LCCC 1950 - Rituximab for Multicentric Castleman Disease in Malawi, A Single-Arm Phase II Safety/Efficacy Trial
Phase: PHASE2
Conditions: Multicentric Castleman Disease
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  
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P R O T O C O L A M E N D M E N T # 1  
L C C C 1 9 5 0 : RI T U XI M A B  F O R  M U L TI C E N T RI C  C A S T L E M A N  DI S E A S E  I N  
M A L A WI, A SI N G L E -A R M P H A S E II S A F E T Y/ E F FI C A C Y T RI A L  
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) 
T he  pri m ar y  p ur p ose  of  t his  pr ot oc ol  a me n d me nt  is  t o  u p date  t he  sec o n dar y  a n d  
e x pl orat or y o bjec ti ves, clarif y t he  ti mi n g of scree ni n g e val uati o ns a n d assess me nts, a me n d 
t he eli gi bilit y criteria , a n d clarif y t he deter mi nati o n of s u bject ris k classificati o n base d o n 
a ne mia.  S pecificall y,  the pr ot oc ol n o w lists se veral  sec o n dar y o bjecti ves se paratel y f or 
clarit y. A d diti o nall y , a n e x pl orat or y o bjecti ve has bee n a d de d t o e val uate pre dict ors of 
rela pse or refract or y disease wit h rit u xi ma b-base d treat me nt. Sec o n da r y a n d e x pl orat or y 
e n d p oi nts were als o a d de d  or re or dere d  f or c o m plete ness a n d clarit y a n d t o acc o m pa n y t he 
ne w e x pl orat or y  o bjecti ve. F urt her m ore,  t he  pr ot oc ol  was  re vie we d  a n d  e dite d  f or 
c o nsiste nc y w hile als o u p dati n g ke y pers o n nel.    
E dit ori a l/ A d mi nistr ati ve 
1.
Mec ha nical e dits ma de w here a p pr o priate.
2.
C o -i n vesti gat or list re m o ve d.
3.
Bi ostatisticia n c o ntact i nf or mati o n a d de d.
4. List of a b bre viati o ns u p date d.
5. Secti o n 1 1. 3 H o nest br o ker la n g ua ge u p date d.
6.  A p pe n di x E ( E C O G Perf or ma nce Stat us) a d de d.
Scie nti fic 
1. I n Secti o n 2. 2:
a.
Sec o n dar y o bjecti ves f or o verall s ur vi val , e ve nt-free s ur vi val, a n d Ka p osi
sarc o ma  viral  l oa d  ( 2. 2. 2,  2. 2. 3,  a n d  2. 2. 1 1)  were  liste d se paratel y  f or
clarit y.
b. Sec o n dar y o bjecti ves  2. 2. 4 a n d 2. 2. 5 were clarifie d b y i ncl u di n g t he ti me at
w hic h cli nical res p o nse rates a n d ra di ol o gic res p o nse rates, res pecti vel y,
will be assesse d.
2.
I n Secti o n 2. 3: A n a d diti o nal e x pl orat or y o bjecti ve t o e val uate f or pre dict ors of
rela pse or refract or y disease wit h rit u xi ma b-base d treat me nt was a d de d ( 2. 3. 3) .
3.
Secti o n 3. 2:  Sec o n dar y e n d p oi nts a d de d or a me n de d t o e ns ure eac h sec o n dar y
o bjecti ve ha d a c orres p o n di n g descri pti o n of t he e n d p oi nt ( 3. 2. 1 – 3. 2. 5, a n d 3. 2. 9.
T his i ncl u de d re or deri n g a n d/ or listi n g se paratel y e n d p oi nts alrea d y prese nt i n t he
secti o n.

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  
 
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4.  Secti o n 3. 3: E x pl orat or y e n d p oi nts a d de d f or all e x pl orat or y o bjecti ves ( 3. 3. 1 -
3. 3. 3).  
5.  St u d y Sc he ma ( Secti o n 5. 1) f o ot n otes u p date d t o clarif y ris k classificati o n.  
6.  Statistical c o nsi derati o ns ( Secti o n 1 0 . 1) u p date d t o clarif y ris k classificati o n. 
 
T her a pe utic  
1.  Pr o hi bite d  me dicati o ns/treat me nts  ( Secti o n  5. 5)  u p date d  t o  pr o hi bit  s yste mic  
t hera pies f or ot her acti ve mali g na ncies or acti ve i nfecti o ns. 
2.  Q ualit y of Life assess me nts e xte n de d t o  2 4 m o nt hs after t he e n d of treat me nt. 
3.  T he ti mi n g of c orrelati ve testi n g bl o o d sa m ple dra ws was clarifie d i n secti o n 7. 4 
a n d t he T & E ta ble ( Secti o n 8. 0). 
4.  T & E ta ble u p date s: 
a. A dj ust me nts were ma de t o e ns ure all ti me p oi nts are calc ulate d fr o m t he start 
of treat me nt.  
b.  F oll o w- u p visit s pecifie d at 1 2 wee ks f or c o nsiste nc y wit h o bjecti ves a n d 
e n d p oi nts. 
c. L o n g ter m f oll o w u p c ol u m n a d de d f or clarit y. 
d.  C orrelati ve bl o o d dra ws c o m bi ne d i nt o o ne r o w f or clarit y. 
e. R o ws f or t u m or bi o ps y, s ur vi val , a n d treat me nts a d de d f or c o m plete ness.  
f. F o ot n otes u p date d t o reflect ot her u p dates ma de t hr o u g h o ut t he pr ot oc ol a n d 
t o ca pt ure a d diti o nal i nf or mati o n (see # 6 bel o w).  
5.  C D 4 c o u nt a n d HI V viral l oa d  l o n g ter m f oll o w u p ti me p oi nts u p date d t o 1 2 a n d 
2 4 m o nt hs f or s u bjects t hat are HI V p ositi ve. 
6.  Secti o ns 8. 2 t hr o u g h 8. 4. 2 re m o ve d a n d w here a p pr o priate i nf or mati o n m o ve d t o 
T & E.  
 
Eli gi bilit y  
1.  Secti o n 4. 0 was c larifie d t o s pecif y t hat t he all o wa ble scree ni n g e val uati o n wi n d o w 
pri or t o e nr oll me nt  is 2 1 da ys. 
2.  Criteri o n 4. 1. 7 was a me n de d t o clarif y q ualif yi n g a ne mia.  
3.  Criteri o n 4. 1. 9 was a me n de d t o e xte n d t he ti me t hat breastfee di n g is pr o hi bite d after 
treat me nt. 
4.  Criteri o n 4. 1. 1 0 was a me n de d t o e xte n d t he ti me t hat birt h c o ntr ol s h o ul d be ta ke n 
b y fe males after treat me nt.  
5.  Criteri o n 4. 1. 1 1 was a me n de d t o e xte n d t he ti me t hat birt h c o ntr ol s h o ul d be ta ke n 
b y males after treat me nt.  
6.  Criteri o n 4. 1. 1 2 was a d de d t o a d dress t he c o n diti o ns of c ortic oster oi d use 
7.  Criteri o n 4. 2. 7 was a me n de d t o clarif y t he c o n diti o ns of c ortic oster oi d use a n d t he 
re q uire me nt of ster oi d was h o ut pri or t o e nr oll me nt.  
8.  Criteri o n 4. 2. 1 1 was a d de d t o e ns ure pre g na nt a n d/ or breastfee di n g w o me n are n ot 
e nr olle d. 
 
 
T H E A T T A C H E D V E R SI O N Dece m ber 2 0 , 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 
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i 
LI S T O F A B B R E VI A TI O N S   
A C T G  
AI D S Cli nical Trials Gr o u p  
A E  
A d verse e ve nt  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A M C  
AI D S Mali g na nc y C o ns orti u m  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A R T  
A ntiretr o viral t hera p y  
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T  
As partate a mi n otra nsferase  
BI D  
Bis i n die  (t wice dail y) 
B S A  
B o d y s urface area  
C B C  
C o m plete bl o o d c o u nt  
C D  
Cl uster of differe ntiati o n  
C H O P  
C ycl o p h os p ha mi de, vi ncristi ne, d o x or u bici n, a n d pre d nis o ne  
C M P  
C o m plete meta b olic pa nel  
C P O  
Cli nical Pr ot oc ol Office  
Cr  
Creati ni ne  
C R  
C o m plete res p o nse  
C R P  
C -reacti ve pr otei n 
C T  
C o m p uter t o m o gra p h y  
C T C A E  
C o m m o n ter mi n ol o g y criteria f or a d verse e ve nts  
D A L Y  
Disa bilit y -a dj uste d life year  
D L B C L  
Diff use lar ge B cell l y m p h o ma  
D S M B  
Data safet y m o nit ori n g b oar d  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E F S  
E ve nt -free s ur vi val 
E O R T C Q L Q -C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Trai ni n g i n Ca ncer Q ualit y of Life 
Q uesti o n naire i n ca ncer patie nts  
G C P  
G o o d cli nical practices  
G -C S F  
Gra n ul oc yte c ol o n y -sti m ulati n g fact or 
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 C  
Hi g h -i nc o me c o u ntries 
HI V  
H u ma n i m m u n o deficie nc y vir us  
I g 
I m m u n o gl o b uli n 
I H C 
I m m u n o hist oc he mistr y 
I L 
I nterle u ki n 
I N F 
I nterfer o n 
I R B 
I nstit uti o nal re vie w b oar d 
I V 
I ntra ve n o us 
K S  
Ka p osi sarc o ma  
K S H V  
Ka p osi sarc o ma her pes vir us  
L A N A  
L ate nc y-ass ociate d n uclear a nti ge n  
L C C C  
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
L D H  
Lactate de h y dr o ge nase  
L N  
L y m p h n o de  
L T F U  
L ost t o f oll o w -u p  

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M C D  
M ultice ntric Castle ma n disease  
M C D -S S  
M ultice ntric Castle ma n Disease -S y m pt o m Sc ore  
M RI  
Ma g netic res o na nce I ma gi n g  
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  
N H L  
N o n -H o d g ki n l y m p h o ma  
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 D  
Pr o gressi ve disease  
P E T  
P ositr o n emissi o n to m o gra p h y  
P F S  
Pr o gressi o n free s ur vi val  
PI  
Pri nci pal i n vesti gat or  
P O  
B y m o ut h ( per os)  
P R  
Partial res p o nse  
P R C  
Pr ot oc ol re vie w c o m mittee  
P R O  
Patie nt re p orte d o utc o me  
P R O Pr  
Patie nt re p orte d o utc o mes prefere nce  
Q D  
Q u a q ue die  ( o nce dail y) 
R A  
R he u mat oi d art hritis  
R B C  
Re d bl o o d cell  
R E S  
Retic ul oe n d ot helial s yste m  
S A E  
Seri o us a d verse e ve nt  
S A R  
S us pecte d a d verse reacti o n  
s.c. 
s u bc uta ne o us 
S D  
Sta ble disease  
S O C  
Sta n dar d of care  
S OI  
Start of i nf usi o n  
S O P  
Sta n dar d o perati n g pr oce d ure  
S P D  
S u m of t he pr o d uct of dia meters  
S S A  
S u b -Sa hara n Africa  
T L S  
T u m or l ysis s y n dr o me  
T N F α  
T u m or necr osis fact or α  
T P F  
Tiss ue Pr oc ure me nt Facilit y  
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  
W H O  
W orl d Healt h Or ga nizati o n  
 
 
 

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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  
M ultice ntric Castle ma n Disease  ............................................................................ 1 
1. 3  
Rit u xi ma b  .............................................................................................................. 2 
1. 4  
Et o p osi de ............................................................................................................... 3  
1. 5  
Rati o nale f or Cli nical St u d y  .................................................................................. 4 
1. 6  
C orrelati ve St u dies  ................................................................................................ 5 
2. 0  
S T U D Y O B J E C TI V E S  ........................................................................................... 7 
2. 1  
Pri mar y O bjecti ves  ................................................................................................ 7 
2. 2  
Sec o n dar y O bjecti ves  ............................................................................................ 7 
2. 3  
E x pl orat or y O bjecti ves  .......................................................................................... 8 
3. 0  
S T U D Y E N D P OI N T S  ............................................................................................. 8 
3. 1  
Pri mar y E n d p oi nt .................................................................................................. 8  
3. 2  
Sec o n dar y E n d p oi nts ............................................................................................. 8  
3. 3  
E x pl orat or y E n d p oi nts  ........................................................................................... 9 
4. 0  
S U B J E C T E LI GI BI LI T Y  .................................................................................... 1 0 
4. 1  
I ncl usi o n Criteria ................................................................................................. 1 0 
4. 2  
E xcl usi o n Criteria  ................................................................................................ 1 1 
5. 0  
T R E A T M E N T P L A N  ........................................................................................... 1 2 
5. 1  
Sc he ma  ................................................................................................................ 1 2 
5. 2  
Treat me nt D osa ge a n d A d mi nistrati o n  ............................................................... 1 3 

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5. 3  
T o xicities a n d D osi n g Dela ys/ D ose M o dificati o ns ............................................. 1 4  
5. 4  
C o nc o mita nt Me dicati o ns/ Treat me nts/ S u p p orti ve Care All o we d  ...................... 1 5 
5. 5  
Pr o hi bite d Me dicati o ns/ Treat me nts  .................................................................... 1 7 
5. 6  
Ot her M o dalities or Pr oce d ures  ........................................................................... 1 7 
5. 7  
D urati o n of T hera p y  ............................................................................................ 1 7 
5. 8  
D urati o n of F oll o w U p ........................................................................................ 1 7  
5. 9  
St u d y Wit h dra wal ................................................................................................ 1 8  
6. 0  
D R U G I N F O R M A TI O N  ...................................................................................... 1 8 
6. 1  
Rit u xi ma b  ............................................................................................................ 1 8 
6. 2  
Et o p osi de Descri pti o n a n d Ma na ge me nt ............................................................. 2 2  
7. 0  
C LI NI C A L A S S E S S M E N T S  ............................................................................... 2 5 
7. 2  
Cli nical La b orat or y Assess me nts  ........................................................................ 2 7 
7. 3  
Q ualit y of life assess me nt  ................................................................................... 2 8 
7. 4  
C orrelati ve St u dies  .............................................................................................. 2 8 
8. 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  ............................................................ 2 9 
8. 1  
Ti me a n d E ve nts Ta ble ( Ta ble 7)  ........................................................................ 2 9 
8. 2  
Ha n dli n g of Bi os peci me ns C ollecte d f or C orrelati ve Researc h  .......................... 3 2 
8. 3  
Assess me nt of Safet y  .......................................................................................... 3 3 
8. 4  
Assess me nt of Efficac y  ....................................................................................... 3 3 
9. 0  
A D V E R S E E V E N T S  ............................................................................................ 3 3 
9. 1  
Defi niti o ns  ........................................................................................................... 3 3 
9. 2  
D oc u me ntati o n of n o n- seri o us A Es or S A Rs ...................................................... 3 5 
9. 3  
S A Es or Seri o us S A Rs  ........................................................................................ 3 5 
9. 4  
A d verse E ve nt Re p orti n g .................................................................................... 3 5  

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9. 5  
Data a n d Safet y M o nit ori n g Pla n  ........................................................................ 3 6 
1 0. 0  S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................ 3 6 
1 0. 1  
St u d y Desi g n/ St u d y E n d p oi nts ............................................................................ 3 6  
1 0. 2  
Sa m ple Size, Accr ual a n d D urati o n of Accr ual  .................................................. 3 7 
1 0. 3  
Safet y m o nit ori n g  ................................................................................................ 3 7 
1 0. 4  
Data A nal ysis Pla ns  ............................................................................................. 3 8 
1 0. 5  
Sec o n dar y O bjecti ves  .......................................................................................... 3 8 
1 0. 6  
E x pl orat or y O bjecti ves  ........................................................................................ 3 9 
1 1. 0  S T U D Y M A N A G E M E N T  .................................................................................... 4 0 
1 1. 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 .................................. 4 0 
1 1. 2  
Re q uire d D oc u me ntati o n..................................................................................... 4 0  
1 1. 3  
Data Ma na ge me nt a n d M o nit ori n g/ A u diti n g  ...................................................... 4 1 
1 1. 4  
A d here nce t o t he Pr ot oc ol ................................................................................... 4 1  
1 1. 5  
A me n d me nts t o t he Pr ot oc ol ............................................................................... 4 3  
1 1. 6  
Rec or d Rete nti o n ................................................................................................. 4 3  
1 1. 7  
O bli gati o ns of I n vesti gat ors  ................................................................................ 4 3 
1 2. 0  R E F E R E N C E S  ...................................................................................................... 4 4 
1 3. 0  A P P E N DI C E S  ....................................................................................................... 4 7 

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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  
 
I n  s u b-Sa hara n  Africa  ( S S A),  Ka p osi  sarc o ma  her pes vir us  ( K S H V) -relate d  ca ncers  
acc o u nt f or 1 0 -3 5 % of mali g na ncies 1- 3 a n d > 1 0 % of ca ncer -relate d deat hs.3 M ultice ntric 
Castle ma n disease ( M C D) is a life -t hreate ni n g l y m p h o pr oliferati ve dis or der c haracterize d 
b y s yste mic i nfla m mati o n a n d l y m p ha de n o pat h y. M C D is str o n gl y ass ociate d wit h K S H V 
a n d h u ma n i m m u n o deficie nc y vir us ( HI V). K S H V ser o pre vale nce i n S S A is > 4 0 %, 4 ,5 t he 
hi g hest of a n y re gi o n i n t he w orl d; li ke wise, t he pre vale nce of HI V is hi g h.6 S u bsta ntial  
k n o wle d ge ga ps  re mai n re gar di n g treat me nt f or M C D, i ncl u di n g o utc o mes, safet y, a n d 
c ost-effecti ve ness, partic ularl y  i n S S A.  
M C D  ca n  be  c o ntr olle d  wit h  c he m ot hera p y.   Whe n  c he m ot hera p y  is  disc o nti n ue d,  
h o we ver, ra pi d rela pses or de vel o p me nt of n o n-H o d g ki n l y m p h o ma ( N H L) occ ur wit h hi g h 
m ortalit y. 7 ,8  L o n g-ter m re missi o n is ac hie ve d i n m ost patie nts wit h rit u xi ma b, a n a nti-
C D 2 0 m o n ocl o nal a nti b o d y, as descri be d i n  s mall cli nical trials i n hi g h-i nc o me c o u ntries 
( HI C).9- 1 1 H o we ver, rit u xi ma b has n ot bee n e val uate d f or M C D i n S S A, n or are t here 
p u blis he d safet y data f or rit u xi ma b fr o m t he re gi o n.  
I n t his st u d y, we ai m t o deter mi ne t he safet y a n d efficac y of first-li ne, ris k-stratifie d 
rit u xi ma b-base d M C D treat me nt i n Mala wi i n a si n gle -ar m, p hase II cli nical trial.  We will 
e nr oll  2 7  s u bjects wit h  ne wl y  dia g n ose d  or  pre vi o usl y  treate d  M C D 
( w h o  ha ve  n ot  
pre vi o usl y  recei ve d  rit u xi ma b)  re q uiri n g  treat me nt  ( B  s y m pt o ms  or  he m o gl o bi n  < 1 0  
g/ d L). 1 2 S u bject s will be treate d wit h f o ur wee kl y d oses of rit u xi ma b. Hi g h-ris k s u bjects 
( defi ne d  as  patie nts  wit h  Easter n  C o o perati ve  O nc ol o g y  Gr o u p  ( E C O G)  perf or ma nce 
stat us > 2 or he m o gl o bi n < 8 g/ d L) 9 ,1 0 ,1 3 -1 6 will als o recei ve et o p osi de   c he m ot hera p y.9 ,1 1 
S u bject s will be f oll o we d f or o ne year f or t o xicit y a n d t w o years f or s ur vi val. T he pri mar y 
o utc o me will be safet y, defi ne d as t he fre q ue nc y of ≥G ra de 3 treat me nt-relate d C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( A Es). Sec o n dar y o utc o mes will be e ve nt -free 
s ur vi val ( deat h, pr o gressi o n, or de vel o p me nt of N H L) a n d 1- a n d 2-year o verall s ur vi val 
( O S). We als o ai m t o  c o m pare t he c ost -effecti ve ness of first -li ne rit u xi ma b treat me nt f or 
M C D i n Mala wi t o c he m ot hera p y ( usi n g o ur hist orical c o ntr ols). 
1. 2  
M ultice ntric C astle m a n Dise ase  
M C D is a u ni q ue, life -t hreate ni n g l y m p h o pr oliferati ve dis or der c haracterize d b y s yste mic 
i nfla m mati o n a n d l y m p ha de n o pat h y t hat  is str o n gl y ass ociate d wit h K S H V a n d HI V. 
K S H V  viral  pr otei ns,  i ncl u di n g  a  viral  h o m ol o g  of  i nterle u ki n -6  (I L -6),  are  ca usall y  
ass ociate d wit h t he c yt o ki ne st or m t hat is c haracteristic of M C D. HI V -i nfecti o n is als o a 
si g nifica nt ris k fact or f or M C D. I n a lar ge M C D c o h ort i n Fra nce, 8 3 % of M C D case s 
occ urre d  i n  HI V -i nfecte d  i n di vi d uals.1 7 M C D  c o nsists  of  t w o   bi ol o gicall y-disti nct 
s u bt y pes: K S H V -ass ociate d a n d i di o pat hic. T his pr o p osal f oc us es o n K S H V -ass ociate d 
M C D, t he varia nt t hat is far m ore c o m m o n i n S S A. 1 8  

