v e c o ntr ol ar m.  
1 2. 3  
P h ar m a c o ki n eti c s  
T h e p h ar m a c o ki n eti c s of br e nt u xi m a b v e d oti n  w er e e v al u at e d i n p h a s e 1 tri al s a n d i n a 
p o p ul ati o n p h ar m a c o ki n eti c a n al y si s of d at a fr o m 3 1 4 p ati e nt s .  T h e p h ar m a c o ki n eti c s of  t hr e e 
a n al yt e s w er e d et er mi n e d:  t h e A D C, M M A E, a n d t ot al a nti b o d y.  T ot al a nti b o d y h a d t h e gr e at e st 
e x p o s ur e a n d  h a d a si mil ar P K pr ofil e a s t h e A D C .  H e n c e, d at a o n t h e P K of t h e A D C a n d 
M M A E h a v e b e e n s u m m ari z e d.  
A b s or pti o n  
M a xi m u m c o n c e ntr ati o n s of A D C w er e t y pi c all y o b s er v e d cl o s e t o t h e e n d of i nf u si o n .  A 
m ulti e x p o n e nti al d e cli n e i n A D C  s er u m c o n c e ntr ati o n s w a s o b s er v e d wit h a t er mi n al h alf -lif e of 
a p pr o xi m at el y 4 t o 6 d a y s .  E x p o s ur e s w er e a p pr o xi m at el y d o s e pr o p orti o n al  fr o m 1. 2 t o 
2. 7  m g/ k g .  S t e a d y-st at e of t h e A D C w a s a c hi e v e d wit hi n 2 1 d a y s  wit h e v er y 3 -w e e k d o si n g of 
A D C E T RI S , c o n si st e nt wit h t h e t er mi n al h alf-lif e e sti m at e.  Mi ni m al t o n o a c c u m ul ati o n of A D C 
w a s o b s er v e d wit h m ulti pl e d o s e s at t h e e v er y 3- w e e k s c h e d ul e . 
T h e ti m e t o m a xi m u m c o n c e ntr ati o n  f or M M A E r a n g e d fr o m a p pr o xi m at el y 1 t o 3 d a y s.  Si mil ar 
t o t h e A D C, st e a d y -st at e of M M A E w a s a c hi e v e d wit hi n  2 1 d a y s wit h e v er y 3 w e e k d o si n g of 
A D C E T RI S .  M M A E e x p o s ur e s d e cr e a s e d wit h c o nti n u e d a d mi ni str ati o n  of A D C E T RI S  wit h 
a p pr o xi m at el y 5 0 % t o 8 0 % of t h e e x p o s ur e of t h e fir st d o s e b ei n g o b s er v e d at s u b s e q u e nt 
d o s e s.  
Di stri b uti o n  
I n vitr o, t h e bi n di n g of M M A E t o h u m a n pl a s m a pr ot ei n s r a n g e d fr o m 6 8 – 8 2 % .  M M A E i s n ot 
li k el y t o di s pl a c e or t o b e di s pl a c e d b y hi g hl y pr ot ei n-b o u n d dr u g s .  I n vitr o, M M A E w a s a 
s u b str at e of P -g p a n d w a s n ot a p ot e nt i n hi bit or of P -g p.  


