Brentuximab Vedotin With Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (BV-CHEP) for the Treatment of Adult T-Cell Leukemia/Lymphoma: A Pilot Study of the Rare Lymphoma Working Group
Phase: PHASE2
Conditions: Lymphoma, Adult T-Cell Leukemia/Lymphoma, Lymphatic Diseases
Sponsor: UNC Lineberger Comprehensive Cancer Center

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
S U M M A R Y O F C H A N G E S  
Pr ot oc ol A me n d me nt # 9  
L C C C 1 6 3 7:  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y of t he R are L y m p h o m a W or ki n g Gr o u p  
A M E N D M E N T I N C O R P O R A T E S:  
_ X   E dit orial, a d mi nistrati ve c ha n ges  
_ _  Scie ntific c ha n ges  
_ _  T hera p y c ha n ges  
_ _   Eli gi bilit y C ha n ges  
R ati o n ale f or a me n d me nt: T h is a me n d me nt clarifies a c ha n ge i n t he f u n di n g 
s o urce fr o m Sea ge n t o Pfizer a n d pr o vi des a n u p date i n  safet y re p orti n g la n g ua ge.  
E dit ori al, a d mi nistr ati ve c h a n ges:  
1.
T he f u n di n g s o urce o n t he title pa ge was c ha n ge d fr o m Sea ge n t o Pfizer.
2.
Secti o n 5: All la n g ua ge pertai ni n g t o Sea ge n as t he pr o vi der of bre nt u xi maa b
ve d oti n was re place d wit h Pfizer.
3.
Secti o n 7. 3. 3: Safet y re p orti n g i nf or mati o n was u p date d t o a p pr o priate Pfizer
c o ntacts f or a d verse e ve nts.
T H E A T T A C H E D V E R SI O N D A T E D J u ly 1 2 , 2 0 2 4 I N C O R P O R A T E S T H E 
A B O V E R E VI SI O N S   

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
 
 
L C C C 1 6 3 7:  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S (c hec k all t h at a p pl y):  
X  E dit orial, a d mi nistrati ve c ha n ges  
X  Scie ntific c ha n ges (I R B a p pr o val)  
    T hera p y c ha n ges (I R B a p pr o val)  
    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
T he p ur p ose of t his a me n d me nt is t o re m o ve c orrelati ve st u dies a n d ass ociate d bl o o d 
s peci me n c ollecti o ns d ue t o t he de part ure of Da vi d Wei nst oc k at D F CI fr o m t he st u d y 
tea m. We ha ve als o e x pa n de d t he t y pe of sca ns t hat are acce pta ble f or scree ni n g fr o m j ust 
P E T/ C T t o C T C A P  i n sit uati o ns t hat w o ul d affect s u bject safet y. T his c ha n ge will 
s u p p ort accr uals w hile all o wi n g f or sta gi n g a n d assess me nts. 
 
E dit ori al, a d mi nistr ati ve C h a n ges:  
1.  C T C A P a d de d t o t he a b bre viati o ns list .  
 
Scie ntific  C h a n ges:  
1.  Secti o n 1. 7 C orrelati ve St u dies  was delete d .  
2.  Secti o n 2. 3. 2 descri bi n g A T L L xe n o grafts was delete d.  
3.  Secti o n 6. 1 Ti me a n d E ve nts ta ble,  
a. R o w wit h Bl o o d f or c orrelati ve st u dies  was re m o ve d fr o m t he ta ble.  
b.  F o ot n ote s 1 9 a n d 2 0 were re m o ve d.  
c. C o nte nt i n F o ot n ote 4 was a dj uste d t o i ncl u de t he acce pta bilit y of C T C A P i n 
sit uati o ns t hat w o ul d affect patie nt safet y. 
4.  C o nte nt i n Secti o n 6. 3 a n d 6. 4. 1 relate d t o t he c ollecti o n of bl o o d f or c orrelati ve st u dies 
was delete d.  
5.  C o nte nt i n Secti o n 6. 3  was a dj uste d t o i ncl u de t he use  of C T C A P f or scree ni n g i n 
sit uati o ns t hat w o ul d affect patie nt safet y. 
6.  C o nte nt i n Secti o n 6. 7  descri bi n g t he de vel o p me nt of A T L L xe n o graft m o dels i n t he 
Wei nst oc k la b at D F CI was re m o ve d.  
a. Secti o n 6. 7. 1 descri bi n g t he ha n dli n g a n d st ora ge of bi os peci me ns was delete d.  
 
T H E A T T A C H E D V E R SI O N D A T E D M arc h 9, 2 0 2 2 , I N C O R P O R A T E S T H E 
A B O V E R E VI SI O N S  
 
P R O T O C O L A M E N D M E N T # 8  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
 
P R O T O C O L A M E N D M E N T # 7  
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
X   E dit orial, a d mi nistrati ve c ha n ges  
X  Scie ntific c ha n ges (I R B a p pr o val)  
    T hera p y c ha n ges (I R B a p pr o val)  
    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he p ur p ose of t his a me n d me nt is t o all o w f or s u bjects t o be e val ua ble as earl y as after 
t he 2 n d c ycle of B V-C H E P if t he y are eli gi ble t o pr ocee d t o a  ste m cell tra ns pla nt. T his 
als o i ncl u des a c ha n ge i n t he E n d of Treat me nt visit occ urri n g after treat me nt 
disc o nti n uati o n. Pre vi o usl y, t he e n d of treat me nt visit w o ul d occ ur 3 0 da ys ( ± o ne wee k), 
f oll o wi n g disc o nti n uati o n of st u d y t hera p y. T he e n d of treat me nt visit s h o ul d occ ur 2 1 
da ys ( ± o ne wee k) after disc o nti n uati o n of st u d y t hera p y.  It is clarifie d t hat trial 
partici pa nts wit h C D 3 0 - disease will recei ve i n vesti gati o nal bre nt u xi ma b ve d oti n, 
s u p plie d f or free b y Sea ge n. T his a me n d me nt als o i ncl u des a na me c ha n ge b y t he f u n di n g 
s o urce. 
 
E dit ori al/ a d mi nistr ati ve C h a n ges:  
2.  T he f u n di n g s o urce o n t he title pa ge is c ha n ge d fr o m Seattle Ge netics t o Sea ge n.  
3.  I n Secti o n 5. 1 t he li n k t o t he bre nti x u ma b ve d oti n prescri bi n g i nf or mati o n is c ha n ge d fr o m 
htt p:// w w w.seattle ge netics.c o m/a p plicati o n/files/ 2 5 1 5/ 1 0 5 9/ 6 7 2 8/ A D C E T RI S _ U S PI _ U S
P -B V P -2 0 1 5 -0 1 6 2 5 p df. p df  t o htt ps://sea ge n d ocs.c o m/ A dcetris _ F ull _ Ltr _ Master. p df  
a. Als o, it is clarifie d t hat trial partici pa nts wit h C D 3 0- disease will recei ve 
i n vesti gati o nal bre nt u xi ma b ve d oti n, s u p plie d f or free b y Sea ge n. 
4.  Refere n ces t o Seattle Ge netics i n secti o ns 5. 1. 1, 5. 1. 2, 5. 1. 7, a n d 7. 3. 3 are c ha n ge d t o 
Sea ge n.   
5.  Secti o n 6. 1 Ti me a n d E ve nts ta ble,  
a. F o ot n ote 5: c orrecte d t y p o gra p hical err or.   
6.  Secti o n 6. 2 Ti me a n d E ve nts Ta ble  
a. F o ot n ote 8 : delete d a re peate d se nte nce. 
 
Scie ntific C h a n ges:  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
1.  .Secti o ns 2. 1, 2. 2. 1, 2. 2. 5, 2. 4. 1, 4. 1 ( Sc he ma), 4. 2. 1(f o ot n ote 1), 4. 7, 6. 1 ( Ti me 
a n d E ve nts Ta ble N ote), a n d 6. 6 ha ve bee n u p date d t o c ha n ge t he desi g nati o n of 
s u bjects recei vi n g 4-6 c ycles of B V -C H E P t o 2 -6 c ycles.  
2.  Secti o n 6. 1 Ti me a n d E ve nts ta ble,  
a. F o ot n ote 1: C ha n ge d e n d of treat me nt ti mi n g fr o m 3 0 da ys t o 2 1 da ys.  
3.  Secti o n 6. 2  
a. F o ot n ote 1: C ha n ge d e n d of mai nte na nce treat me nt ti mi n g fr o m 3 0 da ys t o 
2 1 da ys.  
 
 
T H E A T T A C H E D V E R SI O N D A T E D  Fe br u ary 2 5,  2 0 2 1,  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 6  
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
X   E dit orial,  a d mi nistrati ve c ha n ges  
X  Scie ntific c ha n ges (I R B a p pr o val)  
X  T hera p y c ha n ges (I R B a p pr o val)  
X  Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he p ur p ose of t his a me n d me nt is t o reflect a c ha n ge i n t he desi g n of t he st u d y. T he st u d y 
will n o w be a pil ot st u d y rat her t ha n a p hase 2 st u d y. Acc or di n gl y, la n g ua ge t hr o u g h o ut 
t he pr ot oc ol a n d statistical desi g n ha ve  bee n re vise d t o reflect t his ne w desi g n.  
A d diti o nall y, t he o pti o n of oral et o p osi de was a d de d as a n alter nati ve t o I V et o p osi de  a n d 
a n I V o pti o n f or c ortic oster oi ds was a d de d, if nee de d, i n place of oral pre d nis o ne . 
A d mi nistrati ve c ha n ges were ma de t o pr o vi de clarificati o n o n scree ni n g la bs.  
 
E dit ori al/ A d mi nistr ati ve C h a n ges  
1.  Title a n d Si g nat ure Pa ge: C ha n ge d title t o reflect t he ne w desi g nati o n of a pil ot 
st u d y. 
2.  Mec ha nical e diti n g t hr o u g h o ut . 
3.  A d de d G -C S F t o a b bre viati o ns ta ble  
4.  Secti o n 1. 2: Clarificati o n o n n u m ber of sites  
5.  Secti o n 3. 1. 7 a n d Ti me a n d E ve nts Ta ble: A d de d clarificati o n t o t he s pecificit y of 
t he scree ni n g la b tests me nti o ne d. 
6.  Secti o n 4. 1. 1 0: u p date d secti o n  
7.  Secti o n 4 .1 1: Secti o n a d de d t o defi ne Off -St u d y Criteria.  
8.  Secti o n 5. 3. 8: U p date d et o p osi de a d verse e ve nt la n g ua ge.  
9.  Secti o n 6. 1: Ti me a n d E ve nts Ta ble: U p date d F o ot n otes t o a da pt t o t he a d diti o n of 
ne w F o ot n otes ( # 3 , 1 5 a n d 1 6) relate d t o t he a d diti o n of oral et o p osi de, I V 
c ortic oster oi d o pti o n  a n d c orrecte d F o ot n ote desi g nati o ns f or A d verse E ve nts 
Assess me nt, I V Bre nt u xi ma b ve d oti n, a n d F oll o w -u p . 
1 0.  Secti o ns 6. 1 Ti me a n d E ve nts Ta ble f o ot n ote 2 1 a n d Secti o n 6. 2 Ti me a n d e ve nts 
ta ble f o ot n ote 8: A d de d la n g ua ge t o clarif y s ur vi val f oll o w-u p o nl y f or s u bjects 
t hat c o me off st u d y t hera p y a n d c ha n ge re gi me n  
1 1.  Secti o ns 6. 4. 1, 6. 4. 3, 6. 4. 4, a n d 6. 4. 5: U p date d f o ot n ote refere nces.  
1 2.  Secti o n 6. 6: Clarifie d f oll o w -u p pr oce d ures f or s u bjects c o mi n g off st u d y t hera p y 
a n d starti n g a ne w t hera p y.  
1 3.  Secti o n s 7. 3. 3, 9. 3, 9. 4, 9. 5, a n d 9. 6: A d de d u p date d m ultice nter la n g ua ge a n d 
c o ntacts w here a p pr o priate.  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
1 4.  Secti o n 1 0: Citati o ns u p date d  
 
Scie ntific C h a n ges:  
1.  Secti o n 1. 1: Re visi o ns t o t he St u d y S y n o psis t o reflect t he c ha n ge t o a pil ot st u d y  
2.  Secti o n 4. 1: C ha n ge d Sc he ma t o reflect ne w st u d y desi g n.  
a. La n g ua ge relate d t o t he sc he ma a n d st u d y desi g n u p date d.  
b.  Re vise d la n g ua ge t o i n dicate a c ha n ge i n re gi me n res ults i n t he s u bject 
bei n g f oll o we d f or s ur vi val a n d n ot c o mi n g off st u d y.  
3.  Secti o ns 8. 1 -8. 3: Re vise d statistical pla n a n d e nr oll me nt n u m bers t o reflect t he 
ne w st u d y desi g n.  
 
T her a p y C h a n ges:  
1.  Secti o n s 4. 2, 4. 2. 1 a n d Ti me a n d E ve nts Ta ble F o ot n ote # 1 5 : A d de d i nf or mati o n 
pr o vi di n g t he o pti o n f or use of oral et o p osi de i n place of I V et o p osi de at a n y p oi nt 
i n w hic h et o p osi de is a d mi nistere d t o t he s u bject. A d diti o nall y, e xce pti o ns were 
i n dicate d i n Secti o n 6. 4. 2 a n d t he Ti me a n d E ve nts Ta ble (F o ot n otes # 3 a n d # 1 6 ) 
relate d t o t he c ollecti o n of vital si g ns a n d a d verse e ve nts o n da ys 2 a n d 3, w hic h 
w o ul d o nl y be d o ne if  t he s u bject w o ul d be recei vi n g I V et o p osi de. 
2.  Secti o ns 4. 2, 4. 2. 1 a n d t he Ti me a n d E ve nts Ta ble a d de d F o ot n ote # 1 6: Pr o vi de d a 
pr o visi o n t o use a n I V c ortic oster oi d of e q ui vale nt d ose t o 1 0 0 m g pre d nis o ne, if 
i n dicate d f or s u bjects t hat ma y ha ve pr o ble ms wit h oral me dicati o ns. 
3.  Secti o n 4. 2. 1, Ta ble : A d de d la n g ua ge t hat a n y G-C S F is all o we d per i nstit uti o nal 
sta n dar d. 
 
Eli gi bilit y C h a n ges:  
1.   Criteri o n 3. 2. 2: Re m o ve d t he c o nti n ge nc y relate d t o s u bjects bei n g disease free 
fr o m ca ncer f or 5 years. 
 
T H E A T T A C H E D V E R SI O N D A T E D  A P RI L 3 0 , 2 0 2 0, I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
P R O T O C O L A M E N D M E N T # 5  
 
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A P h ase II Tri al of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X  E dit orial, a d mi nistrati ve c ha n ges  
_ X   Scie ntific c ha n ges (I R B a p pr o val)  
_   _ T hera p y c ha n ges (I R B a p pr o val)  
_     Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he maj or c ha n ge i n t his pr ot oc ol a me n d me nt is t o c ha n ge t he l ot of bre nt u xi ma b ve d oti n 
t o c o m mercial s u p pl y f or all s u bjects o n t his st u d y w h ose disease falls wit hi n t he F D A 
a p pr o ve d i n dicati o n ( C D 3 0 + disease). Gi ve n t hat s u bjects will recei ve eit her c o m mercial 
s u p pl y or i n vesti gati o nal s u p pl y of bre nt u xi ma b ve d oti n de pe n di n g o n w het her t he y ha ve 
C D 3 0 + or C D 3 0 - disease, t he pr ot oc ol has als o bee n  a me n de d t o re q uire t hat C D 3 0 
e x pressi o n be deter mi n e d d uri n g scree ni n g a n d eli gi bilit y e val uati o n .  I n a d diti o n, t he 
pr ot oc ol has bee n a me n de d t o re m o ve t he a d verse e ve nt assess me nt o n da ys 4 a n d 5 of 
c ycle s 1 t hr o u g h 6 of treat me nt wit h b re nt u xi ma b v e d oti n c o m bi ne d wit h 
cycl o p h os p ha mi de, d o x or u bici n, et o p osi de, a n d P re d nis o ne ( B V-C H E P) .  T he a d verse 
e ve nt assess me nt has bee n dee me d  u n necessar y o n da ys 4 a n d 5 as it is alrea d y re q uire d 
o n da ys 1, 2, 3, 8, a n d 1 5 of c ycles 1 t hr o u g h 6 of B V -C H E P treat me nt.  A d diti o nal 
c ha n ges ha ve bee n ma de  t o clarif y t hat t he i nf usi o n ti mes f or c ycl o p h o s p hami de, 
d o x or u bici n, et o p osi de, a n d bre nt u xi ma b ve d oti n are a p pr o xi mate .  T he ter m “st u d y 
e ntr y” has  als o bee n re place d wit h t he p hrase “si g ni n g t he mai n c o nse nt f or m ” f or 
clarificati o n p ur p oses.   
 
C h a n ges:  
•  A d mi nistrati ve c ha n ges t hr o u g h o ut i ncl u di n g u p dati n g t he ter m “ U N C C N” t o 
“ m ultice nter” a n d “affiliate” t o “ m ultice nter”  
•  Secti o n 1. 4 –  T his secti o n descri bi n g bre nt u xi ma b ve d oti n has bee n u p date d t o 
i ncl u de t he ne wl y a p pr o ve d i n dicati o n f or t he dr u g i n pre vi o usl y u ntreate d 
s yste mic a na plastic lar ge cell l y m p h o ma (sA L C L) or ot her C D 3 0 -e x pressi n g 
peri p heral T -cell l y m p h o mas ( P T C L), i n c o m bi nati o n wit h c he m ot hera p y . 
•  Secti o n 3. 1. 1 2 –  T his i ncl usi o n criteri o n has bee n re vise d t o clarif y t hat s u bjects 
m ust be pre vi o usl y u ntreate d or ha ve recei ve d a ma xi m u m of o ne c ycle of a n y 
c o m bi nati o n c he m ot hera p y (e. g. C H O P, C H O E P, D A -E P O C H, C O D O X -
M/I V A C, H y per C V A D) wit hi n 4 wee ks of  si g ni n g t he mai n c o nse nt f or m.  T he 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
p hrase “si g ni n g t he mai n c o nse nt f or m” re places t he p hrase “st u d y e ntr y” f or 
clarificati o n p ur p oses.    
•  Secti o n 3. 1. 1 3 –  T his i ncl usi o n criteri o n has bee n a d de d t o re q uire t hat C D 3 0 
e x pressi o n  be assesse d pri or t o e nr oll me nt o n t he st u d y .  
•  Secti o n 4. 1 –  T he ke y eli gi bilit y criteri o n  liste d i n t he sc he ma has bee n re vise d t o 
clarif y t hat pre vi o usl y u ntreate d A T L L or t h ose wit h A T L L w h o ha ve recei ve d a 
ma xi m u m of o ne c ycle of c o m bi nati o n c he m ot hera p y (i.e. C H O P, C H O E P, D A -
E P O C H, etc.) or a ntiretr o viral t hera p y (i.e. A Z T a n d/ or I F N) wit h i n 4 wee ks of 
si g ni n g t he mai n c o nse nt f or m are eli gi ble f or e nr oll me nt.  T he p hrase “si g ni n g 
t he mai n c o nse nt f or m” re places t he p hrase “st u d y e ntr y” f or clarificati o n 
p ur p oses.    
•  Secti o n 4. 2. 1 –   
o  T he Bre nt u xi ma b Ve d oti n wit h C ycl o p h o p ha mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P)  D osi n g Sc he d ule has bee n re vise d 
as f oll o ws: 
i. t o clarif y t hat t he i nf usi o n ti mes f or c ycl o p h o p has p ha mi de, 
d o x or u bici n, et o p osi de, a n d bre nt u xi ma b ve d oti n are a p pr o xi mate.   
ii. t o a d d a f o otn ote stati n g t hat s u bjects wit h C D 3 0 + disease will 
recei ve c o m mercial bre nt u xi ma b ve d oti n  pr o d uct a n d s u bjects wit h 
C D 3 0 - disease will recei ve i n vesti gati o nal s u p pl y of bre nt u xi ma b 
ve d oti n .  T he f o ot n ote als o defi nes C D 3 0 + disease as C D 3 0 
e x pressi o n a b o ve 1 perce nt.   
o  T he B V Mai n te na nce D osi n g Sc he d ule has  als o bee n re vise d as f oll o ws: 
i. t o clarif y t hat t he i nf usi o n ti me f or bre nt u xi ma b ve d oti n is 
a p pr o xi mate.   
ii. t o defi ne C D 3 0 + disease as C D 3 0 e x pressi o n a b o ve 1 perce nt.   
•  Secti o n 4. 5 –  T his secti o n has bee n re vise d t o clarif y t hat u p -t o-date vacci nati o ns 
are s u g geste d, b ut n ot ma n dat or y, pri or t o a patie nt si g ni n g t he mai n c o nse nt 
f or m.  T he p hrase “a patie nt si g ni n g t he mai n c o nse nt f or m” re places t he p hrase 
“st u d y e ntr y” f or clarificati o n p ur p ose s.   
•  Secti o n 5. 1. 2 - T his secti o n has bee n u p date d t o state t hat i n vesti gati o nal dr u g 
s u p pl y of bre nt u xi ma b ve o dti n  will be s u p plie d b y Seattle Ge netics f or C D 3 0 - 
patie nts o nl y, a n d C D 3 0 + patie nts will recei ve c o m mercial s u p pl y.  
•  Secti o n 5. 1. 7 - T his secti o n re gar di n g acc o u nta bilit y , ret ur n a n d rete nti o n of 
bre nt u xi ma b ve d oti n has bee n u p date d t o clarif y t hat t hese re q uire me nts a p pl y t o 
i n vesti gati o nal s u p plies of bre nt u xi ma b ve d oti n.   
•  Secti o n 5. 2 - T he re q uire me nts f or t he ret ur n a n d rete nti o n of t he st u d y dr u g ha ve 
bee n u p date d t o disti n g uis h bet wee n ha n dli n g of i n vesti gati o nal l ot a n d 
c o m mercial s u p pl y.  
•  Secti o n 6. 1 –  T he Ti me a n d E ve nts Ta ble f or B V -C H E P has bee n re vise d : 
o  t o re m o ve t he a d verse e ve nt assess me nt o n da ys 4 a n d 5 of c ycles 1 
t hr o u g h 6 of B V -C H E P . 
o  t o i ncl u de a f o ot n ote s pecif yi n g t hat C D 3 0 + s u bjects will recei ve 
c o m mercial bre nt u xi ma b ve d oti n w hile C D 3 0 - s u bjects will recei ve 
i n vesti gati o nal l ot a n d t o defi ne C D 3 0 + disease as C D 3 0 e x pressi o n a b o ve 
1 perce nt.  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
•  Secti o n 6. 2 –  T he n ote u n der t he Ti me a n d E ve nts Ta ble f or B V Mai nte na nce 
T hera p y was u p date d t o defi ne C D 3 0 + disease as C D 3 0 e x pressi o n a b o ve 1 
perce nt.  
•  Secti o n 6. 4. 2 –  T his secti o n has bee n re vise d t o state t hat t o xicit y will be assesse d 
o n da ys 2 a n d 3 o nl y of c ycles 1 t hr o u g h 6 of B V -C H E P  
•  Secti o n  6. 7 C orrel ati ve St u dies Pr oce d ures –  A state me nt has bee n a d de d t o t his 
secti o n t o clarif y  t hat if a partici pa nt a grees t o pr o vi de t he o pti o nal peri p heral 
bl o o d sa m ple f or c orrelati ve researc h, it will c ollecte d a n d st ore d e ve n if t he 
partici pa nt is deter mi ne d n ot eli gi ble f or t he mai n st u d y.   
•  Secti o n 7. 3. 3 Re p orti n g was u p date d t o re m o ve i nter nal pr ocesses t hat are 
dictate d b y S O P  
•  Secti o n 7. 4 –  T his secti o n has bee n re vise d t o re m o ve la n g ua ge re q uiri n g t hat 
meeti n gs/telec o nfere nces f or data a n d safet y m o nit ori n g be hel d i n c o ns ultati o n 
wit h t he st u d y Bi ostatisticia n  a n d t o reflect ne w titles of i ncl u de d parties  
•  Secti o n 9. 4 –  T his secti o n has bee n u p date d i n acc or da nce wit h L C C C pr oce d ures 
f or data ma na ge me nt a n d m o nit ori n g a n d a u diti n g.  
•  Secti o n 9. 5. 3 –  T his secti o n has bee n a me n de d t o clarif y t he re p orti n g 
re q uire me nt f or pr ot oc ol de viati o ns t o U N C I R B.  
 
 
T H E A T T A C H E D V E R SI O N D A T E D J A N U A R Y 2 1, 2 0 1 9 , I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 4  
 
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A P h ase II Tri al of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X  E dit orial, a d mi nistrati ve c ha n ges  
_ X   Scie ntific c ha n ges (I R B a p pr o val)  
_   _ T hera p y c ha n ges (I R B a p pr o val)  
_     Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he pr ot oc ol is a me n de d t o all o w f or a c o m p ute d t o m o gra p h y ( C T ) sca n or a p ositr o n 
e missi o n t o m o gra p h y ( P E T / C T) sca n i nstea d of a ma n date d P E T/ C T sca n : 
 
•  o n Da y 1 of c ycle 3  of B V -C H E P treat me nt ,  
•  d uri n g B V mai nte na nce treat me nt , 
•  at t he e n d of treat me nt visit f or B V mai nte na nce , a n d 
•  d uri n g f oll o w u p .   
 
T his c ha n ge is c o nsiste nt wit h t he res p o nse criteria f or l y m p h o ma  f or t he p ur p ose of 
disease m o nit ori n g.  A c o m bi ne d P E T/ C T sca n of dia g n ostic q ualit y will c o nti n ue t o be 
re q uire d at scree ni n g f or sta gi n g p ur p oses a n d o n Da y 1 of c ycle 5 a n d at t he e n d of 
c ycle 6  of B V -C H E P f or t he p ur p ose of deter mi ni n g res p o nse a n d ma ki n g treat me nt 
decisi o n s (i.e. w het her t o ta ke patie nt t o all o S C T).   
 
Scie ntific  c h a n ges:  
•  Secti o n 4. 1 –  T he sc he ma has bee n re vise d t o clarif y t hat a P E T/ C T or C T sca n is 
re q uire d after t he first t w o c ycles of B V-C H E P  
•  Secti o n 4. 2 –  re vise d t o state t hat i ma gi n g sca ns will be d o ne i nstea d of P E T/ C T 
sca ns si nce a P E T/ C T or C T sca n is all o we d o n d a y 1 of c ycle 3  a n d a c o m bi ne d 
P E T/ C T sca n is re q uire d o n d a y 1 of c ycle 5 a n d at t he e n d of c ycle 6 ; als o 
clarifie d t hat sca ns will be d o ne o n d a y 1 of c ycles 3 a n d 5 a n d at t he e n d of c ycle 
6  
•  Secti o n 6. 1 Ti me a n d E ve nts Ta ble ( B V + C H E P) has bee n u p date d as f oll o ws:  
o  T o re m o ve “( dia g n ostic q ualit y P E T/ C T)” after t he  re q uire me nt f or 
i ma gi n g st u dies  
o  T o clarif y i n f o ot n ote 3 t hat a P E T/ C T sca n is re q uire d at scree ni n g, da y 1 
of c ycle 5  (-7 da ys) , a n d da y 2 1 of c ycle 6 ( +/-7 da ys) a n d t o clarif y t hat a 
P E T / C T sca n or C T sca n is re q uire d o n da y 1 of c ycle 3 (-7 da ys).  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
o  T o clarif y i n f o ot n ote 1 7 t hat t he i ma gi n g sca ns d o ne d uri n g f oll o w u p ca n 
be eit her P E T / C T sca ns or C T sca ns.  
•  Secti o n 6. 2 Ti me a n d E ve nts Ta ble ( B V Mai nte na nce T hera p y) has bee n u p date d 
as f oll o ws: 
o  T o re m o ve “( dia g n ostic q ualit y P E T/ C T)” after t he re q uire me nt f or 
i ma gi n g st u dies  
o  T o  c ha n ge f o ot n ote 3 t o state t hat a P E T / C T or C T sca n s h o ul d be d o ne 
e ver y 8 c ycles  a n d at t he e n d of st u d y treat me nt visit.  
o  T o clarif y i n f o ot n ote 8 t hat t he i ma gi n g sca ns d o ne d uri n g f oll o w u p ca n 
be eit her P E T / C T sca ns or C T sca ns.  
•  Secti o n 6. 3 has bee n re vise d t o re m o ve t he re q uire me nt f or I V c o ntrast f or t he 
P E T/ C T sca n at scree ni n g  
•  Secti o n 6. 4. 1 has be e n re vise d t o all o w f or t he disease meas ure me nts at c ycle 3 of 
B V -C H E P t o be d o ne wit h a P E T/ C T or C T sca n , t o clarif y t hat a P E T/ C T sca n 
be d o ne at c ycle 5  a n d at t he e n d of c ycle 6  of B V -C H E P , a n d t o re m o ve t he 
re q uire me nt f or t he sca ns t o be d o ne wit h I V c o ntrast 
•  Secti o n 6. 4. 5 has bee n re vise d t o re m o ve t he re q uire me nt t hat t he P E T/ C T sca n at 
t he e n d of B V/ C H E P treat me nt visit be d o ne wit h c o ntrast  
•  Secti o n 6. 5. 1 has bee n re vise d t o all o w f or t he disease meas ure me nts e ver y 8 
c ycles of B V mai nte na nce t o be d o ne wit h a P E T/ C T or C T sca n  a n d t o re m o ve 
t he re q uire me nt f or t he sca ns t o be d o ne wit h c o ntrast. 
•  Secti o n 6. 5. 2 has bee n re vise d t o all o w f or t he disease meas ure me nts at t he e n d of 
B V mai nte na nce treat me nt t o be d o ne wit h a P E T / C T or C T sca n  a n d t o re m o ve 
t he re q uire me nt t hat t he sca n be d o ne wit h c o ntrast 
•  Secti o n 6. 6 has bee n re vise d t o clarif y  t hat t he i ma gi n g sca ns re q uire d d uri n g 
f oll o w u p ma y be eit her P E T/ C T or C T sca ns  
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D A P RI L 1 7 , 2 0 1 8, I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 3  
 
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A P h ase II Tri al of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X  E dit orial, a d mi nistrati ve c ha n ges  
_      Scie ntific c ha n ges (I R B a p pr o val)  
_ X _ T hera p y c ha n ges (I R B a p pr o val)  
_ X   Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he pr ot oc ol is a me n de d t o clarif y ma xi m u m d ose le vels f or bre nt u xi ma b ve d oti n ( B V), 
t o a d d uric aci d a n d p h os p h or us testi n g bac k t o t he pr ot oc ol o n da ys 1 a n d 8 of c ycle 1 of 
B V -C H E P treat me nt per F D A’s re q uest , t o pr o hi bit eli gi bilit y si n gle s u bject e xce pti o ns 
u n der a n y circ u msta nces, a n d t o pr o vi de a d diti o nal i nf or mati o n re gar di n g st u d y 
m o nit ori n g re q uire me nts.  
 