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K S H V  ser o pre vale nce  is  
> 4 0 %  i n  S S A, 4 ,5 ,1 9  t he 
hi g hest of a n y re gi o n i n t he 
w orl d ( Fi g ure 1).   K S H V  is 
us uall y tra ns mitte d t hr o u g h 
sali va
 wit h
 pri mar y
 
i nfecti o n
 bei n g
 
as y m pt o matic.
 I n
 s o me
 
cases, K S H V is reacti vate d 
i n  a  l ytic  state  w hic h  ca n  
pr o m ote  de vel o p me nt  of  
mali g na ncies. 2 0 I n  Mala wi,  
K S H V pre vale nce is 5 4 % i n 
a d ults a n d 7 4 % i n i n HI V -
i nfecte d a d ults.2 1 
T he b ur de n of HI V is li ke wise hi g h i n S S A, ra n gi n g fr o m 3 -2 0 %. 6 T h e pre vale nce of HI V 
a m o n g a d ults i n Mala wi is 1 0 %. T he last deca de has see n maj or stri des i n scale -u p of a nti -
retr o viral  t hera p y  ( A R T)  i n  S S A,  a n d  it  is  n o w  esti mate d  t hat  6 7 %  of  HI V-i nfecte d 
i n di vi d uals i n Mala wi are o n A R T a n d 5 9 % are vir ol o gicall y s u p presse d. 2 2 
Gi ve n t he str o n g li n k t o K S V H a n d HI V, a n d hi g h pre vale nce of t hese vir uses i n S S A, 
M C D is li kel y u n der dia g n ose d i n S S A.  T he u n der- dia g n osis of M C D is li kel y d ue t o 
li mite d pat h ol o g y ser vices a n d li mite d a ware ness of M C D. H o we ver, re gi o nal ce nters ha ve 
rece ntl y re p orte d  M C D  dia g n oses  i n  S S A.2 3 ,2 4 I n  o ur  pr os pecti ve  c o h ort  of  
l y m p h o pr oliferati ve dis or ders i n Mala wi, we ha ve f o u n d t hat M C D c o nstit utes 2 5/ 3 6 0 
( 7 %) of all dia g n oses a n d 2 5/ 1 8 9 ( 1 3 %) of dia g n oses a m o n g HI V-i nfecte d s u bjects.8 ,2 5 -2 7  
M C D b ur de n i n S S A will li kel y i ncrease as A R T access e x pa n ds a n d life e x pecta nc y of 
HI V -i nfecte d s u bjects i m pr o ves. M C D is ass ociate d wit h ol der a ge, hi g her C D 4 c o u nt, a n d 
l o n ger ti me o n A R T c o m pare d t o K S,9 ,1 7 ,2 8 N H L , or H o d g ki n l y m p h o ma. 2 6 U nli ke K S, 
M C D is n ot c o ntr olle d wit h A R T al o ne.
2 9 
1. 3  
Rit u xi m a b  
Rit u xi ma b,  a n  a nti -C D 2 0  m o n ocl o nal  a nti b o d y,  i n d uces  l o n g -ter m  re missi o ns  a n d  
decreases t he ris k of N H L i n s mall cli nical trials f or M C D i n HI C .9 ,1 0 ,1 6 ,3 0 Rit u xi ma b is a 
c hi meric m o n ocl o nal a nti b o d y a gai nst C D 2 0, a pr otei n o n t he s urface of B -cells w hic h 
lea ds t o B-cell de pleti o n via c o m ple me nt - a n d a nti b o d y-me diate d c yt ot o xicit y. I n t w o 
p hase II trials of si n gle -a ge nt rit u xi ma b f or M C D, t he o ne -year e ve nt-free s ur vi val (E F S ) 
was 9 2 % a n d 7 1 %. 1 0 ,1 5 After l o n ger f oll o w -u p, fi ve -year E F S was 7 8 % a n d fi ve -year O S 
was 8 8 %. 3 1 Li ke wise, rit u xi ma b has bee n s h o w n t o si g nifica ntl y decrease t he ris k of 
N H L. 9 ,3 0 ,3 1 
M ortalit y ofte n occ urs i n t he first m o nt h of treat me nt wit h rit u xi ma b m o n ot hera p y, b ut t his 
ris k ca n be miti gate d wit h c o nc o mita nt c he m ot hera p y. Deat h i n t he first f o ur wee ks occ urs 
i n 5 % of M C D s u bjects treate d wit h rit u xi ma b al o ne.1 0 ,1 3 -1 5 ,3 1 Ris k fact ors f or earl y deat h 
i ncl u de E C O G perf or ma nce stat us > 2, he m o p ha g oc ytic s y n dr o me, a n d se vere he m ol ytic 
a ne mia. T he  ris k  of  deat h  decrease s wit h  t he  a d diti o n  of  et o p osi de 9 or  li p os o mal  

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d o x or u bici n. 1 6 A m o n g s u bjects wit h M C D a n d pre -e xisti n g K S, t he ris k of K S e xacer bati o n 
f oll o wi n g rit u xi ma b m o n ot hera p y is 3 6- 7 5 %.9 ,1 0 H o we ver, deat h fr o m K S pr o gressi o n is 
rarel y re p orte d. 
Rit u xi ma b has n ot bee n e val uate d as first -li ne t hera p y f or M C D i n S S A.  Gi ve n hi g h 
o p p ort u nistic i nfecti o n b ur de n a n d li mite d s u p p orti ve care i nfrastr uct ure  i n S S A, re gi o n-
s pecific safet y a n d efficac y data f or rit u xi ma b are nee de d. W he n a d de d t o c o m bi nati o n 
c he m ot hera p y  f or  N H L  i n  HI C ,  rit u xi ma b  has  bee n  ass ociate d  wit h  a n  i ncrease  i n  
treat me nt-relate d i nfecti o ns a n d m ortalit y i n HI V-i nfecte d s u bjects wit h a C D 4 c o u nt < 5 0 
cells/ µl, w hile be nefiti n g t h ose wit h hi g her C D 4 c o u nts. 3 2 ,3 3 Rit u xi ma b -base d treat me nt +/ - 
et o p osi de is li kel y t o be less t o xic t ha n c o m bi nati o n c he m ot hera p y, b ut re q uires f or mal 
safet y assess me nt. Pre vi o us st u dies of rit u xi ma b f or M C D fr o m HI C ha ve f o u n d a rate of 
n o n- he mat ol o gic ≥Gra de 3 A Es of ar o u n d 2 0 %. 9 ,1 0 ,1 5 ,1 6 
E ve n if rit u xi ma b is safe a n d effecti ve, c ost -effecti ve ness is a critical c o nsi derati o n. T he 
W orl d Healt h Or ga nizati o n ( W H O) lists rit u xi ma b as a c o m ple me ntar y me dici ne o n  t he 
Esse ntial Me dici nes list. 3 4 H o we ver, rit u xi ma b has n ot bee n a p pr o ve d f or r o uti ne use b y 
t he Mala wi P har mac y, Me dici nes, a n d P ois o ns B oar d a n d is n ot r o uti nel y a vaila ble i n 
Mala wi, li ke m ost p u blic sect or healt h s yste ms i n S S A. C ost -effecti ve ness a nal ysis d o ne 
i n t he a p pr o priate, l ocal c o nte xt is esse ntial t o hel p p olic y ma kers all ocate li mite d healt h 
res o urces.3 5 T o o ur k n o wle d ge, s uc h a nal yses ha ve n ot bee n p u blis he d b ut are ur ge ntl y 
nee de d.  A  de m o nstrati o n  of  c ost -effecti ve ness  w o ul d  s u p p ort  t he  pri oritizati o n  of  
rit u xi ma b  as  a  s o u n d  p u blic  healt h  i n vest me nt  t o  treat  t his  e mer gi n g  HI V-ass ociate d 
c o m or bi dit y.  
1. 4  
Et o p osi de  
Et o p osi de  is  a  t o p ois o merase  II  i n hi bit or  t hat  ca uses  D N A  d o u ble  stra n d  brea ks  a n d  
a p o pt osis  of  ra pi dl y  di vi di n g  cells,  es peciall y  ca ncer  cells.  Et o p osi de  is  a  c o m m o n  
c he m ot hera pe utic a ge nt  use d  i n  t he  treat me nt  of  a  n u m ber  of  ne o plas ms,  i ncl u di n g 
l y m p h o ma, KS , testic ular ca ncer, E wi n g sarc o ma, a n d s mall cell l u n g ca ncer, a m o n g 
ot hers. It is ofte n gi ve n i n c o m bi nati o n wit h ot her c he m ot hera pies b ut w he n gi ve n as 
m o n ot hera p y , et o p osi de is c o m m o nl y ass ociate d wit h a n u m ber of A Es . C o m m o n A Es 
i ncl u de  al o pecia,  c o nsti pati o n,  diarr hea,  a ne mia,  t hr o m b oc yt o pe nia,  le u k o pe nia,  a n d  
i nf usi o n reacti o ns (eit her l ocal site reacti o ns or h y p ote nsi o n). Less c o m m o n A E s i ncl u de 
na usea, v o miti n g, ras h, fe ver, a n d m o ut h s ores. Rare b ut seri o us A E s i ncl u de sec o n dar y 
mali g na ncies, es peciall y ac ute m yel oi d le u ke mia.  
 
Et o p osi de p h ar m ac o ki netics  
After  i ntra ve n o us  (I V) i njecti o n,  t here  is  a  bi p hasic  patter n  of  cleara nce  wit h  a  
ter mi nal t1/ 2 of a b o ut 6 – 8 h o urs i n patie nts wit h n or mal re nal f u ncti o n. A p pr o xi matel y 4 0 % 
of a n a d mi nistere d d ose is e xcrete d i ntact i n t he uri ne. I n patie nts wit h c o m pr o mise d re nal 
f u ncti o n, d osa ge s h o ul d be re d uce d i n pr o p orti o n t o t he re d ucti o n i n creati ni ne cleara nce . 
I n patie nts wit h a d va nce d li ver disease, i ncrease d t o xicit y ma y res ult fr o m a l o w ser u m 
al b u mi n  ( decrease s dr u g  bi n di n g)  a n d  ele vate d  bilir u bi n  ( dis places  e t o p osi de  fr o m  
al b u mi n); g ui deli nes f or d ose re d ucti o n i n t his circ u msta nce ha ve n ot bee n defi ne d.  
 
Et o p osi de f or K a p osi s arc o m a i n S S A 

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Et o p osi de has bee n use d s uccessf ull y as a si n gle -a ge nt treat me nt f or K S , i ncl u di n g i n 
S S A .3 6 H o we ver, ot her re gi me ns ha ve rece ntl y bee n s h o w n t o be s u peri or t o et o p osi de f or 
K S  treat me nt i n S S A.3 7 I n t he A C T G 5 2 6 4/ A M C-0 6 7 trial of u p -fr o nt vers us as-nee de d 
et o p osi de f or K S i n S S A, t he rate of ≥G ra de 3 A Es was 5 0 % i n t he u p -fr o nt gr o u p vers us 
4 4 % i n t he as-nee de d gr o u p. T he maj orit y of A Es were he mat ol o gic ( 4 7/ 6 5; 7 2 %). T here 
were n o st u d y -relate d deat hs. T hat st u d y was c o n d ucte d wit h oral et o p osi de 5 0-1 0 0 m g 
dail y da ys 1 -7 of 1 4- da y  c ycles b ut pr o vi des t he best e vi de nce f or treat me nt i n HI V -
i nfecte d patie nts i n S S A. 
 
Et o p osi de f or M C D  
A m ore rele va nt st u d y  b y B o wer, et al 9 use d a si milar ris k -a da pte d treat me nt f or M C D  a n d 
use d I V et o p osi de at 1 0 0 m g/ m2. T he st u d y was n ot pr os pecti ve a n d  re p orte d ver y li mite d 
data o n A Es . No st u d y -relate d deat hs were i de ntifie d i n patie nts recei vi n g et o p osi de. T he 
rate of K S pr o gressi o n a m o n g t h ose wit h baseli ne K S was 9/ 2 4 ( 3 8 %) a n d di d n ot differ 
bet wee n t h ose w h o recei ve d et o p osi de + rit u xi ma b or rit u xi ma b al o ne. I n t his pr ot oc ol, we 
si milarl y pr o p ose t he use of I V et o p osi de at 1 0 0 m g/ m 2.  
1. 5  
R ati o n ale f or Cli nic al St u d y 
M C D  ca n  be  treate d  wit h  c he m ot hera p y . Ma n y  si n gle -a ge nt  or  c o m bi nati o n  
c he m ot hera pies ha ve bee n utilize d. 7 ,8 ,2 9 ,3 8 H o we ver,  w he n c he m ot hera p y is disc o nti n ue d, 
ra pi d  rela pses  or  de vel o p me nt  of  N H L  ofte n  occ ur  a n d  are  ass ociate d  wit h  hi g h  
m ortalit y. 7 ,8 ,3 8 Rela pse after ter mi nati o n of c he m ot hera p y is al m ost u ni versal, a n d 1- year 
E F S is < 2 0 %. 7 ,8 1 5-2 5 % of s u bjects treate d wit h c he m ot hera p y de vel o p N H L, a rate ~ 1 5 x 
hi g her t ha n HI V -i nfecte d i n di vi d uals wit h o ut M C D.1 7 ,2 9 ,3 9 S ur vi val f or M C D s u bjects 
treate d wit h tra diti o nal c he m ot hera p y is als o p o or wit h 2- year O S of 4 2 % i n o ne st u d y. 9  
Si milarl y, o utc o mes f or M C D s u bjects treate d wit h c he m ot hera p y i n Mala wi are  als o p o or. 
Of t he 2 5 M C D patie nts i n o ur c o h ort, 2 die d bef ore starti n g c he m ot hera p y. Of 2 3 patie nts 
treate d wit h c he m ot hera p y, o nl y 3 ( 1 3 %) re mai n i n re missi o n after 5, 1 3, a n d 1 5 m o nt hs 
res pecti vel y, si milar t o re p orts fr o m HI C . First-li ne c he m ot hera p y c o nsiste d of et o p osi de 
( 1 7 patie nts) or c ycl o p h os p ha mi de, vi ncristi ne, a n d pre d nis o ne (si x patie nts). A m o n g 2 3 
treate d patie nts, 1 0 ( 4 3 %) c o m plete d first-li ne c he m ot hera p y wit h o ut disease pr o gressi o n. 
T he  re mai ni n g  1 3  patie nts  were  s witc he d  t o  a n  alter nati ve  t hera p y  beca use  of  p o or  
res p o nse. Of t he te n patie nts w h o c o m plete d first-li ne treat me nt, se ve n rela pse d, after a 
me dia n 2 9 da ys (ra n ge 1 4 -1 4 7). O ne -year E F S was 1 0 % ( 9 5 % CI 2 - 2 6) ( Fi g ure 2; P a nel 
A).  
Rit u xi ma b has bee n s uccessf ull y use d b y o ur gr o u p i n Mala wi as a c o m passi o nate -use 
i nter ve nti o n f or patie nts wit h M C D refract or y t o c he m ot hera p y, a n d i n a n o n g oi n g cli nical 
trial f or diff use lar ge B cell l y m p h o ma ( D L B C L). As i n m ost S S A p u blic healt h s ystems, 
rit u xi ma b  is  n ot  c urre ntl y  a p pr o ve d  n or  a vaila ble i n  Mala wi.  Wit h  s u p p ort  fr o m  t he 
U ni versit y of N ort h Car oli na ( U N C ) Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  ( L C C C), 
we are c urre ntl y e val uati n g rit u xi ma b pl us c ycl o p h os p ha mi de, vi ncristi ne, d o x or u bici n, 
a n d pre d nis o ne ( C H O P) c he m ot hera p y f or D L B C L ( N C T 0 2 6 6 0 7 1 0), wit h 3 9 of 4 0 patie nts 
e nr olle d as of Se pte m ber  2 0 1 9. T o date, t here ha ve bee n 1 9 n o n - he mat ol o gic Gra de 3 or 
w orse  A Es,  a n d  1- year  O S  is  7 0 %, w hic h  c o m pares fa v ora bl y  t o  o ur  pre vi o us  w or k 
e val uati n g a hist orical c o h ort of patie nts treate d wit h C H O P. 4 0  

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Gi ve n hi g h m ortalit y, a bse nt alter nati ve t hera pies f or s uc h patie nts, a n d t he a vaila bilit y of 
rit u xi ma b  fr o m  t his  trial,  we  s o u g ht  a  c o m passi o nate  use  e xe m pti o n  fr o m  Mala wi  
re g ulat or y a ut h orities t o treat patie nts wit h M C D refract or y t o c he m ot hera p y. As of Ja n uar y 
2 0 1 9, te n patie nts ha ve recei ve d rit u xi ma b as sal va ge t hera p y f or M C D. T here was o ne 
G ra de 3 h y perse nsiti vit y reacti o n b ut n o ot her seri o us A Es. Earl y cli nical o utc o mes ha ve 
bee n  e nc o ura gi n g.  A m o n g  t hese  1 0 patie nts, 9 ac hie ve d  re missi o n  a n d  7 remai n  i n  
re missi o n after a me dia n 7 m o nt hs (ra n ge 1-2 2). O nl y o ne patie nt w h o recei ve d rit u xi ma b 
die d ( M C D pr o gressi o n). O ne -year E F S after recei vi n g rit u xi ma b f or rela pse d/refract or y 
M C D was 7 8 % ( 9 5 % CI 3 7 - 9 4) ( Fi g ure 2; P a nel B). 
1. 6  
C orrel ati ve St u dies  
C ore  bi o ps y  s pecim e ns ta ke n  f or  r o uti ne  dia g n ostic  p ur p oses  will  be  u se d t o m a ke 
f or mali n-fi xe d paraffi n em be d de d tiss ue bl oc ks wit h o ut a n y a d diti o nal researc h bi o psies . 
T hese  s p ecim e ns  will  all o w  for  viral  a n d  ge n o mi c  i n vesti gatio ns.  Ge ne  e x pres si o n 
p r ofili n g a n d ne xt- ge nerati o n se q ue nci n g a nal yses of  hist o pat h ol o gicall y c o nfir me d  M C D 
s pecim e ns o nl y will be c o n d uct ed at t he U N C Ge n o me A nal ysis F acilit y a n d t he U N C 
Hi g h- T hr o u g h p ut  Se q ue nci n g Faci lit y  i n  N ort h  Car o lin a. Viral  se q ue nci n g  will  be  
c o n d ucte d b y t he U N C Vir o n o mics C ore. T hese st u dies wi ll n ot i nfl ue nce treatm e nt f or 
e nr olle d patients i n real ti me, as ‘tar g ete d’ ca ncer t herap ies are n ot c ur re ntly a vai la ble in 
Mala wi. R at her, we  i nte n d t o e xa m i ne t he e x pressi o n si g nat ure of M C D wit h res pect t o 
s pecific ge nes w hic h are clearl y estab lis he d as i nflue nci n g p he n ot y pic  clin ical b e havi or of  
l ym p h o m as,  i ncl u di n g  ge nes   in v ol ve d  i n  l y m p h oc yte  pr oli ferati on ,  activati o n, a n d 
di ffere ntiati o n, as ha s bee n previ o usl y e xte n si vel y descri b e d i n sem i nal pa pers i n  t he 
fiel d.2 7 , 2 8   
 
T h o u g h e xte nsi ve st u dies ha ve bee n c o n d ucte d i n l y m p h o ma, little is k n o w n a b o ut ge ne 
e x pressi o n pr ofiles i n patie nts wit h M C D. T hes e e x peri me nts are i nte n de d  t o  ide nti fy 
mec ha nis m s of, a n d ris k fact ors f or, de vel o p me nt of M C D. Cr y o preser v e d ser u m  o btai ne d 
at e nr oll me nt  a n d  pres pecifie d   f oll o w-u p  v isits  o nl y  will b e  sto re d t o  all o w  basic  
c orrelati ve st u dies of  pre dicti ve a n d pr o g n o stic b i om ar kers i n a  setti n g w here a d va n ce d 
i ma gi n g for l y m p h o m a res p o nse assess m e nt after treatm e nt is n ot a vai la ble. T hese sa m ples 
will be use d f or c yt o ki ne a n d i m m u n ol o gic pr ofili n g of patie nts wit h M C D. M C D is a 
p ol ycl o nal  disease  t hat  de vel o ps  i n  t he  setti n g  of  i m m u ne  d ysre g ulati o n  b ut  t he  
i m m u n ol o gic  mec ha nis ms  of  t his  d ysre g ulati o n  ha ve  n ot  bee n  well  esta blis he d.  