1 6  
 
I n h u m a n s, t h e m e a n st e a d y st at e v ol u m e of di stri b uti o n w a s a p pr o xi m at el y 6 – 1 0  L f or A D C. 
M et a b oli s m  
I n vi v o d at a i n a ni m al s a n d h u m a n s s u g g e st t h at o nl y  a s m all fr a cti o n of M M A E r el e a s e d fr o m 
br e nt u xi m a b v e d oti n  i s m et a b oli z e d.  I n vitr o d at a i n di c at e t h at t h e M M A E m et a b oli s m t hat 
o c c ur s i s pri m aril y  vi a o xi d ati o n  b y C Y P 3 A 4/ 5 .  I n vitr o st u di e s u si n g h u m a n li v er mi cr o s o m e s  
i n di c at e t h at M M A E i n hi bit s C Y P 3 A 4/ 5 b ut n ot ot h er C Y P i s of or m s .  M M A E di d n ot i n d u c e a n y 
m aj or C Y P 4 5 0 e n z y m e s i n pri m ar y c ult ur e s of h u m a n h e p at o c yt e s.  
Eli mi n ati o n  
M M A E a p p e ar e d t o f oll o w m et a b olit e ki n eti c s, wit h t h e eli mi n ati o n of M M A E a p p e ari n g t o b e 
li mit e d b y it s r at e of r el e a s e fr o m A D C.  A n e x cr eti o n st u d y w a s u n d ert a k e n i n p ati e nt s w h o 
r e c ei v e d a d o s e of 1. 8 m g/ k g of A D C E T RI S .  A p pr o xi m at el y 2 4 % of t h e t ot al M M A E 
a d mi ni st er e d a s p art of t h e A D C  d uri n g a n  A D C E T RI S  i nf u si o n w a s r e c o v er e d i n b ot h uri n e a n d 
f e c e s o v er a 1-w e e k p eri o d .  Of t h e r e c o v er e d M M A E, a p pr o xi m at el y 7 2 % w a s r e c o v er e d i n t h e 
f e c e s a n d t h e m aj orit y of  t h e e x cr et e d M M A E w a s  u n c h a n g e d.  
S p e cifi c P o p ul ati o n s  
R e n al I m p air m e nt :  [s e e U s e i n S p e cifi c P o p ul ati o n s  (8. 6 )]. 
H e p ati c I m p air m e nt :  [s e e U s e i n S p e cifi c P o p ul ati o n s  (8. 7 )]. 
Eff e ct s of G e n d er, A g e , a n d  R a c e :  B a s e d o n t h e p o p ul ati o n p h ar m a c o ki n eti c a n al y si s ; 
g e n d er, a g e , a n d r a c e d o n ot h a v e a m e a ni n gf ul eff e ct o n t h e p h ar m a c o ki n eti c s  of 
br e nt u xi m a b v e d oti n . 
1 3  N O N C LI NI C A L T O XI C O L O G Y  
1 3. 1  
C ar ci n o g e n e si s, M ut a g e n e si s, I m p air m e nt of F ertilit y  
C ar ci n o g e ni cit y st u di e s wit h br e nt u xi m a b v e d oti n  or t h e s m all m ol e c ul e (M M A E ) h a v e n ot b e e n 
c o n d u ct e d.  
M M A E w a s g e n ot o xi c  i n t h e r at b o n e m arr o w mi cr o n u cl e u s st u d y t hr o u g h a n a n e u g e ni c 
m e c h a ni s m .  T h i s eff e ct i s c o n si st e nt wit h t h e p h ar m a c ol o gi c al eff e ct of M M A E a s a mi cr ot u b ul e 
di s r u pti n g a g e nt.  M M A E w a s n ot m ut a g e ni c i n t h e b a ct eri al r e v er s e m ut ati o n a s s a y ( A m e s t e st) 
or t h e L 5 1 7 8 Y m o u s e l y m p h o m a f or w ar d m ut ati o n a s s a y.  
F ertilit y  st u di e s wit h br e nt u xi m a b v e d ot i n or M M A E h a v e n ot b e e n c o n d u ct e d .  H o w e v er, r e s ult s 
of r e p e at -d o s e t o xi cit y st u di e s i n r ats i n di c at e t h e p ot e nti al f or br e nt u xi m a b v e d oti n  t o i m p air 
m al e r e pr o d u cti v e f u n cti o n a n d f ertilit y .  In a 4- w e e k  r e p e at-d o s e t o xi cit y st u d y i n r ats wit h 
w e e k l y d o s i n g at 0. 5,  5, or  1 0  m g/ k g  br e nt u xi m a b v e d oti n, s e mi nif er o u s t u b ul e d e g e n er ati o n, 
S ert oli c ell v a c u ol ati o n, r e d u c e d s p er m at o g e n e si s , a n d a s p er mi a w er e o b s er v e d .  Eff e ct s i n 
a ni m al s w er e s e e n m ai nl y at 5 a n d 1 0  m g/ k g of br e nt u xi m a b v e d oti n .  T h e s e d o s e s ar e 
a p pr o xi m at el y 3 a n d 6 -f ol d t h e h u m a n r e c o m m e n d e d d o s e of 1. 8 m g/ k g, r e s p e cti v el y, b a s e d o n 
b o d y w ei g ht.  


