Brentuximab Vedotin Plus AD in Non-bulky Limited Stage Hodgkin Lymphoma
Phase: PHASE2
Conditions: Hodgkin Lymphoma
Sponsor: Massachusetts General Hospital



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 )].