E dit ori al, a d mi nistr ati ve c h a n ges:  
•  Secti o n 9. 4 has bee n re vise d t o i ncl u de a d diti o nal i nf or mati o n re gar di n g st u d y 
m o nit ori n g re q uire me nts.  
 
T her a p y c h a n ges:  
•  T he f oll o wi n g secti o ns were u p date d: Secti o n 4. 2. 1, secti o n 4. 3. 1. 1 a n d secti o n 
5. 1. 4. n oti n g t hat f or patie nts wei g hi n g greater t ha n 1 0 0 k g, t he d ose of B V s h o ul d 
be calc ulate d base d o n a wei g ht of 1 0 0 k g.   
•  Ta ble i n secti o n 4. 3. 1. 1 reflects ma x d ose of B V t hat ca n be gi ve n base d o n 
all o we d d ose re d ucti o ns i n t he st u d y  
•  U p date d li n k t o B V pac ka ge i nsert i n secti o n 5. 1  
•  Secti o n 6. 1, secti o n 6. 4. 1, a n d secti o n 6. 4. 3 were re vise d t o a d d uric aci d a n d 
p h os p h or us testi n g bac k t o t he pr ot oc ol o n da ys 1 a n d 8 of c ycle 1 of B V -C H E P 
treat me nt per F D A’s re q uest 
 
Eli gi bilit y c h a n ges:  
•  Secti o n 9. 5. 2 has bee n re vise d t o pr o hi bit eli gi bilit y si n gle s u bject e xce pti o ns 
u n der a n y circ u msta nces a n d t o clarif y t hat ot her t y pes of si n gle s u bject 
e xce pti o ns ma y be all o we d if pr o per re g ulat or y re vie w has bee n c o m plete d i n 
acc or da nce wit h Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter’s Si n gle S u bject 
E xce pti o ns P olic y.  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D J A N U A R Y 4, 2 0 1 8,  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
P R O T O C O L A M E N D M E N T # 2  
 
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A P h ase II Tri al of t he R are L y m p h o m a W or ki n g Gr o u p  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X    E dit orial, a d mi nistrati ve c ha n ges  
_ X   Scie ntific c ha n ges (I R B a p pr o val)  
_ _   T hera p y c ha n ges (I R B a p pr o val)  
_ X    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
T he pr ot oc ol was  re vise d t o i ncl u de assess me nt of peri p heral bl o o d per  a d ult T-cell 
le u ke mia/l y m p h o ma N C C N  g ui deli nes versi o n 2. 2 0 1 7 f or t h ose s u bjects wit h a le u ke mic 
c o m p o ne nt  t o t heir disease at baseli ne.  Eli gi bilit y criteria were re vise d a n d st u d y 
assess me nts were re vise d i n t he ti me a n d e ve nts ta bles. I n a d diti o n, clarificati o ns were 
ma de t o t he d ose m o dificati o n ta bles a n d t he l o n g -ter m f oll o w u p pla ns were  clarifie d.   
 
E dit ori al c h a n ges  
•  E dit orial c ha n ges ma de t o secti o n 1. 1  
•  E dit orial c ha n ges ma de t o Sec o n dar y o bjecti ves 2. 2. 1 -2. 2. 4  t o n ote t hat O R R, P F S, 
d urati o n of res p o nse, O S will be dete r mi ne d i n s u bjects t hat recei ve B V -C H E P  a n d 
t o xicit y will be deter mi ne d f or s u bjects t hat recei ve B V-C H E P a n d B V mai nte na nce  
t hera p y secti o n 2. 2. 5.  A d d e d n ote after sec o n dar y o bjecti ve 2. 2. 5 t o clarif y t he 
p ossi ble gr o u ps of partici pa nts after c o m pleti o n or wit h dra wal fr o m B V -C H E P.  
•  
E nz y me -li n ke d i m m u n os or be nt assa y (E LI S A) is bei n g a d de d t o t he t y pes of c o nfir mat or y 
tests t hat ma y be use d f or p ositi ve H T L V-1 a nti b o d y testi n g i n i ncl usi o n criteri o n 3. 1. 4.   
•  Ref or matte d i ncl usi o n/e xcl usi o n criteria  t o li n k t o str uct ure of t his d oc u me nt ( Secti o n 
3. 1 a n d 3. 2)  
•  E dit orial c ha n ges ma de t o Secti o n  4. 1 a n d i n secti o n  4. 2 t o ta bles i n 4. 2. 1 f or B V -
C H E P a n d B V Mai nte na nce D osi n g Sc he d ules  
•  E dit orial c ha n ge t o title of secti o n 4. 3 t o clearl y s pecif y t hat d ose le vels are f or B V  
•  M o ve d secti o n ( 4. 6) u p t o a ne w p ositi o n i n t he pr ot oc ol a s 4. 4. 1. 2 a n d m o difie d title 
f or clarit y t o s pecif y ma na ge me nt g ui deli nes f or re nal a n d he patic A Es relate d t o 
st u d y treat me nts rat her t ha n j ust A Es. 
•  Clarifie d d urati o n of f oll o w u p = 5 years after last c ycle of st u d y treat me nt (i.e. B V -
C H E P or B V mai nte na nce) i n secti o n 4. 8 f or all patie nts i n t his st u d y 
•  Li n k u p date d i n secti o n 4. 9 per te m plate  
•  Re vise d li n ks i n secti o n 5. 1. 8  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
•  Clarifie d t hat P E T/ C T sca ns are t o be of dia g n ostic q ualit y i n Ti me a n d E ve nts Ta bles 
(secti o ns 6. 1 a n d 6. 2) 
•  Re vise d Prest u d y Assess me nts i n secti o n 6. 3 t o ali g n wit h ta ble 6. 1  
•  Re vise d treat me nt assess me nts i n secti o n 6. 4 i ncl u di n g 6. 4. 1-6. 4. 5 t o ali g n wit h 
re visi o ns ma de t o ta ble 6. 1 
•  Re vise d B V Mai nte na nce Assess me nts i n secti o n 6. 5 i ncl u di n g 6. 5. 1 -6. 5. 2 t o ali g n 
wit h c ha n ges ma de t o ta ble 6. 2  
•  Re m o ve d D 8 assess me nts fr o m ta ble 6. 2 a n d c orres p o n di n g visit details relate d t o t his 
visit da y  
•  Re vise d t he a m o u nt of bl o o d t o be c ollecte d f or c orrelati ve st u dies fr o m 3 m Ls t o 
1 0  m Ls of bl o o d  i n secti o ns 6. 1 (f o ot n ote # 1 4), 6. 3 a n d 6. 7 
•  Re vise d w or di n g i n secti o n 6. 6 t o clarif y pla ns f or p ost treat me nt f oll o w u p  
•  Clarifie d re p orti n g p olic y f or S A Es t o U N C I R B i n secti o n 7. 3. 3  
•  C orrecte d N CI C T C A E versi o n n u m ber i n secti o n 8. 3  
•  Mi n or s pelli n g a n d gra m mar c orrecti o ns ma de t hr o u g h o ut pr ot oc ol  
 
 
Scie ntific  c h a n ges  
•  Secti o ns 2. 4 a n d 6. 9 are u p date d t o clarif y efficac y e n d p oi nts/criteria f or assess me nt 
of peri p heral bl o o d if a p plica ble  
•  U p date d t he s u g geste d a nti micr o bial pr o p h yla xis  g ui deli nes f or s u p p orti ve care i n  
secti o n 4. 2. 2  
a) Re m o ve d s u g geste d d osi n g of Bactri m ( M, W, F)  
b)  Re m o ve d “ mi ni mal” fr o m s u b hea di n g 
•  Re vise d d ose m o dificati o n ta ble 4. 4. 1. 1 f or B V + C H E P re gi me n  
•  Re visi o ns ma de t o 4. 4. 1. 3 D ose M o dificati o n ta ble  f or B V Mai nte na nce T hera p y 
•  Ti me a n d E ve nts Ta ble i n Secti o n 6. 1 of t he pr ot oc ol as f oll o ws:  
a) A d de d  p h ysical e xa m f or  e n d of T xt visit  
b)  Clarifie d ti mi n g of P E T/ C T sca n f or e n d of c ycle 6  
c) Clarifie d ti mi n g of pre g na nc y test i n g 
d)  A d de d B o ne Marr o w bi o ps y t o e n d of T xt visit t o c o nfir m C R if p ositi ve 
i nitiall y 
e) Clarifie d t hat G 6 P D/ uric aci d/ p h os p h or us will be meas ure d d uri n g 
scree ni n g visit 
f) Re m o ve d p h os p h or us a n d uric aci d fr o m cli nical c he mistr y pa nel  
g)  C ha n ge d c o nc o mita nt me dicati o n re vie w t o D 1 of eac h c ycle t o i m pr o ve 
efficie nc y a n d eli mi nate c hec ki n g eac h da y d uri n g B V -C H E P  
h)  Re m o ve d H L A Si bli n g t y pi n g  
i) A d de d I ntrat hecal c he m ot hera p y a n d pr o p h yla xis treat me nt r o ws wit h 
C S F t o acc o u nt f or t he t w o p ossi ble treat me nt sce nari os  
j) Clarifie d t hat C T or M RI of brai n will o nl y be c o n d ucte d at t he scree ni n g 
visit  u nless t he test if  p ositi ve.  If p ositi ve at scree ni n g, it will be re peate d 
at t he e n d of B V -C H E P treat me nt visit.  
k)  Delete d c oa g ulati o n la bs a n d re m o ve d f o ot n ote relate d t o t his assess me nt 
( # 1 2) a n d re n u m bere d f o ot n otes t o acc o u nt f or deleti o n of t his assess me nt 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
l) A d de d re q uire me nt f or i ma gi n g sca ns a n d he mat ol o g y la bs d uri n g t he first 
2 years of f oll o w u p  
m)  Re vise d n ote u n der Ti me a n d E ve nts ta ble t o clarif y t he p ossi ble gr o u ps of 
partici pa nts after c o m pleti o n or wit h dra wal fr o m B V -C H E P  
n)  Delete d i nf or mati o n a b o ut l o n g ter m f oll o w u p fr o m f o ot n ote # 1 a n d 
descri be d f oll o w u p i n f o ot n ote # 1 6  
o)  A d de d r o w f or f oll o wi n g s ur vi val  
p)  Clarifie d ti mi n g of t he e n d of treat me nt visit i n f o ot n ote 1  
q)  Clarifie d t he ti mi n g of t he P E T/ C T sca n f or c ycle 6  
•  Ti me a n d E ve nts Ta ble 6. 2 re vise d as f oll o ws:  
a) A d de d re q uire me nt f or E C O G perf or ma nce stat us at t he 
e n d of treat me nt of visit  
b)  Clarifie d ti mi n g of pre g na nc y testi n g 
c) Re m o ve d P T a n d I N R testi n g fr o m he mat ol o g y 
assess me nts at baseli ne  
d)  Re m o ve d Uric Aci d fr o m Cli nical c he mistr y assess me nts at 
baseli ne  
e) Re m o ve d i nitiate /re ne w pr o p h ylactic me dicati o ns  
f) Re vise d ti mi n g of P E T/ C T i ma gi n g d uri n g mai nte na nce 
t hera p y fr o m e ver y 4 t o 5 c ycles t o e ver y 8 c ycles 
g)  A d de d r o w t o e ns ure d oc u me ntati o n of s ur vi val f or u p t o 5 
years or u ntil deat h ( w hic he ver occ urs first) after t he 
s u bject disc o nti n ues B V mai nte na nce . 
h)  A d de d re q uire me nt f or i ma gi n g sca ns a n d he mat ol o g y la bs 
d uri n g t he first 2 years of f oll o w u p  
i) A d de d f o ot n ote # 1 t o clarif y visit sc he d ule wi n d o ws a n d 
e n d of treat me nt wi n d o ws d uri n g B V mai nte na nce  
j) Re vise d l o n g ter m f oll o w u p sc he d ule i n f o ot n ote # 8 t o 
e xte n d s ur vi val f oll o w u p fr o m 3 years t o 5 years a n d t o 
i ncl u de i ma gi n g a n d he mat ol o g y la b re q uire me nts d uri n g 
f oll o w u p f or 2 years  
 
Eli gi bilit y  C h a n ges:  
•  Re vise d i ncl usi o n criteri o n 3. 1. 6 t o clarif y re q uire me nts f or i ncl usi o n of patie nts 
p ositi ve f or H B V/ H C V i nfecti o n or e x p os ure  
•  Re vise d i ncl usi o n criteri o n 3. 1. 7 t o eli mi nate assess me nts f or c oa g ulati o n testi n g.  
•  A d de d e xcl usi o n criteri o n 3. 2. 1 0 t o disall o w e nr oll me nt of patie nts wit h pare nc h y mal 
brai n met astases 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D N O V E M B E R 2 9 , 2 0 1 7 I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 1  
 
 
L C C C 1 6 3 7 :  Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A P h ase II Tri al of t he R are L y m p h o m a W or ki n g Gr o u p  
 
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X  E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ X _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
•  Re m o ve d c o nti n u o us I V i nf usi o n ( CI VI) fr o m t he a b bre viati o ns list 
•  C ha n ge d e pir u bici n t o et o p osi de f or B V -C H E P , C H E P , a n d C H O E P i n t he 
a b bre viati o ns list  
•  Secti o n 6. 1 Ti me a n d E ve nts Ta ble : 
o  T o be c o nsiste nt wit h secti o n 6. 3  Pre -St u d y Assess me nts , clarifie d t hat 
testi n g f or gl uc ose 6 p h os p hate de h y dr o ge nase (G 6 P D ) deficie nc y is d o ne 
o nl y d uri n g scree ni n g  
o  A d de d f o ot n ote 9 t o ec h ocar di o gra m ( E C H O )/m ulti gate d a cq uisiti o n _  
( M U G A) sca n liste d f or D 1 t o clarif y t hat patie nts wit h baseli ne left 
ve ntric ular ejecti o n fracti o n ( L V E F ) of 4 0 % t o 5 5 % s h o ul d ha ve re peat 
assess me nt perf or me d pri or t o c ycle 4  
•  Secti o n 6. 3  Pre -St u d y Assess me nts  –  T o be c o nsiste nt wit h t he Ti me a n d E ve nts 
Ta ble, clarifie d t hat H T L V -1 Ser ol o g y/ HI V/ H C V/ H B V testi n g is re q uire d d uri n g 
scree ni n g 
 
T hera p y C ha n ges:  
•  Secti o ns 4. 2. a n d 4. 2. 2 - clarifie d t he d urati o n of t he et o p osi de i nf usi o n as o ne 
h o ur eac h da y f or da ys 1 -3 of eac h c ycle of B V -C H E P t hera p y 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D J u ne 3 0, 2 0 1 7  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
L C C C 1 6 3 7 : Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y  of t he R are L y m p h o m a W or ki n g Gr o u p  
 
S h ort Title : B V-C H E P c he m ot hera p y f or A d ult T cell le u ke mia or l y m p h o ma 
 
 
Pri nci p al I n vesti g at or  
C hrist o p her Ditt us, D O, M P H  
U ni versit y of N ort h Car oli na at C ha pel Hill  
1 7 0 Ma n ni n g Dri ve, C B 7 3 0 5  
C ha pel Hill, N C 2 7 5 9 9  
E mail: c hris _ ditt us @ me d. u nc.e d u  
P h o ne/(fa x): 9 1 9 -9 6 2 -8 5 6 5  / (9 1 9 -9 6 6 -7 6 2 9)  
 
 
Bi ost atistici a n  
Xia n mi n g Ta n , P h D 
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter ( 2 0-0 2 2)  
T he U ni versit y of N ort h Car oli na at C ha pel Hill  
4 5 0 West Dri ve, 2 n d Fl o or, C B # 7 2 9 5  
C ha pel Hill, N C 2 7 5 9 9 -7 2 9 5  
E -m ail: xia n mi n g @e mail. u nc.e d u     P h o ne:  ( 9 1 9) 9 6 2-8 6 1 0   
 
Cli nic al Tri als  Office  
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
T he U ni versit y of N ort h Car oli na at C ha pel Hill  
4 5 0 West Dri ve, 3 r d Fl o or, C B # 7 2 9 5  
C ha pel Hill, N C 2 7 5 9 9 -7 2 9 5  
 
U ni versit y of N ort h C ar oli n a  C a ncer Net w or k M ultice nter  Pr oject M a n a ger : 
E mail: C P O M ultice nter @ me d. u nc.e d u  
 
S p o ns or :  Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
 
F u n di n g S o urce : Pfizer  
Versi o n: A me n d me nt # 9  
Versi o n d ate : J ul y 1 2, 2 0 2 4 
I N D #: 1 3 5 4 7 0  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
J ul y 1 2, 2 0 2 4 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
L C C C  1 6 3 7 : Bre nt u xi m a b Ve d oti n  wit h C ycl o p h os p h a mi de, D o x or u bici n, 
Et o p osi de, a n d Pre d nis o ne ( B V -C H E P) f or t he tre at me nt of A d ult T -Cell 
Le u ke mi a/ L y m p h o m a: A Pil ot St u d y  of t he R are L y m p h o m a W or ki n g Gr o u p  
 
S h ort Title: B V -C H E P c he m ot hera p y f or A d ult T cell le u ke mia or l y m p h o ma  
 
 
Pri nci p al I n vesti g at or  
C hrist o p her Ditt us, D. O., M. P. H . 
U ni versit y of N ort h Car oli na at C ha pel Hill  
1 7 0 Ma n ni n g Dri ve, C B 7 3 0 5  
C ha pel Hill, N C 2 7 5 9 9  
E mail: c hris _ ditt us @ me d. u nc.e d u  
P h o ne/(fa x): 9 1 9 -9 6 2 -8 5 6 5 / ( 9 1 9 -9 6 6 -7 6 2 9)  
 
 
 
 
 
Si g n at ure P a ge  
 
T he si g nat ure bel o w c o nstit utes t he a p pr o val of t his pr ot oc ol a n d t he attac h me nts, a n d 
pr o vi des t he necessar y ass ura nces t hat t his trial will be c o n d ucte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d 
acc or di n g t o l ocal le gal a n d re g ulat or y re q uire me nts a n d a p plica ble U. S. fe deral re g ulati o ns 
a n d I C H g ui deli nes.  
 
Pri nci p al I n vesti g at or ( PI) N a me : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
PI Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Versi o n: A me n d me nt # 9  
Versi o n d ate : J ul y 1 2, 2 0 2 4 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
i 
LI S T O F A B B R E VI A TI O N S  
T he a b bre viati o ns lists ca n be m o difie d/ u p date d  WI T H O U T t he nee d f or a pr ot oc ol 
a me n d me nt. It is pr o vi de d O N L Y  as a hel pf ul g ui de t o t he rea der  a n d is n ot a f or mal part 
of t he pr ot oc ol d oc u me nt . 
A D C  
A nti b o d y dr u g c o nj u gate  
A E  
A d verse e ve nt 
all o S C T 
All o ge neic ste m cell tra ns pla nt  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
A T L L  
A d ult T -cell le u ke mia/l y m p h o ma  
A Z T  
azi d ot h y mi di ne  
β -H C G  
Beta – h u ma n c h ori o nic g o na d otr o pi n  
BI D  
Bis i n die  (t wice dail y) 
BI D M C  
Bet h Israel Deac o ness Me dical Ce nter  
B M C  
B ost o n Me dical Ce nter  
B P  
Bl o o d press ure  
B V  
Bre nt u x ima b Ve d oti n  
B V -C H E P  
Bre nt u xi ma b ve d oti n, c ycl o p h os p ha mi de, d o x or u bici n, 
et o p osi de, pre d nis o ne 
C B C  
C o m plete bl o o d c o u nt  
C O D O X -M/I V A C  
D o x or u bici n, c ycl o p h os p ha mi de, c ytara bi ne, vi ncristi ne, 
met h otre xate/ Et o p osi de, if osfa mi de, c ytara bi ne, met h otre xate  
C H E P  
C ycl o p h os p ha mi de, d o x or u bici n, et o p osi de, pre d nis o ne  
C H O P  
C ycl o p h os ha mi de, d o x or u bici n, vi ncristi ne, pre d nis o ne  
C H O E P  
C ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, et o p osi de, 
pre d nis o ne  
D A -E P O C H  
D ose a dj uste d et o p osi de, vi ncristi ne, d o x or u bici n, b ol us 
c ycl o p h os p ha mi de, pre d nis o ne  
C L  
C hl ori de  
C M P  
C o m plete meta b olic pa nel  
C N S  
Ce ntral ner v o us s yste m  
C O 2  
Bicar b o nate  
C P O  
Cli nical pr ot oc ol office  
C R  
C o m plete res p o nse  
C R A  
Cli nical Researc h Ass ociate  
Cr Cl  
Creati ni ne cleara nce  
C R F  
Case re p ort f or m  
C R P  
C -reacti ve pr otei n 
C S F  
Cere br os pi nal fl ui d  
C T  
C o m p uter t o m o gra p h y  
C T C A P  
C o m p uter t o m o gra p h y of t he c hest, a b d o me n, a n d pel vis  
C Y P  
C yt oc hr o me P 4 5 0  
D 1  
Da y 1  
D F CI  
Da na -Far ber I nstit ute ( D F CI)  
E C H O  
Ec h ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G 6 P D  
Gl uc ose -6 -p h os p hate de h y dr o ge nase  
G C P  
G o o d cli nical practice 
G -C S F  
Gra n ul oc yte -c ol o n y sti m ulati n g fact or  
GI  
Gastr oi ntesti nal  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
ii 
H Bs -A g  
He patitis B s urface a nti ge n  
H Bc  
He patitis B c ore  
H B V  
He patitis B vir us  
H C V  
He patitis C vir us  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H L A  
H u ma n le uc oc yte a nti ge n  
Hr  
H o ur  
H S V  
Her pes si m ple x vir us  
H T L V  
H u ma n T -l y m p h otr o pic vir us 
H y per -C V A D  
H y perfracti o nate d  c ycl o p h os p ha mi de, vi ncristi ne, d o x or u bici n, 
de xa met has o ne  
I B 
I n vesti gat or’s Br oc h ure  
I D S 
I n vesti gati o nal dr u g ser vice  
I D S L 
I nte grate d Data Sta n dar ds Li brar y 
I H C 
I m m u n o hist oc he mistr y 
I F N 
I nterfer o n 
I N R 
I nter nati o nal n or malize d rati o 
I P 
I ntra perit o neal 
I R B 
I nstit uti o nal re vie w b oar d 
I T 
I ntrat hecal 
I V 
I ntra ve n o us 
K  
P otassi u m  
K g  
Kil o gra m  
L D H  
Lactate de h y dr o ge nase  
L N  
L y m p h n o de  
L V E F  
Left ve ntric ular ejecti o n fracti o n  
µ g/ k g  
Micr o gra m per kil o gra m  
Mi n  
Mi n ute  
M g  
milli gra ms  
M G H  
Mass Ge neral H os pital  
M M A E  
M o n o met h yl a uristati n E  
m L  
Milliliter  
M RI  
Ma g netic res o na nce I ma gi n g  
M U G A  
M ulti gate d ac q uisiti o n  
Na  
S o di u m  
N C C N  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k  
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute –  C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts  
O R R  
O verall res p o nse rate  
O S  
O verall s ur vi val  
P B M C  
Peri p heral bl o o d m o n o n uclear cells  
P C R  
P ol y merase c hai n reacti o n  
P D  
Pr o gressi ve disease  
P E  
P h ysical E xa m  
P E T  
P ositr o n E missi o n T o m o gra p h y  
P F S  
Pr o gressi o n free s ur vi val 
P F T  
P ul m o nar y f u ncti o n test  
P g p  
P -gl yc o pr otei n  
PJ P  
P ne u m oc ystis jir o veci p ne u m o nia  
P M L  
Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
P O  
Per os  ( b y m o ut h) 
P R  
Partial res p o nse  
P T  
Pr ot hr o m bi n ti me  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
iii 
P T C L  
Peri p heral T cell l y m p h o ma  
P T T  
Partial t hr o m b o plasti n ti me  
Q D  
Q u a q ue die  ( o nce dail y) 
R B C  
Re d bl o o d cell  
R N A  
Ri b o n ucleic aci d  
R L W G  
Rare L y m p h o ma W or ki n g Gr o u p  
S A E  
Seri o us a d verse e ve nt  
s.c. 
s u bc uta ne o us 
S D  
Sta ble disease  
SJ S  
Ste ve n J o h ns o n’s s y n dr o me  
S m Pc  
S u m mar y of pr o d uct c haracteristics  
S U S A R  
Seri o us u ne x pecte d a d verse reacti o n  
T E N  
T o xic e pi der mal necr ol ysis  
T X T  
Treat me nt  
U L N  
U p per li mit of n or mal  
U N C  
U ni versit y of N ort h Car oli na  
V Z V  
Varicella vir us  
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
i v 
T A B L E O F C O N T E N T S  
 