1 7  
 
1 4  C LI NI C A L S T U DI E S  
1 4. 1  
H o d g ki n L y m p h o m a  
T h e effi c a c y of A D C E T RI S  i n p ati e nt s wit h H L w h o r el a p s ed aft er a ut ol o g o u s st e m c ell 
tr a n s pl a nt w a s e v al u at e d i n o n e o p e n -l a b el, si n gl e-ar m, m ulti c e nt er tri al.  O n e h u n dr e d t w o 
p ati e nt s w er e tr e at e d wit h 1. 8 m g/ k g of A D C E T RI S  i ntr a v e n o u sl y o v er 3 0 mi n ut e s e v er y 
3 w e e k s .  A n i n d e p e n d e nt r e vi e w f a cilit y p erf or m e d effi c a c y e v al u ati o n s w hi c h i n cl u d e d o v er all 
r e s p o n s e r at e (O R R = c o m pl et e r e mi s si o n  [ C R] + p arti al r e mi s si o n  [ P R]) a n d d ur ati o n of 
r e s p o n s e a s d efi n e d b y cli ni c al a n d r a di o gr a p hi c m e a s ur e s i n cl u di n g c o m p ut e d t o m o gr a p h y 
( C T) a n d p o sitr o n-e mi s si o n t o m o gr a p h y ( P E T) a s d efi n e d i n t h e 2 0 0 7 R e vi s e d R e s p o n s e 
Crit eri a f or M ali g n a nt L y m p h o m a ( m o difi e d ). 
T h e 1 0 2  p ati e nt s r a n g e d i n a g e fr o m 1 5 – 7 7 y e ar s ( m e di a n, 3 1 y e ar s) a n d m o st w er e f e m al e 
( 5 3 %) a n d w hit e ( 8 7 %).  P ati e nt s h a d r e c ei v e d a m e di a n of 5 pri or t h er a pi e s  i n cl u di n g 
a ut ol o g o u s st e m c ell tr a n s pl a nt . 
T h e effi c a c y r e s ul t s ar e s u m m ari z e d i n T a bl e  3.  D ur ati o n of r e s p o n s e i s c al c ul at e d fr o m d at e of  
fir st r e s p o n s e t o d at e of pr o gr e s si o n or d at a c ut off d at e.  
T a bl e  3: 
Effi c a c y R e s ult s i n P ati e nt s w it h H o d g ki n L y m p h o m a  
 