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F urt her m ore,  if  certai n  c yt o ki nes  are  f o u n d  t o  be  of  s pecial  si g nifica nce  i n  t he  
pat h o p h ysi ol o g y of M C D i n HI V -i nfecte d patie nts, c yt o ki ne-tar gete d t hera pies ma y be 
e m pl o ye d i n f ut ure st u dies t o treat t his disease wit h decrease d si de effects, as has bee n 
co m plete d pre vi o usl y i n i di o pat hic M C D. 4 1 S uc h tre at me nts are li kely t o be sa fer a n d m ore 
effecti ve th a n c o n ve nti ona l c yt ot ox ic th era p y i n t he Mala wia n  co nte xt, w he re s u p p orti ve 
care i ncl udi n g he m at o p oietic gr o wt h fact ors a n d transf usi o n s u p p ort a re e xtre mel y lim ite d, 
a n d w here i nfecti o us b ur de n is hi g h.4 Ge n o m ic data will be a nal yze d b y  st u d y i n vesti gat ors 
i ncl udi n g Ma la wia n c o lleag ues, wit h bi oi n f or matics s u p p ort  ad diti o n all y pr o vi de d fr o m 
U N C- C h a pel Hi ll as n ecessar y.  
 
 

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2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ves  
2. 1. 1  T o d eter mi ne  t he safet y a n d treat me nt relate d m ortalit y  of a ris k -a dj uste d treat me nt 
pr ot oc ol  f or  t he treat me nt of M C D wit h rit u xi ma b wit h or wit h o ut  et o p osi de i n 
Mala wi.  
2. 2  
Sec o n d ar y O bjecti ves   
2. 2. 1  T o pr os pecti vel y c haracterize M C D prese ntati o n i n Mala wi.  
2. 2. 2  T o deter mi ne o verall s ur vi val rate.  
2. 2. 3  T o deter mi ne e ve nt -free s ur vi val rate. 
2. 2. 4  T o descri be t he efficac y of t he ris k -a dj uste d treat me nt pr ot oc ol as deter mi ne d b y 
cli nical res p o nse rates at e n d of treat me nt a n d 1 2 wee ks after start of treat me nt.  
2. 2. 5  T o descri be  ra di ol o gic res p o nse rates at e n d of treat me nt a n d  1 2 wee ks  after start 
of treat me nt . 
2. 2. 6  T o f urt her c haracterize t he safet y b y descri b i n g t he fre q ue nc y of all A E s wit h ris k-
a dj uste d treat me nt-pr ot oc ol f or  M C D i n Mala wi.  
2. 2. 7  T o descri be t he rate of Ka p osi sarc o ma e xacer bati o n, as defi ne d b y s y m pt o matic or 
cli nical  ( der mat ol o gic  or  visceral  or ga n)  e xacer bati o n  of  disease  i n  patie nts  
recei vi n g t he ris k-a dj uste d treat me nt pr ot oc ol. 
2. 2. 8  T o descri be t he q ualit y of life of patie nts wit h  M C D bef ore, d uri n g a n d after 
treat me nt wit h a rit u xi ma b-base d, ris k -a dj uste d treat me nt pr ot oc ol, as assesse d b y 
t he M C D s y m pt o m sc ore a n d P R Os .4 2 
2. 2. 9  T o descri be t he tre n ds i n he m o gl o bi n, platelet c o u nt, C- reacti ve pr otei n (C R P ), a n d 
I L- 6 bef ore, d uri n g, a n d after a ris k -a dj uste d, rit u xi ma b -base d treat me nt pr ot oc ol 

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pre-tra nsf usi o n  he m o gl o bi n val ue will be c o nsi dere d  w he n deter mi ni n g ris k 
classificati o n . 
4. 1. 8  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test wit hi n 
t hree da ys pri or t o re gistrati o n.  
•  N ote t hat f e males are c o nsi dere d of c hil d beari n g p ote ntial u nless t he y are s ur gicall y 
sterile  ( ha ve  u n der g o ne  a  h ysterect o m y,  bilateral  t u bal  li gati o n,  or  bilateral  
o o p h orect o m y) or t he y are nat urall y p ost me n o pa usal f or at least 1 2 c o nsec uti ve 
m o nt hs. D oc u me ntati o n of p ost me n o pa usal stat us m ust be pr o vi de d.    
4. 1. 9  Fe males m ust a gree t o a bstai n fr o m breast -fee di n g d uri n g t hera p y a n d f or 6 m o nt hs  
after t he c o m pleti o n of t hera p y.  
4. 1. 1 0  Fe males of c hil d beari n g p ote ntial m ust be willi n g t o a bstai n fr o m heter ose x ual 
acti vit y or t o use t w o f or ms of effecti ve met h o ds of c o ntrace pti o n fr o m t he ti me of 
i nf or me d  c o nse nt  u ntil 1 2  m o nt hs  after  treat me nt  disc o nti n uati o n.  T he  t w o  
c o ntrace pti o n  met h o ds  ca n  be  c o m prise d  of  t w o  barrier  met h o ds,  or  a  barrier  
met h o d pl us a h or m o nal met h o d , or  a n i ntra uteri ne de vice t hat meets < 1 % fail ure 
rate f or pr otecti o n fr o m pre g na nc y i n t he pr o d uct la bel.  
4. 1. 1 1  Male s u bject s wit h fe male part ners m ust ha ve ha d a pri or vasect o m y or a gree t o use  
a n a de q uate met h o d of c o ntrace pti o n  (i.e., d o u ble barrier met h o d: c o n d o m pl us 
s per mici dal a ge nt) starti n g wit h t he first d ose of st u d y t hera p y t hr o u g h 6 m o nt hs  
after t he last d ose of st u d y t hera p y.   
4. 1. 1 2   At least  7 da y s wit h o ut c ortic oster oi d use  pri or t o start of treat me nt.  
4. 2  
E xcl usi o n Criteri a  
All s u bjects meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria at ti me of e nr oll me nt will be 
e xcl u de d fr o m st u d y partici pati o n. 
4. 2. 1  S y m pt o matic, e xte nsi ve -sta ge K S ( T 1 b y t he A C T G sta gi n g s yste m; T 1 i ncl u des 
ulcerati o n or e de ma fr o m K S, raise d or n o n -har d palate oral lesi o ns, or a n y visceral 

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i n v ol ve me nt) re q uiri n g ur ge nt treat me nt, t o a v oi d p ote ntial rit u xi ma b-i n d uce d K S 
w orse ni n g. 
4. 2. 2  Pre vi o us rit u xi ma b use f or M C D. 
4. 2. 3  Sec o n d acti ve mali g na nc y re q uiri n g s yste mic t hera p y. 
4. 2. 4  If HI V ne gati ve a n d a) he patitis B vir us s urface a nti ge n p ositi ve or u nless o n 
te n of o vir  or  la mi v u di ne.  All  HI V-i nfecte d  patie nts  m ust  be  o n  te n of o vir  or  
la mi v u di ne as part of t he i ncl usi o n criteria. 
4. 2. 5  Acti ve i nfecti o n re q uiri n g s yste mic t hera p y. 
4. 2. 6  Treat me nt wit h a n y i n vesti gati o nal dr u g wit hi n  2 8 da ys pri or t o re gistrati o n.   
4. 2. 7  M ore t ha n  7 da ys of c ortic oster oi ds  i m me diatel y pri or t o e nr oll me nt. If s u bject is 
ta ki n g c ortic oster oi ds f or m ore t ha n 7 da ys, t he y re q uire a 7 da y was h o ut peri o d 
bef ore e nr oll me nt .  
4. 2. 8  Bilir u bi n > 3 m g/ d L . 
4. 2. 9  Creati ni ne cleara nce < 3 0 ml/ mi n b y C oc kcr oft -Ga ult f or m ula . 
4. 2. 1 0  E C O G perf or ma nce stat us > 3. 
4. 2. 1 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).  
 
5. 0  
T R E A T M E N T P L A N  
5. 1  
Sc he m a  
 

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Cli nic al tri al sc he m a f or ne wl y di a g n ose d p atie nts wit h M C D re q uiri n g tre at me nt.  
1 “ Hi g h-ris k disease” defi ne d as E C O G perf or ma nce stat us > 2 or he m o gl o bi n < 8 g/ d L at 
t he ti me of scree ni n g or e nr oll me nt la bs. N ote t hat a patie nt  recei vi n g a bl o o d tra nsf usi o n 
d ue t o he m o gl o bi n < 8 g/ d L wit hi n 1 m o nt h  of e nr oll me nt will be c o nsi dere d hi g h-ris k. 
2 See Ti me a n d E ve nts Ta ble ( 8. 1) f or detaile d st u d y visit c o m p o ne nts. 
3 M C D -S S = M C D s y m pt o m sc ore  
 
We will c o n d uct a si n gle ar m, p hase II cli nical trial f or safet y a n d efficac y of ris k -stratifie d 
treat me nt wit h rit u xi ma b +/- c he m ot hera p y f or M C D. Eli gi ble patie nts will be e nr olle d a n d 
treate d acc or di n g t o t he st u d y sc he ma. Hi g h -ris k patie nts ( defi ne d as patie nts wit h E C O G 
perf or ma nce stat us > 2 or he m o gl o bi n < 8 g/ d L  at t he t he ti me of  scree ni n g or e nr oll me nt 
la bs)9 ,1 0 ,1 3 -1 6 will recei ve f o ur wee kl y d oses of rit u xi ma b ( 3 7 5 m g/ m 2) a n d et o p osi de ( 1 0 0 
m g/ m 2) as i n B o wer, et al.9 L o w -ris k patie nts will recei ve t he sa me d ose of rit u xi ma b al o ne.  
 
T he pla n ne d sa m ple size is 2 7 patie nts a n d t he pri mar y o utc o me is safet y. Sec o n dar y 
o utc o mes i ncl u de o ne - a n d t w o-year E F S (c o m bi nati o n of rela pse, de vel o p me nt of N H L, 
or deat h), O S, a n d K S e xacer bati o n rates.  
 
We will als o c ollect cli nical, la b orat or y, vir ol o gic data, a n d st ore d sa m ples at baseli ne a n d 
e n d- of-treat me nt  t o  b ot h  descri be  t he  prese ntati o n  of  M C D  i n  o ur  p o p ulati o n  a n d  t o  
e val uate ris k fact ors f or deat h or rela pse.  
 
Fi nall y, we will c o n d uct c o m pre he nsi ve micr oc osti n g a nal ysis a n d a Mar k o v m o del c ost -
effecti ve ness a nal ysis.  
5. 2  
Tre at me nt D os a ge a n d A d mi nistr ati o n  
Treat me nt will be a d mi nistere d o n a n o ut patie nt basis i n t he Ka m uz u Ce ntral H os pital 
ca ncer cli nic, as per T a ble 1,  w here c he m ot hera p y is c urre ntl y a d mi nistere d. 

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T a ble 1: R E GI M E N D E S C RI P TI O N  
A ge nt  
Pre me dic ati o ns  
D ose  a n d R o ute  
Sc he d ule  
Rit u xi ma b  
Pre me dicate wit h 
di p he n h y dra mi ne 
5 0 m g I V a n d 
aceta mi n o p he n 
6 5 0 m g P O 1 
h o ur pri or t o 
rit u xi ma b. 
 
 
3 7 5 m g/ m 2 r o u n de d t o t he nearest 1 0 0 m g t o 
a v oi d vial waste ( dil ute i n n or mal sali ne or 5 % 
de xtr ose t o a fi nal c o nce ntrati o n of 1 -4 m g/ ml.  
 
A d mi nister via sl o w I V i nf usi o n, starti n g at 
5 0 m g/ hr a n d i ncreasi n g b y 5 0 m g/ hr e ver y 3 0 
mi n utes t o a ma xi m u m i nf usi o n rate of 
4 0 0 m g/ hr.  
 
C A U TI O N : D O N O T A D MI NI S T E R A S 
A N I N T R A V E N O U S P U S H O R B O L U S. 
I V p u m ps s uc h as t he I M E D 9 6 0 ma y be 
use d wit h t he rit u xi ma b i nf usi o n.  
 
D O N O T I N F U S E C O N C O MI T A N T L Y 
wit h a n ot her I V s ol uti o n or I V me dicati o ns. 
Pri me t he li ne wit h t he rit u xi ma b s ol uti o n 
s uc h t hat a p pr o xi matel y 3 0 m L are deli vere d. 
T his will sat urate t he filter a n d t u bi n g.  
Da y s 1, 8, 1 5, 2 2 
Et o p osi de  
n/a  
1 0 0 m g/ m 2 ( dil ute t o fi nal c o nce ntrati o n 0. 2-
0. 4 m g/ m L i n eit her n or mal sali ne of 5 % 
de xtr ose)  
 
I V o ver 1 h o u r after c o m pleti o n of rit u xi ma b  
Da y s 1, 8, 1 5, 2 2 
 
5. 3  
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 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 ( Secti o n 8 . 1). T o xicit y will be assesse d 
acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI ) C T C A E, v 5. 0. D ose a dj ust me nts 
s h o ul d be ma de acc or di n g t o t he s yste m s h o wi n g t he greatest de gree of t o xicit y. 
See T a bles 2- 4  bel o w f or rec o m me n de d d ose dela ys/ d ose m o dificati o ns.  
 
Assi g ni n g ca use of deat h is ofte n diffic ult i n Mala wi beca use  dia g n ostic ca pa bilities 
are li mite d a n d deat hs fre q ue ntl y occ ur o utsi de of healt h facilities . T o a d dress t his 
c halle n ge,  t w o se ni or n o n-st u d y cli nicia ns will be e nliste d t o re vie w all st u d y data 
f or decease d patie nts a n d assi g n ca use of deat h as eit her li kel y treat me nt-relate d, 
M C D -relate d, relate d t o a n ot her ca use, or u na ble t o deter mi ne. I n t he e ve nt of 
disc or da nt c o ncl usi o ns, a t hir d se ni or cli nicia n will ser ve as a tie brea ker.  
 
T a ble 2: He m at ol o gic al to xicit y d ose re d ucti o ns 
A N C  
Pl atelets  
Acti o n  
≥ 0. 5 x 1 0 3/µ L 
≥ 5 0  x 1 0 3/µ L 
N o ne.  

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< 0. 5 x 1 0 3/µ L 
< 5 0  x 1 0 3/µ L 
FI R S T E PI S O D E: H ol d c urre nt et o p osi de d ose u ntil A N C ≥ 0. 5 x 
1 0 3/µ L a n d platelets ≥ 5 0  x 1 0 3/µ L .  Restart ne xt treat me nt at 7 5 m g/ m 2. 
D o N O T h ol d or re d uce  rit u xi ma b d ose . 
 
S E C O N D E PI S O D E: H ol d c urre nt et o p osi de d ose u ntil A N C ≥ 0. 5 x 
1 0 3/µ L a n d platelets ≥ 5 0  x 1 0 3/µ L .  Restart ne xt treat me nt at 5 0 m g/ m 2. 
D o N O T h ol d or re d uce rit u xi ma b d ose . 
 
G oal is t o re place d oses a n d c o m plete f ull  c o urse of f o ur d oses of b ot h 
et o p osi de a n d rit u xi ma b.  
 
T a ble 3:  N o n -he m at ol o gic al to xicit y d ose re d ucti o ns  f or rit u xi m a b 
N CI C T C Gr a de  
 
0 -2  
N o c ha n ge fr o m ori gi nal d ose.  
3 -4  
 
  Wait u ntil res ol ve d t o < Gra de 2, n o d ose re d ucti o n.  
Sec o n d e pis o de of G ra de 
3 or 4 t o xicit y  
H ol d u ntil res ol ve d t o < Gra de 2, n o d ose re d ucti o n.  
T hir d e pis o de of G ra de 3 
or 4 t o xicit y  
Re m o ve s u bject fr o m trial  
 
T a ble 4: He p atic a n d re n al d ysf u ncti o n d ose a dj ust me nt f or et o p osi de  
E ve nt  
Acti o n  
Re n al d ysf u ncti o n  
Cr cleara nce > 5 0 ml/ mi n  
N o ne  
Cr cleara nce  1 5 -5 0 ml/ mi n  
Decrease d ose t o 7 5 m g/ m 2  
Cr cleara nce < 1 5 ml/ mi n  
Decrease d ose t o 5 0 m g/ m 2 
He p atic d ysf u ncti o n  
Bilir u bi n < 1. 5 m g/ dl  
N o ne  
  Bilir u bi n 1. 5 -3. 0 m g/ dl  
Decrease d ose t o 5 0 m g/ m 2 
  Bilir u bi n  > 3. 0 m g/ dl  
H ol d u ntil bilir u bi n < 3. 0 m g/ dl  
5. 4  
C o nc o mit a nt Me dic ati o ns/ Tre at me nts / S u p p orti ve C are All o we d 
5. 4. 1  He m at o p o ietic gr o wt h f act ors  
•  Rec o m bi na nt  gra n ul oc yte  c ol o n y -sti m ulati n g  fact or  ( G-C S F)  a n d  
rec o m bi na nt er yt hr o p oieti n will n ot be r o uti nel y a vaila ble, as is t y pical of 
c urre nt p u blic sect or sta n dar ds of care i n Mala wi a n d m ost S S A  setti n gs. 
5. 4. 2  Tr a nsf usi o ns a n d blee di n g  
•  R B C tra nsf usi o ns ca n be gi ve n per treati n g pr o vi der discreti o n. Bl o o d f or 
tra nsf usi o n is n ot u ni versall y a vaila ble i n Mala wi a n d st u d y treat me nt will 
n ot be hel d a waiti n g tra nsf usi o ns as a ne mia is a pri mar y ma nifestati o n of 
M C D. F or patie nts recei vi n g acti ve et o p osi de t hera p y, tra nsf usi o n f or a 
he m o gl o bi n  < 7  g/ d L  is  ge nerall y  rec o m me n de d.  F or  t h ose  recei vi n g  
rit u xi ma b o nl y, tra nsf usi o n is ge nerall y rec o m me n de d f or a he m o gl o bi n < 6 
g/ d L, b ut i n b ot h sce nari os pr o vi der discreti o n will be t he pri mar y dri ver f or  
tra nsf usi o n decisi o ns. 
•  Platelet tra nsf usi o ns will be rec o m me n de d f or platelet c o u nt < 2 0, 0 0 0/ µl, or 
< 5 0, 0 0 0/ µl wit h blee di n g or per treati n g pr o vi der discreti o n. 