LI S T O F A B B R E VI A TI O N S  ........................................................................................... i 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  ..................................................................1  
1. 1  
St u d y S y n o psis  ......................................................................................................1  
1. 2  
A d ult T -Cell Le u ke mia/ L y m p h o ma Bac k gr o u n d  .................................................1  
1. 3  
N o Clear Sta n dar d of Care i n t he U nite d States  ....................................................2  
1. 4  
I n vesti gati o nal A ge nt: Bre nt u xi ma b Ve d oti n ( B V) ..............................................3  
1. 5  
Ot her A ge nts: C ycl o p h os p ha mi de, D o x or u bici n, Et o p osi de, a n d Pre d nis o ne 
( C H E P) .............................................................................................................................3  
1. 6  
Rati o nale f or B V -C H E P  ........................................................................................3  
1. 7  
C orrelati ve St u dies  .............................................. Err or! B o o k m ar k n ot defi ne d.  
2. 0  
S T U D Y O B J E C TI V E S  ...........................................................................................5  
2. 1  
Pri mar y O bjecti ve  .................................................................................................5  
2. 2  
Sec o n dar y O bjecti ves  ............................................................................................5  
2. 3  
E x pl orat or y O bjecti ves  ..........................................................................................5  
2. 4  
E n d p oi nts  ...............................................................................................................5  
3. 0  
P A TI E N T E LI GI BI LI T Y  ......................................................................................6  
3. 1  
I ncl usi o n Criteria ...................................................................................................6  
3. 2  
E xcl usi o n Criteria  ..................................................................................................8  
4. 0  
T R E A T M E N T P L A N  .............................................................................................1  
4. 1  
Sc he ma  ..................................................................................................................1  
4. 2  
Treat me nt D osa ge a n d A d mi nistrati o n  .................................................................1  
4. 3  
All o wa ble D ose Le vel Re d ucti o ns of Bre nt u xi ma b Ve d oti n  ................................4  
4. 4  
T o xicities a n d D osi n g Dela ys/ D ose M o dificati o ns  ...............................................4  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
v  
4. 5  
C o nc o mita nt Me dicati o ns/ Treat me nts  ..................................................................7  
4. 6  
Ot her M o dalities or Pr oce d ures  .............................................................................8  
4. 7  
D urati o n of T hera p y  ..............................................................................................8  
4. 8  
D urati o n of F oll o w U p  ..........................................................................................8  
4. 9  
Re m o val of Patie nts fr o m Pr ot oc ol T hera p y  .........................................................9  
4. 1 0  
St u d y Wit h dra wal  ..................................................................................................9  
4. 1 1  
Off -St u d y Criteria  .................................................................................................9  
5. 0  
D R U G I N F O R M A TI O N  ........................................................................................9  
5. 1  
Bre nt u xi ma b ve d oti n ( A dcetris ®)  .........................................................................9  
5. 2  
Ret ur n a n d Rete nti o n of St u d y Dr u g  ...................................................................1 1  
5. 3  
C H E P C he m ot hera p y  ..........................................................................................1 2  
6. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  ............................................................1 5  
6. 1  
Ti me a n d E ve nts Ta ble ( B V + C H E P)  ..................................................................1 5  
6. 2  
Ti me a n d E ve nts Ta ble ( B V Mai nte na nce T hera p y)  ..........................................1 8  
6. 3  
Pre -St u d y Assess me nts  .......................................................................................2 0  
6. 4  
Treat me nt Assess me nts ( See Ta ble 6. 1)  .............................................................2 0  
6. 5  
B V Mai nte na nce Treat me nt ( C D 3 0 -p ositi ve A T L L o nl y –  see Ta ble 6. 2) ........2 2  
6. 6  
P ost -Treat me nt F oll o w -u p Assess me nts  .............................................................2 3  
6. 7  
C orrelati ve St u dies Pr oce d ures  ...........................................................................2 4  
6. 8  
Assess me nt of Safet y  ..........................................................................................2 4  
6. 9  
Assess me nt of Efficac y  .......................................................................................2 4  
7. 0  
A D V E R S E E V E N T S  ............................................................................................2 4  
7. 1  
Defi niti o ns  ...........................................................................................................2 4  
7. 2  
D oc u me ntati o n of n o n -seri o us A Es or S A Rs ......................................................2 6  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
vi  
7. 3  
S A Es or Seri o us S A Rs  ........................................................................................2 6  
7. 4  
Data a n d Safet y M o nit ori n g Pla n  ........................................................................3 1  
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................3 1  
8. 1  
St u d y Desi g n/ St u d y E n d p oi nts  ............................................................................3 1  
8. 2  
Sa m ple Size a n d Accr ual  .....................................................................................3 2  
8. 3  
Data A nal ysis Pla ns  .............................................................................................3 2  
9. 0  
S T U D Y M A N A G E M E N T  ....................................................................................3 3  
9. 1  
I nstit uti o nal Re vie w B oar d (I R B) A p pr o val a n d C o nse nt ..................................3 3  
9. 2  
Re q uire d D oc u me ntati o n .....................................................................................3 3  
9. 3  
Re gistrati o n Pr oce d ures .......................................................................................3 4  
9. 4  
Data Ma na ge me nt a n d M o nit ori n g/ A u diti n g  ......................................................3 4  
9. 5  
A d here nce t o t he Pr ot oc ol  ...................................................................................3 4  
9. 6  
A me n d me nts t o t he Pr ot oc ol  ...............................................................................3 6  
9. 7  
Rec or d Rete nti o n  .................................................................................................3 7  
9. 8  
O bli gati o ns of I n vesti gat ors  ................................................................................3 7  
1 0. 0  R E F E R E N C E S  ......................................................................................................3 8  
1 1. 0  A P P E N DI C E S  .......................................................................................................4 0  
1 1. 1  
A p pe n di x A: Re vise d res p o nse criteria f or l y m p h o ma ( C hes o n, et al. J Cli n 
O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8)  .........................................................................................4 1  
1 1. 2  
A p pe n di x B - Re nal I m pair me nt G ui deli nes  .......................................................4 4  
1 1. 3  
A p pe n di x C - C hil d -P u g h He patic I m pair me nt Sc ore  ........................................4 5  
1 1. 4  
A p pe n di x D:  Pr o hi bite d Me dicati o ns or T h ose t o be use d wit h Ca uti o n  ...........4 6  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1  
 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
St u d y S y n o psis  
A d ult T -cell le u ke mia/l y m p h o ma ( A T L L) is a n H T L V -1 -ass ociate d mali g na nc y 
t hat is e n de mic i n t he Cari b bea n isla n ds, Wester n Africa, Brazil, Ira n, a n d Ja pa n. 
T he maj orit y of A T L L cases i n t he U nite d States occ ur al o n g t he Easter n 
sea b oar d d ue t o e mi grati o n fr o m t he Cari b bea n isla n ds. Patie nts wit h t he t w o 
a g gressi ve A T L L s u bt y pes, ac ute a n d l y m p h o mat o us, res p o n d dis mall y t o 
tra diti o nal treat me nt a p pr oac hes. T here e xists n o sta n dar d of care f or t his hi g hl y 
m or bi d disease. I n t his pil ot st u d y, we will c ollect p reli mi nar y data a b o ut t he 
efficac y of  a n o vel re gi me n, bre nt u xi ma b ve d oti n  wit h c ycl o p h os p ha mi de, 
d o x or u bici n, et o p osi de, a n d pre d nis o ne ( B V -C H E P). T he pri mar y o bjecti ve is t o 
deter mi ne t he pr o p orti o n of s u bjects wit h c o m plete res p o nse ( C R) t o B V -C H E P.  
We  ai m t o e nr oll  1 4  e val ua ble s u bjects. We h y p ot hesize t hat B V -C H E P 
a d mi nistere d t o patie nts wit h A T L L will  ha ve a C R rate of  ar o u n d 4 5 %  i n t his 
p o p ulati o n . 
 
1. 2  
A d ult T -Cell Le u ke mi a/ L y m p h o m a B ac k gr o u n d  
A d ult T -cell le u ke mia/l y m p h o ma ( A T L L) is a n H T L V -1 -ass ociate d mali g na nc y 
t hat is e n de mic i n t he Cari b bea n isla n ds, Wester n Africa, Brazil, Ira n, a n d Ja pa n 
[1 , 2 ]. T he maj orit y of A T L L cases i n t he U nite d States occ ur al o n g t he Easter n 
sea b oar d d ue t o e mi grati o n fr o m t he Cari b bea n isla n ds. Massac h usetts has t he 
U nite d States’ t hir d lar gest p o p ulati o n of Haitia n i m mi gra nts, wit h t he maj orit y of 
t his p o p ulati o n resi di n g i n B ost o n [3 ]. T his ma kes B ost o n o ne of t he A T L L 
e pice nters i n t he U nite d States. A d diti o nall y, ot her Easter n sea b oar d re gi o ns 
har b or patie nts wit h A T L L, i ncl u di n g t he state wi de catc h me nt area of t he 
U ni versit y of N ort h Car oli na at C ha pel Hill.  
 
A T L L is varia bl y C D 3 0 p ositi ve, a n d, n ota bl y, C D 3 0 p ositi vit y ma y be ass ociate d 
wit h a w orse pr o g n osis  [4 ].  Patie nts wit h t he t w o a g gressi ve A T L L s u bt y pes, 
ac ute a n d l y m p h o mat o us, res p o n d dis mall y t o tra diti o nal treat me nt a p pr oac hes. 
T here e xists n o sta n dar d of care f or t his hi g hl y m or bi d disease.  T he Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k ( N C C N) g ui deli nes s u g gest cli nical trial 
partici pati o n as first li ne t hera p y; h o we ver, cli nical trial o pti o ns are li mite d.  
 
T he Rare L y m p h o ma W or ki n g Gr o u p ( R L W G) ar ose fr o m c o nse ns us at t he 
L y m p h o ma Researc h F o u n dati o n ( L R F) Ne w E n gla n d meeti n gs d ue t o t he nee d 
f or c o o perati o n a m o n gst i nstit uti o ns t o i m pr o ve A T L L treat me nt strate gies. T he 
R L W G ori gi nall y e nc o m passe d t he B ost o n -area h os pitals: B ost o n Me dical Ce nter 
( B M C), Bet h Israel Deac o ness Me dical Ce nter ( BI D M C), Massac h usetts Ge neral 
H os pital ( M G H), a n d Da na -Far ber Ca ncer I nstit ute ( D F CI), a n d has n o w 
e x pa n de d t o i ncl u de t he U ni versit y of N ort h Car oli na at C ha pel Hill ( U N C) , as 
well as sites i n N Y C a n d Mia mi . T his br oa d partici pati o n will e na ble accr ual of 
A T L L patie nts i n cli nical trials al o n g t he Easter n Sea b oar d. T he R L W G offers a n 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
2  
 
u n prece de nte d m o del f or i nstit uti o nal c olla b orati o n t hat will be use d t o st u d y 
ot her rare l y m p h o mas i n t he f ut ure.  
 
B M C , BI D M C, M G H, a n d D F CI eac h treat 3 -5 cases per year. U N C treats 
a p pr o xi matel y 1 -2 cases per year. A d diti o nall y, ot her re gi o nal i nstit uti o ns ha ve 
a gree d t o refer ne w A T L L cases t o a partici pati n g R L W G i nstit uti o n. Wit h t his 
c olla b orati ve eff ort, it is esti mate d t hat a mi ni m u m of 1 5 eli gi ble patie nts will be 
care d f or eac h year. A d diti o nall y, t he rate of  A T L L a p pears t o be i ncreasi n g 
nati o nall y. Fr o m t he peri o d bet wee n 2 0 0 2 a n d 2 0 1 1, t here has bee n a statisticall y 
si g nifica nt 6. 6 % perce nt a n n ual i ncrease i n A T L L cases ( A P C) [5 ]. 
 
C o nsi dera ble eff ort will be ma de t o ca pt ure all eli gi ble patie nts.  I nf or me d 
c o nse nt f or ms will be a vaila ble i n m ulti ple rele va nt la n g ua ges. Pre -treat me nt wit h 
bis p h os p h o nates t o c o ntr ol h y percalce mia will be per mitte d, as will o ne c ycle of 
c o m bi nati o n c he m ot hera p y, if i m me diate disease c o ntr ol is warra nte d.  
1. 3  
N o Cle ar St a n d ar d of C are  i n t he U nite d St ates 
T he m ost c o m pelli n g  ra n d o mize d trial f or A T L L was c o n d ucte d i n Ja pa n, a n d 
use d  t he i nte nsi ve c he m ot hera pe utic re gi men L S G 1 5 ( V C A P -A M P -V E C P)  [6 ]. 
T his re gi me n  s h o we d a n i m pr o ve me nt i n C R rate o ver bi wee kl y 
c ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, a n d pre d nis o ne ( C H O P -1 4) ( 4 0 % vs. 
2 1 %), b ut still  o nl y ha d  a 3-year O S of 2 4 % . I m p orta ntl y, se veral of t he a ge nts 
use d i n t his re gi me n are n ot a vaila ble i n t he U nite d States.  R ece nt researc h i n 
Ja pa n has s h o w n a C R rate of 5 2 %  w he n a n o vel C C R-4 i n hi bit or, 
m o ga m uliz u ma b , is use d i n c o m bi nati o n wit h L S G 1 5 [7 ]. U nf ort u natel y, a  rece nt 
st u d y re veale d a n i ncrease d ris k of se vere a n d c ortic oster oi d -refract or y graft-
vers us -h ost disease, n o n -rela pse m ortalit y, a n d o verall m ortalit y i n patie nts 
treate d wit h m o ga m uliz u ma b pri or t o all o ge neic ste m cell tra ns pla nt (all o S C T) 
[8 ]. A d diti o nall y, m o ga m uliz u ma b  is n ot c urre ntl y a vaila ble i n t he U nite d States. 
I n ot her st u dies, the s m ol deri n g a n d c hr o nic t y pes of A T L L ha ve bee n s h o w n t o 
res p o n d well t o a ntiretr o viral t hera p y wit h zi d o v u di ne a n d i nterfer o n al p ha [9 -1 1 ]. 
F or t he ac ute t y pe, t he be nefits of a ntiretr o virals are m uc h less dra matic, wit h a  
me dia n s ur vi val of 9 m o nt hs. N ota bl y, t he l y m p h o mat o us t y pe has t he w orst 
res p o nse t o a ntiretr o viral t hera p y wit h a me dia n s ur vi val of o nl y 7 m o nt hs a n d 
li mite d n u m bers of patie nts s ur vi vi n g after fi ve years fr o m dia g n osis [9 ].  O verall, 
t here is n o c urre nt sta n dar d of care re gi me n i n t he U nite d States f or A T L L, 
treat me nt o pti o ns are li mite d, a n d a vaila ble t hera pies ha ve l o w res p o nse rates a n d 
s o meti mes se vere si de effects.  
 
Des pite t he lac k of a sta n dar d i nitial treat me nt f or A T L L, m ost pr o vi ders feel t hat 
all o S C T i n first re missi o n is a sta n dar d a p pr oac h. T he best e vi de nce f or t his 
c o mes fr o m st u dies c o n d ucte d i n Ja pa n, w here ap pr o xi matel y 1 2 0 patie nts 
u n der g o all o S C T f or A T L L yearl y. O ne st u d y f o u n d t hat  patie nts w h o recei ve d a n 
all o S C T fr o m a H L A -matc he d d o n or ha d a 3 -year O S of 4 1 %, w hile t h ose w h o 
recei ve d u nrelate d b o ne marr o w ha d a 3-year O S of 3 9 %  [1 2 ]. A n ot her  st u d y 
e val uate d l o n g -ter m o utc o mes after re d uce d-i nte nsit y c o n diti o ni n g a n d f o u n d t hat 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
3  
 
1 0 of 2 9 patie nts s ur vi ve d f or a me dia n of 8 2 m o nt hs wit h a 5 -year O S of 3 4 %  
[1 3 ]. W hile n ot c urati ve f or m ost patie nts, t hese fi n di n gs s h o w t hat certai n 
patie nts ca n ha ve l o n g -ter m s ur vi val, w hic h is n ot p ossi ble wit h o ut all o S C T. 
1. 4  
I n vesti g ati o n al A ge nt : Bre nt u xi m a b Ve d oti n ( B V) 
Bre nt u xi ma b ve d oti n is a n o vel a nti b o d y -dr u g c o nj u gate ( A D C) t hat c o m bi nes a n 
a nti-C D 3 0 m o n ocl o nal a nti b o d y wit h m o n o met h yl a uristati n E ( M M A E), w hic h is 
a micr ot u b ule -disr u pti n g a ge nt. O nce B V bi n ds t o C D 3 0 o n t he s urface of t he 
A T L L cell, it is i nter nali ze d a n d releases M M A E. T his t he n disr u pts t he 
micr ot u b ule net w or k, lea di n g t o G 2/ M cell c ycle arrest a n d a p o pt osis  [1 4 ]. 
C urre ntl y, B V is a p pr o ve d f or si n gle-a ge nt use i n rela pse d/refract or y classical 
H o d g ki n l y m p h o ma, hi g h -ris k H o d g ki n l y m p h o ma after a ut ol o g o us ste m cell 
tra ns pla nt, a n d rela pse d/refract or y a na plastic lar ge cell l y m p h o ma. I n N o ve m ber 
2 0 1 8, B V was als o a p pr o ve d f or use i n pre vi o usl y u ntreate d s yste mic a na plastic 
lar ge cell l y m p h o ma (sA L C L) or ot her C D 3 0 -e x pressi n g  peri p heral T -cell 
l y m p h o mas ( P T C L), i n c o m bi nati o n wit h c he m ot hera p y.  
 
Bre nt u xi ma b ve d oti n has se veral, well -descri be d t o xicities. T he m ost i m p orta nt of 
w hic h is peri p heral ne ur o pat h y. Beca use of t his t o xicit y, t he c he m ot hera p y 
bac k b o ne  f or L C C C 1 6 3 7 d oes n ot i ncl u de a vi nca al kal oi d. Ot her c o m m o n 
t o xicities are na usea, diarr hea, fati g ue, al o pecia, d ys p nea, c o nsti pati o n, c o u g h, 
a n d fe brile ne utr o pe nia. T he maj orit y of t hese are gra de 1 or 2  [1 4 ]. 
1. 5  
Ot her A ge nts : C ycl o p h os p h a mi de, D o x or u bici n, E t o p osi de, a n d Pre d nis o ne 
(C H E P)  
T he ot her a ge nts t hat will be use d i n c o m bi nati o n wit h B V i n t his trial are: 
c ycl o p h os p ha mi de, d o x or u bici n, et o p osi de, a n d pre d nis o ne. T hese a ge nts ha ve 
bee n st u die d e xte nsi vel y i n vari o us c o m bi nati o ns ( C H O P, C H O E P, D A -E P O C H). 
T hese re gi me ns are t he sta n dar d of care f or t he treat me nt of a g gressi ve B -cell a n d 
T -cell l y m p h o mas.  
1. 6  
R ati o n ale  f or B V-C H E P  
B V has bee n st u die d i n A T L L. A p hase I m ultice nter trial was c o n d ucte d t o 
e val uate t he safet y a n d efficac y of B V i n C D 3 0 -p ositi ve peri p heral T -cell 
l y m p h o mas ( P T C L) [1 5 ]. T his st u d y e val uate d t w o gr o u ps of patie nts: se q ue ntial 
( 2 c ycles of B V f oll o we d b y 6 c ycles of C H O P) a n d c o m bi nati o n ( B V-C H P; 
c ycl o p h os p ha mi de, d o x or u bici n, pre d nis o ne). T he B V d ose use d i n c o m bi nati o n 
wit h C H P was 1. 8 m g/ k g, w hic h is t he sta n dar d d ose w he n use d as a si n gle a ge nt. 
T his d ose was well -t olerate d w he n c o m bi ne d wit h C H P. Of t he 3 9 patie nts 
e val uate d i n t his st u d y, 2 ha d A T L L. B ot h of t hese A T L L patie nts were i n t he 
B V -C H P gr o u p a n d b ot h e x perie nce d a c o m plete res p o nse ( C R). S pecificall y, o ne 
p atie nt ha d  sta ge I V A T L L wit h a n I PI sc ore of 3 a n d ha d a pr o gressi o n free 
s ur vi val ( P F S) of 7. 1 m o nt hs. T he ot her patie nt was sta ge I V wit h a n I PI sc ore of 
5 a n d ha d a P F S of 4 1. 4 m o nt hs. C urre ntl y, a p hase 3 trial is e nr olli n g patie nts t o 
c o m pare B V -C H P wit h C H O P (c ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, a n d 
pre d nis o ne) i n t he i nitial treat me nt of C D 3 0 -p ositi ve mat ure T -cell l y m p h o mas 1 4. 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
4  
 
B ot h of t hese st u dies f oc us o n peri p heral T -cell l y m p h o mas ( P T C Ls ), t he vast 
maj orit y of w hic h will n ot be A T L L cases. H o we ver, base d o n t he p hase I trial 
res ults, B V has pr o misi n g efficac y i n A T L L. As a res ult, w e pr o p ose c o m bi ni n g 
B V wit h a n et o p osi de -c o ntai ni n g re gi me n: c ycl o p h os p ha mi de, d o x or u bici n, 
et o p osi de, a n d pre d nis o ne ( C H E P). T he a d diti o n of et o p osi de t o t he alrea d y 
st u die d re gi me n, B V-C H P, is base d o n t he i m pr o ve d efficac y of et o p osi de -
c o ntai ni n g re gi me ns i n P T C L  [1 6 , 1 7 ]. 
 
T he c urre nt a vaila ble literat ure str o n gl y s u p p orts B V’s cli nical efficac y i n C D 3 0 -
p ositi ve l y m p h o mas, as well as t he efficac y of et o p osi de -c o ntai ni n g re gi me ns i n 
P T C L. M ore o ver, B V is efficaci o us i n c uta ne o us C D 3 0 -p ositi ve T -cell l y m p h o ma  
re gar dless of baseli ne le vels of C D 3 0 e x pressi o n. T his was de m o nstrate d i n 4 8 
patie nts wit h C D 3 0 -p ositi ve l y m p h o pr oliferati ve dis or ders or m yc osis f u n g oi des 
w h o recei ve d 1. 8 m g/ k g of B V e ver y 2 1 da ys ; t hese patie nts ha d eit her l o w 
(< 1 0 % ), me di u m (1 0 % t o 5 0 % ), or hi g h  ( ≥ 5 0 % ) e x pressi o n  le vels of s ol u ble 
C D 3 0 at baseli ne  [ 1 8].  I n 2 8 patie nts wit h m yc osis f u n g oi des/ Sezar y s y n dr o me, 
5 0 % of patie nts ( 5 o ut of 1 0 patie nts) wit h l o w e x pressi o n, 5 8 % of patie nts  ( 7 of 
1 2 patie nts)  wit h me di u m e x pressi o n, a n d 5 0 %  of patie nts  ( 3 of 6 patie nts) wit h 
hi g h e x pressi o n of C D 3 0  res p o n de d t o B V.  All patie nts wit h l y m p h o mat oi d 
pa p ul osis ( n = 9) a n d pri mar y c uta ne o us a na plastic T -cell l y m p h o mas ( n = 2) 
res p o n de d wit h a me dia n d urati o n of res p o nse of 2 6 wee ks (ra n ge, 6 t o  4 4 wee ks);  
s ol u ble baseli ne C D 3 0 le vels were l o west i n c o m plete res p o n ders (P  = 0. 0 3 6). 
Ta ke n, t o get her, w e belie ve t hat patie nts wit h A T L L w o ul d greatl y be nefit fr o m 
f urt her i n vesti gati o n i nt o t he efficac y of B V use d i n c o m bi nati o n wit h C H E P 
( B V-C H E P).  I n o ur st u d y, patie nts wit h C D 3 0-p ositi ve A T L L w h o are n ot 
ca n di dates f or B M T after c o m pleti n g B V -C H E P will be offere d mai nte na nce 
t hera p y wit h B V a n d C D 3 0-ne gati ve patie nts will be i neli gi ble f or B V 
mai nte na nce.  
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
5  
 
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ve  
T o defi ne t he pr o p orti o n of s u bjects wit h C R  after 2 -6 c ycles of  bre nt u xi ma b 
ve d oti n i n c o m bi nati o n wit h c ycl o p h os p ha mi de, d o x or u bici n, et o p osi de, a n d 
pre d nis o ne ( B V -C H E P) i n t he treat me nt of a d ult T -cell le u ke mia/l y m p h o ma . 
2. 2  
Sec o n d ar y O bjecti ves  
2. 2. 1  T o esti mate t he o verall res p o nse rate ( O R R) ass ociate d wit h  2 -6 c ycles of  B V -
C H E P  t hera p y i n patie nts wit h a d ult T-cell le u ke mia/l y m p h o ma.   
2. 2. 2  T o deter mi ne pr o gressi o n -free s ur vi val ( P F S) f or B V-C H E P  i n patie nts wit h a d ult 
T -cell le u ke mia/l y m p h o ma  w h o  recei ve d or di d n ot recei ve  B V mai nte na nce * .  
2. 2. 3  T o deter mi ne d urati o n of res p o nse t o B V -C H E P i n  patie nts wit h  a d ult T-cell 
le u ke mia/l y m p h o ma w h o recei ve d or di d n ot recei ve B V mai nte na nce * . 
2. 2. 4  T o deter mi ne o verall s ur vi val  ( O S) of patie nts wit h a d ult T -cell 
le u ke mia/l y m p h o ma treate d wit h B V-C H E P  w h o recei ve d or di d n ot recei ve  B V 
mai nte na nce t hera p y * . 
2. 2. 5  T o e val uate t he t o xicit y a n d t olera bilit y of  B V -C H E P a n d B V mai nte na nce  
t hera p y via t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts ( N CI -C T C A E v 4 . 0 3). 
 
* N ote : After c o m pleti o n or wit h dra wal fr o m B V -C H E P  t hera p y, patie nts will 
se gre gate i nt o o ne of t he f oll o wi n g gr o u ps: 1) t h ose w h o pr o gresse d o n B V -
C H E P; 2) t h ose w h o c o m plete d  2 -6 c ycles of B V -C H E P a n d we nt  o n t o 
all o ge neic tra ns pla nt; 3) t h ose w h o c o m pleted  6 c ycles of B V -C H E P b ut were 
C D 3 0 ne gati ve a n d i neli gi ble f or mai nte na nce t hera p y ; a n d 4) t h ose w h o 
c o m plete d  6 c ycles of B V -C H E P, were C D 3 0 p ositi ve , b ut c o nti n ue d  st u d y 
treat me nt o n B V i n t he mai nte na nce p hase of t he st u d y. 
 
2. 3  
E x pl or at or y O bjecti ves  
2. 3. 1  
 
2. 4  
E n d p oi nts  
2. 4. 1  Pri m ar y E n d p oi nt  
Criteria f or C R after 2 -6 c ycles of B V -C H E P  will be base d o n t he I nter nati o nal 
W or ks h o p t o sta n dar dize res p o nse criteria f or mali g na nt l y m p h o mas (i .e., L u ga n o 
Criteria per C hes o n, et al. J Cli n O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8; See A p pe n di x A: 
Re vise d res p o nse criteria f or l y m p h o ma * ).  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
6  
 
2. 4. 2  Sec o n d ar y E n d p oi nts  
2. 4. 2. 1  Criteria f or o verall res p o nse will be base d o n t he I nter nati o nal W or ks h o p t o 
sta n dar dize res p o nse criteria f or mali g na nt l y m p h o mas (i.e., L u ga n o Criteria per 
C hes o n, et al. J Cli n O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8; See A p pe n di x A: Re vise d 
res p o nse criteri a f or l y m p h o m a * ). 
2. 4. 2. 2  P F S is defi ne d as ti me fr o m D 1 of treat me nt u ntil disease pr o gressi o n ( base d o n 
L u ga n o criteria * ) or deat h fr o m a n y ca use. 
2. 4. 2. 3  D urati o n of res p o nse is defi ne d as t he ti me fr o m d oc u me ntati o n of t u m or 
res p o nse per L u ga n o criteria*  t o disease pr o gressi o n. 
2. 4. 2. 4  O S is defi ne d as t he ti me fr o m D 1 of treat me nt u ntil deat h fr o m a n y ca use . 
2. 4. 2. 5  T o xicit y a n d t olera bilit y of t hera p y will be assesse d via t he N CI C T C A E v 4. 0 3 . 
 
* N ote : S u bjects wit h a le u ke mic c o m p o ne nt t o t heir disease at baseli ne will ha ve 
peri p heral bl o o d assesse d per a d ult T -cell le u ke mia/l y m p h o ma N C C N G ui deli nes  
versi o n 2. 2 0 1 7  o utli ne d i n secti o n 6. 9 . 
 
3. 0  
P A TI E N T E LI GI BI LI T Y  
3. 1  
I ncl usi o n Criteri a 
S u bjects m ust meet all of  t he f oll o wi n g i ncl usi o n criteria t o partici pate i n t his 
st u d y: 
3. 1. 1  Inf or me d c o nse nt  a n d HI P A A a ut h orizati o n f or release of pers o nal healt h 
i nf or mati o n o btai ne d .  
3. 1. 2  A ge ≥ 1 8 years at t he ti me of c o nse nt.  
3. 1. 3  E C O G Perf or ma nce Stat us of 0 -2 . 
3. 1. 4  Hist ol o gical c o nfir mati o n of bi o ps y -pr o ve n peri p heral T -cell le u ke mia/l y m p h o ma 
c o nsiste nt wit h A T L L  
•  
I ncl u de d s u bt y pes will be: ac ute, l y m p h o mat o us, a n d c hr o nic u nfa v ora ble. 
C hr o nic u nfa v ora ble is defi ne d as t he c hr o nic varia nt wit h at least o ne of 
t he f oll o wi n g: L D H > U L N, B U N > U L N, Al b u mi n < L L N 
•  
P ositi ve H T L V -1 a nti b o d y testi n g wit h c o nfir mat or y testi n g via Wester n 
bl ot , e nz y me -li n ke d i m m u n os or be nt assa y ( E LI S A), or m olec ular testi n g 
( P C R).  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
8  
 
A d diti o nall y, a patie nt ma y ha ve ta ke n  a ntiretr o viral t hera p y ( e. g. A Z T a n d/ or 
I F N) at a n y ti me pri or t o st u d y e nr oll me nt.  
3. 1. 1 3  C D 3 0 e x pressi o n  deter mi ne d b y fl o w c yt o metr y or I H C.  N O T E : If C D 3 0 testi n g 
was pre vi o usl y d o ne o n t he bi o ps y sa m ple fr o m dia g n osis, t his i nf or mati o n will 
be c ollecte d.  If C D 3 0 testi n g was n ot d o ne, a n arc hi val sa m ple fr o m t he bi o ps y 
use d f or dia g n osis will be re q ueste d a n d teste d f or C D 3 0.  C D 3 0 testi n g will al s o 
be d o ne o n t he b o ne marr o w tiss ue c ollecte d fr o m t he b o ne marr o w e xa m.  If we 
are u na ble t o o btai n a n arc hi val sa m ple or if t he b o ne marr o w e xa m is ne gati ve, a 
ne w bi o ps y will be perf or me d t o c o nfir m t he dia g n o sis a n d test f or C D 3 0. 
 