N = 1 0 2  
P er c e nt ( 9 5 % CI)  
D ur ati o n of R e s p o n s e, i n m o nt h s  
M e di a n ( 9 5 % CI)  
R a n g e  
C R  
3 2 ( 2 3, 4 2)  
2 0. 5 ( 1 2. 0, N E*)  
1. 4 t o 2 1. 9 +  
P R  
4 0 ( 3 2, 4 9)  
3. 5 ( 2. 2, 4. 1)  
1. 3 t o 1 8. 7  
O R R  
7 3 ( 6 5, 8 3)  
6. 7 ( 4. 0, 1 4. 8)  
1. 3 t o 2 1. 9 +  
*N ot e sti m a bl e  
+ F oll o w u p w a s o n g oi n g at t h e ti m e of d at a s u b mi s si o n.  
1 4. 2  
S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
T h e effi c a c y of A D C E T RI S  i n p ati e nt s wit h r el a p s e d s A L C L w a s  e v al u at e d i n o n e p h a s e 2  o p e n -
l a b el, si n gl e-ar m, m ulti c e nt er tri al.  T hi s tri al i n cl u d e d p ati e nt s w h o h a d s A L C L  t h at w a s r el a p s e d 
aft er pri or t h er a p y .  Fift y -ei g ht  p ati e nt s w er e tr e at e d wit h 1. 8 m g/ k g of A D C E T RI S  a d mi ni st er e d 
i ntr a v e n o u sl y o v er 3 0 mi nut e s  e v er y 3 w e e k s .  A n i n d e p e n d e nt r e vi e w f a cilit y p erf or m e d effi c a c y 
e v al u ati o n s w hi c h  i n cl u d e d o v er all r e s p o n s e r at e (O R R = c o m pl et e r e mi s si o n  [ C R] + p arti al 
r e mi s si o n [ P R]) a n d d ur ati o n of r e s p o n s e a s d efi n e d b y cli ni c al a n d r a di o gr a p hi c m e a s ur e s 
i n cl u di n g c o m p ut e d t o m o gr a p h y ( C T ) a n d p o sitr o n -e mi s si o n t o m o gr a p h y ( P E T) a s d efi n e d i n 
t h e 2 0 0 7 R e vi s e d R e s p o n s e Crit eri a f or M ali g n a nt L y m p h o m a ( m o difi e d ). 
T h e 5 8 p ati e nt s r a n g e d i n a g e fr o m 1 4 – 7 6  y e ar s ( m e di a n , 5 2  y e ar s) a n d m o st w er e m al e ( 5 7 %) 
a n d w hit e  (8 3 %) .  P ati e nt s h a d r e c ei v e d a m e di a n of 2 pri or t h er a pi e s ; 2 6 % of p ati e nt s h a d 
r e c ei v e d pri or a ut ol o g o u s st e m c ell tr a n s pl a nt .  Fift y p er c e nt ( 5 0 %) of p ati e nt s w er e r el a p s e d 
a n d 5 0 % of p ati e nt s w er e r efr a ct or y t o t h eir m o st r e c e nt pri or t h er a p y .  S e v e nt y -t w o p er c e nt 
( 7 2 %) w er e a n a pl a sti c l y m p h o m a ki n a s e ( A L K )-n e g ati v e.  


1 8  
 
T h e eff i c a c y r e s ult s ar e s u m m ari z e d i n T a bl e  4.  D ur ati o n of r e s p o n s e i s c al c ul at e d fr o m d at e of 
fir st r e s p o n s e t o d at e of pr o gr e s si o n or d at a c ut off d at e.  
T a bl e  4: 
Effi c a c y R e s ult s i n P ati e nt s w it h S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
 
N = 5 8  
P er c e nt ( 9 5 % CI)  
D ur ati o n of R e s p o n s e, i n m o nt h s  
M e di a n ( 9 5 % CI)  
R a n g e  
C R  
5 7 ( 4 4, 7 0)  
1 3. 2 ( 1 0. 8, N E*)  
0. 7 t o 1 5. 9 +  
P R  
2 9 ( 1 8, 4 1)  
2. 1 ( 1. 3, 5. 7)  
0. 1 t o 1 5. 8 +  
O R R  
8 6 ( 7 7, 9 5)  
1 2. 6 ( 5. 7 , N E* ) 
0. 1 t o 1 5. 9 +  
*N ot e sti m a bl e  
+ F oll o w u p w a s o n g oi n g at t h e ti m e of d at a s u b mi s si o n.  
1 5  R E F E R E N C E S  
1.    O S H A H a z ar d o u s Dr u g s .  O S H A .  [ A c c e s s e d o n 3 0 J ul y  2 0 1 3, fr o m  
htt p:// w w w. o s h a. g o v/ S L T C/ h a z ar d o u s dr u g s/i n d e x . ht ml] 
1 6  H O W S U P P LI E D/ S T O R A G E  A N D H A N D LI N G  
1 6. 1  
H o w S u p pli e d  
A D C E T RI S  ( br e nt u xi m a b v e d oti n) f or I nj e cti o n i s s u p pli e d a s a st eril e, w hit e t o off -w hit e 
pr e s er v ati v e -fr e e l y o p hili z e d c a k e or p o w d er i n i n di vi d u all y -b o x e d si n gl e -u s e vi al s:  
• 
N D C ( 5 1 1 4 4-0 5 0 -0 1), 5 0 m g br e nt u xi m a b v e d oti n.  
1 6. 2  
St or a g e  
St or e vi al at 2 – 8° C ( 3 6– 4 6° F) i n t h e ori gi n al c art o n  t o pr ot e ct fr o m li g ht. 
1 6. 3  
S p e ci al H a n dli n g  
A D C E T RI S  i s a n a nti n e o pl a sti c pr o d u ct.  F oll o w  s p e ci al h a n dli n g a n d di s p o s a l pr o c e d ur e s 1 . 
1 7  P A TI E N T C O U N S E LI N G  I N F O R M A TI O N 
• P eri p h er al n e ur o p at h y  
A d vi s e p ati e nt s t h at A D C E T RI S c a n c a u s e a p eri p h er al n e ur o p at h y .  T h e y s h o ul d b e a d vi s e d t o 
r e p ort t o t h eir h e alt h c ar e pr o vi d er a n y n u m b n e s s or ti n gli n g of t h e h a n d s or f e et or a n y m u s cl e 
w e a k n e s s [ s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 1 )]. 
• F e v er/ N e utr o p e ni a 
A d vi s e p ati e nt s t o c o nt a ct t h eir h e alt h c ar e pr o vi d er  if a f e v er of 1 0 0. 5° F or gr e at er or ot h er 
e vi d e n c e of p ot e nti al i nf e cti o n s u c h a s c hill s, c o u g h, or p ai n o n uri n ati o n d e v el o p s [ s e e 
W ar ni n g s a n d Pr e c a uti o n s ( 5. 3 )]. 