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•  Tra ne xa mi c  aci d  will be rec o m me n de d f or  blee di n g  a n d  platelet  c o u nt  
< 5 0, 0 0 0/ µl, or per treati n g pr o vi der discreti o n, w he n a vaila ble l ocall y. T he 
sta n dar d d ose is 1 3 0 0 m g P O t hree ti mes dail y f or t he d urati o n of blee di n g 
e pis o de a n d 2 4 h o urs after blee di n g st o ps. 
5. 4. 3  A nti -i nfecti ve pr o p h yl a xis 
•  HI V -i nfecte d  i n di vi d uals  will recei ve  dail y  cotri m o xaz ole  t hr o u g h o ut 
treat me nt per Mala wi nati o nal HI V treat me nt g ui deli nes 
5. 4. 4  A ntiretr o vir al t her a p y  
A ntiretr o viral t hera p y ( A R T) is n ot prescri be d b y t he st u d y pr ot oc ol a n d , acc or di n g 
t o Mala wi nati o nal g ui deli nes, is left t o t he discreti o n of treati n g HI V cli nicia ns. 
S t u d y cli nicia ns will c olla b orate wit h HI V cli nicia ns t o e ns ure recei pt of A R T 
c o nc urre ntl y  wit h  c he m ot hera p y.  Zi d o v u di ne -base d  treat me nt  will  be  str o n gl y  
disc o ura ge d t o a v oi d a d diti o nal m yel os u p pressi o n. 
5. 4. 5  I nfecti o ns 
Fe brile ne utr o pe nia t o be t reate d per U N C Pr oject Mala wi fe brile ne utr o pe nia 
sta n dar d o perati n g pr ot oc ol ( S O P) (A p pe n di x A. Fe brile Ne utr o pe nia S O P ). 
5. 4. 6  N a use a a n d v o miti n g 
A ntie metic pr o p h yla xis f or et o p osi de is per U N C Pr oject Mala wi a ntie metic S O P 
(A p pe n di x B. U N C Pr oject Mala wi A ntie metic S O P ). America n S ociet y of Cli nical 
O nc ol o g y ( A S C O ) c o nsi ders et o p osi de a l o w e met o ge nic a ge nt. All patie nts will 
recei ve t he f oll o wi n g as a ntie metic pr o p h yla xis: 
•  5- H T 3 a nta g o nist 
o  Gra nisetr o n 2 m g P O or 1 m g I V 
o  O R O n da nsetr o n 8 m g P O Q 6 h o urs x 2 d oses or 8 m g I V x 1 d ose 
•  A N D de xa met has o ne 8 m g P O or I V 
5. 4. 7  E xtr a v as ati o n 
If  t here  is  e vi de nce  of  c he m ot hera p y  lea ka ge or  s welli n g  d uri n g  or  f oll o wi n g 
c he m ot hera p y a d mi nistrati o n, l ocal care will be pr o vi de d per U N C Pr oject  Mala wi 
e xtra vasati o n S O P  (A p pe n di x C. U N C Pr oject Mala wi E xtra vasati o n S O P ). T he 
e xtra vasati o n S O P is a p pe n de d t o t his pr ot oc ol a n d i ncl u des s ur gical c o ns ultati o n. 
5. 4. 8  Et o p osi de a n a p h yl a xis 
A na p h yla xis has bee n re p orte d e xtre mel y rarel y d uri n g et o p osi de i nf usi o n. I n t he 
case of  s uc h  a  reacti o n,  patie nts  will  be  treate d  per   sta n dar d  h y perse nsiti vit y 
reacti o n pr ot oc ol  ( A p pe n di x D. U N C Pr oject Mala wi H y perse nsiti vit y/I nf usi o n 
Reacti o n S O P ). 
5. 4. 9  H y perse nsiti vit y re acti o ns fr o m rit u xi m a b  
•  Patie nts  ma y  e x perie nce  h y perse nsiti vit y  reacti o ns  d uri n g  i nf usi o n  of  
rit u xi ma b. Rit u xi ma b will be a d mi nistere d via sl o wl y titrate d i nf usi o n as 

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per  i nstr ucti o ns  i n  secti o n  5. 2  t o  mi ni mize  t he  ris k  of  h y perse nsiti vit y  
reacti o ns. 
•  If h y perse nsiti vit y s y m pt o ms occ ur d uri n g rit u xi ma b i nf usi o n, t he i nf usi o n 
will be st o p pe d, a n d a l ocal st u d y i n vesti gat or will be n otifie d t o e val uate 
t he patie nt i m me diatel y. F or patie nts recei vi n g t heir first rit u xi ma b i nf usi o n, 
a l ocal st u d y i n vesti gat or will directl y s u per vise t he e ntire i nf usi o n u ntil 
c o m pleti o n. 
•  I nitial s u g geste d ma na ge me nt of h y perse nsiti vit y s y m pt o ms is base d o n 
se verit y per A p pe n di x D. U N C Pr oject Mala wi H y perse nsiti vit y/I nf usi o n 
Reacti o n S O P . Ot her treat me nts a n d res uscitati o n will be a d mi nistere d as 
cli nicall y i n dicate d. 
•  If h y perse nsiti vit y s y m pt o ms occ ur d uri n g rit u xi ma b i nf usi o n, t he patie nt 
will be o bser ve d f or at least t w o h o urs after c o m pleti o n of t he i nf usi o n, a n d 
u ntil all s y m pt o ms res ol ve. If s y m pt o ms persist wit h o ut res ol uti o n f or m ore 
t ha n t w o h o urs after t he i nf usi o n, t he patie nt will be a d mitte d t o t he h os pital 
f or c o nti n ue d o bser vati o n. 
5. 5  
Pr o hi bite d Me dic ati o ns/ Tre at me nts  
S yste mic t hera pies f or ot her acti ve mali g na ncies or acti ve i nfecti o ns.  
5. 6  
Ot her M o d alities or Pr oce d ures  
N o ot her treat me nt m o dalities ( i.e., ra diati o n or s ur ger y) will be part of M C D 
treat me nt i ncl u de d i n t his pr ot oc ol as t he y are n ot sta n dar d of care t hera pies f or 
M C D.  
5. 7  
D ur ati o n of T her a p y  
I n t he a bse nce of treat me nt dela ys d ue t o A Es , treat me nt ma y c o nti n ue f or 4 wee kl y 
d oses or u ntil o ne or m ore of t he f oll o wi n g occ ur: 
•  Disease pr o gressi o n  
•  I nter-c urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of treat me nt  
•  U nacce pta ble A E (s) 
•  Pre g na nc y 
•  S u bject deci des t o wit h dra w fr o m st u d y  treat me nt 
•  Ge neral or s pecific c ha n ges i n t he s u bject’s c o n diti o n re n der t he s u bject 
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  
5. 8  
D ur ati o n of F oll o w U p 
F or deter mi nati o n of st u d y e n d p oi nts, a ll s u bjects will be f oll o we d f or u p t o 2 4 
m o nt hs 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.   
 
S u bject s 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 f or  
res ol uti o n or sta bilizati o n of t he A E (s). All  s u bjects (i ncl u di n g t h ose wit h dra w n f or 
A Es)  s h o ul d be f oll o we d after re m o val fr o m st u d y treat me nt as sti p ulate d i n t he 
pr ot oc ol.   
 

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Alt h o u g h  st u d y  f oll o w -u p  is  f or  2 4  m o nt hs,  patie nts  will  be  c o nse nte d  t o  be  
c o ntacte d at 3 0, 3 6, 4 2, 4 8, 5 4, a n d 6 0 m o nt hs si m pl y t o assess vital stat us after 
c o m pleti o n of st u d y pr oce d ures. 
5. 9  
St u d y Wit h dr a w al  
S u bject s will be re m o ve d fr o m t he st u d y, re m o ve d fr o m pr ot oc ol  ma n date d  t hera p y 
(i.e. f urt her t hera p y will be at discreti o n of t he treati n g pr o vi der), a n d t he st u d y PI 
n otifie d  w he n  a n y  of  t he  criteria  liste d  i n  secti o n  5. 7  a p pl y.  T he  reas o n  f or  
disc o nti n uati o n of pr ot oc ol t hera p y will be d oc u me nte d i n t he electr o nic case re p ort 
f or m (e C R F).   
 
If a s u bject 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) 
a n eff ort will  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 .  At t he ti me of wit h dra wal, t he i n vesti gat or will  atte m pt 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 will  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 l o n g-ter m 
f oll o w- u p o bjecti ves (e. g., s ur vi val) 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 
will  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 will  be d oc u me nte d i n t he e C R F.  
•  
If t he reas o n f or re m o val of a s u bject fr o m t he st u d y is a n A E , t he pri nci pal 
s pecific e ve nt will be rec or de d i n t he e C R F.  
 
E xcessi ve s u bject wit h dra wals  fr o m pr ot oc ol t hera p y or fr o m t he st u d y ca n re n der 
t he st u d y u n-i nter preta ble; t heref ore, u n necessar y wit h dra wal of s u bjects s h o ul d be 
a v oi de d. 
6. 0  
D R U G I N F O R M A TI O N  
6. 1  
Rit u xi m a b  
Rit u xi ma b f or t his st u d y will be s u p plie d as Re dit u x  ( Dr. Re d d y’s La b orat ories, 
I n dia).  F or  e xte nsi ve  pr o d uct  i nf or mati o n,  pre parati o n  i nstr ucti o ns,  a n d  A Es  
i nf or mati o n, please refer t o t he U nite d States F o o d a n d Dr u g A d mi nistrati o n  r o d uct 
g ui deli nes
 here:
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 0/ 1 0 3 7 0 5s 5 3 1 1l bl. p df  
 
Rit u xi ma b is t he sta n dar d t hera p y f or M C D i n HI C , b ut p u blis he d data is missi n g 
o n t he safet y of rit u xi ma b i n S S A . Rit u xi ma b will be pr o vi de d free of c har ge t o all 
st u d y partici pa nts. 
6. 1. 1  Descri pti o n  
Rit u xi ma b is a ge neticall y e n gi neere d c hi meric m uri ne/ h u ma n m o n ocl o nal I g G 1 
ka p pa a nti b o d y directe d a gai nst t he C D 2 0 a nti ge n. Rit u xi ma b has a n a p pr o xi mate 

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m olec ular wei g ht of 1 4 5 k D. Rit u xi ma b has a bi n di n g affi nit y f or t he C D 2 0 a nti ge n 
of a p pr o xi matel y 8. 0 n M. It is pr o d uce d b y ma m malia n cell ( C hi nese Ha mster 
O var y)  s us pe nsi o n  c ult ure  i n  a  n utrie nt  me di u m  c o ntai ni n g  t he  a nti bi otic  
ge nta mici n. Ge nta mici n is n ot detecta ble i n t he fi nal pr o d uct. 
6. 1. 2  St or a ge a n d H a n dli n g  
Rit u xi ma b s h o ul d be st ore d at 2 -8° C. D o N O T  freeze or st ore at r o o m te m perat ure. 
T he pr o d uct is a pr otei n. H A N D L E G E N T L Y A N D A V OI D F O A MI N G. T he 
a v oi da nce of f oa mi n g d uri n g pr o d uct ha n dli n g, pre parati o n a n d a d mi nistrati o n is 
i m p orta nt, as f oa mi n g ma y lea d t o t he de nat uri n g of t he pr o d uct pr otei ns. 
6. 1. 3  P h ar m ac ol o g y 
P har mac o ki netics : I n pri or st u dies patie nts treate d at t he 3 7 5 m g/ m 2 d ose le vels 
e x hi bite d detecta ble a nti b o d y c o nce ntrati o ns t hr o u g h o ut t he treat me nt peri o d.  
M ost patie nts e x hi bite d i ncreasi n g pre-i nf usi o n a nti b o d y c o nce ntrati o ns wit h eac h  
s u bse q ue nt i nf usi o n. I n ni ne patie nts, t he T 1/ 2 f oll o wi n g t he first a nti b o d y i nf usi o n 
was 5 9. 8 h o urs ( 1 1. 1 -1 0 4. 6 hr) wit h a C ma x of 2 7 1 mc g/ m L. F oll o wi n g t he f o urt h 
a nti b o d y i nf usi o n w he n circ ulati n g B cells ha d bee n de plete d a n d a nti ge nic sites 
c oate d, t he  T 1/ 2 was 1 7 4 hr ( 2 6. 4- 4 4 2. 3 hr) a n d C ma x 4 9 6. 7 mc g/ m L. 
 
D urati o n:  Detecta ble  i n  ser u m  3 -6  m o nt hs  after  treat me nt c o m pleti o n;  B-cell 
rec o ver y be gi ns al m ost 6 m o nt hs f oll o wi n g treat me nt c o m pleti o n; me dia n B -cell 
le vels ret ur n t o n or mal b y 1 2 m o nt hs f oll o wi n g treat me nt c o m pleti o n.  
 
A bs or pti o n: I ntra ve n o us: I m me diate a n d res ults i n a ra pi d a n d s ustai ne d de pleti o n 
of circ ulati n g a n d tiss ue -base d B cells.  
 
Half -life eli mi nati o n: Me dia n ter mi nal half -life: 2 2 da ys (ra n ge: 6- 5 2 da ys)  
 
E xcreti o n: 
U ncertai n;  ma y  u n der g o  p ha g oc yt osis  a n d  cata b olis m  i n  t he  
retic ul oe n d ot helial s yste m ( R E S). 
6. 1. 4  F or m ul ati o n  
1 0 0 m g ( 1 0 m L) a n d 5 0 0 m g ( 5 0 ml) p har mace utical gra de vials at a c o nce ntrati o n of 
1 0 m g of pr otei n per m L (act ual c o nce ntrati o n s h o ul d be n ote d o n t he pr o d uct la bel). 
6. 1. 5  Ret ur n a n d Rete nti o n of St u d y Dr u g  
Ret ur n a n d rete nti o n of rit u xi ma b will be d o ne per U N C Pr oject  Mala wi dr u g 
destr ucti o n S O P use d i n s u p p ort of o n g oi n g a n d c o m plete d cli nical trials .  
6. 1. 6  A d verse E ve nts Ass oci ate d wit h I n vesti g ati o n al Dr u g  
H u ma n T o xic ol o g y: Si n gle d oses of u p t o 2 2 7 5 m g/ m 2 a n d wee kl y x 4 d oses of  
3 7 5 m g/ m 2 ha ve bee n a d mi nistere d wit h o ut d ose li miti n g t o xicit y. A Es  are m ost 
c o m m o n d uri n g t he i nitial a nti b o d y i nf usi o n a n d us uall y c o nsist of Gra de 1 or 2 
fe ver ( 7 3 %), ast he nia ( 1 6 %), c hills ( 3 8 %), na usea ( 1 9 %), v o miti n g ( 1 1 %), ras h 
( 1 4 %) a n d t u m or site pai n ( 3 %). Gra de 1 or 2 h y p ote nsi o n ( 8 %) ma y be treate d 

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wit h  I V  fl ui ds.  He mat ol o gic  t o xicit y  is  us uall y  mil d  a n d  re versi ble.  Tra nsie nt  
decreases i n t he W B C or platelet c o u nt ha ve bee n o bser ve d - es peciall y i n patie nts 
wit h hi g h le vels of circ ulati n g t u m or cells or b o ne marr o w i n v ol ve me nt. T w o 
patie nts ha ve ha d late-o nset Gra de 4 ne utr o pe nia at f o ur a n d te n m o nt hs t hat was 
attri b ute d t o a n u n k n o w n ca use, was tra nsie nt , a n d res ol ve d. I nfecti o ns ( Gra de 1 
a n d 2) ha ve n ot bee n relate d t o d ose le vel. S y m pt o ms are ge nerall y ass ociate d wit h 
t he  i nitial  a nti b o d y  i nf usi o ns  a n d  di mi nis h  i n  fre q ue nc y  wit h  eac h  s uccessi ve  
i nf usi o n. A re p ort i n t he literat ure descri be d a n i ncrease i n fatal i nfecti o n i n HI V-
relate d l y m p h o ma patie nts w he n rit u xi ma b was use d i n c o m bi nati o n wit h C H O P 
c he m ot hera p y as c o m pare d t o C H O P al o ne. 
 
Se vere  I nf usi o n  a n d  H y perse nsiti vit y  Reacti o ns :  Rit u xi ma b  has  ca use d  se vere  
i nf usi o n reacti o ns. I n s o me cases, t hese reacti o ns were fatal. A n i nf usi o n-relate d 
s y m pt o m  c o m ple x  c o nsisti n g  of  fe ver  a n d  c hills/ri g ors  has  occ urre d i n  ma n y 
patie nts d uri n g t he first rit u xi ma b i nf usi o n. Si g ns a n d s y m pt o ms of se vere i nf usi o n 
reacti o ns  ma y  i ncl u de  urticaria,  h y p ote nsi o n,  a n gi oe de ma,  h y p o xia,  or  
br o nc h os pas m. T he m ost se vere ma nifestati o ns a n d se q uelae i ncl u de p ul m o nar y 
i nfiltrates, ac ute res pirat or y distress s y n dr o me , m y ocar dial i nfarcti o n, ve ntric ular 
fi brillati o n, car di o ge nic s h oc k, a n d a na p h ylactic a n d a na p h ylact oi d e ve nts. T hese 
reacti o ns ge nerall y occ urre d wit hi n 3 0 mi n utes t o 2 h o urs of be gi n ni n g t he first 
i nf usi o n, a n d res ol ve d wit h sl o wi n g or i nterr u pti o n of the rit u xi ma b i nf usi o n a n d 
wit h s u p p orti ve care (i ncl u di n g, b ut n ot li mite d t o I V sali ne, di p he n h y dra mi ne, a n d 
aceta mi n o p he n). 
 
T u m or L ysis S y n dr o me:  Rit u xi ma b ra pi dl y decreases be ni g n a n d mali g na nt C D 2 0 
p ositi ve cells. T u m or l ysis s y n dr o me has bee n re p orte d t o occ ur wit hi n 1 2 t o 2 4 
h o urs after t he first rit u xi ma b i nf usi o n i n patie nts wit h hi g h n u m bers of circ ulati n g 
mali g na nt l y m p h oc ytes. Patie nts wit h hi g h t u m or b ur de n ( b ul k y lesi o ns) ma y als o 
be at ris k. Patie nts at ris k f or de vel o pi n g t u m or l ysis s y n dr o me s h o ul d be f oll o we d 
cl osel y a n d a p pr o priate la b orat or y m o nit ori n g perf or me d. 
 