3. 2  
E xcl usi o n Criteri a  
S u bjects w h o  meet a n y of t he f oll o wi n g criteria s h o ul d be e xcl u de d fr o m st u d y 
partici pati o n : 
3. 2. 1  Pre g na nt or breastfee di n g ( N O T E: breast mil k ca n n ot be st ore d f or f ut ure use 
w hile t he m ot her is bei n g treate d o n st u d y).  
3. 2. 2  Has a k n o w n a d diti o nal mali g na nc y t hat is acti ve a n d/ or pr o gressi ve re q uiri n g 
treat me nt; e xce pti o ns i ncl u de basal cell or s q ua m o us cell s ki n ca ncer, i n sit u 
cer vical or bla d der ca ncer, or ot her ca ncer f or w hic h t he s u bject has bee n disease -
free. 
3. 2. 3  Pre vi o us e x p os ure t o bre nt u xi ma b ve d oti n ( B V) . 
3. 2. 4  Hist or y of aller gic res p o nse t o B V -C H E P  or its c o m p o ne nts or t o a n y of t he 
re q uire d pr o p h ylactic me dicati o ns or reas o na ble alter nati ves. 
3. 2. 5  S y m pt o matic car diac disease i ncl u di n g ve ntric ular d ysf u ncti o n, left ve ntric ular 
ejecti o n fracti o n < 4 0 %, s y m pt o matic c or o nar y arter y disease or s y m pt o matic 
arr h yt h mias 
3. 2. 6  S u bjects wit h se vere he patic i ns ufficie nc y C hil d -P u g h Sc ore  > 6  (see 1 1. 3  
A p pe n di x C) . 
3. 2. 7  S u bjects wit h se vere re nal i m pair me nt (i.e., creati ni ne cleara nce ≤ 3 0 m L/ mi n; see 
A p pe n di x B - Re nal I m pair me nt G ui deli nes ). 
3. 2. 8  E xcl u de patie nts wit h pre -e xisti n g ne ur o pat h y gra de 2 or hi g her.  
3. 2. 9  Patie nts recei vi n g pr o hi bite d me dicati o ns liste d i n t he patie nt ha n d o ut pr o vi de d i n 
1 1. 4  A p pe n di x D:  Pr o hi bite d Me dicati o ns or T h ose t o be use d wit h Ca uti o n  (i.e., 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
9  
 
ket oc o naz ole, itrac o naz ole, rit o na vir, macr oli de a nti bi otics, er yt hr o m yci n 
p he n yt oi n, p he n o bar bital, car ba maza pi ne, a n d val pr oic aci d ).  
3. 2. 1 0  Patie nts wit h a pare nc h y mal brai n lesi o n t h o u g ht t o be  c o nsiste nt wit h acti ve 
l y m p h o ma o n scree ni n g C T/ M RI. Of n ote, patie nts wit h C S F i n v ol ve me nt al o ne 
are n ot e xcl u de d.  
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
3  
 
 
 
 
 
1.  B V mai nte na nce will be gi ve n t o patie nts wit h C D 3 0 + e x pressi o n o nl y.   S u bjects wit h C D 3 0 
e x pressi o n a b o ve 1 perce nt will be c o nsi dere d t o ha ve C D 3 0 +  disease . 
2.  B V mai nte na nce will be gi n 2 1 da ys after last d ose of B V -C H E P. Will all o w f or a o ne -wee k 
wi n d o w.  
3.  Ca n start at D L -1  ( 1. 2 m g/ k g) or D L -2  ( 0. 9 m g/ k g) if necessar y f or t o xicit y. 
4.  Ma xi m u m d ose of B V is 1 8 0 m g per c ycle.  T he d ose f or patie nts wei g hi n g greater t ha n 1 0 0 k g 
s h o ul d be calc ulate d base d o n a wei g ht of 1 0 0 k g 
4. 2. 2  S u p p orti ve C are   
Al l patie nts are re q uire d t o  recei ve s u p p orti ve care f or ac ute or c hr o nic t o xicit y, 
i ncl u di n g bl o o d c o m p o ne nts or a nti bi otics, a n d ot her i nter ve nti o ns (e.g ., 
c orrecti o n of electr ol yte a b n or malities)  as a p pr o priate. S u p p orti ve care g ui deli nes 
f or a d mi nistrati o n of c he m ot hera p y s h o ul d be f oll o we d per i nstit uti o nal 
g ui deli nes . S u g gesti o ns are: 
1. PJ P pr o p h yla xis wit h Bactri m D S ( or si milar a ge nt)  
2. A nti viral pr o p h yla xis f or her pes si m ple x vir us ( H S V) a n d Varicella vir us 
( V Z V): Ac ycl o vir or valac ycl o vir   
3. A nti f u n gal pr o p h yla xis if A N C < 5 0 0: Fl uc o naz ole at pr o p h yla xis  d osi n g  
4. Bacterial pr o p h yla xis if  A N C < 5 0 0: Fl u or o q ui n ol o ne at pr o p h yla xis  d osi n g  
5. T u m or l ysis pr o p h yla xis f or at least 1 wee k after treat me nt i n d ucti o n: 
All o p uri n ol  
6. Tra nsf usi o n of platelets if c o u nts < 1 0, 0 0 0  cells/ m m 3 
 
I ntr at hec al C he m ot her a py: 
C N S pr o p h yla xis will be use d f or all patie nts starti n g wit h t he first c ycle of B V-
C H E P. T he a ge nt(s) ( met h otre xate, c ytara bi ne, or a c o m bi nati o n of met h otre xate 
a n d c ytara bi ne) a n d d osi n g sc he d ule will be at t he discreti o n of t he i n di vi d ual 
pr o vi der. I ntrat hecal c he m ot hera p y will n ot be c o nti n ue d d uri n g t he mai nte n a nce 
p hase of B V.  
 
If t he patie nt has acti ve C N S i n v ol ve me nt, as e vi de nce d b y p ositi ve cere br os pi nal 
fl ui d (C S F ) c yt ol o g y or fl o w c yt o metr y, will nee d t o i ncrease sc he d ule t o wee kl y 
i ntrat hecal c he m ot hera p y u ntil t he l y m p h o ma is cleare d fr o m t he C S F. At t hat 
p oi nt, t he sc he d ule ca n ret ur n t o a n or mal pr o p h ylactic sc he d ule at t he discreti o n 
of t he pr o vi der.  
 
S u p p ortive C are f or H y perc alce mi a: 
I ntra ve n o us fl ui ds (I V F) a n d bis p h os p h o nate t hera p y s h o ul d be i nstit ute d i n all 
patie nts t o pre ve nt  c o m plicati o ns fr o m h y percalce mia acc or di n g t o i nstit uti o nal 
g ui deli nes.  
4. 2. 3  Pre me dic ati o n/ H y dr ati o n  
Pre me dicati o n (i ncl u di n g pr o p h ylactic a ntie metics) a n d h y drati o n s h o ul d be 
pr o vi de d as per i nstit uti o nal g ui deli nes a n d per sta n dar d of care f or C H O P or 
C H O E P a d mi nistrati o n.  
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
4  
 
I nf usi o n-relate d reacti o ns (i ncl u di n g a na p h yla xis) ma y occ ur d uri n g t he i nf usi o n 
of B V. T heref ore, t he i nf usi o n s h o ul d be a d mi nistere d at a site pr o perl y e q ui p pe d 
a n d staffe d t o ma na ge a na p h yla xis s h o ul d it occ ur.  M o nit or patie nts d uri n g 
i nf usi o n. If a na ph yla xis occ urs i m me diatel y a n d per ma ne ntl y disc o nti n ue 
a d mi nistrati o n of B V a n d a d mi nister a p pr o priate me dical t hera p y per i nstit uti o nal 
sta n dar ds. If a mil d or m o derate i nf usi o n-relate d reacti o n occ urs, t he i nf usi o n 
s h o ul d be i nterr u pte d or t he rate of i nf usi o n sl o we d a n d a p pr o priate me dical 
ma na ge me nt i nstit ute d. Patie nts w h o e x perie nce d pri or i nf usi o n -relate d reacti o n 
t o B V s h o ul d be pre-me dicate d f or s u bse q ue nt i nf usi o ns per i nstit uti o nal 
sta n dar ds. Pre me dicati o n ma y i ncl u de aceta mi n o p he n, a n a nti hista mi ne a n d a 
c ortic oster oi d.  
4. 3  
All o w a ble D ose Le vel Re d ucti o ns of Bre nt u xi m a b Ve d oti n  
4. 3. 1. 1  D ose Le vel Re d ucti o n of B V  
D ose Le vel  
Bre nt u xi m a b  ve d oti n  
M a xi m u m d ose  
0  
1. 8 m g/ k g  
1 8 0 m g  
-1  
1. 2 m g/ k g  
1 2 0 m g  
-2  
0. 9 m g/ k g  
9 0 m g  
* T he d ose f or patie nts wei g hi n g greater t ha n 1 0 0 k g s h o ul d be calc ulate d 
base d o n a wei g ht of 1 0 0 k g.  
4. 4  
T o xicities a n d D osi n g Del a ys/ D ose M o dific ati o ns  
A n y patie nt w h o recei ves treat me nt o n t his pr ot oc ol will be e val ua ble f or t o xicit y.  
Eac h patie nt will be assesse d re g ularl y f or t he de vel o p me nt of a n y t o xicit y 
acc or di n g t o t he Ti me a n d E ve nts ta ble ( Secti o n  6. 0 ).  T o xicit y will be assesse d 
acc or di n g t o t he N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 
( C T C A E), versi o n 4. 03 . A s us pecte d a d verse reacti o n ( S A R) is a n y A E f or w hic h 
t here is a reas o na ble p ossi bilit y t hat t he dr u g is t he ca use.  See secti o n 7. 2  f or 
a d diti o nal i nf or mati o n o n S A Rs.  
4. 4. 1. 1  D ose M o dific ati o ns/ Del a ys f or  B V  + C H E P  
( N ote: T hese d ose m o dificati o ns a p pl y t o B V o nl y u nless ot her wise s pecifie d)  
T o xicit y  
≤Gr a de 2  
≥Gr a de 3  
N o n he mat ol o gic 
(e xcl u di n g 
ne ur o pat h y)  
C o nti n ue at sa me d ose le vel  
H ol d  B V u ntil t o xicit y has res ol ve d t o 
≤Gra de 2 or has ret ur ne d t o baseli ne a 
 
He mat ol o gic  
C o nti n ue at sa me d ose le vel  
F or ne utr o pe nia < 5 0 0, ma na ge b y 
a d di n g a nti micr o bial a n d a ntif u n gal 
pr o p h yla xis. M ust be a nti bi otic wit h 
gra m -ne gati ve c o vera ge (i.e. 
le v ofl o xaci n) a n d a ntif u n gal wit h 
Ca n di da c o vera ge (i.e. fl uc o naz ole)  
F or t hr o m b oc yt o pe nia, pr ocee d 
acc or di n g t o i nstit uti o nal g ui deli nes.  
F or a ne mia, ma na ge per i nstit uti o nal 
g ui deli nes.  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
7  
 
Peri p heral  
Ne ur o pat h y  
Gr a de 1  
C o nti n ue at 
sa me d ose 
le vel 
Gr a de 2 or 3  
D osi n g s h o ul d be wit h hel d u ntil 
ne ur o pat h y i m pr o ves t o Gra de 1 or 
baseli ne a n d t he n restarte d at 
1. 2  m g/ k g. If t o xicit y persists at 
1. 2 m g/ k g d osi n g, h ol d B V u ntil 
ne ur o pat h y i m pr o ves t o gra de 1  or 
baseli ne , a n d restart at 0. 9 m g/ k g. If 
ne ur o pat h y rec urs at d ose of 
0. 9  m g/ k g, d o n o t res u me B V. 
F or mai nte na nce o nl y, if ne ur o pat h y d oes 
n ot i m pr o ve b y 6 wee ks, per ma ne ntl y 
disc o nti n ue.  
Gr a de 4  
Disc o nti n ue 
treat me nt 
wit h B V.  
a. S u bjects  w h o de vel o p Gra de 3 or 4 electr ol yte la b orat or y a b n or malities s h o ul d ha ve t hese re ple nis he d 
a n d ma y c o nti n ue st u d y treat me nt wit h o ut i nterr u pti o n.  
4. 5  
C o nc o mit a nt Me dic ati o ns/ Tre at me nts  
U p -t o-date vacci nati o ns are s u g geste d, b ut n ot ma n dat or y , pri or t o a patie nt 
si g ni n g t he mai n c o nse nt f or m. Vacci nati o n(s) d uri n g st u d y treat me nt m ust be 
a p pr o ve d b y t he treati n g p h ysicia n.  
 
T he use of tra nsf usi o ns, platelet a n d/ or c ol o n y -sti m ulati n g fact ors per i nstit uti o nal 
practice is per mitte d d uri n g t hera p y at t he I n vesti gat or’s discreti o n.  Patie nts ma y 
n ot recei ve ot her i n vesti gati o nal dr u gs, i m m u n os u p pressi ve me dicati o ns ( ot her 
t ha n de xa met has o ne or pre d nis o ne f or use as a nti-e metics, or if ster oi ds are 
nee de d t o treat a n i nf usi o n reacti o n), or a nti ne o plastic t hera p y d uri n g t he st u d y.  
T he r o uti ne use of ster oi ds as pre me dicati o n pri or t o B V is disc o ura ge d.  
 
If a n i nf usi o n-relate d reacti o n occ urs, t he i nf usi o n s h o ul d be i nterr u pte d, a n d 
a p pr o priate me dical ma na ge me nt i nstit ute d per i nstit uti o nal g ui deli nes . Patie nts 
w h o ha ve e x perie nce d a pri or i nf usi o n -relate d reacti o n t o a n y of t he st u d y 
me dicati o ns s h o ul d be pre me dicate d f or s u bse q ue nt i nf usi o ns. Pre me dicati on ma y 
i ncl u de aceta mi n o p he n, a n a nti hista mi ne, a n d a c ortic oster oi d.  
4. 5. 1  C o ntr ai n dic ati o ns ( W ar ni n gs a n d Prec a uti o ns)  
I n-vitr o data i n dicate t hat m o n o met h yl a uristati n E  (i.e., dr u g c o nj u gate of B V) is 
a s u bstrate a n d i n hi bit or of t he P 4 5 0 is oe nz y me C Y P 3 A 4.  Patie nts w h o are 
recei vi n g str o n g C Y P 3 A 4 i n hi bit ors s uc h as ket oc o naz ole wit h B V s h o ul d be 
cl osel y m o nit ore d f or a d verse reacti o ns.  C o -a d mi nistrati o n wit h p ote nt C Y P 3 A 4 
i n d ucers, s uc h as rifa m pi n, s h o ul d be a v oi de d.  B V is n ot e x pecte d t o alter t he 
e x p os ure t o dr u gs t hat are meta b olize d b y C Y P 3 A 4 e nz y mes.  A fre q ue ntl y  
u p date d  list of C Y P 3 A 4 i n hi bit ors a n d i n d ucers can be f o u n d at 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ . 
 
Dr u gs w hic h i n d uce C Y P 3 A 4 (e.g ., barb it urates, p he n yt oi n, car ba maze pi ne, 
rifa m pi n) ma y e n ha nce t he meta b olis m of c ortic oster oi ds a n d re q uire t hat t he 
d osa ge of t he c ortic oster oi d be i ncrease d. Dr u gs w hic h i n hi bit C Y P 3 A 4 (e .g ., 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
8  
 
ket oc o naz ole, itrac o naz ole, rit o na vir, i n di na vir, macr oli de a nti bi otics s uc h as 
er yt hr o m yci n) ha ve t he p ote nt ial t o i ncrease plas ma c o nce ntrati o ns of 
c ortic oster oi ds. C oa d mi nistrati o n of ot her dr u gs t hat are meta b olize d b y C Y P 3 A 4 
(e.g ., i n di na vir, er yt hr o m yci n) ma y i ncrease t heir cleara nce, res ulti n g i n decrease d 
plas ma  c o nce ntrati o n. C oa d mi nistrati o n of c ortic oster oi ds a n d warfari n us uall y 
res ults i n i n hi biti o n of res p o nse t o warfari n. 
 
I ncrease d he mat ot o xicit y a n d/ or i m m u n os u p pressi o n ma y res ult fr o m t he 
c o m bi ne d effect of c ycl o p h os p ha mi de a d mi nistere d wit h ot her c yt ot o xic a ge nts. 
I ncrease car di ot o xicit y ma y res ult w he n c ycl o p h os p ha mi de is gi ve n wit h 
a nt hrac ycli nes (i .e., d o x or u bici n). F urt her m ore, c o nc urre nt treat me nt wit h 
cycl o p h os p ha mi de wit h d o x or u bici n has bee n re p orte d t o e xacer bate 
c ycl o p h os p ha mi de -i n d uce d he m orr ha gic c ystitis. 
 
C o nc o mita nt use of a ntie pile ptic me dicati o ns i ncl u di n g p he n yt oi n, p he n o bar bital, 
car ba maze pi ne, a n d val pr oic aci d is ass ociate d wit h i ncrease d  cleara nce a n d 
re d uce d efficac y of et o p osi de. 
 
Please refer t o t he F D A -a p pr o ve d pac ka ge i nserts f or  B V,  c ycl o p h os p ha mi de, 
d o x or u bici n, et o p osi de a n d pre d nis o ne f or m ore e xte nsi ve pr o d uct i nf or mati o n 
a n d a c o m pre he nsi ve list of a d verse e ve nts , war ni n gs a n d preca uti o ns a n d 
p ote ntial dr u g i nteracti o ns . 
4. 6  
Ot her M o d alities or Pr oce d ures  
T he re are n o ot her m o dalities t hat are i ncl u de d wit hi n t he st u d y para meters. Of 
n ote, it is hi g hl y s u g geste d t hat patie nts w h o are eli gi ble, recei ve a n all o ge neic 
ste m cell tra ns pla nt i n first re missi o n. 
4. 7  
D ur ati o n of T her a p y  
Patie nts s h o ul d c o nti n ue pr ot oc ol t hera p y as descri be d a b o ve u ntil:  
• 
Eli gi ble f or B M T t hera p y (i .e., after 2 - 6 c ycle of B V + C H E P)  
•  
Disease pr o gressi o n  
• 
I nter-c urre nt ill ness 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)  
• 
Patie nt deci des t o wit h dra w fr o m t he st u d y, O R  
• 
Ge neral or s pecific c ha n ges i n t he patie nt’s c o n diti o n re n der t he patie nt 
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or.  
4. 8  
D ur ati o n of F oll o w U p  
All p atients will be f oll o we d f or u p t o 5  years  or u ntil deat h ( w hic he ver occ urs 
first) after re m o val  fr o m st u d y treat me nt (i.e., B V-C H E P or B V mai nte na nce) .  
Patie nts re m o ve d fr o m st u d y treat me nt  f or u nacce pta ble A Es will be f oll o we d 
u ntil res ol uti o n or sta bilizati o n of t he e ve nt(s).  See  Ti me a n d E ve nts ta bles i n 
secti o n 6. 0  a n d secti o n 6. 6  f or a d diti o nal details o n P ost  st u d y treat me nt/ F oll o w 
u p Assess me nts .   

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
9  
 
4. 9  
Re m o v al of P atie nts fr o m Pr ot oc ol T her a p y  
Patie nts will be re m o ve d fr o m treat me nt w he n  a n y of t he criteria liste d i n Secti o n 
4. 7  a p pl y , if t he i nteracti o n ca n n ot be res ol ve d b y a me dicati o n c ha n ge or 
st o p pi n g t he n o n-pr ot oc ol treat me nt .  N otif y t he Pri nci pal I n vesti gat or, a n d 
d oc u me nt t he reas o n f or st u d y  treat me nt re m o val a n d t he date t he patie nt was 
re m o ve d i n t he electr o nic Case Re p ort F or m  (e-C R F) .  T he patie nt s h o ul d be 
f oll o we d-u p per pr ot oc ol.      
4. 1 0  
St u d y Wit h dr a w al  
If a patie nt deci des t o wit h dra w fr o m t he st u d y (a n d n ot j ust fr o m pr ot oc ol 
t hera p y) all eff orts s h o ul d be ma de t o c o m plete a n d re p ort st u d y  assess me nts as 
t h or o u g hl y as p ossi ble. T he i n vesti gat or s h o ul d c o ntact t he patie nt or a 
res p o nsi ble relati ve b y tele p h o ne or t hr o u g h a pers o nal visit t o esta blis h as 
c o m pletel y as  p ossi ble t he reas o n f or t he st u d y wit h dra wal.  
•  T he s u bject s h o ul d be as ke d if t he y are willi n g t o all o w f or t he a bstracti o n 
of rele va nt i nf or mati o n fr o m t heir me dical rec or d i n or der t o meet t he l o n g 
ter m f oll o w u p (e. g., s ur vi val) o bjecti ves o utli ne d i n t he pr ot oc ol.  
•  A c o m plete fi nal e val uati o n at t he ti me of t he s u bject’s st u d y wit h dra wal 
s h o ul d be o btai ne d wit h a n e x pla nati o n of w h y t he s u bject is wit h dra wi n g 
fr o m t he st u d y.  
•  If t he s u bject is n o nc o m plia nt a n d d oes n ot ret ur n f or a n e n d of st u d y f oll o w 
u p assess me nt, t his s h o ul d be d oc u me nte d i n t he e C R F.  
•  If t he reas o n f or wit h dra wal of a s u bject fr o m t he st u d y is a n a d verse e ve nt, 
t he pri nci pal s pecific e ve nt will be rec or de d o n t he e C R F.  
4. 1 1  
Off -St u d y Criteri a  
S u bjects will be c o nsi dere d off st u d y b y a n y of  t he f oll o wi n g criteria: 
•  S u bject  has  c o m plete d  all st u d y acti vities i ncl u di n g a n y nee de d f oll o w-u p  
acti vities  a n d n o f urt her data c ollecti o n fr o m t he s u bject is nee de d  
•  S u bject wit h dra ws c o nse nt t o be i n t he st u d y ( Secti o n 4. 1 0) 
•  Deat h  
•  L ost t o f oll o w -u p  
•  Sit uati o ns i n w hic h t he treati n g p h ysicia n feels it is i n t he best i nterest f or t he 
s u bject t o n ot c o nti n ue i n t he st u d y. 
5. 0  
D R U G I N F O R M A TI O N  
5. 1  
Bre nt u xi m a b ve d oti n ( A dcetris ® ) 
See t he B V I n vesti gat or’s Br oc h ure (I B) a n d t he prescri bi n g i nf or mati o n f or 
A dcetris ® ( bre nti x u ma b ve d oti n) f or m ore detaile d i nf or mati o n. 
5. 1. 1  Descri pti o n  
B V is a sterile, preser vati ve -free, w hite- 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 c o ntai ni n g 5 0 m g eac h f or rec o nstit uti o n f or 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 0  
 
i ntra ve n o us (I V) a d mi nistrati o n. It will be s u p plie d b y Pfizer at n o c har ge t o st u d y 
s u bjects   
5. 1. 2  P ac k a gi n g a n d L a beli n g  
I n vesti gati o nal dr u g s u p pl y of B V will be s u p plie d b y Pfizer f or C D 3 0- patie nts  
s u p plie d f or free b y Pfizer . C D 3 0 + patie nts will recei ve c o m mercial s u p pl y.   
5. 1. 3  St or a ge a n d H a n dli n g  
Vials c o ntai ni n g B V m ust be refri gerate d at 2 – 8° C i n a c o ntr olle d l ocati o n 
accessi ble o nl y t o t he p har macist, t he I n vesti gat or, or a d ul y desi g nate d pers o n.  It 
is rec o m me n de d t hat B V vials a n d s ol uti o ns be st ore d pr otecte d fr o m direct 
s u nli g ht u ntil t he ti me of use.  
5. 1. 4  D ose, Sc he d ule a n d A d mi nistr ati o n  
See Secti o n 4. 2 .  T he d ose f or patie nts wei g hi n g greater t ha n 1 0 0 k g s h o ul d be 
calc ulate d base d o n a wei g ht of 1 0 0 k g.  
5. 1. 5  Pre p ar ati o n  
See t he B V prescri bi n g i nf or mati o n f or pre parati o n i nstr ucti o ns. T he d ose of B V 
i n t his st u d y will be 1.8  m g/ k g wit h all o wa ble d ose re d ucti o n t o 0. 9 m g/ k g.  
 
T he pre pare d d osi n g s ol uti o n m ust be st ore d at 2 -8° C ( D O N O T F R E E Z E) 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.  See pac ka ge i nsert f or a d diti o nal details.  
5. 1. 6  St a bilit y  
B V f or I njecti o n d oes n ot c o ntai n preser vati ves; t heref ore, o pe ne d a n d 
rec o nstit ute d vials of B V m ust be use d wit hi n t he sa me da y w he n st ore d u n der 
refri gerati o n at 2– 8° C.  Rec o nstit ute d vials m ust n ot be s ha ke n.  
5. 1. 7  Acc o u nt a bilit y, Ret u r n a n d Rete nti o n of B V  
T he i n vesti gat or is res p o nsi ble f or kee pi n g acc urate rec or ds of t he i n vesti gati o nal 
su p plies recei ve d fr o m Pfizer or desi g nee, t he a m o u nt dis pe nse d t o t he s u bjects 
a n d t he a m o u nt re mai ni n g at t he c o ncl usi o n of t he trial.  
 
U p o n c o m pleti o n or ter mi nati o n of t he st u d y,  u n use d vials of i n vesti gati o nal l ot 
will be ha n dle d per i nstr ucti o ns fr o m Pfizer .  T he s p o ns or ma y re q uest t hat  all 
u n use d a n d/ or partiall y use d i n vesti gati o nal pr o d uct will be destr o ye d at t he site 
per i nstit uti o nal p olic y (e. g., U N C I D S dr u g destr ucti o n p olic y). It is t he 
I n vesti gat or’s res p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y c o ntai ners, 
pr o vi de d t hat  pr oce d ures f or pr o per dis p osal ha ve bee n esta blis he d acc or di n g t o 
a p plica ble fe deral, state, l ocal a n d i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d 
pr o vi de d t hat a p pr o priate rec or ds of dis p osal are ke pt . 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 1  
 
5. 1. 8  A d verse E ve nts Ass oci ate d wit h B V  
T he a d verse e ve nts liste d bel o w ha ve bee n re p orte d i n patie nts recei vi n g B V. F or 
f urt her i nstr ucti o n o n t he ma na ge me nt a d verse e ve nts ass ociate d wit h B V t hera p y 
see secti o n 4. 3 . 
•  Peri p heral Ne ur o pat h y: B V peri p heral ne ur o pat h y is c u m ulati ve. Patie nts 
e x perie nci n g ne w or w orse ni n g peri p heral ne ur o pat h y ma y re q uire d ose dela y, 
c ha n ge i n d ose or disc o nti n uati o n of B V  
•  A na p h yla xis a n d i nf usi o n reacti o ns: If a na p h yla xis occ urs, i m me diatel y a n d 
per ma ne ntl y disc o nti n ue B V. I nf usi o n -relate d reacti o ns s h o ul d be ma na ge d 
per i nstit uti o nal sta n dar ds (see rec o m me n dati o ns i n secti o n 4. 5 ) 
•  He mat ol o gic t o xicit y: I ncl u des Gra de 3 or 4 t hr o m b oc yt o pe nia or a ne mia a n d 
fe brile ne utr o pe nia  
•  Seri o us i nfecti o ns or o p p ort u nistic i nfecti o ns: I ncl u des p ne u m o nia, 
bactere mia, a n d se psis or se ptic s h oc k (i ncl u di n g fatal o utc o mes). Patie nts 
s h o ul d be cl osel y m o nit ore d f or t he e mer ge nce of p ossi ble bacterial, f u n gal, or 
viral i nfecti o ns.  
•  T u m or l ysis s y n dr o me: Patie nts wit h hi g h t u m or b ur de n or ra pi dl y 
pr oliferati n g t u m or ma y be at ris k f or t u m or l ysis s y n dr o me.  
•  I ncrease d t o xicit y i n t he prese nce of se vere re nal i m pair me nt: See secti o n f or 
f urt her details. 
•  I ncrease d t o xicit y i n t he prese nces of m o derate or se vere he patic i m pair me nt: 
See secti o n 4. 4. 1. 2  f or f urt her details. 
•  He pat ot o xicit y: Seri o us cases of he pat ot o xicit y ha ve bee n re p orte d c o nsiste nt 
wit h he patic i nj ur y, i ncl u di n g ele vati o ns of tra nsa mi nases or bilir u bi n.  
•  Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L): J o h n C u n ni n g ha m vir us 
res ulti n g i n P M L has occ urre d i n patie nts recei vi n g B V. H ol d B V d osi n g f or 
s us pecte d case of P M L a n d disc o nti n ue B V if dia g n osis is c o nfir me d. 
•  P ul m o nar y t o xicit y: E ve nts of n o ni nfecti o us p ul m o nar y t o xicit y i ncl u di n g 
p ne u m o nitis, i nterstitial l u n g disease, a n d ac ute res pirat or y distress s y n dr o me 
( A R D S), s o me wit h fatal o utc o mes, ha ve bee n re p orte d. I n t he e ve nt of ne w or 
w orse ni n g p ul m o nar y s y m pt o ms, h ol d B V d osi n g d uri n g e val uati o n a n d u ntil 
s y m pt o matic i m pr o ve me nt. 
•  Seri o us der mat ol o gic reacti o ns: Ste ve ns -J o h ns o n s y n dr o me ( SJ S) a n d t o xic 
e pi der mal necr ol ysis ( T E N), i ncl u di n g fatal o utc o mes ha ve bee n re p orte d wit h 
B V  
•  Gastr oi ntesti nal ( GI) c o m plicati o ns: Fatal a n d seri o us GI c o m plicati o ns 
i ncl u di n g perf orati o n, he m orr ha ge, er osi o n, ulcer, i ntesti nal o bstr ucti o n, 
e nter oc olitis, ne utr o pe nic c olitis, a n d ile us ha ve bee n re p orte d wit h B V 
t hera p y. I n t he e ve nt of w orse ni n g GI s y m pt o ms, perf or m a pr o m pt dia g n ostic 
e val uati o n a n d treat a p pr o priatel y.  
5. 2  
Ret ur n a n d Rete nti o n of St u d y Dr u g  
I n vesti g ati o n al L ot 
At t he c o ncl usi o n of t he st u d y, re mai ni n g dr u g will be destr o ye d acc or di n g t o 
U N C I D S  ( or m ultice nter site) i nstit uti o nal p olic y.  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 2  
 
 
C o m merci al S u p pl y  
L ocal re q uire me nts f or dis p osal of hazar d o us dr u gs s h o ul d be f oll o we d at eac h 
partici pati n g cli nical site.  
 