1 9  
 
• I nf u si o n r e a cti o n s 
A d vi s e p ati e nt s  t o c o nt a ct t h eir h e alt h c ar e pr o vi d er  if t h e y e x p eri e n c e si g n s a n d s y m pt o m s of 
i nf u si o n r e a cti o n s i n cl u di n g f e v er, c hill s, r a s h, or br e at hi n g pr o bl e m s wit hi n 2 4 h o ur s of i nf u si o n 
[ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 2 )]. 
• H e p at ot o xi cit y 
A d vi s e p ati e nt s t o r e p ort s y m pt o m s t h at m a y i n di c at e li v er i nj ur y, i n cl u di n g f ati g u e, a n or e xi a, 
ri g ht u p p er a b d o mi n al di s c o mf ort, d ar k uri n e, or j a u n di c e  [s e e W ar ni n g s a n d Pr e c a uti o n s ( 5. 8 )]. 
• Pr o gr e s si v e m ultif o c al l e u k o e n c e p h al o p at h y  
I n str u ct p ati e nt s r e c ei vi n g A D C E T RI S t o i m m e di at el y r e p ort if t h e y h a v e a n y of t h e f oll o wi n g 
n e ur ol o gi c al, c o g niti v e, or b e h a vi or al si g n s a n d s y m pt o m s or if a n y o n e cl o s e t o t h e m n oti c e s 
t h e s e si g n s a n d s y m pt o m s [ s e e B o x e d W ar ni n g , W ar ni n g s a n d Pr e c a uti o n s ( 5. 9 )]: 
• c h a n g e s i n m o o d or u s u al b e h a vi or 
• c o nf u si o n, t hi n ki n g pr o bl e m s , l o s s of m e m or y 
• c h a n g e s i n vi si o n, s p e e c h, or w al ki n g  
• d e cr e a s e d str e n gt h or w e a k n e s s o n o n e si d e of t h e b o d y 
• P ul m o n ar y T o xi cit y  
I n str u ct p ati e nt s t o r e p ort s y m pt o m s t h at m a y i n di c at e p ul m o n ar y t o xi cit y, i n cl u di n g c o u g h or 
s h ort n e s s of br e at h [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 1 0 )]. 
• P a n cr e atiti s 
A d vi s e  p ati e nt s t o c o nt a ct t h eir h e alt h c ar e pr o vi d er if t h e y d e v el o p s e v er e a b d o mi n al p ai n [ s e e 
A d v er s e R e a cti o n s ( 6. 2 )]. 
• Pr e g n a n c y a n d N ur si n g  
A D C E T R I S c a n c a u s e f et al h ar m .  A d vi s e w o m e n r e c ei vi n g A D C E T RI S t o a v oi d pr e g n a n c y .  
A d vi s e p ati e nt s t o r e p ort pr e g n a n c y i m m e di at el y [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 1 2 )].  A d vi s e  
p ati e nt s t o a v oi d n ur si n g w hil e r e c ei vi n g A D C E T RI S  [ s e e U s e i n S p e cifi c P o p ul ati o n s (8. 1 , 8. 3 )]. 
 