He patitis B Reacti vati o n wit h Relate d F ul mi na nt He patitis a n d Ot her Viral  
I nfecti o ns: He patitis B vir us ( H B V) reacti vati o n wit h f ul mi na nt he patitis, he patic 
fail ure,  a n d  deat h  has  bee n  re p orte d  i n  s o me  patie nts  wit h  he mat ol o gic  
mali g na ncies treate d wit h rit u xi ma b. T he maj orit y of  patie nts recei ve d rit u xi ma b i n 
c o m bi nati o n wit h c he m ot hera p y. T he me dia n ti me t o dia g n osis of he patitis was 
a p pr o xi matel y f o ur m o nt hs after t he i nitiati o n of rit u xi ma b a n d a p pr o xi matel y o ne 
m o nt h after t he last d ose. Pers o ns at hi g h ris k of H B V i nfecti o n s h o ul d be scree ne d 
bef ore i nitiati o n of rit u xi ma b. Carriers of he patitis B s h o ul d be cl osel y m o nit ore d 
f or cli nical a n d la b orat or y si g ns of acti ve H B V i nfecti o n a n d f or si g ns of he patitis 
d uri n g a n d f or u p t o se veral m o nt hs f oll o wi n g rit u xi ma b t hera p y. I n patie nts w h o 
de vel o p viral he patitis, rit u xi ma b a n d a n y c o nc o mita nt c he m ot hera p y s h o ul d be 
disc o nti n ue d a n d a p pr o priate treat me nt , i ncl u di n g a nti viral t hera p y, i nitiate d. T here 
are i ns ufficie nt data re gar di n g t he safet y of res u mi n g rit u xi ma b t hera p y i n patie nts 
w h o de vel o p he patitis s u bse q ue nt t o H B V reacti vati o n. T he f oll o wi n g a d diti o nal 
seri o us viral i nfecti o ns, eit her ne w, reacti vate d or e xacer bate d, ha ve been i de ntifie d 

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i n  cli nical  st u dies  or  p ost mar keti n g  re p orts.  T he  maj orit y  of  patie nts  recei ve d  
rit u xi ma b i n c o m bi nati o n wit h c he m ot hera p y or as part of a he mat o p oietic ste m 
cell tra ns pla nt. T hese viral i nfecti o ns i ncl u de d J o h n C u n ni n g ha m vir us, w hic h is 
ass ociate d  wit h  p r o gressi ve  m ultif ocal  le u k oe nce p hal o pat h y,  c yt o me gal o vir us,  
her pes si m ple x vir us, par v o vir us B 1 9, varicella z oster vir us, West Nile vir us, a n d 
he patitis C. I n s o me cases, t he viral i nfecti o ns occ urre d u p t o o ne year f oll o wi n g 
disc o nti n uati o n of rit u xi ma b a n d ha ve res ulte d i n deat h. 
 
Se vere  M uc oc uta ne o us  Reacti o ns :  M uc oc uta ne o us  reacti o ns,  s o me  wit h  fatal  
o utc o me, ha ve  bee n re p orte d i n patie nts treate d wit h rit u xi ma b. T hese re p orts 
i ncl u de d  para ne o plastic  pe m p hi g us  (a n  u nc o m m o n  dis or der  w hic h  is  a  
ma nifestati o n of t he patie nt's u n derl yi n g mali g na nc y), Ste ve ns -J o h nso n s y n dr o me, 
lic he n oi d der matitis, vesic ul o b ull o us der matitis, a n d t o xic e pi der mal necr ol ysis. 
T he o nset of t he reacti o n i n re p orte d cases ha ve varie d fr o m 1 - 1 3 wee ks f oll o wi n g 
rit u xi ma b e x p os ure. Patie nts e x perie nci n g a se vere m uc oc uta ne o us reacti o n s h o ul d 
n ot recei ve a n y f urt her i nf usi o ns a n d see k pr o m pt me dical e val uati o n. S ki n bi o ps y 
ma y  hel p  t o  disti n g uis h  a m o n g  differe nt  m uc oc uta ne o us  reacti o ns  a n d  g ui de  
s u bse q ue nt treat me nt. T he safet y of rea d mi nistrati o n of rit u xi ma b t o patie nts wit h 
a n y of t hese m uc oc uta ne o us reacti o ns has n ot bee n deter mi ne d. 
 
B o wel O bstr ucti o n a n d Perf orati o n:  A b d o mi nal pai n   a n d b o wel o bstr ucti o n a n d 
perf orati o n ( i n s o me cases lea di n g t o deat h) were o bser ve d i n patie nts recei vi n g 
rit u xi ma b  i n  c o m bi nati o n  wit h  c he m ot hera p y  f or  D L B C L.  I n  p ost-mar keti n g 
re p orts,  w hic h  i ncl u ded patie nts  wit h   b ot h l o w-gra de  or  f ollic ular  N H L  a n d  
D L B C L, t he mea n ti me t o o nset of s y m pt o ms was 6 da ys (ra n ge 1 -7 7) i n patie nts 
wit h  d oc u me nte d  gastr oi ntesti nal  perf orati o n.  C o m plai nts  of  a b d o mi nal  pai n,  
es peciall y earl y i n t he c o urse of treat me nt, s h o ul d pr o m pt a t h or o u g h dia g n ostic 
e val uati o n a n d a p pr o priate treat me nt.  
 
Car di o vasc ular:  T he i nci de nce of seri o us car di o vasc ular e ve nts i n t he d o u ble- bli n d  
cli nical trial f or r he u mat oi d art hritis ( R A) patie nts was 1. 7 % a n d 1. 3 % i n rit u xi ma b 
a n d place b o gr o u ps, res pecti vel y. T hree car di o vasc ular deat hs occ urre d d uri n g t he 
d o u ble- bli n d peri o d of t he R A st u dies, i ncl u di n g all rit u xi ma b re gi me ns ( 3/ 7 5 9 = 
0. 4 %) as c o m pare d t o n o ne i n t he place b o gr o u p ( 0/ 3 8 9).  
Si nce patie nts wit h R A are at i ncrease d ris k f or car di o vasc ular e ve nts c o m pare d t o 
t he  ge neral  p o p ulati o n,  patie nts  wit h  R A  s h o ul d  be  m o nit ore d  t hr o u g h o ut  t he  
i nf usi o n a n d rit u xi ma b s h o ul d be disc o nti n ue d i n t he e ve nt of a seri o us or life-
t hreate ni n g car diac e ve nt. Rit u xi ma b i nf usi o ns s h o ul d be disc o nti n ue d i n t he e ve nt 
of seri o us or life -t hreate ni n g car diac arr h yt h mias. Patie nts w h o de vel o p cli nicall y 
si g nifica nt  arr h yt h mias  s h o ul d  u n der g o  car diac  m o nit ori n g  d uri n g  a n d  after  
s u bse q ue nt i nf usi o ns of rit u xi ma b. Patie nts wit h pre -e xisti n g car diac c o n diti o ns 
i ncl u di n g arr h yt h mias a n d a n gi na ha ve ha d rec urre nces of t hese e ve nts d uri n g 
rit u xi ma b t hera p y a n d s h o ul d be m o nit ore d t hr o u g h o ut t he i nf usi o n a n d i m me diate 
p ost-i nf usi o n peri o d. 
 

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Re nal : Rit u xi ma b a d mi nistrati o n has bee n ass ociate d wit h se vere re nal t o xicit y 
i ncl u di n g ac ute re nal fail ure re q uiri n g dial ysis a n d, i n s o me cases,  has le d t o fatal 
o utc o mes i n  he mat ol o gic  mali g na nc y  patie nts.  Re nal  t o xicit y  has  occ urre d  i n  
patie nts  wit h  hi g h  n u m bers  of  circ ulati n g  mali g na nt  cells  ( >  2 5, 0 0 0/ μ L)  or  hi g h 
t u m or b ur de n w h o e x perie nce t u m or l ysis s y n dr o me a n d i n patie nts wit h N H L 
a d mi nistere d c o nc o mita nt cis plati n  t hera p y d uri n g cli nical trials. T he c o m bi nati o n 
of cis plati n a n d rit u xi ma b is n ot a n a p pr o ve d treat me nt re gi me n. If t his c o m bi nati o n 
is use d i n cli nical trials extre me c a uti o n s h o ul d be e xercise d; patie nts s h o ul d be 
m o nit ore d cl osel y f or si g ns of re nal fail ure. Disc o nti n uati o n of rit u xi ma b s h o ul d be 
c o nsi dere d f or t h ose wit h risi n g ser u m creati ni ne or oli g uria.  
 
I m m u nizati o n:  T he  safet y  of  i m m u nizati o n  wit h  li ve  viral  vacci nes  f oll o wi n g  
rit u xi ma b t hera p y has n ot bee n st u die d a n d vacci nati o n wit h li ve vir us vacci nes is 
n ot  rec o m me n de d.  T he  a bilit y  t o  ge nerate  a  pri mar y  or  a na m nestic  h u m oral  
res p o nse t o vacci nati o n is c urre ntl y bei n g st u die d. F or patie nts wit h N H L, t he 
be nefits of pri mar y a n d/ or b o oster vacci nati o ns s h o ul d be wei g he d a gai nst t he ris ks 
of dela y i n i nitiati o n of rit u xi ma b t hera p y.  
 
Carci n o ge nesis, I m pair me nt of Fertilit y, Pre g na nc y, a n d N ursi n g: N o l o n g -ter m 
a ni mal  st u dies  ha ve  bee n  perf or me d  t o  esta blis h  t he  carci n o ge nic  p ote ntial  of  
rit u xi ma b. St u dies als o ha ve n ot bee n c o m plete d t o assess m uta ge nic p ote ntial of 
rit u xi ma b,  or  t o  deter mi ne  p ote ntial  effects  o n  fertilit y  i n  males  or  fe males.  
I n di vi d uals of c hil d beari n g p ote ntial s h o ul d use effecti ve c o ntrace pti ve met h o ds 
d uri n g treat me nt a n d f or u p t o 1 2 m o nt hs f oll o wi n g rit u xi ma b t hera p y. It is n ot 
k n o w n  w het her  rit u xi ma b  is  e xcrete d  i n  h u ma n  mil k.  Beca use  h u ma n  I g G  is  
e xcrete d i n h u ma n mil k a n d t he p ote ntial f or a bs or pti o n a n d i m m u n os u p pressi o n i n 
i nfa nts is  u n k n o w n,  w o me n  s h o ul d  be  a d vise d  t o  disc o nti n ue  n ursi n g  u ntil  
circ ulati n g dr u g le vels are n o l o n ger detecta ble. 
6. 2  
Et o p osi de  Descri pti o n a n d M a n a ge me nt  
Brief Descri pti o n : Et o p osi de is a t o p ois o merase II i n hi bit or t hat ca uses D N A 
d o u ble stra n d brea ks a n d a p o pt osis of ra pi dl y di vi di n g cells, es peciall y ca ncer cells. 
Et o p osi de is a c o m m o n c he m ot hera pe utic a ge nt use d i n t he treat me nt of a n u m ber 
of  ne o plas ms , i ncl u di n g  l y m p h o ma,  Ka p osi  sarc o ma,  testic ular  ca ncer,  E wi n g  
sarc o ma, a n d s mall cell l u n g ca ncer, a m o n g ot hers.  
 
Et o p osi de (als o k n o w n as V P- 1 6) is s ol d b y Pfizer ( Ne w Y or k, U S A). 
 
F ull prescri bi n g i nf or mati o n f or et o p osi de is a vaila ble at: 
htt ps:// w w w. pfizer.c o m/files/ pr o d ucts/ us pi _t o p osar. p df  
 
D os a ge a n d A d mi nistr ati o n: 
Et o p osi de will be a d mi nistere d at 1 0 0 m g/ m 2 i ntra ve n o us o ver o ne h o ur. 
 
St or a ge a n d St a bilit y : 

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U n o pe ne d vials are sta ble f or 2 4 m o nt hs at r o o m te m perat ure. Vials dil ute d at 
rec o m me n de d c o nce ntrati o n of 0. 2 or 0. 4 m g/ ml are sta ble f or 9 6 or 2 4 h o urs, 
res pecti vel y, at r o o m te m perat ure.  
 
H a n dli n g  a n d  Dis p os al : 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 
 
6. 2. 1 
Et o p osi de p h ar m ac o ki netics  
After I V  i njecti o n, t here is a bi p hasic patter n of cleara nce wit h a ter mi nal t1/ 2 of 
a b o ut 6– 8 h i n patie nts wit h n or mal re nal f u ncti o n. A p pr o xi matel y 4 0 % of a n 
a d mi nistere d d ose is e xcrete d i ntact i n t he uri ne. I n patie nts wit h c o m pr o mise d re nal 
f u ncti o n, d osa ge s h o ul d be re d uce d i n pr o p orti o n t o t he re d ucti o n i n creati ni ne 
cleara nce . I n patie nts wit h a d va nce d li ver disease, i ncrease d t o xicit y ma y res ult 
fr o m a l o w ser u m al b u mi n ( decrease d dr u g bi n di n g) a n d ele vate d bilir u bi n ( w hic h 
dis places  et o p osi de  fr o m  al b u mi n);  g ui deli nes  f or  d ose  re d ucti o n  i n  t his  
circ u msta nce ha ve n ot bee n def i ne d.  
6. 2. 1  A d verse e ve nts ass oci ate d wit h et o p osi de  
T he  f oll o wi n g  data  o n  a d verse  reacti o ns  are  base d  o n  b ot h  oral  a n d  I V 
a d mi nistrati o n of et o p osi de as a si n gle a ge nt, usi n g se veral differe nt d ose sc he d ules 
f or treat me nt of a wi de variet y of mali g na ncies.  
 
He mat ol o gic T o xicit y:  M yel os u p pressi o n is d ose relate d a n d d ose li miti n g wit h 
gra n ul oc yte na dirs occ urri n g 7 t o 1 4 da ys after dr u g a d mi nistrati o n a n d platelet 
na dirs occ urri n g 9 t o 1 6 da ys after dr u g a d mi nistrati o n. B o ne marr o w rec o ver y is 
us uall y c o m plete b y da y 2 0, a n d n o c u m ulati ve t o xicit y has bee n re p orte d. T he 
occ urre nce  of  ac ute  le u ke mia  wit h  or  wit h o ut  a  prele u ke mic  p hase  has  bee n  
re p orte d  rarel y  i n  patie nts  treate d  wit h  et o p osi de  i n  ass ociati o n  wit h  ot her  
a nti ne o plastic a ge nts.  
 
Gastr oi ntesti nal  T o xicit y:  Na usea  a n d  v o miti n g  are  t he  maj or  gastr oi ntesti nal  
t o xicities. T he se verit y of s uc h na usea a n d v o miti n g is ge nerall y mil d t o m o derate 
wit h treat me nt disc o nti n uati o n re q uire d i n 1 % of patie nts. Na usea a n d v o miti n g ca n 
us uall y be c o ntr olle d wit h sta n dar d a n tie metic t hera p y. Gastr oi ntesti nal t o xicities 
are sli g htl y m ore fre q ue nt after oral a d mi nistrati o n t ha n after I V i nf usi o n.  
 
H y p ote nsi o n: Tra nsie nt h y p ote nsi o n f oll o wi n g ra pi d I V a d mi nistrati o n has bee n 
re p orte d i n 1 % t o 2 % of patie nts. It has n ot bee n ass ociate d wit h car diac t o xicit y or 
electr ocar di o gra p hic c ha n ges. N o dela ye d h y p ote nsi o n has bee n n ote d. T o pre ve nt 
t his rare occ urre nce, it is rec o m me n de d t hat et o p osi de be a d mi nistere d b y sl o w I V 
i nf usi o n o ver a 3 0- t o 6 0-mi n ute peri o d. If h y p ote nsi o n occ urs, it us uall y res p o n ds 
t o cessati o n of t he i nf usi o n a n d a d mi nistrati o n of fl ui ds or ot her s u p p orti ve t hera p y 

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as a p pr o priate. W he n restarti n g t he i nf usi o n, a sl o wer a d mi nistrati o n rate s h o ul d be 
use d.  
 
Aller gic  Reacti o ns:   A na p h ylactic-li ke  reacti o ns  c haracterize d  b y  c hills,  fe ver,  
tac h ycar dia, br o nc h os pas m, d ys p nea, a n d h y p ote nsi o n ha ve bee n re p orte d  i n 0. 7 % 
t o 2 % of patie nts recei vi n g I V et o p osi de a n d i n less t ha n 1 % of t he patie nts treate d 
wit h oral ca ps ules. Alt h o u g h t hese reacti o ns  ca n be fatal, t he y  us uall y res p o n d 
pr o m ptl y  t o  cessati o n  of  t he  i nf usi o n  a n d  a d mi nistrati o n  of  press or  a ge nts,  
c ortic oster oi ds, a nti hista mi nes , or v ol u me e x pa n ders as a p pr o priate . H y perte nsi o n 
a n d fl us hi n g ha ve als o bee n rep orte d. Bl o o d press ure us uall y n or malizes wit hi n a 
fe w h o urs after cessati o n of t he i nf usi o n. A na p h ylactic-li ke reacti o ns ha ve occ urre d 
d uri n g  t he  i nitial  i nf usi o n  of  et o p osi de.  Facial/t o n g ue  s welli n g,  c o u g hi n g,  
dia p h oresis, c ya n osis, ti g ht ness i n t hr oat, lar y n g os pas m, bac k pai n, a n d/ or l oss of 
c o nsci o us ness ha ve s o meti mes occ urre d i n ass ociati o n wit h t he a b o ve reacti o ns. I n 
a d diti o n, a n a p pare nt h y perse nsiti vit y -ass ociate d a p nea has bee n re p orte d rarel y. 
Ras h, urticaria, a n d/ or pr urit us ha ve i nfre q ue ntl y b ee n re p orte d at rec o m me n de d 
d oses. At i n vesti gati o nal d oses, a ge neralize d pr uritic er yt he mat o us mac ul o pa p ular 
ras h, c o nsiste nt wit h peri vasc ulitis, has bee n re p orte d.  
 
Al o pecia: Re versi ble  al o pecia,  s o meti mes  pr o gressi n g  t o  t otal  bal d ness , was 
o bser ve d i n u p t o 6 6 % of patie nts.  
 
Ot her T o xicities:  T he f oll o wi n g a d verse reacti o ns ha ve bee n i nfre q ue ntl y re p orte d: 
aftertaste, fe ver, pi g me ntati o n, a b d o mi nal pai n, c o nsti pati o n, d ys p ha gia, tra nsie nt 
c ortical  bli n d ness , a n d  a  si n gle  re p ort  of  ra diati o n  recall  der matitis.  He patic  
t o xicit y, ge nerall y i n patie nts recei vi n g hi g her t ha n rec o m me n de d d oses of t he dr u g, 
has bee n re p orte d wit h et o p osi de. Meta b olic aci d osis has als o bee n re p orte d i n 
patie nts recei vi n g t hese hi g her d oses. T he i nci de nces of a d verse reacti o ns i n T a ble 
6  are deri ve d fr o m m ulti ple data bases fr o m st u dies i n 2, 0 8 1 patie nts w he n et o p osi de 
was use d eit her orall y or b y i njecti o n as a si n gle a ge nt.  
 

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T a ble 6 : I nci de nce of a d verse e ve nts i n patie nts recei vi n g et o p osi de acr oss 
m ulti ple st u dies f or m ulti ple ca ncer t y pes.
 
 
7. 0  
C LI NI C A L A S S E S S M E N T S  
Cli nical assess me nts will be perf or me d as o utli ne d  i n t he Ti me a n d E ve nts Ta ble i n Secti o n 
8. 0 . 
7. 1. 1  C o nc o mit a nt Me dic ati o ns  
All  c o nc o mita nt  me dicati o n  a n d  c o nc urre nt  t hera pies  will  be  d oc u me nte d  at  
b aseli ne/ scree ni n g  a n d t hr o u g h o ut t he st u d y as s u m marize d i n t he Ti me a n d E ve nts 
Ta ble i n Secti o n 8. 0 . D ose , r o ute, u nit fre q ue nc y of a d mi nistrati o n, a n d i n dicati o n 
f or a d mi nistrati o n a n d dates of me dicati o n will be ca pt ure d.  
7. 1. 2  De m o gr a p hics  
De m o gra p hic i nf or mati o n ( i.e., date of birt h, ge n der, race) will be rec or de d at 
scree ni n g. 
7. 1. 3  Me dic al Hist or y  
Rele va nt  me dical  hist or y,  i ncl u di n g  hist or y  of  c urre nt  disease,  ot her  perti ne nt  
res pirat or y  hist or y (e. g., t o bacc o  use),  a n d  i nf or mati o n  re gar di n g  u n derl yi n g  
diseases will  be  rec or de d  at  scree ni n g a n d  a  f oc use d  me dical  hist or y  o f 
s y m pt o ms/t o xicit y will be perf or me d t hereafter.  
7. 1. 4  P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e xa mi nati o n i ncl u di n g hei g ht (at scree ni n g o nl y), wei g ht,  
E C O G Perf or ma nce  stat us , l y m p h  n o de  assess me nt,  a n d vital  si g ns   (i.e., 
te m perat ure a n d bl o o d press ure) will be perf or me d b y eit her t he i n vesti gat or or a 
s u b-i n vesti gat or at scree ni n g a n d eac h treat me nt visit.    
 