Please see U N C p olic y o n hazar d o us dr u gs:  
htt p://i ntra net. u nc healt hcare. or g/i ntra net/ h os pital de part me nts/safet y net/ p olicies/ ha
zar d o us dr u gs. p df  
 
5. 3  
C H E P C he m ot her a p y  
 
5. 3. 1  Descri pti o n  
C H E P c o nsists of c ycl o p h os p ha mi de, d o x or u bici n, et o p osi de , a n d pre d nis o ne . 
 
5. 3. 2  Met h o d of Pr oc ure me nt  
C H E P  c o m p o ne nts are c o m merciall y a vaila ble a n d a p pr o ve d b y t he U S F o o d a n d 
Dr u g A d mi nistrati o n f or use i n patie nts wit h m ulti ple t y pes of ca ncer. 
C o m mercial s u p plies of t he i n di vi d ual c o m p o ne nts of C H E P  will be use d f or t his 
st u d y a n d bille d t o patie nts a n d/ or t heir i ns ura nce c o m pa n y. 
 
5. 3. 3  D ose, Sc he d ule a n d A d mi nistr ati o n  
See secti o n  4. 2  
 
5. 3. 4  St or a ge a n d H a n dli n g  a n d dis p os al  
T he i n di vi d ual c o m p o ne nts of C H E P  t hera p y s h o ul d be st ore d a n d ha n dle d per 
i nstit uti o nal g ui deli nes i n acc or da nce wit h t he ma n ufact urer’s prescri bi n g 
i nf or mati o n. 
 
Please see p olic y o n hazar d o us dr u gs:  
htt p:// ne ws. u nc healt hcare. or g/e m p ne ws/att/ 2 0 1 1/ n o v/a d mi n 0 1 8 8/  
 
5. 3. 5  P ac k a gi n g a n d L a beli n g  
T he c o m p o ne nts of C H E P  are c o m merciall y a vaila ble.  
 
5. 3. 6  Pre p ar ati o n  
C H E P  c o m p o ne nts s h o ul d be pre pare d per i nstit uti o nal g ui deli nes i n acc or da nce 
wit h t he ma n ufact urer’s prescri bi n g i nf or mati o n.  
 
5. 3. 7  Ret ur n a n d Rete nti o n of C H E P  
Partiall y use d a n d c o m pletel y use d vials will be destr o ye d per i nstit uti o nal 
g ui deli nes.  
 
5. 3. 8  A d verse E ve nts Ass oci ate d wit h C H E P   
Please refer t o t he F D A -a p pr o ve d pac ka ge i nserts f or c ycl o p h os p ha mi de, 
d o x or u bici n, et o p osi de  a n d pre d nis o ne  f or pr o d uct i nf or mati o n, e xte nsi ve 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 3  
 
pre parati o n i nstr ucti o ns, a n d a c o m pre he nsi ve list of a d verse e ve nts. T he m ost 
c o m m o n t o xicities ass ociate d wit h eac h of t he i n di vi d ual a ge nts are liste d bel o w:  
 
C ycl o p h os p h a mi de : 
•  He mat ol o gic : m yel os u p pressi o n (le u k o pe nia, ne utr o pe nia, 
t hr o m b oc yt o pe nia, a n d a ne mia), se vere i m m u n os u p pressi o n, a n d b o ne 
marr o w fail ure ma y be d ose li miti n g  
•  Uri nar y bla d der t o xicit y : he m orr ha gic c ystitis, p yelitis, ureteritis, a n d 
he mat uria ha ve bee n re p orte d. A de q uate h y drati o n is esse ntial pri or t o 
c ycl o p h os p ha mi de  
•  Car di ot o xicit y : m y ocar ditis, m y o pericar ditis, pericar dial eff usi o n, 
i ncl u di n g car diac ta m p o na de a n d c o n gesti ve heart fail ure ha ve bee n 
re p orte d 
•  P ul m o nar y : p ne u m o nitis, p ul m o nar y fi br osis, p ul m o nar y ve n o-occl usi ve 
disease a n d ot her f or ms of p ul m o nar y t o xicit y lea di n g t o res pirat or y 
fail ure ha ve bee n re p orte d 
•  G o na dal s u p pressi o n  a n d e m br y ofetal t o xicit y : male a n d fe male 
re pr o d ucti ve f u ncti o n a n d fertilit y a n d fetal de vel o p me nt ma y be i m paire d  
b y c ycl o p h os p ha mi de  
•  Gastr oi ntesti nal : na usea, v o miti n g, diarr hea, a b d o mi nal disc o mf ort a n d 
a n ore xia ma y occ ur  
•  Al o pecia  a n d s ki n ras h : hair l oss, h y per pi g me ntati o n of t he s ki n a n d s ki n 
ras h a n d i m pair me nt of w o u n d heali n g 
•  H y p o natre mia : ass ociate d wit h i ncrease t otal b o d y water, a n d s y n dr o me of 
i na p pr o priate secreti o n of a nti di uretic h or m o ne, w hic h ma y be fatal has 
bee n re p orte d  
 
D o x or u bici n:  
•  He mat ol o gic : le u k o pe nia ( d ose-li miti n g), t hr o m b oc yt o pe nia, a ne mia; 
na dir i n 1 0 -1 4 da ys wit h rec o ver y us uall y i n 2 1 da ys  
•  Der mat ol o gic : al o pecia ( us uall y c o m plete; re versi ble); ra diati o n recall 
reacti o ns; i ncrease d se nsiti vit y t o s u nli g ht 
•  Gastr oi ntesti nal : na usea a n d v o miti n g ( d o x or u bici n is ge nerall y 
c o nsi dere d m o deratel y t o hi g hl y e met o ge nic), a n ore xia, diarr hea, 
m uc ositis (st o matitis, es o p ha gitis)  
•  Car di o vasc ular:  car di o m y o pat h y ma y occ ur a n d is relate d t o t otal 
c u m ulati ve lifeti me d ose.  T he ris k f or car di o m y o pat h y i ncreases wit h 
t otal d oses > 4 5 0 m g/ m2.  E C G c ha n ges a n d less ofte n, arr h yt h mias are 
see n.  Rarel y, s u d de n deat h has occ urre d    
 
Et o p osi de :  
•  He mat ol o gic : m yel os u p pressi o n is a m o n g t he m ost c o m m o n si de effects, 
a n d ma y be d ose -li miti n g 
•  Gastr oi ntesti nal : na usea a n d v o miti n g ma y occ ur wit h et o p osi de  is 
ge nerall y c o nsi dere d mil dl y or m o deratel y e met o ge nic . T hese s y m pt o ms 
ca n us uall y be c o ntr olle d wit h sta n dar d a ntie metic t hera p y   

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 4  
 
•  Bl o o d press ure c ha n ges : i nci de nces of h y p o or h y perte nsi o n ha ve bee n 
re p orte d 
•  A na p h ylactic/aller gic reacti o ns : et o p osi de ma y ca use a na p h ylactic -t y pe 
reacti o ns c haracterize d b y c hills, ri g ors, tac h ycar dia, br o nc h os pas m, 
d ys p nea, dia p h oresis, fe ver, pr urit us, h y perte nsi o n or h y p ote nsi o n, l oss  of 
c o nsci o us ness, na usea a n d v o miti n g ha ve bee n re p orte d . S ki n ras hes a n d 
facial fl us hi n g was re p orte d i n patie nts recei vi n g et o p osi de 
•  Ot her : re versi ble al o pecia, s o meti mes pr o gressi n g t o t otal bal d ness ma y 
occ ur i n u p t o 6 6 % of patie nts  
 
Pre d nis o ne : 
•  He mat ol o gic : a ne mia, ne utr o pe nia a n d fe brile ne utr o pe nia 
•  Car di o vasc ular : bra d ycar dia, car diac arrest, arr h yt h mias, e nlar ge me nt a n d 
ot her circ ulat or y e ve nts ma y occ ur . 
•  Der mat ol o gic : ac ne, ac neif or m er u pti o ns, aller gic der matitis, al o pecia, dr y 
a n d scal y s ki n, hirs utis m, etc . are ass ociate d wit h pre d nis o ne . 
•  E n d ocri ne : a dre nal i ns uffi cie nc y, fati g ue wea k ness a me n orr hea, 
p ost me n o pa usal blee di n g a n d ot her me nstr ual irre g ularities, decrease d 
car b o h y drate a n d gl uc ose t olera nce, h y per or h y p ot h yr oi dis m, etc . 
•  Fl ui d a n d electr ol yte dist ur ba nces : fl ui d rete nti o n, s o di u m rete nti o n 
res ulti n g i n e de ma, h y p o kale mic al kal osis, meta b olic al kal osis a n d 
c o n gesti ve heart fail ure i n s usce pti ble patie nts  
•  Ot her : ne gati ve nitr o ge n bala nce d ue t o pr otei n cata b olis m, art hral gi as, 
l oss of m uscle mass, gastr oi ntesti nal dist ur ba nces i ncl u di n g i ncrease 
a p petite a n d wei g ht gai n, ne ur ol o gic a n d ps yc hiatric dist ur ba nces, bl urre d 
visi o n a n d cataract, a n d i ncreases i n i ntra oc ular press ure, 
i m m u n os u p pressi o n a n d mas ki n g of i nfecti o ns, i nso m nia, m o o n face a n d 
p yre xia  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 5  
 
6. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  
6. 1  
Ti me a n d E ve nts T a ble  ( B V + C H E P) 
St u d y Assess me nts  
Scree ni n g 1 
(D -2 8 t o 0)  
B V + C H E P ( 2 1 -D a y C ycle) X 6 c ycles 1 
D 1  
D 2  
D 3  
D 4  
D 5  
D 8  
D 1 5  E n d of T xt  
Visit 1 
F oll o w 
u p 1 9 
Si g ne d I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
Me dical hist or y/ De m o gra p hics  
X  
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria re vie w 
X  
 
 
 
 
 
 
 
 
 
P h ysical E xa m ( P E) 2 
X  
X 2  
 
 
 
 
 
 
X  
 
Vital si g ns  ( B P, p ulse a n d te m perat ure) 
X  
X  
X 3  
X 3  
 
 
X  
 
X  
 
E C O G  perf or ma nce stat us  
X  
X  
 
 
 
 
 
 
X  
 
I ma gi n g st u dies 4  
X 4 
X 4  
 ( Cycles 3 / 5) 
 
 
 
 
 
 
X 4                           
(e n d of c ycle 6) 
X 1 9 
B o ne marr o w as pirati o n a n d bi o ps y 5 
X  
 
 
 
 
 
 
 
X 5 
 
B i o ps y wit h C D 3 0 testi n g ( b y fl o w or I H C) 6  
X  
 
 
 
 
 
 
 
 
 
H T L V -1 Ser ol o g y/ HI V/ H C V/ H B V  Testi n g  
X  
 
 
 
 
 
 
 
 
 
Str o n g yl oi des via ser ol o g y or st o ol  
X  
 
 
 
 
 
 
 
 
 
G 6 P D  
X  
 
 
 
 
 
 
 
 
 
Uric aci d a n d p h os p h or us 7 
X  
X  
 
 
 
 
X  
 
 
 
He mat ol o g y  ( C B C w. differe ntial) 
X  
X  
 
 
 
 
X  
 
X  
X 1 9 
Cli nical C he mistr y  ( C M P/ L D H)8 
X  
X  
 
 
 
 
X  
 
X  
 
S ol u ble I nterle u ki n 2 Rece pt or  
X  
 
 
 
 
 
 
 
X  
 
Ser u m or Uri ne pre g na nc y test  ( W O C B P)9 
X 9  
X 9  
 
 
 
 
 
 
X  
 
I ntrat hecal Pr o p h yla xis wit h C S F  st u dies (cell c o u nt, c yt ol o g y, 
fl o w)1 0  
 
X  
 
 
 
 
 
 
X 1 0 
 
I ntrat hecal Treat me nt (f or acti ve C N S i n v ol ve me nt) wit h C S F 
st u dies (cell c o u nt, c yt ol o g y, fl o w) 1 1 
 
X 1 1 
 
 
 
 
X 1 1 
X 1 1 
X 1 1 
 
C T or M RI Brai n 1 2 
X  
 
 
 
 
 
 
 
X 1 2 
 
E C H O ( M U G A)  
X 1 3 
X 1 3  ( pri or t o c ycle 4) 
 
 
 
 
 
 
 
 
I V Bre nt u xi ma b ve d oti n1 4  
 
X  
 
 
 
 
 
 
 
 
I V C ycl o p h os p ha mi de a n d D o x or u bici n 
 
X  
 
 
 
 
 
 
 
 
I V Et o p osi de1 5  
 
X  
X  
X  
 
 
 
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J ul y 1 2 , 2 0 2 4 
1 6  
 
St u d y Assess me nts  
Scree ni n g 1 
(D -2 8 t o 0)  
B V + C H E P ( 2 1 -D a y C ycle) X 6 c ycles  
D 1  
D 2  
D 3  
D 4  
D 5  
D 8  
D 1 5  
E n d of 
T xt  Visit 1  
F oll o w 
u p 1 9  
P O Pre d nis o ne 1 6  
 
X  
X  
X  
X  
X  
 
 
 
 
C hec k patie nt diar y  
 
X  
 
 
 
 
 
 
X  
 
A d verse e ve nt assess me nt 1 7 
X  
X  
X 1 7  
X 1 7  
 
 
X  
X 1 8 
X  
 
Pri or/c o nc o mita nt me dicati o n re vie w  
X  
X  
 
 
 
 
 
 
X  
 
I nitiate/ Re ne w pr o p h ylactic me dicati o ns 
 
X  
 
 
 
 
 
 
 
 
S ur vi val  
 
 
 
 
 
 
 
 
 
X 1 9 
 
N O T E : After c o m pleti o n of B V-C H E P  s u bjects w h o 1) pr o gresse d o n B V-C H E P t hera p y, 2) recei ve d 2 -6 c ycles of B V -C H E P a n d g o o n t o tra ns pla nt or 3) 
recei ve d 6 c ycles of B V-C H E P a n d are C D 3 0 ne gati ve will e nter f oll o w u p o utli ne d i n t his ta ble. S u bjects wit h C D 3 0 -p ositi ve A T L L  w h o c o m plete 6 c ycles of  
B V -C H E P, are i neli gi ble f or tra ns pla nt, a n d are C D 3 0 + will  c o nti n ue st u d y treat me nt o n B V  mai nte na nce t hera p y as o utli ne d i n Ta ble 6. 2 . 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
1 7  
 
F o ot n otes ( B V + C H E P Tre at me nt C ycles)  
1.  
All scree ni n g assess me nts s h o ul d be c o m plete d wit hi n 2 8  da ys bef ore i nitiati n g st u d y t hera p y  u nless 
ot her wise s pecifie d . If scree ni n g la bs are perf or me d wit hi n 7 2 h o urs of i nitiati n g st u d y treat me nt o n 
D 1/ C 1, t he y d o n ot nee d t o be re peate d.   Eac h sc he d ule d visit s h o ul d occ ur wit hi n ± 2 da ys of  t he 
sc he d ule d visit w hile t he s u bject is recei vi n g st u d y treat me nt.  T he e n d of treat me nt visit s h o ul d occ ur 
2 1  da ys ( +/-1 o ne wee k) after  disc o nti n ui n g st u d y t hera p y a n d all o n g oi n g A Es s h o ul d be  f oll o we d 
u ntil satis fact or y res ol uti o n t o t he l o west ac hie va ble  t o xicit y gra de base d o n t he patie nt’ s healt h 
stat us.   
2.  
A c o m plete p h ysical e xa m ( P E) s h o ul d be c o n d ucte d at scree ni n g i.e., baseli ne i ncl u di n g hei g ht  
( baseli ne o nl y) a n d wei g ht. A tar gete d p h ysical e xa m  i ncl u di n g wei g ht s h o ul d be c o n d ucte d o n D 1 of 
eac h c ycle pri or t o a d mi nistrati o n of B V + C H E P  t hera p y. 
3.  
Vital si g ns will be ta ke n if t he s u bject is i n cli nic t o recei ve I V et o p osi de. 
4.  
Ima gi n g s h o ul d be o btai ne d  at scree ni n g wit hi n 2 1 da ys of i nitiati n g st u d y treat me nt  a n d at C 3 D 1  (-7 
da ys) , C 5 D 1 (-7 da ys) a n d da y 2 1 of c ycle 6 (+/ -7  da ys) or as nee de d , if t here are a n y cli nical 
si g ns/s y m pt o ms of pr o gressi o n.  A P E T/ C T sca n is preferre d f or scree ni n g, C 5 D 1, a n d C 6 D 2 1 b ut a 
C T  C A P is acce pta ble  f or scree ni n g i n sit uati o ns t hat w o ul d affect patie nt safet y.  A P E T/ C T or C T 
sca n is re q uire d f or C 3 D 1.  
5.  
T he b o ne marr o w e xa m will be d o ne f or sta gi n g. O nl y nee d t o re peat  at e n d of treat me nt if  B M 
bi o ps y was p ositi ve i nitiall y  at baseli ne t o c o nfir m C R (if a p plica ble) . 
6.  
If t he bi o ps y d o ne f or dia g n osis is n ot a vaila ble or t he b o ne marr o w bi o ps y d o ne f or sta gi n g is 
ne gati ve , a bi o ps y will be nee de d t o c o nfir m dia g n osis a n d test f or C D 3 0.  
7.  
Uric aci d a n d p h os p h or us will be teste d at scree ni n g a n d o n Da ys  1 a n d 8 of C ycle 1 o nl y.  
8.  
Cli nical c he mistr y will i ncl u de a c o m plete meta b olic pa nel [ B U N, creati ni ne, Na, K, Cl, C O 2, 
gl uc ose, calci u m, al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] + L D H . 
N ote: Creati ni ne cleara nce, bilir u bi n, A S T a n d A L T t o be o btai ne d wit hi n 3 da ys of starti n g st u d y 
treat me nt. See criteri o n 3. 1. 7.  
9.  
Pre g na nc y test m ust be perf or me d wit hi n 7 2 h o urs bef ore  i nitiati n g st u d y treat me nt o n da y 1 of c ycle 
1.  F or s u bse q ue nt c ycles, a pre g na nc y test will be d o ne o n da y 1.  
1 0.  I T pr o p h yl a xis will c o nsist of eit her c ytara bi ne, met h otre xate, a n d h y dr oc ortis o ne, or met h otre xate 
al o ne, or c ytara bi ne al o ne. T his will be a d mi nistere d per i nstit uti o nal g ui deli nes. T he s u g geste d 
re gi me n is: starti n g wit h C1 will c o nsist of 6 t otal treat me nts ( 1 treat me nt per c ycle f or 6 c ycles) . If 
t he patie nt recei ves I T pr o p h yla xis, t he patie nt will n ot recei ve I T treat me nt. C S F will be o btai ne d f or 
all patie nts. C S F st u dies s h o ul d occ ur wit hi n +/-4  da ys a n d will be se nt starti n g wit h C 1 . T he e n d of 
stu d y C S F st u dies will o nl y be se nt f or patie nts w h o ha d a p ositi ve fi n di n g a n d t he C N S has n ot 
res ol ve d.  
1 1.  I T tre at me nt will c o nsist of eit her c ytara bi ne, met h otre xate, a n d h y dr oc ortis o ne, or met h otre xate 
al o ne, or c ytara bi ne al o ne. T his will be a d mi nistere d t o a n y patie nts wit h C S F fi n di n gs c o nsiste nt 
wit h C N S A T L L i n v ol ve me nt ( p ositi ve fl o w or c yt ol o g y).  T his ca n be a d mi nistere d per i nstit uti o nal 
g ui deli nes. T he s u g geste d sc he d ule will c o nsist of treat me nt o n D 1, D 8, a n d D 1 5 u ntil cleara nce o n 
C S F . T he n t he re gi me n will ret ur n t o pr o p h ylactic d osi n g.  If t he patie nt is p ositi ve f or C N S 
i n v ol ve me nt, t he patie nt will f oll o w t he treat me nt sc he d ule n ot t he pr o p h yla xis sc he d ule f or I T 
c he m o t hera p y. C S F st u dies will be o btai ne d f or all patie nts. C S F st u dies s h o ul d occ ur wit hi n + /-4 
da ys a n d will be se nt starti n g wit h C 1. T he e n d of st u d y C S F st u dies will o nl y be se nt f or patie nts 
w h o ha d a p ositi ve fi n di n g a n d t he C N S has n ot res ol ve d.  
1 2.  C T/ M RI  of  brai n will be c o m plete d f or all patie nts d uri n g scree ni n g.  Re peat sa me test at e n d of B V -
C H E P if baseli ne test was p ositi ve.   
1 3.  E C H O at scree ni n g e xcl u des patie nts wit h L V E F < 4 0 %. Patie nts wit h baseli ne L V E F of 4 0 % t o 5 5 % 
s h o ul d ha ve re peat assess me nt perf or me d pri or t o c ycle 4. 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
1 8  
 
1 4.  S u bjects wit h C D 3 0 + disease will recei ve c o m mercial s u p pl y of Bre nt u xi ma b ve d oti n. S u bjects wit h 
C D 3 0 - disease will recei ve i n vesti gati o nal l ot.   S u bjects wit h C D 3 0 e x pressi o n a b o ve 1 perce nt will 
be c o nsi dere d t o ha ve C D 3 0 + disease.  
1 5.  Oral et o p osi de ma y be s u bstit ute d f or I V et o p osi de f or a n y or all da ys i n w hic h et o p osi de is 
a d mi nistere d. See Secti o n 4. 2. 1 f or D osi n g a n d A d mi nistrati o n  of oral et o p osi de .  
1 6.  I V c ortic oster oi d of e q ui vale nt d ose t o 1 0 0 m g pre d nis o ne ma y be s u bstit ute d as cli nicall y i n dicate d.  
1 7.  T o xicit y assess me nt per N CI -C T C A E criteria v. 4. 0 3 . T o xicit y assess me nt o n da ys 2 a n d 3 of eac h 
c ycle will be assesse d o nl y if t he s u bject recei ves I V et o p osi de.  
1 8.  F or Da y 1 5, t he a d verse e v e nt assess me nt is o nl y re q uire d w he n a s u bject is recei vi n g I T treat me nt 
( n ot I T pr o p h yla xis).  T he a d verse e ve nt assess me nt ma y be d o ne b y t he st u d y tea m o ver t he p h o ne.   
1 9.  All s u bjects will  be f oll o we d e ver y 3 m o nt hs ( +/ - 1 m o nt h) f or s ur vi val f or 5 years or u ntil deat h, 
w hic he ver occ urs first, starti n g fr o m ti me t he s u bject disc o nti n ues st u d y treat me nt.  T o d oc u me nt 
s ur vi val, s u bjects will eit her be c o ntacte d directl y, or t heir me dical rec or d will be c hec ke d.  S u bjects 
t hat are re m o ve d fr o m st u d y t hera p y a n d c ha n ge t o a ne w a nti-ca ncer re gi me n will be f oll o we d f or 
s ur vi val o nl y. All ot her su bjects o n f oll o w u p will als o ha ve i ma gi n g sca ns ( P E T or C T) a n d 
he mat ol o g y la b orat or y tests ( C B C wit h differe ntial) e ver y 6 m o nt hs ( +/ -1 m o nt h) f or 2 years or u ntil 
deat h, w hic he ver occ urs first, fr o m t he ti me t he y disc o nti n ue st u d y treat me nt.  S u bjects eli gi ble f or 
B V mai nte na nce  (i.e., ineli gi ble f or tra ns pla nt a n d C D 3 0 + ) s h o ul d c o nti n ue st u d y treat me nt as 
descri be d i n ta ble 6. 2.   See secti o n 6. 6 P ost treat me nt/ F oll o w u p f or a d diti o nal g ui da nce.  
 
6. 2  
Ti me a n d E ve nts T a ble ( B V M ai nte n a nce T her a p y)  
 
St u d y Assess me nts  
D 1 1 
E n d of St u d y  
T xt  Visit 1  
see secti o n 6. 5. 2 
F oll o w 
u p 8 
Tar gete d P E 2 
X  
X  
 
Wei g ht  
X  
X  
 
Vital si g ns  ( B P, p ulse a n d te m perat ure) 
X  
X  
 
E C O G  perf or ma nce stat us  
X  
X  
 
I ma gi n g st u dies 
X 3 
X 3 
X 8 
He mat ol o g y  ( C B C w. differe ntial)   
X  
X  
X 8 
Cli nical C he mistr y  ( C M P/ L D H)4  
X  
X  
 
S ol u ble I nterle u ki n 2 Rece pt or  
 
X  
 
Ser u m or Uri ne pre g na nc y test ( W O C B P)  
X 5 
X  
 
I V Bre nt u xi ma b ve d oti n 
X 6 
 
 
A d verse e ve nt assess me nt 7 
X  
X  
 
Pri or/c o nc o mita nt me dicati o n re vie w  
X  
X  
 
S ur vi val  
 
 
X 8  
N ote: T o be eli gi ble f or B V m ai nte n a nce t her a p y, p atie nts m ust h a ve C D 3 0 p ositi ve A T L L .  S u bjects wit h C D 3 0 
e x pressi o n a b o ve 1 perce nt will be c o nsi dere d t o h a ve C D 3 0 + dise ase.  
 
F o ot n otes ( B V  M ai nte n a nce Tre at me nt C ycles  1 -N ) 
  
1.  
Eac h sc he d ule d visit s h o ul d occ ur wit hi n ± 2 da ys of t he sc he d ule d visit w hile t he s u bject is recei vi n g st u d y 
treat me nt.  T he e n d of mai nte na nce treat me nt visit s h o ul d occ ur 2 1  da ys ( +/- o ne wee k) after  disc o nti n ui n g  
st u d y t hera p y a n d all o n g oi n g A Es s h o ul d be f oll o we d u ntil satisfact or y res ol uti o n t o t he l o west ac hie va ble 
t o xicit y gra de base d o n t he patie nt’s healt h stat us.   