 
M a n uf a ct ur e d b y : 
S e attl e G e n eti c s, I n c.  
B ot h ell, W A 9 8 0 2 1  
1- 8 5 5 -4 7 3 -2 4 3 6  
U. S .  Li c e n s e 1 8 5 3  
 
A D C E T RI S , S e attl e G e n eti c s a n d   
 ar e U S r e gi st er e d tr a d e m ar k s of S e attl e G e n eti c s, I n c. 


 
Pr ot oc ol # 1 5- 1 9 6: Drafte d ( 5/ 7/ 1 5) ( K P)/ R ( 2/ 2 3/ 1 6) ( K L P)/ R ( 4/ 2 5/ 1 7) ( R G H)/ A p pr o ve d ( 4/ 2 7/ 1 7) ( K C) 
 
D A N A- F A R B E R C A N C E R I N S TI T U T E 
N ur si n g Pr ot o c ol E d u c ati o n S h e et 
Pr ot o c ol N u m b er:  
1 5- 1 9 6  
Pr ot o c ol N a m e:  
P h a s e II Br e nt u xi m a b V e d oti n Pl u s A D i n N o n- B ul k y Li mit e d St a g e H o d g ki n L y m p h o m a 
D F CI Sit e PI: 
A n n L a C a s e  
D F CI R e s e ar c h N ur s e: 
R e b e c c a G u y- H a milt o n, K ar e n Fr a n c o e ur, Vi ct ori a P att er s o n, K at hl e e n M c D er m ott, Ki m b erl y 
C ol e m a n 
P a g e t h e D F CI r e s e ar c h n ur s e or D F CI sit e PI if t h er e ar e a n y q u e sti o n s/ c o n c er n s a b o ut t h e pr ot o c ol.   
Pl e a s e al s o r ef er t o O N C 1 5 : O n c ol o g y N ur si n g Pr ot o c ol E d u c ati o n P oli c y 
*** R e m e m b er t o c h e c k t h e A L E R T P A G E*** 
              S P E CI A L N U R SI N G C O N SI D E R A TI O N S U NI Q U E T O T HI S P R O T O C O L 
St u d y 
A g e nt 
 
  
Br e nt u xi m a b v e d oti n i s a n a nti- C D 3 0 a nti b o d y- dr u g c o nju g at e ( A D C) c o n si sti n g of a c hi m eri c m o n o cl o n al 
a nti b o d y, a n a nti mi cr ot u b ul ar a g e nt, a n d a pr ot e a s e cl e a v a bl e li n k er ( S e cti o n 2. 1. 1 a n d 7. 1) 
  
A dri a m y ci n i s a n a nt hr a c y cli n e a nti bi oti c ( S e cti o n 7. 2) 
  
D a c ar b a zi n e i s a n al k yl ati n g a g e nt ( S e cti o n 7. 3) 
  
A c y cl e i s d efi n e d a s 2 8 d a y s ( S e cti o n 1. 1) 
D o s e C al c. 
  
Br e nt u xi m a b i s d o s e d i n m g/ k g ( S e cti o n 5) 
  
A dri a m y ci n a n d D a c ar b a zi n e ar e d o s e d i n m g/ m2 ( S e cti o n 5) 
  
Br e nt u xi m a b d o si n g s h o ul d b e b a s e d o n t h e p arti ci p a nt’ s pr e- d o s e w ei g ht d et er mi n e d at d a y 1 vi sit of e a c h 
c y cl e. D o s e m a y b e r e- c al c ul at e d b a s e d o n w ei g ht o n d a y 1 5 if t h at i s c o n si st e nt wit h t h e i n stit uti o n al st a n d ar d 
of c ar e ( S e cti o n 7. 1. 7) 
  
A dri a m y ci n a n d D a c ar b a zi n e u s e a ct u al w ei g ht t o c al c ul at e B S A a n d d o s e s ( S e cti o n s 7. 2 a n d 7. 3).  
  