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Ne w a b n or mal p h ysical e xa m fi n di n gs m ust be d oc u me nte d a n d will be f oll o we d 
b y a p h ysicia n or ot her q ualifie d staff at t he ne xt sc he d ule d visit. 
7. 1. 5  A d verse E ve nts  
E ve nts s h o ul d be assesse d per N CI -C T C A E criteria v 5. 0. I nf or mati o n re gar di n g 
occ urre nce of  A Es will be ca pt ure d t hr o u g h o ut t he st u d y. D urati o n (start a n d st o p 
dates ),  se verit y/ gra de, o utc o me,  treat me nt , a n d  relati o n  t o  st u d y  dr u g  will  be  
rec or de d i n t he eC R F.  P R O -C T C A E has rece ntl y bee n tra nslate d a n d vali date d i n 
Mala wi a n d will be use d t o ca pt ure patie nt re p orte d a d verse e ve nts.  
7. 1. 6  Cli nic al Dise ase Assess me nt  
Res p o nse assess me nt varies acr oss M C D st u dies, b ut o ur cli nical res p o nse will be 
defi ne d as f oll o ws:  
 
E ve nt -free s ur vi v al will be defi ne d b y t he a bse nce of  a n e ve nt. A n e ve nt i ncl u des 
eit her: rela pse of  s y m pt o matic M C D re q uiri n g re-i nitiati o n of treat me nt as i n t he 
pre vi o us st u d y b y B o wer, et al, deat h, or pr o gressi o n t o n o n -H o d g ki n l y m p h o ma .1 0 
Defi niti o n of s y m pt o matic M C D f or p ur p oses of t his st u d y are t he sa me as i n t he 
“I ncl usi o n Criteria” ( Secti o n 4. 1).  
7. 1. 7  R a di ol o gic 
Dise ase  Assess me nt  ( Re vise d  res p o nse  criteri a  f or  gr oss  
l y m p h a de n o p at h y) 
All  patie nts  will  u n der g o  baseli ne  o n -st u d y  c hest  ra di o gra p h y  a n d  a b d o mi nal  
s o n o gra p h y f or sta gi n g. R es p o nse will be e val uate d via c o m plete s ur ve y of l y m p h 
n o des wit h meas ure me nts a n d p h ysical assess me nt of ot her pal pa ble masses wit h 
meas ure me nts ( usi n g a fle xi ble metric r uler i n t w o di me nsi o ns). C hest ra di o gra p h y 
a n d a b d o mi nal s o n o gra p h y will be re peate d at c o m pleti o n of treat me nt.  
 
Meas ura ble disease will be defi ne d as t he prese nce of at least o ne meas ura ble 
pat h ol o gic l y m p h n o de or ot her mass t hat ca n be acc uratel y meas ure d b y p h ysical 
e xa m i n at least o ne di me nsi o n wit h t he l o n gest dia meter a mi ni m u m size of 1 0 m m 
cali per  meas ure me nt  b y  cli nical  e xa m  (lesi o ns  w hic h  ca n n ot  be  acc uratel y  
meas ure d wit h cali pers s h o ul d be rec or de d as n o n -meas ura ble). All meas ure me nts 
s h o ul d  be  rec or de d  i n  metric  n otati o n  usi n g  cali pers.  All  baseli ne  e val uati o ns  
s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d ne ver m ore t ha n 
f o ur wee ks bef ore t he be gi n ni n g of treat me nt. T he sa me met h o d of assess me nt a n d 
t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h i de ntifie d a n d re p orte d 
lesi o n at baseli ne a n d d uri n g f oll o w-u p. Cli nical lesi o ns will o nl y be c o nsi dere d 
meas ura ble w he n t he y  are  s u perficial  a n d  ≥1 0  m m  dia meter  as  assesse d  usi n g 
cali pers.  
 
All meas ura ble lesi o ns b y p h ysical e xa m or ma xi m u m of fi ve lesi o ns s h o ul d be 
i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d i n t w o di me nsi o ns at 
baseli ne. Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h 
t he l o n gest dia meters) a n d s h o ul d als o be t h ose t hat le n d t he msel ves t o re pr o d uci ble 

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re peate d  meas ure me nts.  A  s u m  of  t he  pr o d uct  of  dia meters  ( S P D,  as  i n  t he  
I nter nati o nal  Har m o nizati o n  Pr o d uct  criteria)  f or  all  tar get  lesi o ns  will  be  
calc ulate d a n d re p orte d as t he baseli ne S P D. T he baseli ne S P D will be use d as 
refere nce t o f urt her c haracterize t he o bjecti ve t u m or res p o nse of t he meas ura ble 
di me nsi o n of t he disease.  
 
All ot her lesi o ns ( or sites of disease), i ncl u di n g lesi o ns e vi de nt o nl y b y c hest x -ra y 
or ultras o u n d gi ve n diffic ulties wit h re pr o d uci bilit y of ra di o gra p hic st u dies i n o ur 
setti n g, s h o ul d be i de ntifie d as n o n-tar get lesi o ns a n d s h o ul d als o be rec or de d at 
b aseli ne. Meas ure me nts are n ot re q uire d, a n d t hese lesi o ns s h o ul d be f oll o we d as 
‘ prese nt’ or ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n.’  
 
A si milar strate g y f or res p o nse assess me nt base d o n tar get lesi o ns d oc u me nte d b y 
p h ysical e xa m al o ne is c urre ntl y bei n g utilize d at U N C Pr oject  Mala wi f or a cli nical 
trial f or l y m p h o ma.  
 
Res p o nse criteria f or l y m p h n o de res p o nse will be as f oll o ws.  
•  C o m plete  res p o nse  ( C R):  Disa p peara nce  of  all  e vi de nt  disease.  A n y  
pat h ol o gical l y m p h n o de ( L N) , w het her tar get or n o n -tar get, m ust ha ve 
decrease d t o < 1 0 m m i n dia meter. A n y n o n -tar get lesi o n e vi de nt b y c hest x-
ra y or ultras o u n d m ust als o be d oc u me nte d t o ha ve res ol ve d b y re peat 
e val uati o n.  
•  Partial res p o nse ( P R):  At least a 5 0 % decrease i n S P D of u p t o si x tar get 
lesi o ns wit h o ut a n y i ncrease i n size of n o n-tar get lesi o ns. 
•  Sta ble disease ( S D):  Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or 
s ufficie nt i ncrease t o q ualif y f or P D.  
•  Pr o gressi ve  disease  ( P D):  A p peara nce  of  a  ne w  lesi o n(s)  > 1 5 m m  i n  
dia meter, at least a 5 0 % i ncrease i n S P D of m ore t ha n o ne n o de, O R  at least 
a 5 0 % i ncrease i n dia meter of a pre vi o usl y i de ntifie d n o de > 1c m. Gi ve n 
n u mer o us  ca uses  of  a de n o pat h y  i n  Mala wi   (partic ularl y  a m o n g  HI V -
i nfecte d i n di vi d uals) a n d i n or der t o e xcl u de alter nati ve n o n -l y m p h o ma 
dia g n oses, a  c o ncerte d  atte m pt  t o  re -bi o ps y  at  t he  ti me  of  rela pse  or  
pr o gressi o n will be ma de u nless patie nts ref use or t he site is n ot a me na ble 
usi n g l ocall y a vaila ble res o urces.  
7. 2  
Cli nic al L a b or at or y Assess me nts  
7. 2. 1  He m at ol o g y  
Bl o o d will be o btai ne d a n d se nt t o t he cli nical site he mat ol o g y la b f or  co m plete 
bl o o d c o u nt ( he m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt, 
w hite bl o o d cell differe ntial, a n d platelet c o u nt) a n d C -reacti ve pr otei n ( CR P ) as 
per ti me a n d e ve nts ta ble (secti o n 8. 0).  

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7. 2. 2  Bl o o d C he mistr y Pr ofile  
Bl o o d will be o btai ne d a n d se nt t o t he cli nical site c he mistr y la b f or deter mi nati o n 
of  ser u m  creati ni ne,  t otal  bilir u bi n,  al b u mi n,  lactate  de h y dr o ge nase,  a n d  t he 
f oll o wi n g as dee me d necessar y per S O C : s o di u m, p otassi u m, c hl ori de, bicar b o nate, 
gl uc ose, bl o o d urea nitr o ge n , as partate a mi n otra nsferase, ala ni ne a mi n otra nsferase, 
a n d al kali ne p h os p hatase.  
7. 2. 3  HI V vir al l o a d a n d C D 4 c o u nt 
Will be assesse d f or all HI V -i nfecte d s u bjects. 
7. 2. 4  He p atitis B ser ol o gies  
He patitis  B  s urface  a nti ge n  will be  assesse d f or  all  HI V  ne gati ve  s u bjects  at  
baseli ne.  
7. 2. 5  Pre g n a nc y Test  
A  uri ne  pre g na nc y  test  will  be  o btai ne d  fr o m  fe male  s u bjects  w h o  are  of  
c hil d beari n g a ge pri or t o t heir partici pati o n i n t he st u d y. 
7. 3  
Q u alit y of life assess me nt  
S y m pt o ms a n d q ualit y of life will be assesse d b y t he M C D s y m pt o m sc ore a n d  
P R O MI S -Prefere nce , as a da pte d f or U N C Pr oject Mala wi pre vi o usl y. 
7. 4  
C orrel ati ve St u dies  
We pla n t o c o n d uct c orrelati ve st u dies , i ncl u di n g viral a n d h ost ge n o mics ( of t he 
t u m or sa m ple o nl y), c yt o ki ne st u dies , a n d K S H V viral l oa d. H ost g e n o mic st u dies 
will be c o m plete d i n t he Vir o n o mic c ore at U N C C ha pel Hill fr o m f or mali n-fi xe d 
paraffi n -e m be d de d  bi o ps y  s peci me ns  a n d  will  f oc us  o n  b ot h  t he  mali g na nt  
plas ma blasts as well as t he s urr o u n di n g t u m or micr oe n vir o n me nt , b ut n o s pecific 
ger mli ne m utati o n testi n g will be c o m plete d. T his bi o ps y is sta n dar d of care a n d is 
re q uire d f or dia g n osis a n d e ntr y i nt o t his st u d y. If i ns ufficie nt tiss ue is a vaila ble, 
s u bjects ca n still partici pate i n t he cli nical trial. Viral ge n o mic st u dies will be 
c o n d ucte d  fr o m  t he  sa me  bi o ps y  s peci me n  or  fr o m  plas ma  sa m ples  ta ke n  f or  
c yt o ki ne st u dies as o utli ne d bel o w. 
 
C yt o ki ne st u dies will re q uire bl o o d dra ws of 1 0 m L  ( 2 he pari n t u bes se parate d i nt o 
plas ma a n d P B M Cs) a n d 1 t u be ( 5 m L) wit h citrate  at baseli ne, mi d-treat me nt ( da y 
1 5), e n d - of-treat me nt ( da y 2 9), first f oll o w- u p ( 1 2 wee ks)after start of treat me nt,  
a n d at all l o n g ter m f oll o w u p visits. Sa m ples will be st ore d at - 8 0 ℃. 
 

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Viral a n d h ost  ge n ot y pi n g  
X  
 
 
 
 
Uri ne pre g na nc y test  
X 1 8  
 
 
 
 
He patitis B  (f or HI V-ne gati ve patie nts)  
X  
 
 
 
 
C D 4 a n d HI V R N A  (if HI V p ositi ve) 
X  
 
 
 
X 1 9  
 
1 Scree ni n g assess me nts m ust be c o m plete d wit hi n 2 1 da ys pri or t o st u d y e nr oll me nt.  
 
2 A wi n d o w of +/ - 7 da ys will a p pl y t o all st u d y visits; h o we ver, l y m p h n o de meas ure me nts m ust ta ke place pri or t o t hat c ycle’s treat me nt.  
 
3 E n d- of -treat me nt visit s h o ul d occ ur 7- 1 4 da ys fr o m fi nal d ose of c he m ot hera p y.  A s u bject w h o is bei n g wit h dra w n f or disease pr o gressi o n or f or ot her reas o ns 
(e. g. u nacce pta ble t o xicit y, etc.) s h o ul d c o m plete a n e n d of treat me nt visit. 
 
4 L o n g ter m f oll o w -u p will occ ur e ver y 3 m o nt hs u ntil 2 4 m o nt hs after t he start of treat me n t u nless ot her wise n ote d. 
 
5 After t he i nitial  visit ( c o m pre he nsi ve  hist or y a n d p h ysical e xa m ) s u bse q ue nt visits will a d dress a f oc use d hist or y a n d p h ysical e xa m.  
 
6 All c o nc o mita nt me dicati o ns will be rec or d e d.  
 
7 See A p pe n di x E. E C O G Perf or ma nce Stat us  
 
8p er N CI C T C A E v 5. 0 f or n otati o n of baseli ne t o xicit y . Assess fr o m i nitial visit t hr o u g h  first f oll o w-u p visit ( 1 2 wee ks ) a n d a gai n at t he fi nal f oll o w u p visit visit 
( 2 4 m o nt hs). 
 
9 Arc hi v al a n d/ or fres h sa m ple . 
 
1 0 S ur vi val will be assesse d at eac h visit t hr o u g h o ut t he d urati o n of treat me nt, f oll o w u p, a n d l o n g ter m f oll o w u p.  
 
1 1 S u bjects wit h l o w ris k disease will recei ve rit u xi ma b at 3 7 5 m g/ m 2 wee kl y f or 4 wee ks. Hi g h ris k s u bjects will recei ve rit u xi ma b  at 3 7 5 m g/ m 2 a n d et o p osi de at 
1 0 0 m g/ m 2 wee kl y f or 4 wee ks.  
 
1 2.Q ualit y of life assess me nt i ncl u des P R O MI S  Gl o bal 1 0,  M C D -S S a n d Q o L will be assesse d t hr o u g h f oll o w u p, a n d at 2 4 m o nt hs d uri n g l o n g ter m f oll o w u p. 
Q o L will als o be assesse d  at t he ti me of a n y rela pse.  
 

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1 3 O mitte d if n o baseli ne a b n or malities o n c hest x -ra y a n d a b d o mi nal ultras o u n d. 
 
1 4 He ma tol o g y assess me nts i ncl u de he m o gl o bi n, w hite bl o o d cell c o u nt, w hi te bl o o d cell differe ntial, a n d plat elet c o u nt. Bl o o d c he mistr y assess me nts i ncl u de 
ser u m creati ni ne, t otal bilir u bi n, al b u mi n, a n d t he f oll o wi n g as dee me d necessar y per S O C : s o di u m, p otassi u m, c hl ori de, bicar b o nate, gl uc ose, bl o o d urea nitr o ge n, 
as partate a mi n otra nsferase, ala ni ne a mi n otra nsferase, a n d al kali ne p h os p hatase.  See t he T & E ta ble f or w he n l actate de h y dr o ge nase  is meas ure d. 
 
1 5 If a patie nt has bee n teste d f or he m o gl o bi n wit hi n 1 m o nt h of e nr oll me nt a n d recei ve d a n d bl o o d tra nsf usi o n d ue t o l o w he m o gl o bi n, t he n t he ori gi nal test wi ll 
dictate treat me nt gr o u p  ( hi g h vs l o w ris k). 
 
1 6 He m o gl o bi n a n d platelet c o u nt will be assesse d per S O C d uri n g treat me nt .  
 
1 7  Bl o o d sa m ple f or c orrelati ves will i ncl u de assess me nts of C -reacti ve pr otei n, K S H V viral l oa d fr o m plas ma a n d P B M Cs , a n d c yt o ki ne le v els ( I L-6, I L -1 0, I L -
2, T N F α, I N Fγ) . K S H C ge n ot y pi n g will occ ur o n t he first dra w o nl y. Bl o o d dra ws will be t w o 1 0 m L  t u bes ( 2 he pari n t u bes se parate d i nt o plas ma a n d P B M Cs) 
a n d 1 t u be ( 5 m L) wit h citrate) . C orrelati ve bl o o d sa m ples c ollecte d d uri n g l o n g ter m f oll o w u p will be st ore d a n d a nal yze d  
 
1 8 I n w o me n u n der 6 0 years of a ge, re q uire d wit hi n 3 da ys of start of treat me nt. 
 
1 9 At 1 2 a n d 2 4 m o nt h l o n g ter m f oll o w u p visits.

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8. 2  
H a n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Rese arc h  
Bi os peci me ns  c ollecte d  f or  t his  st u d y  will  be  st ore d  i n  t he  L C C C  Tiss ue 
Pr oc ure me nt Facilit y ( T P F) , or if nee de d, i n a sec ure off-site st ora ge facilit y. All 
bi os peci me n sa m ples will be o btai ne d i n acc or da nce wit h pr oce d ures o utli ne d i n 
t he L C C C 1 9 5 0  St u d y La b orat or y Ma n ual a n d st ore d i n c o ntai ners wit h c o ntr olle d 
access. Eac h sa m ple will be assi g ne d a u ni q ue c o de n u m ber a n d n o i de ntifia ble 
pers o nal healt h i nf or mati o n ill be o n t he s peci me n la be l. I nf or mati o n a b o ut t he 
s u bject’s disease will be li n ke d t o t he s peci me ns st ore d i n t he re p osit or y data base. 
T P F -ass ociate d researc h staff, L C C C Bi oi nf or matics staff w h o s u p p ort t he T P F 
data base a n d t he L C C C Data Ware h o use, a n d researc hers wit h I R B -a p pr o val f or 
access t o P HI f or eac h s u bject i n t his st u d y will be a ble  t o li n k s peci me ns t o rele va nt 
me dical i nf or mati o n. S o me res ults fr o m la b orat or y a nal yses t hat occ urre d d uri n g 
t he s u bject’s  partici pati o n  i n  t he  cli nical  st u d y  ma y  als o  be  i ncl u de d.  T his  
i nf or mati o n  ma y  be  i m p orta nt  f or  u n dersta n di n g  h o w  t he  s u bject’s  ca ncer 
de vel o pe d a n d res p o n de d t o treat me nt. 
St or a ge Ti me: 
•  T he bi os peci me n will be use d first a n d f ore m ost f or researc h p ur p oses o utli ne d 
wit hi n t he c o nfi nes of t his pr ot oc ol. Sa m ples will be discar de d/ destr o ye d after 
rele va nt data are c ollecte d f or t his st u d y, u nless c o nse nt was o btai ne d fr o m t he 
s u bject t o use tiss ue f or ot her researc h p ur p oses (e. g., T P F c o nse nt f or m was si g ne d 
b y  t he  s u bject).   I n  t his  circ u msta nce,  t here  is  n o  ti me  li mit  o n  h o w  l o n g  
bi os peci me ns ma y be st ore d.  
 
•  T he i n vesti gat or m ust a gree t o a bi de b y p olicies a n d pr oce d ures of t he T P F facilit y 
a n d si g n a letter of researc h a gree me nt f or et hical a n d a p pr o priate c o n d uct of t heir 
researc h t hat utilizes s peci me ns o btai ne d fr o m t he T P F facilit y (e. g., u se of left o ver 
s peci me ns will re q uire a pr ot oc ol o utli ni n g t he researc h pla n f or bi os peci me n use).  
 
C o m pli a nce St ate me nt  
Bi os peci me n c ollecti o n f or t his st u d y will be c o n d ucte d i n f ull acc or da nce t o all 
a p plica ble U N C researc h p olicies a n d p r oce d ures a n d all a p plica ble fe deral a n d 
state  la ws  a n d  re g ulati o ns, i ncl u di n g  4 5  C F R  4 6  a n d  t he  Healt h  I ns ura nce  
P orta bilit y a n d Acc o u nta bilit y Act Pri vac y R ule. A n y e pis o de of n o nc o m plia nce 
will be d oc u me nte d. 
 
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
o btai n c o nse nt a n d asse nt ( u nless a wai ver is gra nte d), a n d will re p ort u ne x pecte d 
pr o ble ms i n acc or da nce wit h U N C I R B P olicies a n d Pr oce d ures a n d all fe deral 
re q uire me nts. C ollecti o n, rec or di n g, a n d re p orti n g of data will be acc urate a n d will 
e ns ure t he pri vac y, healt h, a n d welfare of researc h s u bjects d uri n g a n d after t he 
st u d y.  

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8. 3  
Assess me nt of S afet y  
A n y s u bject w h o recei ves at least o ne d ose of 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  s u bject 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.  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 5. 0.   
8. 4  
Assess me nt of Effic ac y  
All  patie nts  wit h  meas ura ble  disease  w h o  ha ve  recei ve d  at  least  o ne  d ose  of  
treat me nt a n d ha ve t heir disease re-e val uate d will be e val ua ble f or assess me nt of 
efficac y e n d p oi nts. T he pla n ne d disease meas ure me nts are t o occ ur at baseli ne, da y 
1 5, e n d- of-treat me nt, a n d o n l o n g- ter m f oll o w-u p.  
8. 4. 1  T u m or Me as ure me nt  
See 7. 1. 7  f or details of t u m or meas ure me nt a n d res p o nse assess me nt. 
9. 0  
A D V E R S E E V E N T S  
9. 1  
Defi niti o n s  
9. 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 s u bject or 
cli nical i n vesti gati o n s u bject a d mi nistere d a n i n vesti gati o nal 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 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 me dici nal pr o d uct, w he t 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  a 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 s uc h.  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 t he 
i n vesti gat or dee ms it attri b uta ble t o t he st u d y t hera p y. 
9. 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 i n vesti gati o nal pr o d uct 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.  An S A R i m plies a 
lesser de gree of certai nt y a b o ut ca usalit y t ha n a n a d verse reacti o n, w hic h mea ns a n y A E 
ca use d b y a n i n vesti gati o nal pr o d uct.   
 
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  i n vesti gati o nal  pr o d uct 
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 urse of t he disease u n der i n vesti gati o n, 

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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 
deter mi ni n g if a st u d y dr u g ca use d t he A E i ncl u de: 
•  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 i n vesti gati o nal pr o d uct 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  
i n vesti gati o nal  pr o d uct 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 ne 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 i n vesti gati o nal pr o d uct 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 i n vesti gati o nal pr o d uct 
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. 
9. 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 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 n vesti gat or’s Br oc h ure as occ urri n g wit h a class of dr u gs /i n vesti gati o nal pr o d uct 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 pr o d uct u n der i n vesti gati o n.   
9. 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  
•  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  ( 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 a seri o us A E/ S A R ) 
•  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 st u d y 
treat me nt-relate d A E/ S A R 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 s u bject or re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he defi niti o n (for 
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) 

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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 seri o us A E/S A R. 
9. 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 eC R F f or t hat s u bject. 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.  
9. 3  
S A E s or Seri o us S A R s  
9. 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).  
 
F or a n y ot her e x perie nce or c o n diti o n t hat meets t he defi niti o n of a n S A E or a  seri o us S A R, 
rec or di n g of t he e ve nt 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.  
9. 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 d oc u me nte d a n d t he N C C N pr oject ma na ger n otifie d of 
t he e ve nt/reacti o n via e mail wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. 
9. 4  
A d verse E ve nt Re p orti n g  
9. 4. 1  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  U N C I R B p olic y usi n g t he I R B’s we b -base d re p orti n g  
s yste m 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. 
  
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 3 0 da ys  of t he s u bject’s last d ose of st u d y dr u g 
s h o ul d be rec or de d as S A Es.  T he s u bject is t o be disc o nti n ue d i m me diatel y 
fr o m t he st u d y. 
•  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.  

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•  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 U N C st u d y c o or di nat or. 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 in 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.   
9. 5  
D at a a n d S afet y M o nit ori n g Pl a n 
T he st u d y PI will pr o vi de c o nti n u o us m o nit ori n g of s u bject 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 B oar d  ( D S MB).  
 
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, a n d i n 
c o ns ultati o n wit h t he st u d y Bi ostatisticia n. T hese meeti n gs will i ncl u de  t he i n vesti gat ors 
as  well  as  pr ot oc ol  n urse s,  cli nical  researc h  ass ociates,  re g ulat or y  ass ociates,  data  
ma na gers ,  bi ostatisticia ns,  a n d  a n y  ot her  rele va nt  pers o n nel  t he  st u d y  PI  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, et c. 
 
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  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  D S M B .   
 
T he U N C L C C C  D S M B 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 U N C P R C .  
T he  st u d y 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 s u bject s treate d 
2.  S i 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.  P reli mi nar y res p o nse data 
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 fr o m t he D S MB re vie w will be disse mi nate d b y me m o t o t he st u d y PI, U N C P R C, 
a n d U N C I R B.   
1 0. 0  S T A TI S TI C A L C O N SI D E R A TI O N S  
1 0. 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, pr os pecti ve, p hase II cli nical trial f or safet y a n d efficac y of ris k -
stratifie d treat me nt wit h rit u xi ma b +/- c he m ot hera p y f or M C D. Eli gi ble patie nts will be 
e nr olle d a n d treate d acc or di n g t o t he st u d y sc he ma . Hi g h -ris k patie nts ( defi ne d as patie nts 
wit h  E C O G  perf or ma nce  stat us  > 2  or  he m o gl o bi n  < 8  g/ d L  d uri n g  scree ni n g  or  
e nr oll me nt )9 ,1 0 ,1 3 -1 6 will recei ve f o ur wee kl y d oses of rit u xi ma b ( 3 7 5 m g/ m 2) a n d et o p osi de 

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1 0. 4  
D at a A n al ysi s Pl a ns 
1 0. 4. 1  Pri m ar y O bjecti ve: T o descri be t he safet y, as deter mi ne d b y t he rate of G ra de ≥3 
n o n- he mat ol o gic A Es a n d treat me nt -relate d m ortalit y, of a ris k-a dj uste d a p pr oac h 
t o t he treat me nt of M C D wit h rit u xi ma b ( 3 7 5 m g/ m2 wee kl y f or f o ur wee ks) +/ - 
et o p osi de ( 1 0 0 m g/ m 2 wee kl y f or f o ur wee ks) i n Mala wi.   
T he rate will be esti mate d f or i n di vi d ual A Es a n d a s u m mati o n of G ra de ≥3 n o n-
he mat ol o gic A Es will be esti mate d al o n g  wit h a 9 5 % c o nfi de nce i nter val.  
 
T he  rate  of  treat me nt -relate d  m ortalit y  will  be  esti mate d  al o n g  wit h   a  9 5 % 
c o nfi de nce i nter val ar o u n d t he p oi nt esti mate. 
1 0. 5  
Sec o n d ar y O bjecti ves   
1 0. 5. 1  T o better c haracterize M C D prese ntati o n i n Mala wi.  
 
Basic  de m o gra p hics  a n d  baseli ne  la b orat or y  val ues  will  be  s u m marize d  usi n g  
descri pti ve statistics  (i.e., mea ns, me dia ns, a n d varia bilit y meas ures f or c o nti n u o us 
varia ble; rates a n d pr o p orti o ns f or bi nar y varia bles).  
1 0. 5. 2  T o descri be t he efficac y of t he ris k -a dj uste d a p pr oac h as deter mi ne d b y cli nical a n d 
ra di ol o gic res p o nse rates, 9 0- da y, o ne-year , a n d t w o-year E F S a n d O S . 
 
A n e ve nt f or E F S is eit her rela pse   (defi ne d  as “ M C D attac k” i n t he I ncl usi o n 
Criteria (secti o n 4. 1) ), refract or y disease, l ost-t o-f oll o w-u p ( L T F U) , or deat h . We 
will c o nsi der patie nts L T F U  if t he y ca n n ot be c o ntacte d b y p h o ne f or t hree m o nt hs. 
Gi ve n t he hi g h m ortalit y ass ociate d wit h M C D a n d pre vi o usl y p u blis he d literat ure 
s u p p orti n g  a str o n g ass ociati o n bet wee n L T F U a n d m ortalit y i n S S A, we will 
c o nsi der L T F U as a fail ure e ve nt f or b ot h E F S a n d O S. 4 3 Rela pse  f or p ur p oses of 
t his st u d y will be defi ne d as rec urre nce of a n “ M C D attac k” (I ncl usi o n Criteria; 
secti o n 4. 1) re q uiri n g re-i nitiati o n of treat me nt, wit h a str o n g prefere nce f or bi o ps y-
pr o ve n rec urre nce  w he ne ver p ossi ble. We will c o n d uct s ur vi val a nal ysis usi n g 
Ka pla n -Meier  met h o ds.  Ra di ol o gic res p o nse will  be  assesse d  i n  parallel  wit h  
cli nical res p o nse wit h res p o nse criteria defi ne d i n secti o n 7. 1. 7. We will assess t he 
pr o g n ostic  val ue  of  ra di ol o gic  res p o nse  f or E F S  a n d  O S  i n  C o x  pr o p orti o nal  
hazar ds m o del. 1 0 ,1 5 ,1 6 
1 0. 5. 3  T o descri be t he safet y, as deter mi ne d b y t he rate of all A Es d uri n g a  ris k-a dj uste d 
a p pr oac h t o treat me nt of M C D i n Mala wi.  
 
All A Es will be descri be d u p t o 3 0 da ys after fi nal d ose of M C D -directe d treat me nt.  
1 0. 5. 4  T o descri be t h e rate of K S e xacer bati o n, as defi ne d b y s y m pt o matic or cli nical 
( der mat ol o gic or visceral or ga n) e xacer bati o n of disease. 
 

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1 1. 3  
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 at 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. All data will be 
c ollecte d a n d e ntere d i nt o e C R Fs  b y researc h c o or di nat ors.  
 
T he  s p o ns or  will  pr o vi de  direct  access  t o  s o urce  data/ d oc u me nts  f or  trial -relate d 
m o nit ori n g,  a u dits,  I n de pe n de nt  Et hics  C o m mittee  a n d  I R B  re vie w,  a n d  re g ulat or y  
i ns pecti o n. As a n i n vesti gat or -i nitiate d st u d y, t his trial will als o be a u dite d b y t he L C C C  
c o m plia nce c o m mittee e ver y 6 or 1 2 m o nt hs. 
 
Pr o visi o n of D at a t o C orrel ati ve Scie ntists  
I de ntificati o n a n d R ole of t he St u d y C o or di nat or ( or ot her na me d r ole) as t he H o nest 
Br o ker 
 
T he st u d y c o or di nat or ( or ot her na me d r ole) will be i n c har ge of c ollecti n g a n d mai ntai ni n g 
all data p oi nts a n d data ma na ge me nt. T he st u d y c o or di nat or s h o ul d ha ve a de q uate trai ni n g 
t o e nter, ma na ge, a n d dei de ntif y data. T he st u d y c o or di nat or will pr o vi de a u ni q ue st u d y 
n u m ber t o eac h e nr olle d s u bject. All d oc u me ntati o n a n d sa m ples will be la bele d wit h t he 
u ni q ue st u d y n u m ber. T he c orrelati ve tea ms will o nl y be pr o vi de d t his u ni q ue st u d y I D 
n u m ber as o p p ose d t o a n y ot her patie nt i de ntifiers. T he cli nical tea m will be t he o nl y pe o ple 
a ble t o access i de ntifia ble data a n d t he st u d y c o or di nat or will be a c o n d uit t o pr o vi de t he 
de- i de ntifie d data t o t he c orrelati ve tea m.  
 
Re q uests f or a data  
I de ntifia ble data will n ot be gi ve n o ut t o a n y c orrelati ve i n vesti gat ors at a n y ti me. U N C 
c orrelati ve I n vesti gat ors ma y as k t he st u d y c o or di nat or f or a s pecific data set, a n d t he st u d y 
c o or di nat or will ret ur n a dei de ntifie d data set. T his data ma y o nl y be use d f or p ur p oses of 
t he st u d y. A n y use ot her t ha n directl y relate d t o t he st u d y m ust be a p pr o ve d b y t he I R B of 
rec or d. If t here is a nee d f or a n i n vesti gat or t o access i de ntifia ble data d uri n g t he st u d y, 
t he n a ne w I R B a p plicati o n will nee d t o be s u b mitted fr o m t hat i n vesti gat or detaili n g t he 
reas o ns nee de d t o access t hat data. T he st u d y c o or di nat or will als o e ns ure t hat c orrelati ve 
res ults are n ot ret ur ne d fr o m t he c orrelati ve tea m t o t he cli nical tea m t o dictate treat me nt 
or  f oll o w -u p decisi o ns u nless  t his is s pecificall y a p pr o ve d b y t he I R B of  rec or d a n d 
deli neate d i n t he cli nical pr ot oc ol.  
 
1 1. 4  
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 s u bject 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.   
1 1. 4. 1  E mer ge nc y M o dific ati o ns  
U N C ma y i m ple me nt a de viati o n fr o m  or c ha n ge of t he pr ot oc ol t o eli mi nate i m me diate 
hazar d(s) t o trial s u bjects wit h o ut pri or a p pr o val/fa v ora ble o pi ni o n fr o m U N C or t heir 
res pecti ve i nstit uti o n’s I R B. 
 

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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 p ers o n nel  wit hi n fi ve b usi ness da ys of ma ki n g t he c ha n ge . 
1 1. 4. 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 L C C C 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 L C C C  Si n gle S u bject E xce pti o ns 
P olic y. 
1 1. 4. 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 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 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  
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: 
 
Pr ot oc ol  De vi ati o ns:  U N C  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(s) 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.  
De viati o ns s h o ul d be s u m marize d a n d re p orte d t o t he I R B at t he ti me of c o nti n ui n g re vie w.  
 
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 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.   
 
U n a ntici p ate d Pr o ble ms : 
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  I R B 
m ust be re p orte d b y t he s t u d y pers o n nel usi n g t he I R B’s we b- base d re p orti n g s yste m.   

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1 1. 5  
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  st u d y PI 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 s u bject, a 
re vise d c o nse nt f or m mi g ht be re q uire d.   
 
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 
I R B f or a p pr o val pri or t o i m ple me ntati o n.   
1 1. 6  
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  c orres p o n de nce  t o  i n vesti gat ors,  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 s u bject 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/i n vesti gati o nal pr o d uct 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 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 yea rs after c o m pleti 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. 
1 1. 7  
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  st u d y PI is res p o nsi ble f or pers o nall y o verseei n g t he treat me nt of all st u d y 
s u bjects.  T he st u d y PI 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 st u d y PI will be res p o nsi ble f or ass uri n g t hat all re q uire d data will be c ollecte d a n d 
e ntere d i n t he e C R Fs. Peri o dic a u diti n g a n d m o nit ori n g of trials will be c o n d ucte d a n d t he 
st u d y PI 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 data 
e ntr y. At st u d y c o m pleti o n, all e C R Fs will be re vie we d b y t he st u d y PI a n d will re q uire  
t heir fi nal si g nat ure t o verif y acc urac y of t he data. 
 
 

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1 2. 0  R E F E R E N C E S  
  
1. Ms ya m b oza K P, Dza malala C, M d o k we C, et al: B ur de n of ca ncer i n Mala wi; 
c o m m o n t y pes, i nci de nce, a n d tre n ds: nati o nal p o p ulati o n -base d ca ncer re gistr y. B M C 
Researc h N otes 5: 1 4 9, 2 0 1 2 
  
2.  Dr y de n-Peters o n S, Me d hi n H, Ke ba b o n ye -P us oe ntsi M, et al: Ca ncer I nci de nce 
f oll o wi n g E x pa nsi o n of HI V Treat me nt i n B ots wa na. P L o S O ne 1 0:e 0 1 3 5 6 0 2, 2 0 1 5 
  
3. Ferla y  J,  S oerj o matara m  I,  Di ks hit  R,  et  al:  Ca ncer  i nci de nce  a n d  m ortalit y  
w orl d wi de: s o urces, met h o ds a n d maj or patter ns i n G L O B O C A N 2 0 1 2. I nt J Ca ncer 
1 3 6: E 3 5 9- 8 6, 2 0 1 5 
  
4. D ollar d S C, B utler L M, J o nes A M, et al: S u bsta ntial re gi o nal differe nces i n h u ma n 
her pes vir us  8  ser o pre vale nce  i n  s u b -Sa hara n  Africa:  i nsi g hts  o n  t he  ori gi n  of  t he  
" Ka p osi's sarc o ma belt". I nt J Ca ncer 1 2 7: 2 3 9 5- 4 0 1, 2 0 1 0 
  
5. Mesri  E A,  Cesar ma n  E,  B os h off  C:  Ka p osi's  sarc o ma  a n d  its  ass ociate d  
her pes vir us. Nat Re v Ca ncer 1 0: 7 0 7- 1 9, 2 0 1 0 
  
6. W H O: Gl o bal Healt h O bser vat or y Data base, 2 0 1 8  
  
7. O kse n he n dler E, D uarte M, S o ulier J, et al: M ultice ntric Castle ma n’s disease i n 
HI V i nfecti o n: a cli nical a n d pat h ol o gical st u d y of 2 0 patie nts. AI D S 1 0: 6 1- 6 7, 1 9 9 6 
  
8. T o m o ka T, Pai nsc ha b M S, M o nt g o mer y N D, et al: A pr os pecti ve descri pti o n of 
HI V -ass ociate d m ultice ntric Castle ma n disease i n Mala wi. Hae mat ol o gica 1 0 4:e 2 1 5 -
e 2 1 7, 2 0 1 9 
  
9. B o wer M, Ne ws o m -Da vis T, Nares h K, et al: Cli nical Feat ures a n d O utc o me i n 
HI V -Ass ociate d M ultice ntric Castle ma n's Disease. J Cli n O nc ol 2 9: 2 4 8 1 - 6, 2 0 1 1 
  
1 0. Gerar d  L,  Berez ne  A,  Galicier  L,  et  al:  Pr os pecti ve  st u d y  of  rit u xi ma b  i n  
c he m ot hera p y- de pe n de nt  h u ma n  i m m u n o deficie nc y  vir us  ass ociate d  m ultice ntric  
Castle ma n's disease: A N R S 1 1 7 Castle ma B Trial. J Cli n O nc ol 2 5: 3 3 5 0 - 6, 2 0 0 7 
  
1 1. Ul dric k T S, P olizz ott o M N, Ale ma n K, et al: Rit u xi ma b pl us li p os o mal d o x or u bici n 
i n HI V-i nfecte d patie nts wit h K S H V-ass ociate d m ultice ntric Castle ma n disease. Bl o o d 
1 2 4: 3 5 4 4- 5 2, 2 0 1 4 
  
1 2. B o wer M, Dalla Pria A, C o yle C, et al: Dia g n ostic criteria sc he mes f or m ultice ntric 
Castle ma n disease i n 7 5 cases. J o ur nal of Ac q uire d I m m u ne Deficie nc y S y n dr o mes 
6 5:e 8 0- e 8 2, 2 0 1 4  
  
1 3. B uc hler T, D u bas h S, Lee V, et al: Rit u xi ma b fail ure i n f ul mi na nt m ultice ntric 
HI V/ h u ma n  her pes vir us  8 -ass ociate d  Castle ma n's  disease  wit h  m ulti or ga n  fail ure:  
re p ort of t w o cases. AI D S 2 2: 1 6 8 5- 1 6 8 7, 2 0 0 6 
  
1 4. Ne u ville  S,  A g bali ka  F,  Ra bia n  C,  et  al:  Fail ure  of  rit u xi ma b  i n  h u ma n  
i m m u n o deficie nc y vir us-ass ociate d m ultice ntric Castle ma n disease. A m J He mat ol 
7 9: 3 3 7- 9, 2 0 0 5 
  
1 5. B o wer M, P o wles T, Willia ms S, et al: Rit u xi ma b i n HI V -ass ociate d m ultice ntric 
Castle ma n disease. A n nals of I nter nal Me dici ne 1 4 7: 8 3 6 -8 3 9, 2 0 0 7  
  