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
1 9  
 
2.  
A tar gete d p h ysical e xa m i ncl u di n g wei g ht s h o ul d be c o n d ucte d o n D 1 of eac h c ycle pri or t o a d mi nistrati o n of  
B V mai nte na nce t hera p y  i n patie nts wit h C D 3 0 p ositi ve A T L L 
3.  
A P E T/ C T sca n or C T sca n s h o ul d be d o ne e ver y 8  c ycles (+/ -2 1  da ys)  ( or s o o ner, if t here are a n y cli nical 
si g ns/s y m pt o ms of pr o gressi o n) d uri n g mai nte na nce t hera p y.   A P E T/ C T sca n or C T sca n s h o ul d als o be d o ne 
at t he e n d of st u d y treat me nt visit.   
4.  
Cli nical c he mistr y will i ncl u de a c o m plete meta b olic pa nel [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] + L D H  
5.  
Pre g na nc y test (ser u m or uri ne) m ust be perf or me d wit hi n 7 2 h o urs bef ore i nitiati n g B V mai nte na nce t hera p y  
f or c ycle 1.  F or s u bse q ue nt c ycles, a pre g na nc y test will be d o ne o n da y 1.  
6.  
B V ( 1. 8 m g/ k g I V ) a d mi nistrati o n e ver y 2 1 da ys u ntil P D or wit h dra wal f or t o xicit y or ot her reas o ns  
7.  
T o xicit y assess me nt per N CI -C T C A E criteria 4. 0 3   
8.  
All s u bjects will  be f oll o we d e ver y 3 m o nt hs ( +/ - 1 m o nt h) f or s ur vi val f or 5 years or u ntil deat h, w hic he ver 
occ urs first, starti n g fr o m ti me t he s u bject disc o nti n ues st u d y treat me nt.  T o d oc u me nt s ur vi val, s u bjects will 
eit her be c o ntacte d directl y or t heir me dical rec or d will be c hec ke d.  S u bjects t hat are re m o ve d fr o m st u d y 
t hera p y a n d c ha n ge t o a ne w a nti-ca ncer re gi me n will be f oll o we d f or s ur vi val o nl y. All ot her su bjects o n 
f oll o w u p will als o ha ve i ma gi n g sca ns ( P E T/ C T or C T)  a n d he mat ol o g y la b orat or y tests ( C B C wi t h 
differe ntial) e ver y 6 m o nt hs ( +/ -1 m o nt h) f or 2 years or u ntil deat h, w hic he ver occ urs first, fr o m t he ti me t he y 
disc o nti n ue st u d y treat me nt.   F oll o w as o utli ne d a b o ve.  See secti o n 6. 6  P ost treat me nt/ F oll o w u p  f or a d diti o nal 
g ui da nce . 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 0  
 
6. 3  
Pre -St u d y Assess me nts  
Scree ni n g tests a n d e val uati o n will be perf or me d o nl y after a si g ne d, writte n 
I nstit uti o nal Re vie w B oar d (I R B) a p pr o ve d i nf or me d c o nse nt is o btai ne d fr o m 
eac h s u bject.   Scree ni n g will i ncl u de:  
 
Cli nical e val uati o n :  c o m plete hist or y (i ncl u di n g hist or y of he patitis B, C or HI V 
+  H T L V ser ol o g y  a n d str o n g yl oi des test via ser u m or st o ol ), p h ysical e xa mi nati o n 
(i ncl u di n g hei g ht, wei g ht a n d vital si g ns) , E C O G  perf or ma nce stat us  
Car diac e val uati o n : M U G A or E C H O 
St u d y Eli gi bilit y : I ncl usi o n/ E xcl usi o n Criteria re vie w  
La b orat or y st u dies :   
▪ H T L V -1 Ser ol o g y/ HI V/ H C V  a nti b o d y / H B V c ore a nti b o d y/s urface 
a nti b o d y/s urface a nti ge n  
▪ G l uc ose 6 p h os p hate de h y dr o ge nase ( G 6 P D), uric aci d, a n d p h os p h or us 
▪ c o m plete bl o o d c o u nt ( C B C)  wit h differe ntial   
▪ C M P + ot her test;  C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, 
calci u m, al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne 
p h os p hatase] pl us L D H   
▪ S ol u ble i nterle u ki n -2 rece pt or  
▪ Pre g na nc y test: ser u m β -H C G or uri ne (if a p plica ble f or W O C B P) wit hi n 
7 2 hrs of i nitiati n g st u d y treat me nt  
Disease Meas ure me nts : P E T / C T sca n of c hest , a b d o me n a n d pel vis or C T C A P 
(i n sit uati o ns t hat w o ul d affect patie nt safet y) ( o btai ne d wit hi n 2 1 da ys of starti n g 
st u d y me dicati o ns) 
C T or M RI of brai n  
B o ne marr o w e xa m :  A b o ne marr o w as pirati o n a n d bi o ps y will be d o ne f or 
sta gi n g.   
B i o ps y wit h C D 3 0 testi n g ( b y fl o w or I H C) : If C D 3 0 testi n g was pre vi o usl y d o ne 
o n t he bi o ps y sa m ple fr o m dia g n osis, t his i nf or mati o n will be c ollecte d.  If C D 3 0 
testi n g was n ot d o ne, a n arc hi val sa m ple fr o m t he bi o ps y use d f or dia g n osis will 
be re q ueste d  a n d teste d f or C D 3 0 .  C D 3 0 testi n g will  als o be d o ne o n t he b o ne 
marr o w tiss ue c ollecte d fr o m t he b o ne marr o w e xa m.  If we are u na ble t o o btai n 
a n arc hi val sa m ple  or if t he b o ne marr o w e xa m is ne gati ve , a ne w bi o ps y will be 
perf or me d  t o c o nfir m t he dia g n osis a n d test f or C D 3 0.  
T o xicit y: T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3   
C o nc o mita nt me dicati o ns : Re vie w  
6. 4  
Tre at me nt Assess me nts  ( See T a ble 6. 1 ) 
6. 4. 1  D 1 of C ycles 1 -6 ( B V -C H E P)  
Cli nical e val uati o n :  tar gete d hist or y p h ysical e xa mi nati o n (i ncl u di n g wei g ht a n d 
vital si g ns), E C O G  perf or ma nce stat us  
Car diac e val uati o n : M U G A or E C H O re q uire d pri or t o treat me nt i n C 4  f or 
patie nts wit h baseli ne L V E F of  4 0 % t o 5 5 %  
La b orat or y st u dies :   

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 1  
 
▪ co m plete bl o o d c o u nt ( C B C) wit h differe ntial  
▪ C M P + ot her test; C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] pl us 
L D H  
▪ Uric aci d a n d p h os p h or us (c ycle 1 o nl y)  
▪ Pre g na nc y test: ser u m β -H C G or uri ne (if a p plica ble f or W O C B P).  F or da y 1 
of c ycle 1, t he pre g na nc y test m ust be d o ne wit hi n 7 2 h o urs of be gi n ni n g 
treat me nt.  F or s u bse q ue nt c ycles, t he pre g na nc y test will be d o ne o n da y 1.  
Disease Meas ure me nts  ( Cycle 3  a n d C ycle 5  pri or t o starti n g  treat me nt, a n d at t he 
e n d of C ycle 6 or as nee de d if si g ns of P D) : P E T / C T or C T sca n re q uire d f or 
C ycle 3 a n d a P E T / C T sca n of c hest, a b d o me n a n d pel vis re q uire d f or C ycle 5 a n d 
e n d of c ycle 6 . 
C S F : cell c o u nt, c yt ol o g y, a n d fl o w c yt o metr y  
C hec k patie nt diar y  
I T pr o p h yla xis / I T treat me nt: See f o ot n otes 1 0  &  1 1  i n T & E ta ble  
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3   
C o nc o mita nt me dicati o ns : Re vie w 
Pr o p h ylactic me dicati o ns : i nitiate/re ne w as nee de d per sta n dar d of care 
A d mi nister St u d y Me dicati o ns: (see secti o n 4. 2 )  
 
6. 4. 2  D 2, 3, 4 a n d 5 of C ycles 1 -6 ( B V -C H E P)  
Cli nical e val uati o n : (vital si g ns  o nl y D 2 a n d D 3  if t he s u bject is recei vi n g I V 
et o p osi de ) 
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3  
( o nl y D 2 a n d D 3 if t he s u bject is recei vi n g I V et o p osi de) 
A d mi nister St u d y Me dicati o ns: (see secti o n 4. 2 )  
6. 4. 3  D 8 C ycles 1 -6 ( B V -C H E P)  
Cli nical e val uati o n : (vital si g ns  o nl y)  
▪ La b orat or y St u dies : 
▪ C B C wit h differe ntial    
▪ C M P + ot her test; C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] pl us 
L D H   
▪ Uric aci d a n d p h os p h or us (c ycle 1 o nl y ) 
I ntrat hecal treat me nt: per sta n dar d of care  (see f o ot n ote 1 1  i n T & E) 
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3   
6. 4. 4  D 1 5 C ycles 1 -6 ( B V -C H E P)  
I ntrat hecal treat me nt: per sta n dar d of care (see f o ot n ote 1 1  i n T & E) 
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3  f or 
s u bjects w h o are recei vi n g i ntrat hecal c he m ot hera p y treat me nt.  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 2  
 
6. 4. 5  E n d of Tre at me nt ( B V -C H E P)  
Cli nical e val uati o n : p h ysical e xa m f oc use d o n t o xicit y, vital si g ns , E C O G  
perf or ma nce stat us  
La b orat or y st u dies :   
▪ c o m plete bl o o d c o u nt ( C B C) wit h differe ntial  
▪ C M P + ot her test; C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] pl us 
L D H  
▪ S ol u ble i nterle u ki n -2  rece pt or  
▪ Pre g na nc y test: ser u m  or uri ne  β -H C G (if a p plica ble f or W O C B P)  
C hec k patie nt diar y  
C T or M RI of brai n : (sa me test as perf or me d at baseli ne if baseli ne test was 
 
p ositi ve ) 
C S F : cell c o u nt, c yt ol o g y, a n d fl o w c yt o metr y (if teste d p ositi ve f or C N S 
i n v ol ve me nt d uri n g st u d y treat me nt u nless testi n g s h o ws it has cleare d  see 
f o ot n otes 1 0  & 1 1 ) 
B o ne marr o w as pirati o n a n d bi o ps y - See f o ot n ote # 5  
Disease Meas ure me nts : P E T/ C T sca n of c hest, a b d o me n a n d pel vis  (see f o ot n ote 
# 4  u n der Ta ble 6. 1 )  
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3 . 
S u bjects wit h o n g oi n g st u d y treat me nt -relate d t o xicit y s h o ul d be f oll o we d u ntil 
res ol uti o n of ≤ gra de 1 or i n vesti gat or deter mi nes e ve nt res ol uti o n t o mi ni m u m 
le vel t hat ca n be ac hie ve d. 
C o nc o mita nt me dicati o ns : Re vie w 
6. 5  
B V M ai nt en a nce Tre at me nt  ( C D 3 0-p ositi ve A T L L o nl y  –  see T a ble 6. 2 )  
6. 5. 1  D 1 of e ac h c ycle of B V M ai nte n a nce  
Cli nical e val uati o n :  tar gete d p h ysical e xa mi nati o n (i ncl u di n g wei g ht a n d vital 
si g ns), E C O G  perf or ma nce stat us  
La b orat or y st u dies :   
▪ c o m plete bl o o d c o u nt ( C B C) wit h differe ntial  
▪ C M P + ot her test; C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] pl us 
L D H  
▪ Pre g na nc y test: ser u m β -H C G  or uri ne  (f or W O C B P) wit hi n 7 2 h o urs of 
starti n g B V o n da y 1 of c ycle 1. F or s u bse q ue nt c ycles, t he pre g na nc y test will 
be d o ne o n da y 1.  
Disease Meas ure me nts (R e peat e ver y 8  c ycles ( +/- 2 1 da ys) or as nee de d if si g ns 
of P D) : P E T/ C T or C T  sca n of c hest, a b d o me n a n d pel vis (see f o ot n ote #3  of 
Ta ble 6. 2 )  
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3   
C o nc o mita nt me dicati o ns : Re vie w 
A d mi nister B V: (see secti o n 4. 2 )  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 3  
 
6. 5. 2  E n d of B V M ai nte n a nce Tre at me nt  
Cli nical e val uati o n :  tar gete d p h ysical e xa mi nati o n (i nc l u di n g wei g ht a n d vital 
si g ns), E C O G perf or ma nce stat us 
La b orat or y st u dies :   
▪ c o m plete bl o o d c o u nt ( C B C) wit h differe ntial  
▪ C M P + ot her test; C M P [ B U N, creati ni ne, Na, K, Cl, C O 2, gl uc ose, calci u m, 
al b u mi n, t otal pr otei n, t otal bilir u bi n, A L T, A S T, al kali ne p h os p hatase] pl us 
L D H  
▪ S ol u ble i nterle u ki n 2 rece pt or 
▪ Pre g na nc y test: ser u m β -H C G or uri ne (if a p plica ble f or W O C B P). 
Disease Meas ure me nts ): P E T/ C T or C T sca n of c hest, a b d o me n a n d pel vis  
T o xicit y : T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3 . 
Treat me nt relate d t o xicit y. S u bjects wit h o n g oi n g st u d y treat me nt-relate d t o xicit y 
s h o ul d be f oll o we d u ntil res ol uti o n of ≤ gra de 1 or i n vesti gat or deter mi nes e ve nt 
res ol uti o n t o mi ni m u m le vel t hat ca n be ac hie ve d. 
C o nc o mita nt me dicati o ns : Re vie w 
6. 6  
P ost -Tre at me nt  F oll o w -u p Assess me nts  
S u bjects w h o are wit h dra w n fr o m st u d y  treat me nt (i.e., B V-C H E P or B V 
mai nte na nce)  wit h o n g oi n g t o xicit y s h o ul d be f oll o we d u ntil res ol uti o n of 
s y m pt o ms t o gra de ≤1 or i n vesti gat or deter mi nes e ve nt res ol uti o n t o mi ni m u m 
le vel t hat ca n be ac hie ve d.   
 
N ote: A fter c o m pleti o n or wit h dra wal  of B V -C H E P t hera p y , patie nts w ill 
se gre gate  i nt o 4 se parate gr o u ps:  
1)  T h ose w h o pr o gress e d o n B V -C H E P t hera p y  ( Gr o u p 1);  
2 ) T h ose w h o c o m plete 2 -6 c ycles of B V -C H E P a n d  are eli gi ble t o  g o t o 
all o ge neic  tra ns pla nt ( Gr o u p 2); 
3 ) T h ose w h o c o m plete 6 c ycles of B V -C H E P b ut are C D 3 0 ne gati ve  ( Gr o u p 
3) ; a n d 
4 ) T h ose w h o c o m plete d  6 c ycles of B V -C H E P , are C D 3 0 p ositi ve  a n d 
c o nti n ue st u d y treat me nt wit h B V i n  t he mai nte na nce p hase of t he st u d y 
( Gr o u p 4). S u bjects o n B V mai nte na nce will c o nti n ue st u d y treat me nt u ntil 
disease pr o gressi o n or wit h dra wal f or ot her reas o ns e .g ., t o xicit y.  
 
All s u bjects will  be f oll o we d e ver y 3 m o nt hs ( +/ - 1 m o nt h) f or s ur vi val f or 5 
years or u ntil deat h, w hic he ver occ urs first, starti n g fr o m ti me t he s u bject 
disc o nti n ues st u d y treat me nt.  T o d oc u me nt s ur vi val, s u bjects will eit her be 
c o ntacte d directl y or t heir me dical rec or d will be c hec ke d.  S u bjects t hat are 
re m o ve d fr o m st u d y t hera p y a n d c ha n ge  t o a ne w a nti-ca ncer re gi me n will be 
f oll o we d f or s ur vi val o nl y. All ot her su bjects o n f oll o w u p will als o ha ve i ma gi n g 
sca ns ( P E T/ C T or C T) a n d he mat ol o g y la b orat or y tests ( C B C wit h differe ntial) 
e ver y 6 m o nt hs ( +/ -1 m o nt h) f or 2 years or u ntil deat h, w hic he ver occ urs first, 
fr o m t he ti me t he y disc o nti n ue st u d y treat me nt.      

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 4  
 
6. 7  
C orrel ati ve St u dies Pr oce d ures  
C D 3 0 e x pressi o n will be deter mi ne d at baseli ne b y i m m u n o hist oc he mistr y. We 
e x pect t o s h o w a “ d ose -res p o nse” effect, wit h i ncreasi n g efficac y of o ur 
e x peri me ntal re gi me n, B V -C H E P, i n patie nts wit h a hi g her perce nta ge of C D 3 0 
e x pressi o n f or A T L L.  
6. 8  
Assess me nt of S afet y  
A n y patie nt w h o recei ves at least o ne d ose st u d y t hera p y o n t his pr ot oc ol will be 
e val ua ble f or t o xicit y.  Eac h patie nt will be assesse d peri o dicall y f or t he 
de vel o p me nt of a n y t o xicit y acc or di n g t o t he Ti me a n d E ve nts ta ble s.  T o xicit y 
will be assesse d acc or di n g t o t he N CI C T C A E  v 4. 0 3 .   
6. 9  
Assess me nt of Effic ac y  
T he O R R will be e val uate d as t he rate of c o m plete res p o nses ( C R) + partial 
res p o nses ( P R) as defi ne d b y t he I nter nati o nal W or ks h o p t o sta n dar dize res p o nse 
criteria f or mali g na nt l y m p h o mas (i .e., L u ga n o Criteria per C hes o n, et al. J Cli n 
O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8); see A p pe n di x A: Re vise d res p o nse criteria f or 
l y m p h o ma.  
 
A d diti o n all y, f or s u bjects wit h a le u ke mic c o m p o ne nt t o t heir disease at baseli ne  
peri p heral bl o o d will be assesse d per A d ult T -Cell Le u ke mia/ L y m p h o ma N C C N 
g ui deli nes versi o n 2. 2 0 1 7 o utli ne d  i n t he ta ble bel o w. 
 
Res p o nse  
Peri p her al Bl o o d  
C o m plete re missi o n *  
N or mal † 
U ncertifie d c o m plete re missi o n *  
N or mal † 
Partial re missi o n *  
≥5 0 % decrease  
Sta ble disease *  
N o c ha n ge  
Rela pse d or pr o gressi ve disease  
Ne w or ≥5 0 % i ncrease #  
*  Re q uire d t hat eac h criteri o n be prese nt f or a peri o d of at least 4 wee ks.  
†   Pr o vi de d t hat < 5 % of fl o wer cells re mai n, c o m plete re missi o n is j u d ge d t o ha ve bee n attai ne d if t he     
a bs ol ute l y m p h oc yte c o u nt, i ncl u di n g fl o wer cells, is < 4 x 1 0 9/ L. 
# Defi ne d b y ≥5 0 % i ncrease fr o m na dir i n t he c o u nt of fl o wer cells a n d a n a bs ol ute l y m p h oc yte c o u nt,  
i ncl u di n g fl o wer cells > 4 x 1 09/ L. 
 
7. 0  
A D V E R S E E V E N T S  
7. 1  
Defi niti o n s  
7. 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 nt o war d me dical occ urre nce (e. g., a n a b n or mal 
la b orat or y fi n di n g, s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
dr u g) i n a patie nt or cli nical i n vesti gati o n s u bject a d mi nistere d a p har mace utical 
pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h t his 
treat me nt.  A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal la b orat ory fi n di n g), s y m pt o m, or disease te m p orall y 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 5  
 
ass ociate d wit h t he use of a me dici nal pr o d uct, w het her or n ot relate d t o t he 
me dici nal pr o d uct.   
 
H os pitalizati o n f or electi ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he 
res ult of a n A E (e. g., s ur gical i nserti o n of ce ntral li ne) nee d n ot be c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E.  Disease pr o gressi o n s h o ul d n ot be 
rec or de d as a n A E, u nless it is attri b uta ble b y t he i n vesti gat or t o t he st u d y t hera p y. 
7. 1. 2  S us pecte d A d verse Re acti o n  ( S A R) 
A s us pecte d a d verse reacti o n ( S A R) is a n y A E f or w hic h t here is a re as o n a ble 
p ossi bility  t hat t he dr u g is t he ca use.   Re as o n a ble p ossi bility  mea ns t hat t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E.  A 
s us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y a b o ut ca usalit y 
t ha n a d verse reacti o n, w hic h mea ns a n y a d verse e ve nt ca use d b y a dr u g.   
 
Ca usalit y assess me nt t o a st u d y dr u g is a me dical j u d g me nt ma de i n c o nsi derati o n 
of t he f oll o wi n g fact ors: te m p oral relati o ns hi p of t he A E t o st u d y dr u g e x p os ure, 
k n o w n mec ha nis m of acti o n or si de effect pr ofile of st u d y treat me nt, ot her rece nt 
or c o nc o mita nt dr u g e x p os ures, n or mal cli nical c o urs e of t he disease u n der 
i n vesti gati o n, a n d a n y ot her u n derl yi n g or c o nc urre nt me dical c o n diti o ns.  Ot her 
fact ors t o c o nsi der i n c o nsi deri n g dr u g as t he ca use of t he A E: 
•  Si n gle occ urre nce of a n u nc o m m o n e ve nt k n o w n t o be str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, Ste ve ns -J o h ns o n 
S y n dr o me)  
•  O ne or m ore occ urre nces of a n e ve nt n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b ut ot her wise u nc o m m o n i n t he p o p ulati o n (e. g., te n d o n 
r u pt ure); ofte n m ore t ha n o nce occ urre nce fr o m o ne or m ulti ple st u dies 
w o ul d be nee de d bef ore t he s p o ns or c o ul d deter mi ne t hat t here is 
re as o n a ble p ossi bility t hat t he dr u g ca use d t he e ve nt.   
•  A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical trial t hat 
i n dicates t he e ve nts occ ur m ore fre q ue ntl y i n t he dr u g treat me nt gr o u p 
t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
7. 1. 3  U ne x pecte d A E  or S A R  
A n A E or S A R is c o nsi dere d u ne x pecte d if  t he s pecificit y or se verit y of it is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure 
(I B) f or a n u na p pr o ve d i n vesti gati o nal pr o d uct or pac ka ge i nsert/s u m mar y of 
pr o d uct c haracteristics f or a n a p pr o ve d pr o d uct).   U ne x pecte d als o refers t o A Es 
or S A Rs t hat are me nti o ne d i n t he I B as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g, b ut are n ot 
s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.   
7. 1. 4  Seri o us A E  or S A R  
A n A E or S A R is c o nsi dere d seri o us if, i n t he vie w of eit her t he i n vesti gat or or 
s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h;  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 6  
 
•  Is life-t hreate ni n g ( places t he s u bject at i m me diate ris k of deat h fr o m 
t he e ve nt as it occ urre d); 
•  Re q uires i n patie nt h os pitalizati o n ( > 2 4 h o urs) or pr ol o n gati o n of 
e xisti n g h os pitalizati o n; *  
•  Res ults i n  c o n ge nital a n o mal y/ birt h defect;  
•  Res ults i n a persiste nt or si g nifica nt i nca pacit y or s u bsta ntial 
disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns;  
•  I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-
t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d a seri o us 
a d verse dr u g e x perie nce w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt or s u bject a n d ma y re quire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d 
i n t he defi niti o n.  F or re p orti n g p ur p oses, als o c o nsi der t he occ urre nces 
of pre g na nc y as a n e ve nt w hic h m ust be re p orte d as a n i m p orta nt 
me dical e ve nt.  
 
* H os pitalizati o n f or a ntici pate d or pr ot oc ol s pecifie d pr oce d ures s uc h as 
a d mi nistrati o n of c he m ot hera p y, ce ntral li ne i nserti o n, metastasis i nter ve nti o nal 
t hera p y, resecti o n of pri mar y t u m or, or electi ve s ur ger y, will n ot be c o nsi dere d 
seri o us a d verse e vents.  
 
Pre g na nc y t hat occ urs d uri n g t he st u d y m ust als o be re p orte d as a n S A E.  
7. 2  
D oc u me nt ati o n of n o n -seri o us A Es or S A Rs  
F or n o n -seri o us AE s or S A Rs, d oc u me ntati o n m ust be gi n fr o m da y 1 of st u d y 
treat me nt a n d c o nti n ue t hr o u g h t he 3 0-da y f oll o w -u p peri o d after treat me nt is 
disc o nti n ue d.   
 
C ollecte d i nf or mati o n s h o ul d be rec or de d i n t he Case Re p ort F or ms ( C R F) f or 
t hat patie nt.  Please i ncl u de a descri pti o n of t he e ve nt, its se verit y or t o xicit y 
gra de, o nset a n d res ol ve d dates (if a p plica ble), a n d t he relati o ns hi p t o t he st u d y 
dr u g.  D oc u me ntati o n s h o ul d occ ur at least m o nt hl y .  
7. 3  
S A E s or Seri o us S A R s  
7. 3. 1  Ti mi n g  
After i nf or me d c o nse nt b ut pri or t o i nitiati o n of st u d y me dicati o ns, o nl y S A Es 
ca use d b y a pr ot oc ol -ma n date d i nter ve nti o n will be c ollecte d (e. g. S A Es relate d t o 
i n vasi ve pr oce d ures s uc h as bi o psies, me dicati o n was h o ut ).  
S A Es t hat are s u bject t o t hese re p orti n g re q uire me nts are t h ose t hat (i)  occ ur fr o m 
after t he first d ose of t he Pfizer Pr o d uct or t he St u d y s u bject’s e nr oll me nt i n t he 
St u d y ( w hic he ver is later) t hr o u g h t we nt y -ei g ht ( 2 8) da ys after t he last 
a d mi nistrati o n of t he Pfizer Pr o d uct or t he s u bject’s last St u d y visit ( w hic he ver is 
earlier), or l o n ger if s o s pecifie d i n t he Pr ot oc ol; or (ii)  occ ur a n y ti me after t he 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 7  
 
2 8 -da y peri o d if I nstit uti o n or Pri nci pal I n vesti gat or s us pects a ca usal relati o ns hi p 
bet wee n t he Pfizer Pr o d uct a n d t he S A E.  
 
7. 3. 2  D oc u me nt ati o n  a n d N otific ati o n  
S A Es or Seri o us S A Rs m ust be rec or de d i n t he S A E c o ns ole wit hi n O n C ore ™ f or 
t hat patie nt wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  A d diti o nall y, t he 
M ultice nter Pr oject Ma na ger  m ust als o be n otifie d via e mail of all S A Es wit hi n 
2 4 h o urs of lear ni n g of its occ urre nce . T he Re g ulat or y Ass ociate a n d Me dical 
M o nit or m ust  als o be n otifie d via e mail of all S A Es wit hi n 2 4 h o urs of lear ni n g of 
its occ urre nce. 
7. 3. 3  Re p orti n g  
I R B Re p orti n g Re q uire me nts: 
U N C : 
•  T he U N C -I R B will be n otifie d of all S A Es t hat q ualif y as a n 
U na ntici pate d Pr o ble m as per t he U N C I R B P olicies usi n g t he I R B’s we b -
base d re p orti n g s yste m (see secti o n 9. 5. 3)  wit hi n 7 da ys of t he I n vesti gat or 
bec o mi n g a ware of t he pr o ble m.  Please n ote, t hese e ve nts m ust be 
re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of lear ni n g of t he occ urre nce. 
 
M ultice nter sites:   
•  F or m ultice nter sites usi n g a l ocal I R B of rec or d, please s u b mit a d verse 
e ve nts per l ocal I R B p olic y.  
•  F or m ultice nter sites rel yi n g o n t he U N C-I R B, a n y S A Es t hat q ualif y as a n 
U na ntici pate d Pr o ble m will be e ntere d i nt o O n C ore T M  a n d re p orte d t o t he 
U N C I R B b y t he M ultice nter Re g ulat or y Ass ociate usi n g t he I R B’s we b-
base d re p orti n g s yste m (see secti o n 9. 5. 3)  wit hi n 7 da ys of t he I n vesti gat or 
bec o mi n g a ware of t he pr o ble m.   
Pre g na nc y  
Pre g na ncies a n d s us pecte d pre g na ncies (i ncl u di n g a p ositi ve pre g na nc y test 
re gar dless of a ge or disease state) of a fe male s u bject occ urri n g w hile t he s u bject 
is o n st u d y, or wit hi n 2 8 da ys of t he s u bject’s last d ose of st u d y s h o ul d be 
rec or de d as S A Es.  The patie nt is t o be disc o nti n ue d i m me diatel y fr o m t he st u d y.  
 
F or m ultice nter  sites, t he pre g na nc y, s us pecte d pre g na nc y, or p ositi ve pre g na nc y 
test m ust be re p orte d t o t he assi g ne d M ultice nter  Pr oject Ma na ger i m me diatel y 
( wit hi n 2 4 h o urs) via e mail or call M ultice nter mai n li ne 9 1 9 -9 6 6 -7 3 5 9 .  T he 
M ultice nter  Pr oject M a na ger will t he n re p ort t he e ve nt t o t he F u n di n g S o urce (see 
re q uire me nts bel o w).  T he fe male s u bject s h o ul d be referre d t o a n o bstetricia n -
g y nec ol o gist, prefera bl y o ne e x perie nce d i n re pr o d ucti ve t o xicit y f or f urt her 
e val uati o n a n d c o u nseli n g.  
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 8  
 
T he I n vesti gat or will f oll o w t he fe male s u bject u ntil c o m pleti o n of t he pre g na nc y, 
a n d m ust d oc u me nt  t he o utc o me of t he pre g na nc y (eit her n or mal or a b n or mal 
o utc o me)  a n d re p ort t he c o n diti o n of t he fet us or ne w b or n t o t he M ultice nter 
Pr oject Ma na ger . If t he o utc o me of t he pre g na nc y was a b n or mal (e. g., 
s p o nta ne o us or t hera pe utic a b orti o n), t he I n vesti gat or s h o ul d re p ort t he a b n or mal 
o utc o me as a n A E. If t he a b n or mal o utc o me meets a n y of t he seri o us criteria, it 
m ust be re p orte d as a n S A E.   
 