B S A will b e c al c ul at e d wit h t h e D u b oi s f or m ul a, or alt ern at e f or m ul a p er i n stit uti o n al  st a n d ar d ( Fo ot n ot e J St u d y 
C al e n d ar of E v e nt s) 
St u d y Dr u g  
A d mi ni str ati o n 
A g e nt A d mi ni str ati o n  G ui d eli n e s ar e f o u n d i n ( S e cti o n s 5, 6, a n d 7)  
  
All a g e nt s a d mi ni st er e d i ntr a v e n o u sl y o n d a y s 1 a n d 1 5 of e a c h 2 8- d a y c y cl e ( S e cti o n 5) 
 
O n tr e at m e nt d a y s, p arti ci p a nt s will r e c ei v e br e nt u xi m a b f oll o w e d b y A dri a m y ci n a n d D a c ar b a zi n e ( S e cti o n 5) 
 
Br e nt u xi m a b will b e a d mi ni st er e d o v er 3 0 mi n ut e s. N ot e t h e dr u g m a y b e gi v e n at sl o w er i nf u si o n at t h e 
di s cr eti o n of t h e tr e at m e nt t e a m i n t h e s etti n g of pri or h y p er s e n siti vit y r e a cti o n s, c o n si st e nt wit h i n stit uti o n al 
st a n d ar d s ( S e cti o n 7. 1. 7) 
 
A dri a m y ci n a n d d a c ar b a zi n e will b e a d mi ni st er e d vi a i n stit uti o n al st a n d ar d s ( S e cti o n 5)  
  
M a n a g e m e nt of i nf u si o n r el at e d r e a cti o n s a n d pr e m e d s f or s u b s e q u e nt c y cl e s ar e f o u n d i n ( S e cti o n 6. 2. 8)  
 
D o s e  
M o d s & 
T o xi cit y 
Crit eri a t o Tr e at, D o s e M o difi c ati o n s/ D o si n g D el a y f or T o xi cit y  ar e o utli n e d i n ( S e cti o n 6) 
  
T hi s pr ot o c ol u s e s N CI C T C A E crit eri a, v er si o n 4. 0 ( S e cti o n 6) 
  
T o xi cit y m a n a g e m e nt a n d D o s e D el a y’ s/ M o difi c ati o n s c a n b e f o u n d i n ( S e cti o n 6. 2) 
C o n 
M e d s 
C o n c o mit a nt T h er a p y  G ui d eli n e s ar e i n ( S e cti o n 5. 1) 
  
Pl e a s e r e vi e w t h e cit e d s e cti o n s f or p er mitt e d, pr o hi bit e d, a n d “ u s e wit h c a uti o n” m e di c ati o n s/t h er a pi e s/f o o d s 
R e q uir e d  
D at a  
St u d y C al e n d ar a n d A s s e s s m e nt R e q uir e d d at a  ar e o utli n e d i n ( S e cti o n 8 a n d St u d y C al e n d ar of E v e nt s) 
 
Vit al si g n s:  T h e ti m e p oi nt s ar e f o u n d i n ( S e cti o n 8 a n d St u d y C al e n d ar of E v e nt s) 
 
E K G s :  E K G b a s eli n e d uri n g s cr e e ni n g ( S e cti o n 8. 1 a n d St u d y C al e n d ar of E v e nt s)  
 
N e ur o p at h y A s s e s s m e nt s: Ar e f o u n d i n  ( S e cti o n 8 a n d St u d y C al e n d ar of E v e nt s)  
Ti p s 
All st u d y dr u g s r e q uir e d o c u m e nt at i o n of e x a ct a d mi ni str ati o n ti m e. 
 