1 6. Ul dric k T S, P olizz ott o M N, Ale ma n K, et al: Rit u xi ma b pl us li p os o mal d o x or u bici n 
i n  HI V-i nfecte d  pateie nts  wit h  K S H V-ass ociate d  m ultice ntric  Castle ma n  disease.  
Bl o o d 1 2 4: 3 5 4 4- 3 5 5 2, 2 0 1 4 
  
1 7. O kse n he n dler E, B o ut b o ul D, Faj ge n ba u m D, et al: T he f ull s pectr u m of Castle ma n 
disease: 2 7 3 patie nts st u die d o ver 2 0 years. Br J Hae mat ol 1 8 0: 2 0 6 -2 1 6, 2 0 1 8  

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1 8. Wa n g H W, Pittal u ga S, Jaffe E S: M ultice ntric Castle ma n disease: W here are we 
n o w? Se mi n Dia g n Pat h ol 3 3: 2 9 4- 3 0 6, 2 0 1 6 
  
1 9. R o h ner E, W yss N, Trelle S, et al: H H V -8 ser o pre vale nce: a gl o bal vie w. S yst Re v 
3: 1 1, 2 0 1 4 
  
2 0. Li S, Bai L, D o n g J, et al: Ka p osi Sarc o ma -Ass ociate d Her pes vir us: E pi de mi ol o g y 
a n d M olec ular Bi ol o g y, i n Cai Q, Y ua n Z, La n K (e ds): I nfecti o us A ge nts Ass ociate d 
Ca ncers: E pi de mi ol o g y a n d M olec ular Bi ol o g y. Si n ga p ore, S pri n ger Nat ure, 2 0 1 7 
  
2 1. De Sa ntis S M, Pa u C -P, Arc hi bal d L K, et al: De m o gra p hic a n d i m m u ne c orrelates 
of  h u ma n  her pes vir us  8  ser o p ositi vit y  i n  Mala wi,  Africa.  I nter nati o nal  J o ur nal  of  
I nfecti o us Diseases 6: 2 6 6- 2 7 1, 2 0 0 2 
  
2 2. U N AI D S: Mala wi C o u ntr y Facts heet, 2 0 1 9 
  
2 3. Ma hr o u g E R, S her -L oc ketz C, Des mirea n M S, et al: Castle ma n’s disease i n t he 
HI V -e n de mic setti n g. Ca ncer Ma na ge me nt a n d Researc h 1 0: 4 5 5 3 - 4 5 6 3, 2 0 1 8 
  
2 4. Patel  M,  P hili p  V,  La k ha  A,  et  al:  M ultice ntric  Castle ma n’s  Disease,  
I m m u n o pat h ol o g y a n d I m m u n o m o d ulati o n, 2 0 1 5 
  
2 5. G o pal  S,  Kr ysia k  R,  Li o m ba  N G,  et  al:  Earl y  e x perie nce  after  de vel o pi n g  a  
pat h ol o g y  la b orat or y  i n  Mala wi,  wit h  e m p hasis  o n  ca ncer  dia g n oses.  P L o S  O ne  
8:e 7 0 3 6 1, 2 0 1 3 
  
2 6. Kai mila B, va n der Gr o n de T, Kas o n ka nji E, et al: S h ort C o m m u nicati o n: C D 4 
C o u nt a n d HI V R N A Tre n ds f or HI V -Ass ociate d L y m p h o pr oliferati ve Dis or ders i n 
Mala wi. AI D S Researc h a n d H u ma n Retr o vir uses 3 3: 1 0 4 5- 1 0 4 7, 2 0 1 7 
  
2 7. West m orela n d K D, Sta nle y C C, M o nt g o mer y N D, et al: H o d g ki n l y m p h o ma, HI V, 
a n d  E pstei n-Barr  vir us  i n  Mala wi:  L o n git u di nal  res ults  fr o m  t he  Ka m uz u  Ce ntral 
H os pital L y m p h o ma st u d y. Pe diatr Bl o o d Ca ncer 6 4, 2 0 1 7 
  
2 8. P o wles T, Ste b bi n g J, Baze os A, et al: T he r ole of i m m u ne s u p pressi o n a n d H H V -
8 i n t he i ncreasi n g i nci de nce of HI V -ass ociate d m ultice ntric Castle ma n's disease. A n n 
O nc ol 2 0: 7 7 5- 9, 2 0 0 9 
  
2 9. M yl o na E E, Bara b o utis I G, Le ka kis LJ, et al: M ulitce ntric Castle ma n’s disease i n 
HI V i nfecti o n: a s yste matic re vie w of t he literat ure. AI D S Re vie ws 1 0: 2 5 - 3 5, 2 0 0 8 
  
3 0. Gerar d L, Mic h ot J -M, B urc heri S, et al: Rit u xi ma b decreases t he ris k of l y m p h o ma 
i n patie nts wit h HI V-ass ociate d m ultice ntric Castle ma n disease. Bl o o d 1 1 9: 2 2 2 8 - 2 2 3 3, 
2 0 1 2 
  
3 1. Dalla  Pria  A,  Pi nat o  D,  R oe  J,  et  al:  Rela pse  of  H H V 8 -p ositi ve  m ultice ntric  
Castle ma n disease f oll o wi n g rit u xi ma b -base d t hera p y i n HI V -p ositi ve patie nts. Bl o o d 
1 2 9: 2 1 4 3- 2 1 4 7, 2 0 1 7 
  
3 2. Ri bera J M, Ori ol A, M or ga des M, et al: Safet y a n d efficac y of c ycl o p h os p ha mi de, 
a dria m yci n,  vi ncristi ne,  pre d nis o ne  a n d  rit u xi ma b  i n  patie nts  wit h  h u ma n  
i m m u n o deficie nc y vir us-ass ociate d diff use lar ge B -cell l y m p h o ma: res ults of a p hase 
II trial. Br J Haemat ol 1 4 0: 4 1 1- 9, 2 0 0 8 
  
3 3. Ka pla n L D, Lee J Y, A m bi n der R F, et al: Rit u xi ma b d oes n ot i m pr o ve cli nical 
o utc o me i n a ra n d o mize d p hase 3 trial of C H O P wit h or wit h o ut rit u xi ma b i n patie nts 
wit h HI V -ass ociate d n o n -H o d g ki n l y m p h o ma: AI D S -Mali g na ncies C o ns orti u m Trial 
0 1 0. Bl o o d 1 0 6: 1 5 3 8- 4 3, 2 0 0 5 
  
3 4. W H O: W H O M o del List of Esse ntial Me dici nes, 2 0 1 7  

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3 5. H ut u bess y  R,  C his h ol m  D,  Ta n -T orres  E dejer  T,  et  al:  Ge neralize d  c ost -
effecti ve ness  a nal ysis  f or  nati o nal -le vel  pri orit y-setti n g  i n  t he  healt h  sect or.  C ost  
Effecti ve ness a n d Res o urce All ocati o n 1: 8, 2 0 0 3 
  
3 6. H ossei ni p o ur M C, Ka n g M, Kr o w n S E, et al: As-Nee de d Vs I m me diate Et o p osi de 
C he m ot hera p y  i n  C o m bi nati o n  Wit h  A ntiretr o viral  T hera p y  f or  Mil d -t o-M o derate 
AI D S -Ass ociate d Ka p osi Sarc o ma i n Res o urce -Li mite d Setti n gs: A 5 2 6 4/ A M C - 0 6 7 
Ra n d o mize d Cli nical Trial. Cli n I nfect Dis 6 7: 2 5 1 - 2 6 0, 2 0 1 8 
  
3 7. B or o k M, M oser C, Ca m p bell T, et al: S u peri orit y of paclita xel c o m pare d t o eit her 
ble o m yci n/ vi ncristi ne or et o p osi de as i ntial c he m ot hera p y f or a d va nce d AI D S -K S i n 
res o urce-li mite d setti n gs: a m ulti nati o nal r na d o mize d trial of t he A C T G a n d t he AI D S 
Mali g n a nc y C o ns orti u m. Prese nte d at t he I nter nati o nal AI D S C o nfere nce, A mster da m, 
t he Net herla n ds, 2 0 1 8 
  
3 8. Sc ott  D,  Ca bral  L,  Harri n gt o n  WJ:  Treat me nt  of  HI V -ass ociate d  m ultice ntric  
Castle ma n’s disease wit h oral et o p osi de. A merica n J o ur nal of He mat ol o g y 6 6: 1 4 8 -1 5 0, 
2 0 0 1 
  
3 9. O kse n he n dler E, B o ula n ger E, Gallicier L, et al: Hi g h i nci de nce of Ka p osi sarc o ma -
ass ociate d her pes vir us -relate d n o n-H o d g ki n l y m p h o ma i n patie nts wit h HI V i nfecti o n 
a n d m ultice ntric Castle ma n disease. Bl o o d 9 9: 2 3 3 1- 2 3 3 6, 2 0 0 2 
  
4 0. Pai nsc ha b M S, Kas o n ka nji E, Z uze T, et al: Mat ure o utc o mes a n d pr o g n ostic 
i n dices  i n  diff use  lar ge  B-cell  l y m p h o ma  i n  Mala wi:  a  pr os pecti ve  c o h ort.  Br  J  
Hae mat ol 1 8 4: 3 6 4- 3 7 2, 2 0 1 9  
  
4 1. va n R hee F, Gree n wa y A, St o ne K: Treat me nt of I di o pat hic Castle ma n Disease. 
He mat ol O nc ol Cli n N ort h A m 3 2: 8 9 - 1 0 6, 2 0 1 8 
  
4 2. va n R hee F, R ot h ma n M, H o K F, et al: Patie nt -re p orte d O utc o mes f or M ultice ntric 
Castle ma n's Disease i n a Ra n d o mize d, Place b o -c o ntr olle d St u d y of Silt u xi ma b. Patie nt 
8: 2 0 7- 1 6, 2 0 1 5 
  
4 3. Sta nle y  C C,  West m orela n d  K D,  Iti m u  S,  et  al:  Q ua ntif yi n g  bias  i n  s ur vi val  
esti mates res ulti n g fr o m l oss t o f oll o w -u p a m o n g c hil dre n wit h l y m p h o ma i n Mala wi. 
Pe diatr Bl o o d Ca ncer 6 4:e 2 6 3 7 0, 2 0 1 7 
  
4 4. Ha n mer J, De witt B, Y u L, et al: Cr oss -secti o nal  vali dati o n of  t he P R O MI S-
Prefere nce sc ori n g s yste m. P L o S O ne 1 3:e 0 2 0 1 0 9 3, 2 0 1 8 
 
 
 

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•  
A d diti o n al di a g n ostic w or k u p.  
•  
A nti bi otic esc al ati o n.  
o  Pi per acilli n -T az o b act a m  4. 5 g  I V  T D S  O R  Mer o pe ne m  1 g  I V  T D S  
( de pe n di n g o n a v ail a bilit y). 
•  
A d di n g a ntif u n g al t her a p y (i.e. Fl uc o n az ole 4 0 0 m g O D). 
 
C he m ot her a py d ose s h o ul d be m o difie d wit h ne xt c he m ot her a py cycle if re q uire d by 
st u dy pr ot oc ol. 
 
C o nsi der  a nti bi otic  pr o p hyl a xis  t o  preve nt  ne utr o pe nic  fever  wit h  s u bse q ue nt  
c he m ot her a py cycles : 
•  
Ci pr ofl o x aci n 5 0 0 m g P O B D. 
 
M o nit ori n g of ser u m cre ati ni ne s h o ul d be re pe ate d after 5 d ays i n p atie nts receivi n g 
ge nt a mici n.  
 
 
 

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1 3. 1. 2  A p pe n di x B. U N C Pr oj ect M al a wi A ntie metic S O P  
* A ntie metic ris k deri ve d fr o m m ost rece nt A S C O Cli nic al Pr actice G ui deli nes o n 
A ntie metics  
See t a ble: htt ps:// w w w.asc o. or g/sites/ ne w- w w w.asc o. or g/files/c o nte nt-files/ 2 0 1 7- E metic -
Ris k - A nti ne o plastic- A ge nts-c hart. p df 
 
Pr o p h yl a xis a n d as -nee de d a ntie metic rec o m me n d ati o ns f or U N C Pr oject M al a wi.  
 
A ntie metic Ris k  
Treat me nt  
D ose o n da y 1  
D ose ot hers  
Hi g h ( D o x o r u bici n 
+ 
C ycl o p h o p ha mi de  
c o m b o) 
Gra nisetr o n  
O R  
O n da nsetr o n  
2 m g P O or 1 m g I V  
 
8 m g P O Q 6 h o urs x 2 d oses  
or 8 m g I V x 1  
 
De xa met has o ne  
1 2 m g P O or I V  
 
+/ - Ola nza pi n e  
1 0 m g P O  
1 0 m g P O da ys 2 -4  
Hi g h (all ot hers)  
Gra nisetr o n  
O R  
O n da nsetr o n  
2 m g P O or 1 m g I V  
 
8 m g P O Q 6 h o urs x 2 d oses  
or 8 m g I V x 1  
 
De xa met has o ne  
1 2 m g P O or I V  
8 m g P O or I V da ys 
2 -4  
+/ - Ola nza pi n e  
1 0 m g P O  
1 0 m g P O da ys 2 -4  
M o derate  
Gra nisetr o n  
O R  
O n da nsetr o n  
2 m g P O or 1 m g I V  
 
8 m g P O Q 6 h o urs x 2 d oses  
or 8 m g I V x 1  
 
De xa met has o ne  
8 m g P O or I V  
8 m g P O or I V da ys 
2, 3  
L o w  
Gra nisetr o n  
O R  
O n da nsetr o n  
2 m g P O or 1 m g I V  
 
8 m g P O Q 6 h o urs x 2 d oses  
or 8 m g I V x 1  
 
De xa met has o ne  
 
8 m g P O or I V  
 
 

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1 3. 1. 3  A p pe n di x C. U N C Pr oject M al a wi E xt r a v as ati o n S O P 
 
I. 
P ur p ose  
 
E xtra vasati o n occ urs w he n s o me or all t he c he m ot hera p y i nf usi o n fl o ws i nt o t he tiss ues of 
t he s urr o u n di n g area of ca n n ula i nserti o n. T he de gree of e xtra vasati o n will de pe n d o n t he 
site a n d a m o u nt i nfiltrate d c o nce ntrati o n a n d nat ure of t he a ge nt. Necr osis, da ma ge t o 
te n d o ns, ner ves a n d j oi nts ma y occ ur. T he p ur p ose of t his S O P is t o sta n dar dize t he 
rec o g niti o n,  pre ve nti o n,  a n d  ma na ge me nt  of  e xtra vasati o n  a m o n g  ca ncer  patie nts  
recei vi n g c he m ot hera p y at U N C Pr oject Mala wi.  
 
II. 
Sc o pe  
 
T his S O P a p plies t o U N C Pr oject Mala wi  staff i n v ol ve d i n partici pa nt ma na ge me nt of 
e xtra vasti o n. Staff i ncl u de researc h n urses, researc h cli nicia ns, a n d me dical officers. T his 
pr oce d ure a p plies t o all NI H s p o ns ore d Net w or k st u dies ( A M C, H P T N, H V T N, A C T G, 
I M P A A CT, M T N) a n d n o n- net w or k st u dies .   
 
III. 
All o w a ble E xce pti o ns  
 
T his S O P is mea nt t o be f oll o we d wit h o ut de viati o n. H o we ver, it is a n all o wa ble e xce pti o n 
t o f oll o w pr oce d ures s pecifie d i n a pr ot oc ol or St u d y S pecific Pr oce d ure Ma n ual ( S S P) t hat 
ma y de viate fr o m t his S O P.  
 
I V. 
Pr oce d ure  
 
A.  Cli nic al Fe at ures of E xtr a v as ati o n  
•  I m me diate s welli n g 
•  Pai n  
•  B ur ni n g 
•  Sti n gi n g 
•  Er yt he ma or s welli n g ar o u n d t he ca n n ula site  
•  Si g ns  of  p o or  fl o w  via  t he  ca n n ula  (e x. resista nce,  p o or  fl o w  rate, a n d/ or 
i na de q uate bac k fl o w of bl o o d) 
•  Se vere pai n or b ur ni n g, re d ness wit h ulcerati o n 4 8- 9 6 h o urs after i nf usi o n 
 
B.  Ris k F act ors f or E xtr a v as ati o n  
•  M ulti ple ca n n ulati o n/ ve ni p u nct ure  sites. A v oi d nee dle i nserti o n distal t o rece nt 
( < 2 4 hrs) ve ni p u nct ure site. 
•  A v oi d p ositi o ni n g  siti n g ca n n ula i n a ntec u bital f ossa, cr ossi n g j oi nts, o verl yi n g 
vital str uct ures (e. g. ner ves or te n d o ns, i n pre vi o usl y irra diate d areas ) 
•  Fra gile vei ns  
•  S w olle n ar ms  
N ote: If y o u ca n n ot fi n d a g o o d vei n get hel p. D o n ot a d mi nister c he m ot hera p y if 
i n d o u bt. 
 
C.  Pre ve nti o n of E xtr a v as ati o n  

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•  Safe p ositi o ni n g of ca n n ula 
•  Fre q ue nt c hec ks o n ca n n ula site a n d fl o w d uri n g c he m ot hera p y a d mi nistrati o n  
•  A d mi nister v esica nts first 
•  A d mi nister b ol us vesica nt t hr o u g h fast r u n ni n g dri p 
•  E d ucati n g t he patie nt o n h o w t o kee p t he ca n n ula pate nt li ke  pr o per p ositi o ni n g 
of t he ha n d 
 
D.  M a n a ge me nt of E xtr a v as ati o n 
•  St o p t he i nf usi o n  
•  As pirate as m uc h of t he dr u g as p ossi ble fr o m t he e xtra vasati o n site via t he 
ca n n ula 
•  I nf or m the d oct or i m me diatel y 
•  Mar k t he area  
•  Re m o ve t he ca n n ula   
•  Ma ke use of t he e xtra vasati o n kit if a vaila ble  
•  A p pl y c ol d pac k re g ularl y f or 2 4 h o ur s ( wit h t he e xce pti o n of  vi nca al kal oi ds, 
o xali plati n w hic h nee d a war m pac k ) 
•  Ele vate  t he li m b 
•  A p pl y 1 % h y dr oc ortis o ne crea m 
•  Re vie w fre q ue ntl y  
•  Use t he ot her li m b if c he m o is t o be c o nti n ue d 
•  C o ns ult plastics tea m if it’s a vesica nt dr u g t hat’s e xtra vasate d  
 
 

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1 3. 1. 4  A p pe n di x D. U N C Pr oject M al a wi H y perse nsiti vit y /I nf usi o n Re acti o n S O P 
 
Ma na ge me nt of rit u xi ma b h y perse nsiti vit y reacti o ns  
Gra de  
S y m pt o ms  
Me dicati o ns  
N ursi n g 
Care  
Rei nf usi o n  
1 ( mil d)  
Itc hi n g 
Fl us hi n g 
Ras h  
Fe vers  
Ri g ors  
Di p he n h y dra mi ne 
2 5 m g I V 
Vital si g ns 
e ver y 1 0 
mi n utes 
u ntil 
res ol uti o n 
of 
s y m pt o ms 
Res u me at 
half t he 
pre vi o us 
rate o nce 
s y m pt o ms 
c o m pletel y 
res ol ve 
2 
( m o derate) 
D ys p nea  
C hest 
ti g ht ness 
Di p he n h y dra mi ne 
2 5 m g I V 
Ra niti di ne 5 0 m g 
I V 
De xa met has o ne 
2 0 m g I V  
3 (se vere)  
Stri d or  
W heezi n g  
Res pirat or y 
distress  
Ge neralize d 
hi ves 
A n gi oe de ma 
H y p ote nsi o n 
n ot res p o nsi ve 
t o fl ui ds 
Decrease d 
res p o nsi ve ness 
Di p he n h y dra mi ne 
2 5 m g I V 
Ra niti di ne 5 0 m g 
I V 
De xa met has o ne 
2 0 m g I V 
N or mal sali ne 1 
L b ol us 
E pi ne p hri ne 0. 3 
m g I M  
Br o nc h o dilat ors 
D o n ot 
res u me 
 
 
 

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