L a b or at or y Test A b n or m alities  
T he f oll o wi n g la b orat or y a b n or malities s h o ul d be d oc u me nte d a n d re p orte d 
a p pr o priatel y:  
•  a n y la b orat or y test res ult t hat is cli nicall y si g nifica nt or meets t he 
defi niti o n of a n S A E  
•  a n y la b orat or y a b n or malit y t hat re q uire d t he s u bject t o ha ve st u d y dr u g 
disc o nti n ue d or i nterr u pte d  
•  a n y la b orat or y a b n or malit y t hat re q uire d t he s u bject t o recei ve s pecific 
c orrecti ve t hera p y.  
 
O ver d ose  
A n o ver d ose is defi ne d as t he acci de ntal or i nte nti o nal a d mi nistrati o n of a n y d ose 
of a pr o d uct t hat is c o nsi dere d b ot h e xcessi ve a n d me dicall y i m p orta nt. All 
occ urre nces of o ver d ose m ust be re p orte d as a n S A E.  
 
F u n di n g S o urce (e. g. M a n uf act urer) Re p orti n g Re q uire me nts:  
 
Pfizer  Re p orti n g Re q uire me nts : 
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t hat safet y data are re p orte d 
t o Pfizer  as o utli ne d i n t he ta ble bel o w.  
 
* E x pe dite d S A E re p orts m ust i ncl u de all t he i nf or mati o n o utli ne o n t he F D A f or m 
3 5 0 0 A f or m.  
* * S A E l o g m ust i ncl u de S A Es re p orte d e x pe diti o usl y t o t he F D A a n d Pfizer . 
Pfizer  S A E f or m a n d sa m ple S A E a g gre gate listi n g are a vaila ble at 
htt ps:// w w w. pfizersafet yre p orti n g.c o m/ . All S A E f or ms s h o ul d be e maile d t o 
U S A. A E Re p orti n g @ pfizer.c o m  
 
 
F D A E x pe dite d Re p orti n g re q uire me nts  f or st u dies c o n d ucte d u n der a n I N D : 
A s p o ns or m ust re p ort a n y s us pecte d a d verse reacti o n t hat is b ot h seri o us a n d 
u ne x pecte d t o t he F D A. T he s p o ns or m ust re p ort a n a d verse e ve nt as a s us pecte d 
a d verse reacti o n o nl y if t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n 
t he dr u g a n d t he a d verse e ve nt, s uc h as: 
•  A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be 
str o n gl y ass ociate d wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, 
Ste ve ns -J o h ns o n S y n dr o me); 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
2 9  
 
•  O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h 
dr u g e x p os ure, b ut is ot her wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he 
dr u g (e. g. te n d o n r u pt ure);  
•  A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical trial (s uc h as 
k n o w n c o nse q ue nces of u n derl yi n g disease or c o n diti o n u n der i n vesti gati o n 
or ot her e ve nts t hat c o m m o nl y occ ur i n t he st u d y p o p ulati o n i n de pe n de nt of 
dr u g t hera p y) t hat i n dicates  t h ose e ve nts occ ur m ore fre q ue ntl y i n t he dr u g 
treat me nt gr o u p t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p. 
 
T he s p o ns or m ust s u b mit eac h I N D safet y re p ort o n F D A F or m 3 5 0 0 A. Eac h 
n otificati o n t o F D A m ust bear pr o mi ne nt i de ntificati o n of its c o nte nts, i.e., “I N D 
Safet y Re p ort,” a n d m ust be tra ns mitte d t o t he re vie w di visi o n t hat has t he 
res p o nsi bilit y f or re vie w of t he I N D. F or t his st u d y, t he re vie w di visi o n is t he 
Ce nter f or Dr u g  E val uati o n a n d Researc h. I n eac h I N D safet y re p ort, t he s p o ns or 
m ust i de ntif y all I N D safet y re p orts pre vi o usl y s u b mitte d t o F D A c o ncer ni n g a 
si milar s us pecte d a d verse reacti o n, a n d m ust a nal yze t he si g nifica nce of t he 
s us pecte d a d verse reacti o n i n li g ht of pre vi o us, si milar re p orts or a n y ot her rele va nt 
i nf or mati o n.  
 
Ti mi n g  
F D A m ust be n otifie d of p ote ntial seri o us ris ks wit hi n 1 5 cale n dar da ys after t he 
s p o ns or deter mi nes t he e ve nt re q uires re p orti n g. F D A 
m ust be n otifie d of 
u ne x pecte d fatal or life -t hreate ni n g s us pecte d a d verse reacti o ns as s o o n as p ossi ble 
b ut i n n o case l ater t ha n 7 cale n dar da ys after t he s p o ns or’s i nitial recei pt of t he 
i nf or mati o n. T he s p o ns or m ust be n otifie d of t he S A E b y t he i n vesti gat or wit hi n 2 4 
h o urs of t he e ve nt. If  t he res ults of a s p o ns or’s i n vesti gati o n s h o w t hat a n a d verse 
e ve nt n ot i nitiall y  deter mi ne d t o be re p orta ble is re p orta ble, t he s p o ns or m ust re p ort 
s uc h s us pecte d a d verse reacti o n i n a n I N D safet y re p ort as s o o n as p ossi ble, b ut i n 
n o case later t ha n 1 5 cale n dar da ys after t he deter mi nati o n is ma de.  
 
F oll o w -u p  
T he s p o ns or m ust pr o m ptl y i n vesti gate all safet y i nf or mati o n it recei ves. Rele va nt 
f oll o w-u p  i nf or mati o n t o a n I N D safet y re p ort m ust be s u b mitte d as s o o n as t he 
i nf or mati o n is a vaila ble.  
 
N otific ati o n of I nvesti g at ors  
T he s p o ns or m ust n otif y all partici pati n g i n vesti gat ors (i.e., all i n vesti gat ors t o 
w h o m t he s p o ns or is pr o vi di n g dr u g u n der its I N Ds or u n der a n y i n vesti gat or’s 
I N D) i n a n I N D safet y re p ort of p ote ntial seri o us ris ks, fr o m cli nical trials or a n y 
ot her s o u rce, as s o o n as p ossi ble, b ut i n n o case later t ha n 1 5 cale n dar da ys after 
t he s p o ns or deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g.  
 
Pr ocess  
If t he s p o ns or dee ms t hat a n e ve nt is b ot h a seri o us a d verse reacti o n ( S A R) A N D 
u ne x pecte d, it m ust  als o (i n a d diti o n t o O n C ore T M ) be re c or de d  o n t he Me d Watc h 
F or m 3 5 0 0 A as per 2 1 C F R 3 1 2. 3 2. U ne x pecte d a d verse e ve nts or a d verse reacti o n 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 0  
 
refers t o a n e ve nt or reacti o n t hat is n ot liste d i n t he i n vesti gat or’s br oc h ure or is n ot 
liste d at t he s pecificit y or se verit y t hat has bee n o bser ve d; or if a n i n vesti gat or’s 
br oc h ure is n ot re q uire d or a vaila ble, is n ot c o nsiste nt wit h t he ris k i nf or mat i o n 
descri be d i n t he ge neral i n vesti gati o n pla n or else w here i n t he c urre nt I N D 
a p plicati o n.   
 
 
T he Me d Watc h f or m s h o ul d be  e maile d t o t he assi g ne d M ultice nter Pr oject 
Ma na ger a n d als o t o C P O M ultice nter @ me d. u nc.e d u , al o n g wit h s u p p orti n g 
d oc u me ntati o n defi ni n g t he e ve nt a n d ca usalit y. T he M ultice nter Pr oject Ma na ger 
will t he n se n d t he re p ort t o t he F u n di n g S o urce. T he Me d Watc h 3 5 0 0a f or m ca n be 
accesse d at  
htt p:// w w w.f da. g o v/ Safet y/ Me d Watc h/ H o w T o Re p ort/ D o w nl oa d F or ms/ defa ult. ht m .  
 
( Please be s ure a n d access f or m 3 5 0 0a, a n d n ot f or m 3 5 0 0).  
 
O nce t he U N C Pri nci pal I n vesti gat or deter mi nes a n e ve nt is a seri o us S A R A N D 
u ne x pecte d, t he Me d Watc h 3 5 0 0 A f or m will be s u b mitte d t o t he F D A .  
 
T he M ultice nter Pr oject Ma na ger will als o be res p o nsi ble f or i nf or mi n g eac h 
m ultice nter site of all seri o us a n d u ne x pecte d S A Rs  re p orte d t o t he F D A via fa x as 
s o o n as p ossi ble.   
 
A d diti o n al Re p orti n g Re q uire me nts  
T he f oll o wi n g a d diti o nal ite ms m ust be re p orte d via I N D safet y re p ort:  
•  Fi n di n gs fr o m ot her st u dies. T he s p o ns or m ust re p ort a n y fi n di n gs fr o m 
e pi de mi ol o gical st u dies, p o ole d a nal ysis of m ulti ple st u dies, or cli nical 
st u dies, w het her or n ot c o n d ucte d u n der a n I N D, a n d w het her or n ot 
c o n d ucte d b y t he s p o ns or, t hat s u g gest a si g nifica nt ris k t o h u ma ns e x p os e d 
t o t he dr u g.  
•  Fi n di n gs fr o m a ni m al or i n vitr o testi n g. T he s p o ns or m ust re p ort a n y 
fi n di n gs fr o m a ni mal or i n vitr o testi n g, w het her or n ot c o n d ucte d b y t he 
s p o ns or, t hat s u g gest a si g nifica nt ris k i n h u ma ns e x p ose d t o t he dr u g, s uc h 
as re p orts of m uta ge nicit y, terat o ge nicit y, or carci n o ge nicit y, or re p orts of 
si g nifica nt or ga n t o xicit y t or near t he e x pecte d h u ma n e x p os ure. 
•  I ncre ase d r ate of occ urre nce of seri o us s us pecte d a dverse re acti o ns. 
 
A d diti o n al G ui d a nce  
Please refer t o 2 1 C F R 3 1 2. 3 2 a n d “ G ui da nce f or I n d ustr y a n d I n vesti gat ors: Safet y 
Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies” f or a d diti o nal i nf or mati o n 
a n d re p orti n g re q uire me nts. All I N D Safet y Re p orts will be s u b mitte d i n 
acc or da nce wit h t hese re g ulati o ns/ g ui da nces.  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 1  
 
7. 4  
D at a a n d S afet y M o nit ori n g Pl a n  
T he Pri nci p al I n vesti gat or will pr o vi de c o nti n u o us m o nit ori n g of patie nt safet y i n 
t his trial wit h peri o dic re p orti n g t o t he Data a n d Safet y M o nit ori n g C o m mittee 
( D S MC ).  
 
Meeti n gs/telec o nfere nces  will be hel d at a fre q ue nc y de pe n de nt o n st u d y accr ual.  
T hese meeti n gs will i ncl u de  t he i n vesti gat ors as well as st u d y c o or di nat ors , data 
c o or di nat ors , re g ulat or y ass ociates, cli nical data ma na ge me nt ass ociates , a n d a n y 
ot her rele va nt pers o n nel t he pri nci pal i n vesti gat ors ma y dee m a p pr o priate.  At 
t hese meeti n gs, t he researc h tea m will disc uss all iss ues rele va nt t o st u d y 
pr o gress, i ncl u di n g e nr oll me nt, safet y, re g ulat or y, data c ollecti o n, etc.  
 
T he tea m will pr o d uce s u m maries or mi n utes of t hese meeti n gs. T hese s u m maries 
will be a vaila ble f or i ns pecti o n w he n re q ueste d b y a n y of t he re g ulat or y b o dies 
c har ge d wit h t he safet y of h u ma n s u bjects a n d t he i nte grit y of data i ncl u di n g, b ut 
n ot li mite d t o, t he o versi g ht ( Office of H u ma n Researc h Et hics ( O H R E) 
Bi o me dical  I R B, t he O nc ol o g y Pr ot oc ol Re vie w C o m mittee ( P R C) or t he N ort h 
Car oli na Tra C S I nstit ute  Data  a n d Safet y M o nit ori n g B oar d  ( D S M B).   
 
T he U N C L C 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 t he 
st u d y o n a re g ular ( q uarterl y t o a n n uall y) basis, wit h t he fre q ue nc y of re vie w 
base d o n ris k a n d c o m ple xit y as deter mi ne d b y t he U N C Pr ot oc ol Re vie w 
C o m mittee .  T he U N C PI will be res p o nsi ble f or s u b mitti n g t he f oll o wi n g 
i nf or mati o n f or re vie w: 1) safet y a n d accr ual data i ncl u di n g t he n u m ber of 
patie nts treate d; 2) si g nifica nt de vel o p me nts re p orte d i n t he literat ure t hat ma y 
affect t he safet y of partici pa nts or t he et hics of t he st u d y;  3 ) preli mi nar y res p o nse 
data; a n d 4 ) s u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last re p ort.  
Fi n di n gs of t he D S M C  re vie w will be disse mi nate d b y me m o t o t he U N C PI, 
P R C, a n d t he U N C I R B a n d D S M B.   
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
T his is a si n gle -ar m n o n-ra n d o mize d pil ot st u d y  t o e xa mi ne t he efficac y a n d 
safet y of B V-C H E P f or t he treat me nt of A d ult T -Cell Le u ke mia/ L y m p h o ma  a n d 
t he pri mar y efficac y o utc o me is c o m plete res p o nse ( C R).   
 
I n t his pil ot si n gle-ar m st u d y, we will accr ue 1 4  patie nts t o get preli mi nar y data 
o n efficac y of a n o vel re gi me n, bre nt u xi ma b ve d oti n wit h c ycl o p h os p ha mi de, 
d o x or u bici n, et o p osi de, a n d pre d nis o ne ( B V -C H E P) .  We ex pect t he c o m plete 
res p o nse r ate will be a b o ut 45 % . T he st u dy m ay e nr oll u p t o 1 6  p atie nts t o e ns ure 
1 4  are ev al u a ble f or t he pri m ary e n d p oi nt.   
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 3  
 
Ti me -t o-e ve nt o utc o mes li ke P F S, d urati o n of res p o nse a n d o verall s ur vi val will 
be a nal yze d usi n g t he Ka pla n Meier met h o d f or ti me -t o-e ve nt o utc o me, wit h 
me dia n d urati o n of res p o nse  re p orte d wit h 9 5 % c o nfi de nce i nter vals. Descri pti ve 
statistics (fre q ue ncies) of t he t o xicit y a n d t olera bilit y (assesse d via N CI -C T C A E 
v . 4 . 0 3) of B V -C H E P  will als o be re p orte d.  Pr o p orti o n of o verall res p o nse rate 
( O R R) will be re p orte d wit h a n e xact 9 5 % c o nfi de nce i nter val.  
 
E x pl orat or y a nal yses will be c o n d ucte d t o e xa mi ne t he ass ociati o ns bet wee n 
C D 3 0 e x pressi o n a n d P F S usi n g C o x pr o p orti o nal hazar d re gressi o n.  
 
9. 0  
S T U D Y M A N A G E M E N T  
9. 1  
I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt 
It is e x pecte d t hat t he I R B will ha ve t he pr o per re prese ntati o n a n d f u ncti o n i n 
acc or da nce wit h fe derall y ma n date d re g ulati o ns.  T he I R B s h o ul d a p pr o ve t he 
c o nse nt f or m a n d pr ot oc ol.  
 
I n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y 
wit h t he a p plica ble re g ulat or y re q uire me nt(s), a n d s h o ul d a d here t o G o o d Cli nical 
Practice ( G C P) a n d t o et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n 
of Helsi n ki.  
 
 
 
Bef ore recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he patie nt will be gi ve n a f ull 
e x pla nati o n of t he st u d y a n d will be gi ve n t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h c o nse nt f or m m ust i ncl u de all t he rele va nt ele me nts c urre ntl y re q uire d 
b y t he F D A Re g ulati o ns a n d l ocal or state re g ulati o ns. O nce t his esse ntial 
i nf or mati o n has bee n pr o vi de d t o t he patie nt a n d t he i n vesti gat or is ass ure d t hat 
t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he patie nt 
will be as ke d t o gi ve c o nse nt t o partici pate i n t he st u d y b y si g ni n g a n 
I R B-a p pr o ve d c o nse nt f or m.  
 
Pri or t o a patie nt’s partici pati o n i n t he trial, t he writte n i nf or me d c o nse nt f or m 
s h o ul d be si g ne d a n d pers o nall y date d b y t he patie nt a n d b y t he pers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n.  
9. 2  
Re q uire d D oc u me nt ati o n  
Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n m ust be 
pr o vi de d t o t he Cli nical Pr ot oc ol Office ( C P O) at t he U ni versit y of N ort h 
Car oli na.  
 
•  A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d 
i nf or me d c o nse nt 
•  I R B me m bers hi p list 
•  C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y s u b-
i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y. 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 4  
 
•  F or m F D A 1 5 7 2  
•  Fi na ncial discl os ures  
•  C A P a n d C LI A La b orat or y certificati o n n u m bers a n d i nstit uti o n la b 
n or mal val ues  
•  E xec ute d cli nical researc h c o ntract  
9. 3  
Re gistr ati o n Pr oce d ures  
All patie nts m ust be re gistere d wit h t he L C C C C P O  M ultice nter gr o u p at t he 
U ni versit y of N ort h Car oli na bef ore e nr oll me nt t o st u d y.  T o re gister a patie nt call 
t he M ultice nter Pr oject Ma na ger  at 9 1 9 -9 6 6 -7 3 5 9  M o n da y -F ri da y 8: 3 0  a m –  5 : 0 0 
p m E S T . E mail t he  re gistrati o n f or m, si g ne d i nf or me d c o nse nts a n d all s o urce 
d oc u me nts  t o c o nfir m eli gi bilit y t o t he assi g ne d Pr oject Ma na ger (if u n k n o w n, 
e mail C P O M ultice nter @ me d. u nc.e d u) . W he n se n di n g re gistrati o n re q uest wit h 
eli gi bilit y d oc u me ntati o n, please all o w 2 4 h o urs f or s o urce d oc u me nts t o be 
re vie we d. 
 
9. 4  
D at a M a n a ge me nt a n d M o nit ori n g / A u diti n g 
T he C P O M ultice nter Office of t he U N C L C C C will ser ve as t he c o or di nati n g 
ce nter f or t his trial. Data will be c ollecte d t hr o u g h a we b base d cli nical researc h 
platf or m, O n C ore ® .  Ot her st u d y i nstit uti o ns will be gi ve n a pass w or d t o directl y 
e nter t heir o w n data o nt o t he we b site  via electr o nic case re p ort f or ms (e C R Fs) .  
Cli nical Data Ma na ge me nt Ass ociates will re vie w cli nical data e ntere d i n t he 
e C R Fs a n d c o or di nate wit h M ultice nter Pers o n nel t o e ns ure data q ualit y a n d 
i nte grit y wit h q ueries iss ue d o n a n o n g oi n g basis . 
 
All data will be c ollecte d a n d e ntere d i nt o O n C ore® b y researc h c o or di nat ors  fr o m 
U N C L C C C a n d partici pati n g i nstit uti o ns.   T he i n vesti gat or s at eac h site will 
all o w m o nit ors  t o re vie w all s o urce d oc u me nts s u p p orti n g data e ntere d i nt o 
O n C ore ® .  T he Cli nical Data Ma na ge me nt Ass ociate ( C D M A)  ca n be reac he d at 
L C C C _ O n C ore @ me d. u nc.e d u  or 1 -8 7 7 -6 6 8 -0 6 8 3.  
 
All data will be m o nit ore d a n d s o urce data will be verifie d o n selecte d s u bjects. 
Partici pati n g sites m ust se n d s o urce a n d re g ulat or y d oc u me nts t o L C C C u p o n 
re q uest, f or re m ote m o nit ori n g a n d/ or a u dit re vie w.  Q ueries will be iss ue d o n a n 
o n g oi n g basis o n all s u bjects. Partici pati n g sites s h o ul d res p o n d t o data q ueries 
wit hi n 1 4 da ys of recei pt.  
 
As a n i n vesti gat or i nitiate d st u d y, t he L C C C c o m plia nce c o m mittee or t heir 
desi g nee will a u dit trial sites e ver y si x or t wel ve m o nt hs  w hile still e nr olli n g or 
s u bjects are still o n treat me nt. 
9. 5  
A d here nce t o t he Pr ot oc ol  
E xce pt f or a n e mer ge nc y sit uati o n  i n w hic h pr o per care f or t he pr otecti o n, safet y, 
a n d well -bei n g of t he st u d y patie nt re q uires alter nati ve treat me nt, t he st u d y s hall 
be c o n d ucte d e xactl y as descri be d i n t he a p pr o ve d pr ot oc ol.   

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 5  
 
9. 5. 1  E mer ge nc y M o dific ati o ns  
U N C a n d m ultice nter  i n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n ge 
of, t he pr ot oc ol t o eli mi nate a n i m me diate hazar d(s) t o trial s u bjects wit h o ut pri or 
U N C or t heir res pecti ve i nstit uti o n’s I R B/I E C a p pr o val/fa v ora ble o pi ni o n.   
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B:  
F or a n y s uc h e mer ge nc y m o dificati o n i m ple me nte d, a U N C I R B m o dificati o n 
f or m m ust be c o m plete d b y U N C Researc h Pers o n nel  wit hi n fi ve ( 5) b usi ness 
da ys of ma ki n g t he c ha n ge.   
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B:  
F or m ultice nter  i n vesti gat ors rel yi n g o n t heir o w n i nstit uti o n’s I R B, as s o o n as 
p ossi ble after t he m o dificati o n has bee n ma de, t he i m ple me nte d de viati o n or 
c ha n ge a n d t he reas o ns f or it s h o ul d be s u b mitte d t o:  
 
•  T o U N C Pri nci pal I n vesti gat or f or a gree me nt  
•  T he m ultice nter  i nstit uti o n’s I R B f or re vie w a n d a p pr o val.  ( O nce 
I R B’s res p o nse is recei ve d, this s h o ul d be f or war de d t o t he 
M ultice nter  Re g ulat or y Ass ociate).  
9. 5. 2  Si n gle P atie nt/ S u bject E xce pti o ns  
Eli gi bilit y si n gle s u bject e xce pti o ns are n ot per mitte d f or Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter I n vesti gat or I nitiate d Trials u n der a n y 
circ u msta nces. Ot her t y pes of si n gle s u bject e xce pti o ns ma y be all o we d if pr o per 
re g ulat or y re vie w has bee n c o m plete d i n acc or da nce wit h Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter’s Si n gle S u bject E xce pti o ns P olic y.  
 
9. 5. 3  Ot her Pr ot oc ol De vi ati o ns/ Vi ol ati o ns  
Acc or di n g t o U N C’s I R B, a pr ot oc ol de viati o n  is a n y u n pla n ne d varia nce fr o m a n 
I R B a p pr o ve d pr ot oc ol t hat:  
•  Is ge nerall y n ote d or rec o g nize d after it occ urs 
•  Has n o s u bsta nti ve effect o n t he ris ks t o researc h partici pa nts  
•  Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n 
or t he val ue of t he data c ollecte d  
•  Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol varia nce is c o nsi dere d a vi olati o n  if t he varia nce meets 
a n y of t he f oll o wi n g criteria :  
•  Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h 
partici pa nts.  
•  Has da ma ge d t he scie ntific i nte grit y of t he data c ollecte d f or t he st u d y. 
•  Res ults fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s). 
•  De m o nstrates seri o us or c o nti n ui n g n o nc o m plia nce wit h fe deral 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 6  
 
re g ulati o ns, State la ws, or U ni versit y p olicies. 
 
If a de viati o n or vi olati o n occ urs please f oll o w t he g ui deli nes bel o w: 
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B : 
Pr ot oc ol De vi ati o ns: U N C or m ultice nter site pers o n nel will rec or d t he de viati o n 
i n O n C ore® , a n d re p ort t o a n y s p o ns or, I R B, or data a n d safet y m o nit ori n g 
c o m mittee i n acc or da nce wit h t heir p olicies.   
 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p orte d b y U N C pers o n nel wit hi n o ne 
( 1) wee k of t he i n vesti gat or bec o mi n g a ware of t he e ve nt usi n g t he sa me I R B 
o nli ne mec ha nis m use d t o re p ort U na ntici pate d Pr o ble ms.   
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B:  
I n a d diti o n t o a d heri n g t o t he p olicies re gar di n g pr ot oc ol c o m plia nce set f ort h b y 
y o ur i nstit uti o n’s I R B, t he f oll o wi n g is als o re q uire d: 
 
Pr ot oc ol De vi ati o ns: I n t he e ve nt a de viati o n fr o m pr ot oc ol pr oce d ures is 
i de ntifie d, rec or d t he de viati o n i n O n C ore® . 
 
Pr ot oc ol Vi ol ati o ns: A n y pr ot oc ol vi olati o n t hat occ urs m ust be re p orte d t o y o ur 
I R B per i nstit uti o nal p olicies a n d re p orte d t o t he M ultice nter Pr oject Ma na ger 
wit h i n 5 da ys . U N C-C H will  deter mi ne if t he vi olati o n affects t he safet y of t he 
patie nt a n d i nte grit y of t he data.   O nce y o ur i nstit uti o n’s I R B res p o nse is r ecei ve d, 
please f or war d t o t he M ultice nter Re g ulat or y Ass ociate.  
 
U n a ntici p ate d Pr o ble ms : 
M ultice nter Sites:  
A n y e ve nts t hat meet t he criteria f or “ U na ntici pate d Pr o ble ms ( U Ps)” m ust be 
re p orte d t o t he M ultice nter Pr oject Ma na ger i n a d diti o n t o t he I R B.   T he 
M ultice nter Re g ulat or y Ass ociate  will re p ort t he e ve nt t o t he U N C I R B usi n g t he 
I R B’s we b-base d re p orti n g s yste m.  E xa m ples of s uc h U Ps i ncl u de a l ost or st ole n 
la pt o p c o m p uter t hat c o ntai ns se nsiti ve st u d y i nf or mati o n. 
 
U N C  
A n y e ve nts t hat meet t he criteria f or “ U na ntici pate d Pr o ble ms” as defi ne d b y 
U N C’s I R B m ust be re p orte d b y t he st u d y tea m usi n g t he I R B’s we b -base d 
re p orti n g s yste m.   
9. 6  
A me n d me nts t o t he Pr ot oc ol  
S h o ul d a me n d me nts t o t he pr ot oc ol be re q uire d, t he a me n d me nts will be 
ori gi nate d a n d d oc u me nte d b y t he Pri nci pal I n vesti gat or at U N C.  It s h o ul d als o 
be n ote d t hat w he n a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y 
desi g n or t he p ote ntial ris k t o t he patie nt, a re vise d c o nse nt f or m mi g ht be 
re q uire d.   
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 7  
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B : 
T he writte n a me n d me nt, a n d if re q uire d t he a me n de d c o nse nt f or m, m ust be se nt 
t o U N C’s I R B f or a p pr o val pri or t o i m ple me ntati o n.   
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B:  
I n vesti gat ors m ust s u b mit t he a me n d me nt t o t heir i nstit uti o n’s I R B f or a p pr o val.  
F or m ultice nter st u dies, a n y m ultice nter site m ust s u b mit t heir i nfor me d c o nse nt 
re visi o ns t o t he M ultice nter Re g ulat or y Ass ociate  pri or t o s u b missi o n t o t heir 
I R B.   
9. 7  
Rec or d Rete nti o n  
St u d y d oc u me ntati o n i ncl u des all e C R Fs, data c orrecti o n f or ms or q ueries, s o urce 
d oc u me nts, S p o ns or -I n vesti gat or c orres p o n de nce, m o nit ori n g l o gs/letters, a n d 
re g ulat or y d oc u me nts (e. g., pr ot oc ol a n d a me n d me nts, I R B c orres p o n de nce a n d 
a p pr o val, si g ne d patie nt c o nse nt f or ms).  
 
S o urce d oc u me nts i ncl u de all rec or di n gs of o bser vati o ns or n otati o ns of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y f or t he e val uati o n a n d 
rec o nstr ucti o n of t he cli nical researc h st u d y. 
 