 
 


3 
 
F U L L P R E S C RI BI N G I N F O R M A TI O N  
 
1 
I N DI C A TI O N S A N D U S A GE 
1. 1  
H o d g ki n L y m p h o m a  
A D C E T RI S  ( br e nt u xi m a b v e d oti n) i s i n di c at e d f or tr e at m e nt of p ati e nt s wit h H o d g ki n l y m p h o m a 
( H L) aft er f ail ur e of a ut ol o g o u s st e m c ell tr a n s pl a nt ( A S C T) or  aft er  f ail ur e of at l e a st t w o pri or 
m ulti -a g e nt c h e m ot h er a p y r e gi m e n s  i n p ati e nt s w h o ar e n ot A S C T c a n di d at e s. 
T hi s i n di c ati o n i s a p pr o v e d u n d er a c c el er at e d a p pr o v al b a s e d o n o v er all r e s p o n s e r at e  [ s e e 
Cli ni c al St u di e s ( 1 4. 1 )].  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or s ur vi v al h a s n ot b e e n 
e st a bli s h e d .  C o nti n u e d a p pr o v al f or t hi s i n di c a ti o n m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d 
d e s cri pti o n of cli ni c al b e n efit i n c o nfir m at or y tri al s.  
1. 2  
S y st e mi c A n a pl a sti c L ar g e C ell L y m p h o m a  
A D C E T RI S  i s i n di c at e d f or tr e at m e nt of p ati e nt s wit h s y st e mi c a n a pl a sti c l ar g e c ell l y m p h o m a  
( sA L C L)  aft er f ail ur e of at l e a st o n e pri or m ulti -a g e nt c h e m ot h er a p y r e gi m e n . 
T hi s i n di c ati o n i s a p pr o v e d u n d er a c c el er at e d a p pr o v al b a s e d o n o v er all r e s p o n s e r at e  [ s e e 
Cli ni c al St u di e s ( 1 4. 2 )].  A n i m pr o v e m e nt i n p ati e nt -r e p ort e d o ut c o m e s or s ur vi v al h a s n ot b e e n 
e st a bli s h e d .  C o nti n u e d a p pr o v al f or t hi s i n di c ati o n m a y b e c o nti n g e nt u p o n v erifi c ati o n a n d 
d e s cri pti o n of cli ni c al b e n efit i n c o nfir m at or y tri al s.  
2 
D O S A G E A N D A D MI NI S T R A TI O N  
2. 1  
D o s a g e R e c o m m e n d ati o n s  
A d mi ni st er A D C E T RI S  a s a n i ntr a v e n o u s i nf u si o n o v er 3 0  mi n ut e s e v er y 3 w e e k s  u ntil di s e a s e 
pr o gr e s si o n or u n a c c e pt a bl e t o xi cit y .  S e e T a bl e  1 f or t h e r e c o m m e n d e d st arti n g d o s a g e. 
T a bl e  1: 
R e c o m m e n d e d A D C E T RI S D o s a g e  
 
R e c o m m e n d e d St arti n g D o s a g e  
N or m al r e n al a n d h e p ati c f u n cti o n  
1. 8 m g/ k g u p t o 1 8 0 m g  
R e n al i m p air m e nt  
Mil d ( cr e ati ni n e cl e ar a n c e > 5 0 – 8 0 m L/ mi n) or 
m o d er at e ( cr e ati ni n e cl e ar a n c e  3 0 – 5 0 m L/ mi n ) 
1. 8 m g/ k g u p t o 1 8 0 m g  
S e v er e ( c r e ati ni n e c l e ar a n c e l e s s t h a n 3 0 m L/ mi n ) 
A v oi d u s e  
[ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 6 )] 
H e p ati c i m p air m e nt  
Mil d ( C hil d -P u g h A)  
1. 2 m g/ k g u p t o 1 2 0 m g  
M o d er at e ( C hil d -P u g h B) or s e v er e ( C hil d -P u g h C)  
A v oi d u s e  
[ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 7 )] 
W A R NI N G: P R O G R E S SI V E  M U L TI F O C A L L E U K O E N C E P H A L O P A T H Y ( P M L) 
 
J C vir u s i nf e cti o n r e s ulti n g i n P M L a n d d e at h c a n o c c ur i n p ati e nt s r e c ei vi n g 
A D C E T RI S [ s e e W ar ni n g s a n d Pr e c a uti o n s (5. 9 ), A d v er s e R e a cti o n s ( 6. 1 )].