G o ver n me nt a ge nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y 
d oc u me ntati o n pertai ni n g t o t he c o n d uct of a cli nical trial m ust be retai ne d b y t he 
st u d y i n vesti gat or.  I n t he case of a st u d y wit h a dr u g see ki n g re g ulat or y a p pr o val 
a n d mar keti n g, t hese  d oc u me nts s hall be retai ne d f or at least t w o years after t he 
last a p pr o val of mar keti n g a p plicati o n i n a n I nter nati o nal C o nfere nce o n 
Har m o nizati o n (I C H) re gi o n.  I n all ot her cases, st u d y d oc u me nts s h o ul d be ke pt 
o n file u ntil t hree years after t he c o m pl eti o n a n d fi nal st u d y re p ort of t his 
i n vesti gati o nal st u d y. 
9. 8  
O bli g ati o ns of I n vesti g at ors  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical trial at t he 
site i n acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he 
Declarati o n of Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y 
o versee i n g t he treat me nt of all st u d y patie nts.  T he Pri nci pal I n vesti gat or m ust 
ass ure t hat all st u d y site pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y 
staff me m bers, a d here t o t he st u d y pr ot oc ol a n d all F D A/ G C P/ N CI re g ulati o ns 
a n d g ui deli nes re gar di n g  cli nical trials b ot h d uri n g a n d after st u d y c o m pleti o n.  
 
T he Pri nci pal I n vesti gat or at eac h i nstit uti o n or site will be res p o nsi ble f or 
ass uri n g t hat all t he re q uire d data will be c ollecte d a n d e ntere d i nt o t he e C R Fs. 
Peri o dicall y, m o nit ori n g visits will be c o n d ucte d a n d t he Pri nci pal I n vesti gat or 
will pr o vi de access t o his/ her ori gi nal rec or ds t o per mit verificati o n of pr o per 
e ntr y of data. At t he c o m pleti o n of t he st u d y, all e C R Fs will be re vie we d b y t he 
Pri nci pal I n vesti gat or a n d will re q uire his/ her fi nal si g nat ure t o verif y t he 
acc urac y of t he data.  
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 8  
 
 
1 0. 0  R E F E R E N C E S  
 
1.  
Bazar bac hi, A., et al., H o w I tre at a d ult T -cell le uke mi a/ly m p h o m a.  Bl o o d, 2 0 1 1. 
1 1 8 ( 7): p. 1 7 3 6-4 5.  
2.  
Pr oietti, F. A., et al., Gl o b al e pi de mi ol o gy of H T L V -I i nfecti o n a n d ass oci ate d 
dise ases.  O nc o ge ne, 2 0 0 5. 2 4 ( 3 9): p. 6 0 5 8-6 8.  
3.  
A meric a n C o m m u nity S urvey Briefs: T he p o p ul ati n wit h H aiti n a a ncetry i n t he 
U nite d St at d: 2 0 0 9 . 2 0 1 0: U. S. Ce ns us B urea u. 
4.  
Ca m p uza n o -Z ul ua ga G, P. A., Diaz L A C ha p ma n -Fre deric ks J R, Ra m os J C. , 
C D 3 0 ex pressi o n is ass oci ate d wit h decre ase d s urviv al i n p atie nts wit h ac ute a n d 
u nf av or a ble c hr o nic ty pes of a d ult t -cell l ueke mi a -ly m p h o m a. 2 0 1 3. 1 2 2 ( 2 1). 
5.  
S E E R I nci de nce R ates a n d A n n u al Perce nt C h a n ge by A ge at Di a g n osis, All 
R aces, B ot h Sexes, 2 0 0 2 -2 0 1 1. All Ly m p h oi d Ne o pl as ms wit h Det aile d N o n -
H o d gki n Ly m p h o m a S u bty pes.   1 2/ 1/ 2 0 1 4].  
6.  
Ts u kasa ki, K., et al., V C A P -A M P -V E C P c o m p are d wit h bi weekly C H O P f or a d ult 
T -cell le uke mi a-ly m p h o m a: J a p a n Cli nic al O nc ol o gy Gr o u p St u dy J C O G 9 8 0 1. J 
Cli n O nc ol, 2 0 0 7. 2 5 ( 3 4): p. 5 4 5 8-6 4.  
7.  
Is hi da, T., et al., D ose -i nte nsifie d c he m ot her a py al o ne or i n c o m bi n ati o n wit h 
m o g a m uliz u m a b i n ne wly di a g n ose d a g gressive a d ult T -cell le uk ae mi a -
ly m p h o m a: a r a n d o mize d p h ase II st u dy. Br J Hae mat ol, 2 0 1 5. 1 6 9 ( 5): p. 6 7 2-8 2.  
8.  
F uji, S., et al., Pretr a ns pl a nt ati o n A nti -C C R 4 A nti b o dy M o g a m uliz u m a b A g ai nst 
A d ult T -Cell Le uke mi a/ Ly m p h o m a Is Ass oci ate d Wit h Si g nific a ntly I ncre ase d 
Risks of Severe a n d C ortic oster oi d -Refr act ory Gr aft -Vers us -H ost Dise ase, 
N o nrel a pse M ort ality, a n d Over all M ort ality.  J Cli n O nc ol, 2 0 1 6. 3 4 ( 2 8): p. 
3 4 2 6 -3 3.  
9.  
Bazar bac hi, A., et al., Met a -a n alysis o n t he use of zi d ov u di ne a n d i nterfer o n -alf a 
i n a d ult T-cell le uke mi a/ly m p h o m a s h o wi n g i m pr ove d s urviv al i n t he le uke mic 
s u bty pes. J Cli n O nc ol, 2 0 1 0. 2 8 ( 2 7): p. 4 1 7 7-8 3.  
1 0.  
Bazar bac hi, A. a n d O. Her mi ne, Tre at me nt wit h a c o m bi n ati o n of zi d ov u di ne a n d 
al p h a -i nterfer o n i n n aive a n d pretre ate d a d ult T-cell le uke mi a/ly m p h o m a 
p atie nts.  J Ac q uir I m m u ne Defic S y n dr H u m Retr o vir ol, 1 9 9 6. 1 3 S u p pl 1 : p. 
S 1 8 6 -9 0.  
1 1.  
Her mi ne, O., et al., A pr os pective p h ase II cli nic al tri al wit h t he use of zi d ov u di ne 
a n d i nterfer o n -al p h a i n t he ac ute a n d ly m p h o m a f or ms of a d ult T -cell 
le uke mi a/ly m p h o m a. He mat ol J, 2 0 0 2. 3 ( 6): p. 2 7 6-8 2.  
1 2.  
His hiza wa, M., et al., Tr a ns pl a nt ati o n of all o ge neic he m at o p oietic ste m cells f or 
a d ult T -cell le uke mi a: a n ati o n wi de retr os pective st u dy.  Bl o o d, 2 0 1 0. 1 1 6 ( 8): p. 
1 3 6 9 -7 6.  
1 3.  
C h oi, I., et al., L o n g -ter m o utc o mes after he m at o p oietic S C T f or a d ult T-cell 
le uke mi a/ly m p h o m a: res ults of pr os pective tri als. B o ne Marr o w Tra ns pla nt, 2 0 1 1. 
4 6 ( 1): p. 1 1 6-8.  
1 4.  
O' C o n n or O A, P. B., Illi d ge T, et al., P h ase 3 tri al of bre nt uxi m a b ve d oti n i n t he 
fr o nt -li ne tre at me nt of p atie nts wit h C D 3 0 + m at ure T-cell ly m p h o m as. .  J o ur nal 
of Cli nical O nc ol o g y, 2 0 1 4. 3 2 (s u p pl): p. 5 S. 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
3 9  
 
1 5.  
Fa nale, M. A., et al., Bre nt uxi m a b ve d oti n i n t he fr o nt -li ne tre at me nt of p atie nts 
wit h C D 3 0 + peri p her al T -cell ly m p h o m as: res ults of a p h ase I st u dy.  J Cli n 
O nc ol, 2 0 1 4. 3 2 ( 2 8): p. 3 1 3 7-4 3.  
1 6.  
Sc h mitz, N., et al., Tre at me nt a n d pr o g n osis of m at ure T -cell a n d N K-cell 
ly m p h o m a: a n a n alysis of p atie nts wit h T-cell ly m p h o m a tre ate d i n st u dies of t he 
Ger m a n Hi g h -Gr a de N o n -H o d gki n Ly m p h o m a St u dy Gr o u p.  Bl o o d, 2 0 1 0. 
1 1 6 ( 1 8): p. 3 4 1 8-2 5.  
1 7.  
Elli n, F., et al., Re al -w orl d d at a o n pr o g n ostic f act ors a n d tre at me nt i n peri p her al 
T -cell ly m p h o m as: a st u dy fr o m t he S we dis h Ly m p h o m a Re gistry.  Bl o o d, 2 0 1 4. 
1 2 4 ( 1 0): p. 1 5 7 0-7.  
1 8.  
D u vic, M., et al., Res ults of a P h ase II Tri al of Bre nt uxi m a b Ve d oti n f or C D 3 0 + 
C ut a ne o us T -Cell Ly m p h o m a a n d Ly m p h o m at oi d P a p ul osis.  J Cli n O nc ol, 2 0 1 5. 
3 3 ( 3 2): p. 3 7 5 9-6 5.  
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 0  
 
 
1 1. 0  A P P E N DI C E S  
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 1  
 
1 1. 1  
A p pe n di x A: Re vise d res p o nse criteri a f or l y m p h o m a  (C hes o n, et al. J Cli n O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 8 ) 
R es p o ns e a n d Sit e  
P E T -C T -B as e d R es p o ns e  
C T -B as e d R es p o ns e  
C o m pl et e  
C o m pl et e m et a b olic r es p o ns e  
C o m pl et e r a di ol o gic r es p o ns e ( all of t h e f oll o wi n g)  
L y m p h n o d es a n d extr a-ly m p h atic 
sit es 
Sc or e 1, 2, or 3 * wit h or wit h o ut a r esi d u al m ass 5 P S †  
It is r ec o g niz e d t h at i n W al d ey er’s ri n g or extr a n o d al 
sit es wit h hi g h p h ysi ol o gic u pt a k e or wit h acti v ati o n 
wit hi n s pl e e n or m arr o w ( e .g ., wit h c h e m ot h er a py or 
m y el oi d c ol o ny -sti m ul ati n g f act ors), u pt a k e m a y b e 
gr e at er t h a n n or m al m e di asti n u m a n d/ or liv er. I n t his 
circ u mst a nc e, c o m pl et e m et a b olic r es p o ns e m a y b e 
i nt err e d if u pt a k e at sit es f i niti al i n v olv e m e nt is n o 
gr e at er t h a n s urr o u n di n g n or m al tiss u e e v e n if t h e 
tiss u e h as hi g h p hysi ol o gic u pt a k e 
T ar g et n o d es/ n o d al m ass es m ust r e gr ess t o ≤ 1. 5  c m i n L Di 
N o extr aly m p h atic sit es of dis e as e  
N o n m e as ur e d l esi o n  
N ot a p plic a bl e  
A bs e nt  
Or g a n e nl ar g e m e nt  
N ot a p plic a bl e  
R e gr ess t o n or m al  
N e w l esi o ns  
N o n e  
N o n e  
B o n e m arr o w  
N o e vi d e nc e of F D G -a vi d dis e as e i n m arr o w  
N or m al by m or p h ol o gy; if i n d et er mi n at e, I H C n e g ati v e 
P arti al  
P arti al m et a b olic r es p o ns e  
P arti al r e missi o n ( all of t h e f oll o wi n g)  
L y m p h n o d es a n d extr a-ly m p h atic 
sit es 
Sc or e of 4 or 5 † wit h r e d uc e d u pt a k e c o m p ar e d wit h 
b as eli n e a n d r esi d u al m ass( es) of a n y siz e  
At i nt eri m, t h es e fi n di n gs i n dic at e r es p o n di n g dis e as e 
At e n d of tr e at m e nt, t h es e fi n di n gs i n dic at e r esi d u al 
dis e as e  
 
≥5 0 % d ecr e as e i n S P D of u p t o 6 t ar g et m e as ur a bl e n o d es a n d 
extr a n o d al sit es  
W h e n a l esi o n is t o o s m all t o m e as ur e o n C T, assi g n 5  m m X 5 
m m as t h e d ef a ult v al u e  
W h e n n o l o n g er visi bl e, 0 x 0 m m  
F or a n o d e > 5 m m X 5 m m, b ut s m all er t h a n n or m al, us e act u al 
m e as ur e m e nt f or c alc ul ati o n  
N o n m e as ur e d l esi o ns  
N ot a p plic a bl e  
A bs e nt/ n or m al, r e gr ess e d, b ut n o i ncr e as e  
Or g a n e nl ar g e m e nt  
N ot a p plic a bl e  
S pl e e n m ust h a v e r e gr ess e d b y > 5 0 % i n l e n gt h b ey o n d n or m al  
N e w l esi o ns  
N o n e  
N o n e  
B o n e m arr o w  
R esi d u al u pt ak e hi g h er t h a n u pt a k e i n n or m al m arr o w 
b ut r e d uc e d c o m p ar e d w/ b as eli n e ( diff us e u pt a k e 
c o m p ati bl e w. r e acti v e c h a n g es fr o m c h e m ot h er a py 
all o w e d). If t h er e ar e p ersist e nt f oc al c h a n g es i n t h e 
m arr o w i n t h e c o nt ext of a n o d al r es p o ns e, 
c o nsi d erati o n s h o ul d b e gi v e n t o f urt h er e v al u ati o n w/ 
M RI or bi o psy or a n i nt er v al sc a n  
N ot a p plic a bl e  

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 2  
 
R e vis e d Crit eri a f or R es p o ns e Ass ess m e 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 m a (L u g a n o Crit eri a)  
C o nti n u e d fr o m pr e vi o us p a g e  
R es p o ns e a n d Sit e  
P E T -C T -B as e d R es p o ns e  
C T -B as e d R es p o ns e  
N o r es p o ns e or st a bl e dis e as e  
N o m et a b olic r es p o ns e  
St a bl e dis e as e  
T ar g et n o d es/ n o d al m ass es, 
extr a n o d al l esi o ns  
Sc or e 4 or 5 wit h n o si g nific a nt c h a n g e i n F D G u pt a k e 
fr o m b as eli n e at i nt eri m or e n d of tr e at m e nt 
< 5 0 % d ecr e as e fr o m b as eli n e i n S P D of u p t o 6 d o mi n a nt, 
m e as ur a bl e n o d es a n d extr a n o d al sit es; n o crit eri a f or 
pr o gr essi v e dis e as e ar e m et  
N o n m e as ur e l esi o ns  
N ot a p plic a bl e  
N o i ncr e as e c o nsist e nt wit h pr o gr essi o n  
Or g a n e nl ar g e m e nt  
N ot a p plic a bl e  
N o i ncr e as e c o nsist e nt wit h pr o gr essi o n  
N e w l esi o ns  
N o n e  
N o n e  
B o n e m arr o w  
N o c h a n g e fr o m b as eli n e  
N ot a p plic a bl e  
Pr o gr essiv e dis e as e  
Pr o gr essiv e m et a b olic dis e as e  
Pr o gr essiv e dis e as e r e q uir es at l e ast 1 of t h e f oll o wi n g  
I n di vi d u al t ar g et n o d es/ n o d al 
m ass es  
Sc or e 4 or 5 wit h a n i ncr e as e i n i nt e nsity of u pt a k e fr o m 
b as eli n e a n d/ or  
P P D pr o gr essi o n:  
Extr a n o d al l esi o ns  
N e w F D G -a vi d f oci c o nsist e nt wit h l y m p h o m a at i nt eri m 
or e n d -of -tr e at m e nt ass ess m e nt 
A n i n di vi d u al n o d e/l esi o n m ust b e a b n or m al wit h:  
L Di > 1. 5 c m a n d 
I ncr e as e b y ≥ 5 0 % fr o m P P D n a dir a n d a n i ncr e as e i n L Di or S Di 
fr o m n a dir 
0. 5 c m f or l esi o ns ≤ 2 c m  
1. 0 c m f or l esi o ns > 2 c m  
I n t h e s etti n g of s pl e n o m e g aly, t h e s pl e nic l e n gt h m ust i ncr e as e 
b y > 5 0 % of t h e ext e nt of its pri or i ncr e as e b e y o n d b as eli n e 
( e.g ., a 1 5-c m s pl e e n m ust i ncr e as e t o > 1 6 c m). If n o pri or 
s pl e n o m e g aly, m ust i ncr e as e b y at l e ast 2 c m fr o m b as eli n e 
N e w or r ec urr e nt s pl e n o m e g al y  
N o n m e as ur e d l esi o ns  
N o n e  
N e w or cl e ar pr o gr essi o n of pr e existi n g n o n m e as ur e d l esi o ns  
N e w l esi o ns  
N e w F D G -a vi d f oci c o nsist e nt wit h l y m p h o m a r at h er 
t h a n a n ot h er eti ol o g y ( e.g ., i nf ecti o n, i nfl a m m ati o n). 
If u nc ert ai n r e g ar di n g eti ol o gy of n e w l esi o ns, bi o psy 
or i nt erv al sc a n m a y b e c o nsi d er e d  
R e gr o wt h of pr e vi o usly r es ol v e d l esi o ns  
A n e w n o d e > 1. 5 c m i n a n y axis  
A n e w extr a n o d al sit e > 1. 0 c m i n a ny a xis; if < 1. 0 c m i n a n y 
axis, its pr es e nc e m ust b e u n e q ui v oc al a n d m ust b e 
attri b ut a bl e t o l y m p h o m a  
Ass ess a bl e dis e as e of a n y siz e u n e q ui v oc ally attri b ut a bl e t o 
l y m p h o m a 
B o n e m arr o w  
N e w or r ec urr e nt F D G -a vi d f oci  
N e w or r ec urr e nt i n v olv e m e nt  
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 3  
 
 
R e vis e d R es p o ns e Crit eri a c o nti n u e d fr o m pr e vi o us p a g e ( T a bl e K e y)  
A b br evi ati o ns : 5 P S, 5-p oi nt sc al e, C T c o m p ut e d t o m o gr a p h y; F D G, fl u or o d e ox y gl uc os e; I H C, i m m u n o hist oc h e mistr y; L Di , l o n g est tr a ns v ers e di a m et er of a l esi o n; 
M RI, m a g n etic r es o n a nc e i m a gi n g; P E T, p ositr o n e missi o n t o m o gr a p h y; P P D cr oss pr o d uct of t h e L Di a n d p er p e n dic ul ar di a m et er; S Di, s h ort est axis 
p er p e n dic ul ar t o t h e L Di; S P D, s u m of t h e pr o d uct of t h e p er p e n dic ul a r di a m et ers f or m ulti pl e l esi o ns. 
* A sc or e of 3 i n m a n y p ati e nts i n dic at es a g o o d pr o g n osis wit h st a n d ar d tr e at m e nt, es p eci all y if at t h e ti m e of a n i nt eri m sc a n. H o w e v er, i n tri als i n v ol vi n g P E T 
w h er e d e -esc al ati o n is i n v esti g at e d, it m a y b e pr ef er a bl e t o c o nsi d er a sc or e of 3 as i n a d e q u a t e r es p o ns e (t o a v oi d u n d ertr e at m e nt). M e as ur e d d o mi n a nt 
l esi o ns: U p t o 6 of t h e l ar g est d o mi n a nt n o d es, n o d al m ass es, a n d extr a n o d al l esi o ns s el ect e d t o b e cl e arl y m e as ur e a bl e i n t wo di a m et ers. N o d es s h o ul d 
pr ef er a bl y b e fr o m dis p ar at e r e gi o ns of t h e b o d y  a n d s h o ul d i ncl u d e, w h er e a p plic a bl e, m e di asti n al a n d r etr o p erit o n e al ar e as. N o n -n o d al l esi o ns i ncl u d e t h os e 
pr ef er a bl y b e fr o m dis p ar at e r e gi o ns of t h e b o d y a n d s h o ul d i ncl u d e, w h er e a p plic a bl e, m e di asti n al a n d r etr o p erit o n e al ar e as.  N o n -n o d al l esi o ns i ncl u d e t h os e i n 
s oli d or g a ns ( e.g ., li v er, s pl e e n, ki d n e ys, l u n gs), GI i n v ol v e m e nt, c ut a n e o us l esi o ns, or t h os e n ot e d o n p al p ati o n. N o n m e as ur e l esi o ns: A n y dise as e n ot s el ect e d as 
m e as ur e, d o mi n a nt dis e as e a n d tr ul y ass ess a bl e dis e as e s h o ul d b e c o nsi d er e d n ot m e as ur e d. T h es e sit es i ncl u d e a n y n o d es, n o d al m ass es, a n d extr a n o d al sit es 
n ot s el ect e d as d o mi n a nt or m e as ur a bl e or t h at d o n ot m e et t h e r e q uir e m e nts f or m e as ur a bility b ut ar e still c o nsi d er e d a b n or m al, as w ell as tr ul y ass ess a bl e 
dis e as e, w hic h is a n y sit e of s us p ect e d dis e as e t h at w o ul d b e diffic ult t o f oll o w q u a ntit ati v el y wit h m e as ur e m e nt, i ncl u di n g pl e ur al eff usi o ns, a scit es, b o n e 
l esi o ns, l e pt o m e ni n g e al dis e as e, a b d o mi n al m ass es, a n d ot h er l esi o ns t h at c a n n ot b e c o nfir m e d a n d f oll o w e d b y i m a gi n g. I n W al d e y er’s ri n g or i n extr a n o d al 
sit es ( e.g ., GI tr act, li v er, b o n e m arr o w), F D G u pt a k e m a y b e gr e at er t h a n i n t h e m e di asti n u m wit h c o m pl et e m et a b olic r es p o ns e, b ut s h o ul d b e n o hi g h er t h a n 
s urr o u n di n g n or m al p h ysi ol o gic u pt a k e ( e.g ., wit h m arr o w acti v ati o n as a r es ult of c h e m ot h er a p y or m y el oi d gr o wt h f act ors). 
† P E T 5 P S : 1, n o u pt a k e a b o v e b ac k gr o u n d; 2 u pt a k e ≤ m e di asti n u m; 3, u pt a k e > m e di asti n u m b ut ≤ li v er; 4, u pt a k e m o d er at el y > li v er; 5, u pt a k e m ar k e dl y 
hi g h er t h a n li v er a n d/ or n e w l esi o ns; X, n e w ar e as of u pt a k e u nli k el y t o b e r el at e d t o l y m p h o m a.  
R ef er e nc e : C h es o n B D, et al. R ec o m m e n d ati o ns f or i niti al e v al u ati o n, st a gi n g, a n d r es p o ns e ass ess m e 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 m a: t h e l u g a n o 
cl assific ati o n. J Cli n O nc ol. 2 0 1 4; 3 2: 3 0 5 9 -3 0 6 7.  
 
 
 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 4  
 
1 1. 2  
A p pe n di x B - Re n al I m p air me nt G ui deli nes  
 
Gr o u p  
Descri pti o n  
Esti mate d Creati ni ne Cleara nce 
( m L/ mi n) 
1  
N or mal re nal f u ncti o n  
8 0 m L/ mi n  
2  
Mil d re nal i m pair me nt  
5 0 -8 0 m L/ mi n  
3  
M o derate re nal i m pair me nt 
3 0 -5 0 m L/ mi n  
4  
Se vere re nal i m pair me nt  
< 3 0 m L/ mi n  
5  
E n d -sta ge re nal disease 
Re q uiri n g dial ysis  
 
 
C oc k cr oft-Ga ult  
Esti mate d creati ni ne cleara nce ( m L/ mi n) = ( 1 4 0-a ge i n years) X ( wei g ht i n k g)  
 
 
 
 
 
      7 2 X (ser u m creati ni ne i n m g/ d L)  
 
F or fe males, use 8 5 % of calc ulate d creati ni ne cleara nce val ue . 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 5  
 
1 1. 3  
A p pe n di x C - C hil d -P u g h He p atic I m p air me nt Sc ore  
 
F act or  
1 p oi nt  
2 p oi nts  
3 p oi nts  
T otal bilir u bi n 
( µ m ol/ L) 
< 3 4  
3 4 -5 0  
> 5 0  
Ser u m al b u mi n 
( g/ L) 
> 3 5  
2 8 -3 5  
< 2 8  
P T I N R  
< 1. 7  
1. 7 1 -2. 3 0  
> 2. 3 0  
Ascites  
N o ne  
Mil d  
M o derate t o 
se vere 
He patic 
e nce p hal o pat h y  
N o ne  
Gra de I -II  
( or s u p presse d 
wit h me dicati o n)  
Gra de III -
I V  
( or 
refract or y) 
 
 
 
Cl ass A  
Cl ass B  
Cl ass C  
T otal p oi nts  
5 -6  
7 -9  
1 0 -1 5  
1 -year s ur vi val 
1 0 0 %  
8 0 %  
4 5 %  
 
A vaila ble at: htt p:// w w w. 2 mi n ute me dici ne.c o m/t he -c hil d-p u g h -sc ore-pr o g n osis -i n-
c hr o nic-li ver-disease -a n d-cirr h osis -classics-series/  ( Last u p date d A u g ust 4, 2 0 1 5). 
 
 

L C C C 1 6 3 7  
 
C O N FI D E N TI A L  
PI:  C hrist o p her Ditt us, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A me n d me nt 9  
 
J u l y 1 2, 2 0 2 4 
4 6  
 
1 1. 4  
A p pe n di x D:  Pr o hi bite d Me dic ati o ns or T h ose t o be use d wit h C a uti o n  
 
Se veral st u d y me dicati o ns y o u are recei vi n g d uri n g t his cli nical trial i nteracts wit h 
s o me dr u gs t hat are pr ocesse d b y y o ur li v er. Beca use of t his, it is ver y i m p orta nt 
t o tell y o ur st u d y d oct ors a b o ut all of y o ur me dici ne bef ore y o u start t his st u d y. It 
is als o ver y i m p orta nt t o tell t he m if y o u st o p ta ki n g a n y re g ular me dici ne, or if 
y o u st art ta ki n g a ne w me dici ne w hile y o u ta ke part i n t his st u d y. W he n y o u tal k 
a b o ut y o ur me dici ne wit h y o ur  st u d y d oct or, i ncl u de me dici ne y o u b u y wit h o ut a 
prescri pti o n at t he dr u g st o re ( o ver-t he c o u nter re me d y), or a n yt hi n g t hat y o u b u y 
fr o m t he healt h f o o d st ore or gr ocer y st ore ( her bal s u p ple me nt). Ma n y healt h care 
prescri bers ca n write prescri pti o ns. Y o u m ust als o tell y o ur ot her prescri bers 
( d oct ors, p h ysicia ns’ assista nts or n urse practiti o ners) t hat y o u are ta ki n g part i n a 
cli nical trial. Bri n g t his p a per  wit h y o u .  
 
•  S o me of t he st u d y me dic ati o ns are pr ocesse d b y a certai n e nz y me i n t he 
li ver calle d C Y P 3 A 4.  Dr u gs t hat i ncrease t he acti vit y of t his e nz y me are 
calle d “i n d ucers”, a n d dr u gs t hat decrease t he acti vit y of t his e nz y me are 
calle d “i n hi bit ors”.  S o me of t he st u d y me dicati o ns m ust be use d ver y 
caref ull y wit h ot her me dici nes t hat are i n d ucers or i n hi bit ors of 
C Y P 3 A 4.   
•  Y o u a n d healt hcare pr o vi ders w h o prescri be dr u gs f or y o u m ust be caref ul 
a b o ut a d di n g or  re mo vi n g a n y dr u g i n t his cate g or y  
•  Bef ore y o u start t he st u d y, y o ur st u d y d oct or will w or k wit h y o ur re g ular 
prescri ber t o s witc h  t he f oll o wi n g me dicati o ns if y o u are ta ki n g t he m: 
ket oc o naz ole, itrac o naz ole, rit o na vir, macr oli de a nti bi otics, er yt hr o m yci n 
p he n yt oi n, p he n o bar bital, car ba maza pi ne, a n d val pr oic aci d . 
•  Y o ur re g ular prescri bers s h o ul d l o o k at t his we b site : 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p t o see if a n y me dici ne 
t he y wa nt t o prescri be is o n a list of dr u gs t o a v oi d.  Y o ur st u d y d oct or 
ma y als o ha v e a list of me dicati o ns f or y o u  t o s h o w y o ur re g ular 
prescri bers i nstea d of, or i n a d diti o n t o, t his we bsite.   
•  If y o u dri n k grapefr uit j uice or eat gra pefr uit, y o u s h o ul d a v oi d t hese u ntil 
t he st u d y is o ver.  
•  Ot her me dici nes ca n be a pr o ble m wit h y o ur st u d y dr u gs.  
o  Y o u s h o ul d c hec k wit h y o ur d oct or or p har macist w he ne ver y o u 
nee d t o use a n o ver -t he-c o u nter  me dici ne or her bal s u p ple me nt.  
o  Y o ur re g ular prescri ber s h o ul d c hec k a me dical refere nce or call 
y o ur st u d y d oct or bef ore  prescri bi n g a n y ne w me dici ne f or y o u. 
Y o ur st u d y d oct or’s na me is _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a n d he or  s he ca n 
be c o ntacte d at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _.