Clinical trial NCT02763319
Conditions: Diffuse Large B-cell Lymphoma
Keywords: Diffuse Large B-cell Lymphoma bendamustine rituximab combination therapy CD19 monoclonal antibody transplant ineligible
Sponsor: Incyte Corporation
Start date: 2016-11-28; Completion date: 2024-06-21
Enrollment: 453 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to compare the safety and efficacy of Tafasitamab with BEN versus RTX with BEN in adult patients with relapsed of refractory DLBCL.

Detailed description:
This is a randomised, two-arm, multicentre, open-label phase II/III efficacy and safety study of Tafasitamab in combination with BEN versus RTX in combination with BEN given to adult patients who have relapsed after or are refractory to at least one but no more than three prior systemic therapies and have failed, or are not candidates for HDC and ASCT, and have thus exhausted their therapeutic options of demonstrated clinical benefit. At least one prior therapy line must have included a CD20-targeted therapy.

Arms: arm 1: Tafasitamab and bendamustine arm 2: Rituximab and bendamustine
Interventions: intervention 1: Rituximab (RTX) intervention 2: Tafasitamab intervention 3: Bendamustine (BEN)
Intervention descriptions: intervention 1: Rituximab: Dose: 375 mg/m2 IV intervention 2: Tafasitamab: Tafasitamab dose: 12 mg/kg intravenously (IV) intervention 3: None

Protocol documents:
Prot_000.pdf: 
Offi ci al   Titl e:  
A  P h as e II/III,   R a n d o  mis e d,   M ulti c e ntr e  St u d y  of   M  O  R 0 0 2 0 8   wit h   B e n d a  m usti n e 
v ers us   Rit u xi  m a b   wit h   B e n d a  m usti n e i n  P ati e nts   wit h   R el a ps e d  or   R efr a ct or y 
Diff us e  L ar g e   B -C ell  L y  m p h o  m a (  R -R   D L  B  C L)   W h o   Ar e   N ot  Eli gi bl e f or   Hi g h -
D os e   C h e  m ot h er a p y (  H  D  C)  a n d   A ut ol o g o us  St e  m -C ell  Tr a ns pl a nt ati o n (  A S  C T) –  
[  B-MI  N  D]  
N  C  T   N u  m b e r:  
N  C T 0 2 7 6 3 3 1 9  
D o c u  m e nt   D at e:  
M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  C T P   A  m e n d  m e nt   N o.  8  1 0 -A pr -2 0 2 4  
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 of  1 3 1  
 
 
 
 
C  LI  NI  C  A  L  T  RI  A  L P  R  O  T  O  C  O  L  
A P h as e II/III,   Ra n d o  mis e d, M ulti c e nt r e   St u d y  of   M  O  R 0 0 2 0 8   wit h 
B e n d a  m usti n e  v e rs us   Rit u xi  m a b   wit h   B e n d a  m usti n e i n P ati e nts   wit h 
R el a ps e d  o r   R ef r a ct o r y   Diff us e   L a r g e   B -C ell   L y  m p h o  m a (  R -  R D  L  B  C  L) W h o 
A r e N ot E li gi bl e f o r H i g h-  Dos e C h e  m ot h e r a p y (  H  D  C) a n d A ut ol o g o us 
S t e  m-  Cell T r a ns pl a nt ati o n (  A S  C  T)   – [  B-MI  N  D ] 
 
 
B ri ef   D es c ri pti o n  of 
St u d y : 
O p e n -l a b el, r a n d o  mis e d tri al t o e v al u at e t h e effi c a c y  a n d s af et y 
of   M  O  R 0 0 2 0 8 wit h b e n d a  m usti n e (  B E  N)  v ers us rit u xi  m a b 
(  R T  X) wit h B E  N i n  a d ult  p ati e nts   wit h R-  R D L  B  C L  
P h as e  of   D e v el o p  m e nt : 
P h as e II/III 
S p o ns o r:  
I n c yt e   C or p or ati o n 
S p o ns o r's   A d d r ess:  
1 8 0 1   A u g usti n e   C ut -Off  
Wil  mi n gt o n,   D E  1 9 8 0 3   U S  A  
St u d y  P r ot o c ol   N u  m b e r:  
M  O  R 2 0 8  C 2 0 4  
I  N  D   N o.: 
1 1 4, 8 5 6  
E u d r a  C  T   N o.:  
2 0 1 4 -0 0 4 6 8 9 -1 1  
D at e  of  P r ot o c ol:  
1 0 -A pr -2 0 2 4  (  V ersi o n 1 1 . 0) 
 
C o nfi d e nti alit y  St at e  m e nt  
T h e  c o n c e pts  a n d i nf or  m ati o n  c o nt ai n e d i n t his  d o c u  m e nt  ar e  c o nsi d er e d  pr o pri et ar y  a n d 
ar e  pr o vi d e d f or t h e e x cl usi v e  us e  of i n v esti g at ors  a n d  ot h er  p ers o ns i n v ol v e d i n t h e st u d y 
w h o  h a v e  a  n e e d t o  k n o  w.  S u bj e ct t o t h e f or e g oi n g, t h e  c o nt e nt  of t his  d o c u  m e nt   m a y  n ot  b e 
dis cl os e d  u nl ess l a  w  or r e g ul ati o ns r e q uir e s u c h  dis cl os ur e,  or I n c yt e   C or p or ati o n  h as  gr a nt e d 
pri or   writt e n  a p pr o v al. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2  of 1 3 1  
I  N  V  E S  TI  G  A  T  O  R' S   A  G  R  E  E  M  E  N  T 
I  h a v e r e a d t h e   M  O  R 2 0 8C 2 0 4  Pr ot o c ol   A  m e n d  m e nt 8  ( d at e d 1 0 -A pr -2 0 2 4 )  a n d  a gr e e t o  c o n d u ct 
t h e st u d y  as  o utli n e d. I  a gr e e t o   m ai nt ai n t h e  c o nfi d e nti alit y  of  all i nf or  m ati o n r e c ei v e d  or 
d e v el o p e d i n  c o n n e cti o n  wit h t his  Pr ot o c ol.  
 
 
 
 
 
( Pri nt e d   N a  m e  of I n v esti g at or) 
 
 
 
 
 
 
 
 
( Si g n at ur e  of I n v esti g at or) 
 
(  D at e) 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 3  of 1 3 1  
P  R  O  T  O  C  O  L   HI S  T  O  R  Y  
V e rsi o n  
D at e  
A  m e n d e d  Pr ot o c ol   C T P  v 1 1. 0  
1 0 -A pr -2 0 2 4  
A  m e n d e d  Pr ot o c ol   C T P  v 1 0. 0  
0 2 -D e c -2 0 2 2  
A  m e n d e d  Pr ot o c ol   C T P  v 9. 0  
2 2 -D e c -2 0 2 1  
A  m e n d e d  Pr ot o c ol   C T P  v 8. 0  
1 4 -F e b -2 0 1 9  
A  m e n d e d  Pr ot o c ol   C T P  v 7. 0  
2 3 -A u g -2 0 1 7  
A  m e n d e d  Pr ot o c ol   C T P  v 6. 0  
2 1 -J ul-2 0 1 7  
A  m e n d e d  Pr ot o c ol   C T P  v 5. 0  
0 5 -A pr -2 0 1 7  
A  m e n d e d  Pr ot o c ol   C T P  v 4. 0  
2 1 -N o v -2 0 1 6  
A  m e n d e d  Pr ot o c ol   C T P  v 3. 0  
0 4 -M ar -2 0 1 6  
A  m e n d e d  Pr ot o c ol   C T P  v 2. 0  
1 8 -D e c -2 0 1 5  
Ori gi n al  Pr ot o c ol   C T P  v 1. 0  
2 5 -N o v -2 0 1 5  
 
A  m e n d e d P r ot o c ol C  T P v 1 1 . 0 (1 0 -A p r -2 0 2 4 ) 
 
O v e r all   R ati o n al e f o r t h e   A  m e n d  m e nt:  
T h e  pri  m ar y  p ur p os e  of t h e a  m e n d  m e nt is t o  u p d at e t h e s p o ns ors hi p fr o  m   M or p h o S ys   A  G t o 
I n c yt e   C or p or ati o n.   
1.  Titl e  P a g e; I n v esti g at o r's   A g r e e  m e nt;  S e cti o n  1,  P r ot o c ol  S y n o psis;  S e cti o n  5,  St u d y 
P u r p os e/  R ati o n al e;  S e cti o n  8. 4,   E n d  of  St u d y;  S e cti o n  1 1. 2,   A d v e rs e   E v e nt  a n d 
S e ri o us   A d v e rs e   E v e nt   R e c o r di n g  a n d   R e p o rti n g;  S e cti o n  1 1. 3,  P r e g n a n ci es; 
S e cti o n  1 3,  St atisti c al   M et h o ds  a n d  Pl a n n e d   A n al ys es ;  S e cti o n  1 4. 4,   R e g ul at o r y  a n d 
Et hi c al   C o nsi d e r ati o ns, I n cl u di n g t h e I nf o r  m e d   C o ns e nt  P r o c ess;  S e cti o n  1 4. 5, 
Q u alit y   C o nt r ol ( St u d y   M o nit o ri n g) ; S e cti o n  1 4. 8,  P u bli c ati o n  P oli c y;  S e cti o n  1 6. 3, 
A p p e n di x   C: O v e r vi e  w  of  p u blis h e d  d at a  o n   N  K  C  C  as  a  p r o g n osti c f a ct o r i n 
D  L  B  C  L  a n d  F  L  
D es c ri pti o n  of  c h a n g e : U p d at e d t h e s p o ns ors hi p fr o  m   M or p h o S ys   A  G t o I n c yt e 
C or p or ati o n . 
R ati o n al e f o r ch a n g e : C h a n g e i n s p o ns ors hi p . 
2.  I n c o r p o r ati o n  of  a d  mi nist r ati v e  c h a n g es. Ot h er  a d  mi nistr ati v e  c h a n g es  h a v e  b e e n 
i n c or p or at e d t hr o u g h o ut t h e  Pr ot o c ol  a n d  ar e  n ot e d i n t h e r e dli n e  v ersi o n  of t h e 
a  m e n d  m e nt. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4  of 1 3 1  
1  P  R  O  T  O  C  O  L S  Y  N  O P SI S  
Titl e  of  St u d y  
A  P h as e II/III,   R a n d o  mis e d,   M ulti c e ntr e  St u d y  of M  O  R 0 0 2 0 8   wit h 
B e n d a  m usti n e  v ers us Rit u xi  m a b   wit h B e n d a  m usti n e i n  P ati e nts   wit h 
R el a ps e d  or   R efr a ct or y   Diff us e  L ar g e   B -C ell  L y  m p h o  m a (  R -R   D L  B  C L) 
W h o   Ar e   N ot  Eli gi bl e f or   Hi g h -D os e   C h e  m ot h er a p y (  H  D  C)  a n d 
A ut ol o g o us  St e  m -C el l  Tr a ns pl a nt ati o n (  A S  C T) –  [B -MI  N  D ] 
P r ot o c ol   N u  m b e r  
M O  R 2 0 8  C 2 0 4  
I  N  D   N u  m b e r 
1 1 4, 8 5 6  
E u d r a  C  T   N u  m b e r  
2 0 1 4 -0 0 4 6 8 9 -1 1  
S p o ns o r  
I n c yt e   C or p or ati o n 
1 8 0 1   A u g usti n e   C ut -Off  
Wil  mi n gt o n,   D E U S  A  1 9 8 0 3  
St u d y  P h as e  
P h as e II/III 
B a c k g r o u n d a n d  St u d y 
R ati o n al e  
D es pit e  a d v a n c es i n t h e first-li n e tr e at  m e nt  of  diff us e l ar g e   B-c ell 
l y  m p h o  m a (  D L  B  C L),  3 0– 4 0  %  of p ati e nts eit h er r el a ps e  or  h a v e r efr a ct or y 
dis e as e.   A p pr o xi  m at el y  5 0  %  of p ati e nts   wit h r el a ps e d or r efr a ct or y (  R-R) 
D L B C L  d o  n ot  a c hi e v e  a l o n g -t er  m r e  missi o n   wit h s u bs e q u e nt t h er a p y  as 
t h e y  eit h er r el a ps e  aft er i nt e nsifi e d  c h e  m ot h er a p e uti c tr e at  m e nt, i n cl u di n g 
hi g h -d os e  c h e  m ot h er a p y (  H  D  C)  a n d  a ut o l o g o us st e  m-c ell tr a ns pl a nt ati o n 
(  A S  C T), or  ar e  n ot  eli gi bl e f or a n i nt e nsifi e d tr e at  m e nt r e gi  m e n. P a ti e nts 
wit h R -R  D L  B  C L  f aili n g i nt e nsifi e d s e c o n d-li n e t h er a p y, or t h os e   w h o  ar e 
i n eli gi bl e f or s u c h t h er a p y, c o nstit ut e  a n  u n  m et   m e di c al  n e e d  as t h e   m e di a n 
o v er all s ur vi v al (  O S) f or t his  p o p ul ati o n is l ess t h a n  o n e  y e ar   wit h  c urr e ntl y 
a v ail a bl e t h er a pi es. 
 
M  O  R 0 0 2 0 8 is  a n  F c -e n h a n c e d ,  h u  m a nis e d,   m o n o cl o n al  a nti b o d y (  m  A b) 
wit h si g nifi c a ntl y  e n h a n c e d  a nti b o d y -d e p e n d e nt  c ell -m e di at e d  c yt ot o xi cit y 
(  A  D  C  C),  a nti b o d y-d e p e n d e nt  c ell -m e di at e d  p h a g o c yt osis (  A  D  C P)  a n d 
dir e ct  c yt ot o xi c  eff e cts ( a p o pt osis)  c o  m p ar e d   wit h its  n o n-e n h a n c e d  
p ar e nt al  a nti b o d y . R es ults  of i n  vitr o  e x p eri  m e nts s u g g est t h at M  O  R 0 0 2 0 8 
l e a ds t o str o n g er   A  D  C  C-m e di at e d t ar g et  c ell l ysis i n  c o  m p aris o n t o 
Rit u xi  m a b (  R T  X)  u n d er  c o n diti o ns i n   w hi c h  n at ur al  kill er (  N  K)  c ells  ar e 
li  mit e d.   B ase d  o n t h e  ass u  m pti o n t h at i n  p ati e nts   wit h l o  w  b as eli n e  n at ur al 
c ell  c o u nt (  N  K  C  C),   N  K  c ell  n u  m b ers  at t h e t u  m o ur sit e   will  n ot  o ut-
n u  m b er t h e  n u  m b er  of t u  m o ur c ells, t h e i n  vitr o  d at a s u p p ort t h e  h y p ot h esis 
t h at   M  O  R 0 0 2 0 8  c o ul d  h a v e  hi g h er t u  m o ur killi n g  c a p a cit y  c o  m p ar e d t o 
rit u xi  m a b i n  p ati e nts   wit h  a  p eri p h er al   N  K  c ell  c o u nt  of  1 0 0 or l ess   N  K 
c ells/ µ L.  M  O  R 0 0 2 0 8  h as s h o  w n  pr eli  mi n ar y  effi c a c y  a n d  a c c e pt a bl e 
t o xi cit y i n p ati e nts   wit h R -R   D L  B  C L, f olli c ul ar l y  m p h o  m a a n d  ot h er 
i n d ol e nt  n o n-H o d g ki n  l y  m p h o  m as (  NH L s).   M  O  R 0 0 2 0 8 is  e x p e ct e d t o 
si g nifi c a ntl y i n cr e as e t h e  cli ni c al  effi c a c y  of  est a blis h e d  c h e  m ot h er a p e uti c 
r e gi  m e ns f or   R-R   D L  B  C L s u c h  as b e n d a  m usti n e ( B E  N ). 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 5 of  1 3 1  
M  O  R 0 0 2 0 8  or taf asit a  m a b 1 (tr a d e  n a  m e   M o nj u vi)  h as  b e e n  a ut h ori z e d f or 
m ar k eti n g i n t h e   U S u n d er t h e  pr o visi o n  of  a c c el er at e d  a p pr o v al  o n 
3 1 -J ul-2 0 2 0  a n d  u n d er t h e tr a d e  n a  m e   Mi nj u vi i n   C a n a d a  ( 1 9-A u g -2 0 2 1) , 
E  U ( 2 6-A u g -2 0 2 1)  a n d   U  K ( 0 8-O ct -2 0 2 1) as  c o n diti o n al  a p pr o v als i n  2 0 2 1 
i n  p ati e nts   wit h   R/  R   D L  B  C L. 
 
T his is  a r a n d o  mi se d, o p e n -l a b el cli ni c al tri al t o  c o  m p ar e t h e s af et y  a n d 
effi c a c y  of   M  O  R 0 0 2 0 8  wit h B E  N v ers us rit u xi  m a b (R T  X) wit h B E  N , a n 
a c c e pt e d st a n d ar d  of  c ar e f or t his  p ati e nt  p o p ul ati o n.  
St u d y   O bj e cti v es  
P RI  M  A  R  Y   O  B J  E  C  TI  V  E : 
T o  d et er  mi n e t h e effi c a c y  of  a  c o  m bi n ati o n  of   M  O  R 0 0 2 0 8  wit h   B E  N  
v ers us  a  c o  m bi n ati o n  of R T  X  wit h B E  N i n t er  ms  of  pr o gr essi o n-fr e e 
s ur vi v al ( P F S) i n:  
•  
A d ult  p ati e nts   wit h   R -R   D L  B  C L  ( o v er all  p o p ul ati o n)  
•  
A s u b gr o u p  of  a d ult  p ati e nts   wit h   R -R   D L  B  C L wit h l o  w  b as eli n e 
p eri p h er al  bl o o d   N  K -c ell  c o u nt (  NK  C  C -l o  w),  d efi n e d  as 1 0 0  or 
l ess   N  K  c ells  p er  µl  bl o o d at  b as eli n e.  
 
S  E  C  O  N  D  A  R  Y   O  B J  E  C  TI  V  E S:  
1.  T o  d et er  mi n e  a n d  c o  m p ar e  b ot h st u d y  ar  ms , M  O  R 0 0 2 0 8  wit h    B E  N 
v ers us   R T  X wit h    B E  N, f or t h e  o v er all  p o p ul ati o n a n d N  K  C  C -l o  w 
s u b gr o u p i n t er  ms  of: 
a) b est o bj e cti v e res p o ns e rat e (  O  R  R  =  c o  m pl et e r es p o ns e [  C  R]  + 
p arti al r es p o ns e [ P  R])  b as e d  o n t h e b est r es p o ns e  a c hi e v e d  at  a n y 
ti  m e  d uri n g t h e st u d y  
b)  d ur ati o n  of res p o ns e (  D o  R)  
c) o v er all sur vi v al (  O S)  
d)  dis e as e  c o ntr ol r at e (  D  C  R  =   C  R  +  P  R  + st a bl e  dis e as e [ S  D])  
e) ti  m e to p r o gr essi o n ( T T P) 
f) ti  m e to n e xt tr e at  m e nt ( T T  N T) 
g)  saf et y , b as e d  o n t h e fr e q u e n c y, i n ci d e n c e a n d s e v erit y  of  a d v ers e 
e v en ts (  A Es) 
h)  q u alit y  of lif e (  Q o L), usi n g  t h e E  O  R T  C   Q L  Q -  C 3 0 a n d  E  Q -5  D -5 L  
q u esti o n n air e s 
2.  T o  ass ess t h e p ot e nti al i  m  m u n o g e ni cit y  of   M  O  R 0 0 2 0 8  
( anti -M  O  R 0 0 2 0 8  a nti b o d y f or  m ati o n)   
3.  T o  ass ess t h e  p h ar  m a c o ki n eti c ( P  K)  pr ofil e  of   M  O  R 0 0 2 0 8 . 
 
E  X P  L  O  R  A  T  O  R  Y   O  B J  E  C  TI  V  E S:  
 
 
 
1 T af asit a  m a b is t h e r e c o  m  m e n d e d I  N  N  a n d   U S  A  N f or   M  O  R 0 0 2 0 8. T af asit a  m a b is  als o  k n o  w n  u n d er t h e  n a  m es 
X  m  A b  ® 5 5 7 4,   M  O  R 2 0 8 , M  O  R 0 0 2 0 8 ,   M o nj u vi  a n d   Mi nj u vi. M  O  R 0 0 2 0 8   w as  n ot r e pl a c e d  i n t his  d o c u  m e nt  as t his is 
a n o n g oi n g tri al. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 6 of  1 3 1  
St u d y   E n d p oi nts  
C  O -P RI  M  A  R  Y  E  N  D P  OI  N  T S : 
1.  P F S  i n t h e o v er all st u d y  p o p ul ati o n ( F  A S) 
2.  P F S i n t h e N  K  C  C -l o  w s u b gr o u p 
 
S  E  C  O  N  D  A  R  Y  E  N  D P  OI  N  T S:  
3.  B est   O  R  R,  D o  R,   O S , D  C  R,  T T P  a n d  T T  N T  
4.  Fr e q u e n c y, i n ci d e n c e  a n d s e v erit y of   A Es  
5.  Q o L  
6.  A nti -M  O  R 0 0 2 0 8  a nti b o d y f or  m ati o n  
7.  P  K  of   M  O  R 0 0 2 0 8  
8.  
 
T h e s e c o n d ar y  e n d p oi nts   will  b e a n al ys e d  i n t h e o v er all  p o p ul ati o n ( F  A S)  
a n d N  K  C  C -lo  w  s u b gr o u p. 
D esi g n  a n d 
M et h o d ol o g y/ P ati e nt 
P o p ul ati o n  
T his is  a r a n d o  mis e d, t  w o -ar  m,   m ulti c e ntr e,  o p e n -l a b el  p h as e II/III effi c a c y 
a n d s af et y st u d y  of M  O  R 0 0 2 0 8 i n  c o  m bi n ati o n   wit h B E  N v ers us   R T  X i n 
c o  m bi n ati o n   wit h B E  N gi v e n t o  a d ult  p ati e nts   w h o  h a v e r el a ps e d  aft er  or 
ar e r efr a ct or y t o  at l e ast  o n e  b ut  n o   m or e t h a n t hr e e   pri or s yst e  mi c t h er a pi es 
a n d h a v e f ail e d ,  or ar e  n ot  c a n di d at es f or   H  D  C  a n d   A S  C T,  a n d  h a v e t h us 
e x h a ust e d t h eir t h er a p e uti c  o pti o ns  of  d e  m o nstr at e d cli ni c al  b e n efit.  At 
l e ast  on e  pri or t h er a p y li n e   m ust  h a v e i n cl u d e d  a   C  D 2 0 -t ar g et e d t h er a p y 
( e. g.   R T  X). 
 
P ati e nts   wit h   R -  R D L  B  C L   w h o   m e et all t h e i n cl usi o n  crit eri a  a n d  h a v e 
n o n e  of t h e  e x cl usi o n  crit eri a   will  b e  e nr oll e d  a n d r a n d o  ml y  assi g n e d t o 
o n e  of t  w o  p ar all el tr e at  m e nt  gr o u ps i n  a r ati o  of  1: 1. B as eli n e   N  K  C  C   will 
b e  d et er  mi n e d  b y fl o  w  c yt o  m etr y.   Hist ol o gi c al  c o nfir  m ati o n  of   D L  B  C L 
di a g n osis ( p ost -r a n d o  mis ati o n)   will  b e  p erf or  m e d  b y  a  c e ntr al  p at h ol o gist. 
 
T h e st u d y   will  b e  p erf or  m e d  a c c or di n g t o  a  gr o u p -s e q u e nti al,  a d a pti v e 
d esi g n   wit h  p ossi bl e s a  m pl e si z e  a dj ust  m e nt  aft er  a  pl a n n e d i nt eri  m 
a n al ysis   wit h  5 0  p er c e nt i nf or  m ati o n r at e.  T h e tri al   will  b e  c o n d u ct e d  at 
a p pr o xi  m at el y  1 8 0 sit es   w orl d  wi d e. 
 
As t h e  c o  m bi n ati o n  of   M  O  R 0 0 2 0 8  a n d   B E  N   will  b e s yst e  m ati c all y 
e v al u at e d f or t h e first ti  m e i n  a  cli ni c al tri al, t h e tri al i n cl u d es  an I niti al 
S af et y E v al u ati o n ( P h as e II  p art  of t h e tri al) w hi c h   will e n a bl e t h e 
I n d e p e n d e nt   D at a   M o nit ori n g   C o  m  mitt e e (I  D  M  C) t o  c o n cl ud e  w h et h er t h e 
c o  m bi n ati o n tr e at  m e nts  ar e s af e. 
 
I n t h e  c o urs e  of I niti al S af et y E v al u ati o n , t h e first t hr e e p ati e nts i n  b ot h 
i n v esti g ati o n al  ar  ms   will  b e  d os e d s e q u e nti all y   wit h  at l e ast  a 4 8  h o urs l a g 
p eri o d  b et  w e e n t h e  e nr o lm e nt s of t  w o  c o ns e c uti v e  p ati e nts  as c o u nt e d fr o  m  
C y cl e  1   D a y   4 (C 1  D 4).   Aft er  c o  m pl eti o n  of t h e first tr e at  m e nt   w e e k 
(  C 1  D8)  b y t h e t hir d  c o ns e c uti v e  p ati e nt i n  e a c h  ar  m ( a p pr o xi  m at el y 
6 p ati e nts i n t ot al) t h e s af et y  d at a   will  b e r e vi e  w e d  b y t h e I  D  M  C.  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 7 of  1 3 1  
F oll o  wi n g  a  p ositi v e r e c o  m  m e n d ati o n of t h e I  D  M  C, s e v e n a d diti o n al 
p ati e nts i n  e a c h  ar  m   m a y  b e  d os e d i n  p ar all el ( a p pr o xi  m at el y  1 4  p ati e nts i n 
t ot al).   A n  a d diti o n al I  D  M  C r e vi e  w   will t a k e  pl a c e  aft er t h e l ast  of 
1 0  p ati e nts i n  e a c h  ar  m ( a p pr o xi  m at el y  2 0  p ati e nts i n t ot al)  h a v e  c o  m pl et e d 
C 3  D 1 visit i n t h eir r es p e cti v e tr e at  m e nt  all o c ati o n  ar  m  ( c o  m pl et e Initi al 
S af et y E v al u ati o n) . 
T h e  e x a ct  n u  m b er  of  p ati e nts  eli gi bl e f or  e v al u ati o n  d e p e n ds  o n t h e 
tr e at  m e nt  all o c ati o n   wit hi n t h e r a n d o  misati o n  bl o c ks.  F or  a s c h e  m ati c  
pr es e nt ati o n  of st u d y  o utli n e , s e e Fi g ur e 1  an d  Fi g ur e   2 i n t h e pr ot o c ol  
S h o ul d t h e I  D  M  C m ai n t ai n t h eir i niti al r e c o  m  m e n d ati o n t hat t h e 
c o  m bi n ati o n tr e at  m e nts  ar e s af e , t he tri al   ma y  pr o c e e d f urt h er   wit h 
r e cr uit  m e nt ( P h as e III  p art  of t h e tri al). S u bs e q u e nt I  D  M  C m e eti n gs   will  b e 
c all e d f or  as o utli n e d i n t h e I  D  M  C C h art er  t hr o u g h o ut t h e  e ntir e tri al. 
E a c h I  D  M  C r e vi e  w   will e n c o  m p ass  t h e  n u  m b er, fr e q u e n c y, s e v erit y a n d 
t y pe of  A Es,  as   w ell  as  cli ni c al l a b or at or y  bi o c h e  mistr y  a n d  h ae  m at ol o g y 
p ar a  m et ers  a n d  ot h er r el e v a nt s af et y  d at a. T h e I  D  M  C   will  als o  a d vis e t h e 
s p o ns or   w h et h er t h e tri al d esi g n r e q uir es   m o difi c ati o ns  or  h as   m et t h e 
pr e- d efi n e d tri al st o p pi n g crit eri a. F urt h er  d et ails ar e  pr o vi d e d i n 
S e cti o ns 9. 8  a nd  1 4. 1  an d t h e I  D  M  C   C h art er. 
F or t h e  p ur p os e  of t h e  pri  m ar y effi c a c y  e n d p oi nt a n al ysis , th e  dis e as e 
r es p o ns e  ass ess  m e nts   will  b e   m a d e c e ntr all y  b y  a n I n d e p e n d e nt 
Ra di ol o g y/ Cli nica l Re vie w C o m mittee (I R C; see Secti o n  1 4. 2 ). 
I n cl usi o n/  E x cl usi o n 
C rit e ri a  
I  N  C  L  U SI  O  N   C  RI  T  E  RI  A: 
Eli gi bl e  p ati e nts   m ust   m e et t h e f oll o  wi n g  crit eri a t o  b e  e nr oll e d i n t h e 
st u d y: 
Di a g n osis/ T ri al P o p ul ati o n  
1.
A g e ≥1 8  y e ars
•
F or  Si n g a p or e  o nl y:  a g e > 2 1  y e ars
2.
Hist ol o gi c all y c o nfir  m e d  di a g n osis,  a c c or di n g t o t h e   W orl d   H e alt h
Or g a ni z ati o n (  W  H  O,  2 0 0 8)  cl assifi c ati o n,  of:
a)
Diff us e l ar g e   B -c ell l y  m p h o  m a  n ot  ot h er  wis e s p e cifi e d (  D L  B  C L
N  O S)
b)
T  c ell/ histi o c yt e ri c h l ar g e   B -c ell l y  m p h o  m a ( T  H  R L  B  C L)
c)
E pst ei n -B arr  vir us ( E  B  V)  p ositi v e   D L  B  C L  of t h e  el d erl y
( E  B  V-p ositi v e   D L  B  C L)
d)
C o  m p osit e l y  m p h o  m a   wit h  a   D L  B  C L  c o  m p o n e nt wit h  a   D L  B  C L
r el a ps e s u bs e q u e nt t o   D L  B  C L tr e at  m e nt
e)
Dis e as e tr a nsf or  m e d fr o  m  a n  e arli er  di a g n osis  of l o  w-gr a d e
l y  m p h o  m a (i. e.  a n i n d ol e nt  p at h ol o g y s u c h  as f olli c ul ar l y  m p h o  m a,
m ar gi n al  z o n e l y  m p h o  m a ) i nt o   D L  B  C L   wit h  a   D L  B  C L r el a ps e
s u bs e q u e nt t o   D L  B  C L tr e at  m e nt.


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 8 of  1 3 1  
3.
Fres h t u m o ur tiss ue for  ce ntral  pa t h ol o g y re vie w  m ust be  pr o vi de d as
a n a dj u nct  to partici pati o n i n t his st u d y. S h o ul d  it n ot  be  p os si ble to
o btai n  a fres h tu m o ur  tiss ue sa m ple, arc hi val  p araffi n e m be d de d
t u m o ur tiss ue ac q uire d ≤3 years pri or t o scree nin g f or t his pr ot oc ol
m ust  b e a vaila ble f or this p ur p ose.
4.
Patie nts m ust  h a ve:
a)
R- R D L B C L (f or defi niti o ns , see Secti o n 8. 1  of  t he pr ot oc ol)
b)
at least o ne bi di me nsi o nall y  m eas ura bl e di sease site. T he lesi o n
m ust ha ve a greatest tra ns verse dia meter of ≥1. 5  c m a nd  g reatest
p er pe n dic ular dia meter of ≥1. 0 c m at baseli ne . T he lesi o n m ust  b e
p o siti ve o n P E T sca n (f or d efi niti o n , see J u wei d et al. (2 0 0 7) ).
c)
recei ve d at least o ne, b ut no m ore  tha n t hree  pre vi o us  syste mic
t hera py  li nes f or t he treat me nt of D L B C L (f or f urt her details see
Secti o ns  8. 6  an d  9. 5 ). At least  o ne pre vi o us  thera p y li ne  must  ha ve
i ncl u de d a CD 2 0 -tar gete d thera p y  (e. g. R T X).
d)
Easter n  C o o perati ve O nc ol o g y  Gro u p  (E C O G)  perf or ma n ce stat us
of  0 t o  2
5 .
Patie nts  after  fail ure of A SC T  or patie nts c o nsi dere d  i n t he o pini o n of
t he i nvesti gat or  c urre ntl y n ot eli gi ble  for  H D C  wit h s ubse q ue nt  A S C T .
D oc u me ntati o n of  the  reas o n f or  ineli gi bilit y f or  AS C T  must  be
prese nt  in  the patie nt’s s o urce data  (f or details , see Secti o n  8. 6 ).
L a b o r at o r y V al u es  
6.
Patie nts m ust  m eet the f oll o wi n g  la b orat or y  criteria at Scr ee ni n g:
a)
abs ol ute ne utr o p hil c o u n t ( A N C) ≥1. 5 × 1 09/ L (u nless sec o n dar y t o 
b o ne  m arr o w  in v ol ve me nt  b y D L B C L  as de m o nstrate d  b y  b o ne  
marr o w  as pirati o n a n d b o ne  m arr o w  bi o ps y  req uire d f or Scree ni n g )
b )
p latelet c o u nt ≥9 0  ×  1 09/ L ( u nless sec o n dar y to  b o n e marr o w  
i n v ol ve me n t b y  D L B C L  as de m o nstrate d b y  b o ne  m arr o w  
as pirati o n a n d b o ne  m arr o w  bi o ps y  req uire d  for  S cree ni n g ) a nd  
a bse nce of  acti ve blee di n g
c)
total ser u m bilir u bi n ≤2. 5  ×  u pper li mit of n o r mal ( U L N) u nless 
sec o n dar y to  Gil bert's  sy n dr o me  (or  pa tter n c o nsiste n t w it h 
Gil bert's)  or d oc u me nte d  li ver in v ol ve me nt  b y l y m p h oma . Patie nts  
w it h Gil bert's  sy n dr o me  or  d oc u me nte d li ver in v ol ve me nt  b y  
l y m p h o ma ma y be i ncl u de d if t heir t o tal bilir u bi n  is ≤5 x U L N
(see e xcl usi o n criteri o n 6e )
d)
alani ne tra nsa mi nase ( A L T), as partate a mi n otra nsferase ( A S T) a n d 
alkali ne p h os p hatase ≤3  ×  U LN  or < 5  ×  U LN  i n case s of  
d oc u me n te d li ver in v ol ve me n t b y l y m p ho ma
e)
ser u m creati ni ne ≤2. 0  x U LN  or  creati ni ne cleara nce m u st b e
≥4 0  m L/ mi n calc ulate d  u si n g a sta n dar d C oc kcr oft - Gault  f or m ula 
( C oc kr oft & Gault , 1 9 7 6 ; see A ppe n di x A  to t he pr o t oc ol)
7.
F or  a fe mal e of  c hil dbeari n g  pote ntial  (F C B P ; f or defi niti o n see  
Secti o n  8 . 9), a negati v e pre g n a nc y t est mu st be c o nfir me d  bef ore  
e nr ol me n t. A n F C B P m ust c o m mit t o  ta ke hi g hl y effecti ve  
c o ntrace pti ve preca uti o ns (see A p pe n di x B ) wit h o ut  interr u pti o n    
d uri n g  the  st u d y a n d f or 3,  6 or  1 2  m o nt hs after  the last  dose  of  
M O R 0 0 2 0 8 , B E N or  RT X  res pecti vel y,  w h ic he ver is later. A n F C B P


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 9 of  1 3 1  
m ust r efr ai n fr o  m  br e astf e e di n g  a n d  d o n ati n g  bl o o d  or  o o c yt es  d uri n g 
t h e  c o urs e  of t h e st u d y  a n d f or  3,  6 or  1 2  m o nt hs  aft er t h e l ast  d os e  of 
M  O  R 0 0 2 0 8,   B E  N  or   R T  X r es p e cti v el y,   w hi c h e v er is l at er.  R estri cti o ns 
c o n c er ni n g  bl o o d  d o n ati o ns  a p pl y  as   w ell t o f e  m al es   w h o  ar e  n ot  of 
c hil d b e ari n g  p ot e nti al.  (A p pli c a bl e i n R e p u bli c  of   K o r e a :  a n  F  C  B P 
m ust c o  m  mit t o t a k e  hi g hl y  eff e cti v e  c o ntr a c e pti v e  pr e c a uti o ns ( s e e 
A p pe n d i x B) wit h o ut  interr u pti o n  an d refrai n  fr o m breastfee di n g a n d 
d o n ati n g  bl o o d  or  o o c yt es  d uri n g t h e  c o urs e  of t h e st u d y  a n d f or 
6 m o nt hs  aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8, 6   m o nt hs  aft er t h e l ast  d os e 
of B E  N  or 1 2   m o nt hs  aft er t h e l ast  d os e  of   R T  X,   w hi c h e v er is l at er.) . 
8.
M al es   m ust  us e   a n eff e cti v e  b arri er   m et h o d  of  c o ntr a c e pti o n wit h o u t
i nt err u pti o n d uri n g t h e st u d y  a n d f or 3, 6 or  1 2 m o nt hs  aft er t h e l ast
d os e of M  O  R 0 0 2 0 8,   B E  N  or   R T  X r es p e cti v el y,   w hi c h e v er is l at er, if
t h e  p ati e nt is s e x u all y  a cti v e   wit h  an  F  C  B P. M al es   m ust r efr ai n fr o  m
d o n ati n g  bl o o d  or s p er  m  d uri n g st u d y  p arti ci p ati o n  a n d f or  3,  6  or
1 2  m o nt hs  aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8,   B E  N  or   R T  X
r es p e cti v el y,   w hi c h e v er is l at er. (A p pli c a bl e i n   R e p u bli c  of   K o r e a :
m al es   m ust r efr ai n fr o  m  d o n ati n g  bl o o d  or s p er  m  a n d, if t h e  p ati e nt is
s e x u all y  a cti v e   wit h  a n  F  C  B P,   m ust  us e  a n  eff e cti v e  b arri er   m et h o d  of
c o ntr a c e pti o n   wit h o ut i nt err u pti o n  d uri n g t h e st u d y  a n d f or  6   m o nt hs
aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8,  6   m o nt hs  aft er t h e l ast  d os e  of B E N
or 1 2   m o nt hs  aft er t h e l ast  d os e  of R T  X,   w hi c h e v er is l at er) .
9.
I n t h e  o pi ni o n  of t h e i n v esti g at or, t h e  p ati e nts   m ust:
a)
b e  a bl e t o  c o  m pl y   wit h  all st u d y -r el at e d  pr o c e d ur es,   m e di c ati o n
us e,  a n d  e v al u ati o ns
b)
b e  a bl e t o  u n d erst a n d  a n d  gi v e  i nf or  m e d  c o ns e nt
c)
n ot b e  c o nsi d er e d t o  b e  p ot e nti all y  u nr eli a bl e  a n d/ or  n ot
c o o p er ati v e.
E X  C  L  U SI  O  N   C  RI  T  E  RI  A:  
Eli gi bl e  p ati e nts   m ust  n ot  h a v e  a n y  of t h e f oll o  wi n g t o  b e  e nr oll e d i n t h e 
st u d y: 
E x cl usi o n a r y Di a g n osis  C rit e ri a  
1.
Patie nts w h o  ha ve:
a)
a n y o t her hist ol o gical ty pe  of  ly m p h o ma  incl u di n g , e. g., pri mar y 
me diasti nal  (t h y mic) lar ge B -cell l y m p h o ma ( P M B L) or B ur kitt’ s 
l y m ph o ma
b)
pri mar y refract or y D L B C L (for  defi niti o n , see Secti o n  8. 1 )
c)
patie nts  wit h kn o w n  "d o u ble/tri ple  h it" D L B C L  ge netics , 
c haracterise d  b y  sim ulta ne o us detecti o n  of  M Y C  wit h  B C L 2     
a n d/ or  B C L 6  tra nsl ocati o n, as defi ne d  b y  fl u oresce nce i n sit u 
h y bri disati o n  ( FI S H). M Y C , B C L 2 , B C L 6  testi n g pri or to st u d y  
e nr ol me nt  is n ot re q uire d .
d )
ce ntral  ne r v o us syste m  (C N S)  ly m p h o ma  in v ol ve me n t in  prese nt 
or  past m e dical  hist or y


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 0  of 1 3 1  
E x cl usi o n a r y P r e vi o us a n d C u r r e nt T r e at  m e nt C rit e ri a  
2.
Patie nts  wh o ha d a  maj or  sur ger y (f or  defi niti o n, see Secti o n  8. 1 ) less 
t ha n 3 0 da ys  pri or  to Da y  1 d osi n g
3.
Pa tie nts wh o ha ve,  wit hin 1 4 da ys  pri or t o Da y 1 d osi n g:
a)
n o t disc o nti n ue d C D 2 0-tar gete d  t hera p y, c he m ot hera p y,  
ra di ot hera p y, i n vesti gati o nal antica ncer  t hera p y or other  
l y m p h o ma-specific t hera p y  (f or e xce pti o ns see Secti o n  9. 5. 3 )
b)
recei ve d  li ve vacci nes (for  defi niti o n , see Secti o n 8. 6 )
c)
req uire d pare nteral  a ntimicr o bial  thera p y  for  acti ve, i nterc urre nt 
s yste mic infecti o ns
4.
Patie nts w h o:
a)
i n t he opi ni o n  of t he i nvesti gat or, ha v e n ot  rec o vere d  s ufficie ntl y 
fr o m the a d verse t o xic effects of  pri or thera pies,  maj or s ur geries 
(f or defi niti o n, see Secti o n 8. 1 ) or  si g nifica nt tra u matic i nj uries
b)
were pre vi o usl y  treate d wit h CD 1 9 -tar gete d  thera p y  or B E N
c)
h a ve  a hist or y of pre vi o us  se vere aller gic reacti o ns  to c o m p o u n ds  
o f si milar biol o gical  or che mical  co m p ositi o n t o  MO R 0 0 2 0 8,  
R T X,  muri ne  protei ns  or B E N , or  the  exci pie nts  co ntai ne d i n t he  
st u d y dr u g f or m ulati o ns
d)
ha ve  u n der g o ne AS C T  wit hi n a p eri o d  of ≤3 m o nt hs  pri or to  
si g ni n g t he inf or me d c o nse nt  for m.  Patie nts  wh o ha ve  a more  
dista nt  hist or y of AS C T  must  ex hi bit  full  hae mat ol o gical  rec o ver y  
bef ore  enr ol me nt  int o t he  st u d y.
e)
ha ve  u n der g o ne pre vi o us  all o ge neic ste m  cell tra ns pla ntati o n
f)
c o nc urre ntl y  use ot her  a ntica ncer or e xperi me ntal  treat me nts (f or 
e xce pti o ns see Secti o n  9. 5. 3 )
E x cl usi o n a r y M e di c al H ist o r y C rit e ri a  
5.
Pri or  hist ory of  mali g na ncies  other  tha n D L B C L,  u nless  the  patie nt has 
b ee n free of  t he di sease f or ≥3  year s pri or  t o Sc ree ni n g. Exce pti o ns  to  
t he ≥3 - year  ti me li mit i ncl u de hist or y of  t he foll o wi n g:
a)
ba sal cell carci n o ma of  the s ki n
b)
s qu a m o us cell  carci n o ma  of the s ki n
c)
carci n o ma i n sit u of  the cer vi x
d )
carci n o ma i n sit u of  the breast
e)
carci n o ma i n sit u of  the  bla d der
f)
i nci de ntal  hist ol o gical fi n di n g of pr ostate  ca ncer
( T u m o ur/ N o de/ Metastasis [ T N M] sta ge of  T1a or  T1 b)
6.
Patie nts  wit h:
a)
p o siti ve he patitis  B a n d/ or C ser ol o g y (for  defi niti o ns , see    
Secti o n  8. 6 )
b)
k n o w n ser o p ositi vit y for  or hist or y of acti ve  viral i nfecti o n wit h 
h u ma n i m m u n o deficie nc y vir us  (HI V)
c)
e vi de nce of  acti ve, se vere u nc o ntr olle d  s yste mic infecti o ns (e. g. , 
t u berc ul osis, o p p ort u nistic i nfecti o ns) or se psis
d)
a hist or y or evi de nce  of se verel y i m m u n oc o m pr o mise d state
e)
a hist or y  or evi de nce of  se vere he patic i m pair me nt (t otal seru m  
bilir u bi n >  3 m g/ d L),  ja u n dice u nless sec o n dar y  to  Gil bert's  
s y n dr o me or  d ocu me nte d l i ver in v ol ve me nt  b y l y m p h o ma  (see 
i ncl usi o n criteri o n 6c)


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 1  of 1 3 1  
f)
a hist or y  or  e vi d e n c e  of cli ni c all y si g nifi c a nt  c ar di o v as c ul ar ,
cere br o vasc ular,  CN S  a n d/ or  other  di sease t hat, i n t he 
i n vesti gat or’s o pini o n , wo ul d  precl u de  partici pati o n i n  the  stu d y or  
c o m pr o mise t he patie nt’s a bilit y t o gi ve i nf or me d c o nse nt (f or 
a d diti o nal  ex pla nati o ns , see Secti on  8. 6 ).
I n v esti g ati o n al   D r u g(s) 
(  N a  m e,   D es c ri pti o n) 
M  O  R 0 0 2 0 8 ( a n  F c -e n h a n c e d ,  h u  m a nis e d,   m o n o cl o n al  a nti b o d y t ar g eti n g 
t h e   B-c ell s urf a c e  a nti g e n   C  D 1 9),   B e n d a  m usti n e (  B E  N: e. g. L e v a ct ® / 
Tr e a n d a ® ) a n d   Rit u xi  m a b (  R T  X: e. g. M a b T h er a
® /  Rit u x a n® ). 
D os e,   R o ut e  of 
A d  mi nist r ati o n, 
T r e at  m e nt   R e gi  m e n  
Tr e at  m e nt wit h st u d y  dr u gs  (M  O  R 0 0 2 0 8  wit h   B E  N  or   R T  X  wit h   B E  N ) 
will  b e  off er e d i n  2 8 -d a y  c y cl es  at s p e cifi e d ti  m e  p oi nts at 
pr ot o c ol -pr es cri b e d d os e l e v els f or  a   m a xi  m u  m  of si x c y cl es.  
T h er e aft er,  p ati e nts   wit h  a r es p o ns e  of  at l e ast  P  R  at t h e  e n d  of   C y cl e  6,  as 
p er l o c al  dis e as e r es p o ns e  ass ess  m e nt, will c o nti n u e anti b o d y m o n ot h er a p y 
tr e at  m e nt (  M  O  R 0 0 2 0 8  or   R T  X) i n  a c c or d a n c e   wit h t h eir  ori gi n al tr e at  m e nt 
all o c ati o n  u ntil dis e as e pr o gr essi o n.  Tr e at  m e nt   m a y  b e st o p p e d  d u e t o 
r e c urr e n c e/ dis e as e  pr o gr essi o n,  u n a c c e pt a bl e t o xi cit y,  d e at h  or 
dis c o nti n u ati o n f or  a n y  ot h er r e as o n,   w hi c h e v er  c o  m es first.  
I n t h e  c as e  of l o c al  c o nfir  m ati o n  of  dis e as e r e c urr e n c e/ pr o gr essi o n, it is  u p 
t o t h e i n v esti g at or t o  d e ci d e  a c c or di n g t o t h e i n di vi d u al ris k/ b e n efit r ati o if 
t h e  p ati e nt s h o ul d  c o nti n u e f urt h er  a nti b o d y tr e at  m e nt (  R T  X  or 
M  O  R 0 0 2 0 8) i n  a c c or d a n c e   wit h t h e i n iti al tr e at  m e nt  all o c ati o n f or  u p t o 
2 4  m o nt hs  i n t ot al (f or  d et ails, s e e S e cti o n  9. 1  of  t h e  pr ot o c ol). 
M  O  R 0 0 2 0 8  d os e : 1 2  m g/ k g  i ntr a v e n o usl y (I  V) 
C y cl e  1 -3: M  O  R 0 0 2 0 8   will  b e  a d  mi nist er e d  o n   D a y  1,   D a y  8,   D a y  1 5  a n d 
D a y  2 2  of  e a c h  c y cl e.   A d diti o n all y , a l o a di n g  d os e   will  b e  a d  mi nist er e d  o n 
D a y  4  of C y cl e  1.  C y cl e 4- u ntil dis e as e pr o gr essi o n :   M  O  R 0 0 2 0 8   will  b e 
a d  mi nist er e d  o n   D a y   1 a n d   D a y  1 5  of  e a c h  c y cl e.  
R  T  X  d os e : 3 7 5   m g/  m 2 I  V 
R T  X   will  b e  a d  mi nist er e d  o n   D a y  1  of  e a c h  c y cl e,   wit h  a  pr e -pl a n n e d 
tr e at  m e nt i nt er v al  of at l e ast 2 8 -d a ys t o t h e s u bs e q u e nt   R T  X 
a d  mi nistr ati o n.  
B  E  N d os e : 9 0   m g/  m 2 I  V 
B E  N   will  b e  a d  mi nist er e d  o n   D a y s  2 +3  of C y cl e  1 . B E  N  a d  mi nistr ati o n  
will  b e r e p e at e d  o n   D a ys  1 + 2  or   D a ys  2 + 3  of t h e s u bs e q u e nt  c y cl es,   wit h  a 
pr e- pl a n n e d tr e at  m e nt i nt er v al of at l e ast 2 8 -d a y s b et  w e e n t h e 
c o  m  m e n c e  m e nt s of t  w o s u c c e e di n g  c y cl es (f or  a d diti o n al i nf or  m ati o n s e e 
Secti o n  9. 1. 3 ). 
B E  N  d os e m a y  b e   m o difi e d i n  a  d e -es c al ati n g f as hi o n  or  dis c o nti n u e d 
b as e d  u p o n  cli ni c al  a n d l a b or at or y fi n di n gs. I n t h e c as e  of  e arl y   B E  N 
dis c o nti n u ati o n , t h e a nti b o d y tr e at  m e nt s h o ul d  c o nti n u e  u nl ess 
c o ntr ai n di c at e d . D et ail e d  g ui d a n c e  o n  h o  w t o   m a n a g e  h ae  m at ol o gi cal 
a n d/ or  ot h er t o xi citi es is pr o vi d e d i n S e cti o n  9. 4  of t h e  pr ot o c ol.  




I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 3  of 1 3 1  
R T  X  wit h B E  N  gr o u p (h a z ar d r ati o [  H  R] of  0. 7 0)  i n t h e  o v er all  p o p ul ati o n. 
A t  w o -st a g e, gr o u p -s e q u e nti al, a d a pti v e  d esi g n   wit h  o n e i nt eri  m  a n al ysis 
will  b e  a p pli e d  usi n g t h e   O’  Bri e n-Fl e  mi n g  a p pr o a c h a n d t h e i n v ers e  n or  m al 
m et h o d f or  pr es er vi n g t h e  o v er all t y p e I  err or r at e (W ass  m er  2 0 0 6 ). 
A t ot al  n u  m b er  of  2 5 6  P F S  e v e nts  ar e r e q uir e d  b as e d  o n  a H  R  of  0. 7 0   wit h 
8 0  %  p o  w er  at fi n al  a n al ysis  f or t h e  F  A S,  usi n g  a t  w o-si d e d l o g-r a n k t est  at 
4. 8  %  al p h a l e v el  a n d  a  1: 1 r a n d o  mi sati o n r ati o  b et  w e e n t h e t  w o tre at  m e nt 
gr o u ps.  T o  g e n er at e t h e r e q uir e d  n u  m b er  of  e v e nts, 2 8 6  e v al u a bl e  p ati e nts 
w o ul d n e e d t o  b e  e nr oll e d , wit h  ass u  m e d  a c cr u al  d ur ati o n  of  1 8   m o nt h s a n d 
a  Foll o  w -  Up  of  1 2   m o nt h s.   A p pl yi n g  a 1 3 %  dr o p -o ut r at e   w o ul d r es ult i n  a 
t ot al  n u  m b er  of e nr oll e d p ati e nts  of  a p pr o xi  m at el y  3 3 0.  
A n i nt eri  m  a n al ysis is  pl a n n e d  aft er t h e  o bs er v ati o n  of  5 0  %  of t h e r e q uir e d 
e v e nts, i. e.,  aft er  1 2 8 P F S e v e nts.  T h e   H  R s will  b e  c al c ul at e d  a n d t hr e e 
o ut c o  m es   will  b e  p ossi b l e  b as e d  o n t h e i nt eri  m r es ult:  T h e st u d y   m a y  b e 
st o p p e d  d u e t o f utilit y, t h e st u d y m a y c o nti n u e   wit h t h e   mi ni  m u  m  pl a n n e d 
n u  m b er  of 3 3 0 p ati e nts  (t o  o bt ai n  2 5 6 P F S e v e nts) ,  or t h e s a  m pl e si z e m a y 
b e i n cr e as e d t o  4 5 0  p ati e nts (t o  o bt ai n  3 6 9  P F S  e v e nts).  E arl y st o p pi n g f or 
effi c a c y is  n ot  all o  w e d.  
T h e s a  m pl e si z e   w as i n cr e as e d t o  4 5 0  p ati e nts  b as e d  o n t h e I  D  M  C 
r e c o  m  m e n d ati o n. 
T h e st u d y i n cl u d es a  c o-pri  m ar y  e n d p oi nt ( P F S i n t h e   N  K  C  C -l o  w 
s u b gr o u p), f oll o  wi n g t h e  e  m er g e n c e  of  d at a s h o  wi n g t h e i  m p ort a n c e  of 
N  K  C  C  as  a  pr o g n osti c f a ct or, a n d p ot e nti all y  a  pr e di cti v e f a ct or  f or 
a nti b o d y  effi c a c y i n   D L  B  C L . 
F or  c o nfir  m at or y  h y p ot h esis t esti n g, t h e  p -v al u es  of t h e st atisti c al t ests f or 
t h e  pri  m ar y  a n d  k e y s e c o n d ar y  e n d p oi nt   will  b e  c o  m bi n e d fr o  m st a g e I 
(i nf or  m ati o n  u p t o I nt eri  m   A n al ysis)  a n d st a g e II (i nf or  m ati o n  b et  w e e n 
int eri  m an al ysis  a n d fi n al an al ysis) of t h e st u d y  usi n g t h e i n v ers e  n or  m al 
m et h o d f or t h e  o v er all  p o p ul ati o n ( F  A S) a n d t h e   N  K  C C- l o  w s u b gr o u p. 
T h e f a  mil y -wis e  err or r at e   will  b e   m ai nt ai n e d  at 4. 8  %  b y s plitti n g t h e  al p h a 
b et  w e e n  F  A S  a n d   N  K  C  C -lo  w s u b gr o u p  a d e q u at el y. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 4  of 1 3 1  
2  T  A B  L  E   O F   C  O  N  T  E  N  T S  
2. 1  O v e r al l   T a bl e  of   C o nt e nts 
TI  T  L  E  P  A  G  E  ........................................................................................................................................... 1 
I  N  V  E S  TI  G  A  T  O  R' S   A  G  R  E  E  M  E  N  T ...................................................................................................... 2 
P  R  O  T  O  C  O  L   HI S  T  O  R  Y  ......................................................................................................................... 3 
1  
P  R  O  T  O  C  O  L S  Y  N  O P SI S  ................................................................................................................ 4 
2  
T  A  B  L  E   O F   C  O  N  T  E  N  T S  ............................................................................................................... 1 4  
2. 1  
O v e r all   T a bl e  of   C o nt e nts  ................................................................................................... 1 4  
2. 2  
List  of   T a bl es  ........................................................................................................................ 1 8  
2. 3  
List  of  Fi g u r es  ....................................................................................................................... 1 8  
3  
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N S   A  N  D   D  E FI  NI  TI  O  N S   O F   T  E  R  M S  ............................................. 1 9  
4  
B  A  C  K  G  R  O  U  N  D  ............................................................................................................................ 2 4  
4. 1  
O v e r vi e  w  of   N o n -H o d g ki n   L y  m p h o  m as  ............................................................................ 2 4  
4. 2  
T r e at  m e nt  of   D  L  B  C  L  .......................................................................................................... 2 4  
4. 3  
B e n d a  m usti n e i n   D  L  B  C  L   T r e at  m e nt  ................................................................................. 2 5  
4. 4  
O v e r vi e  w  of  n at u r al  kill e r (  N  K)  c ells i n l y  m p h o  m a,  r el e v a n c e t o   M  O  R 0 0 2 0 8  .............. 2 6  
4. 5  
O v e r vi e  w  of   C  D 1 9  e x p r essi o n i n   D  L  B  C  L  a n d t r e at  m e nt   wit h   M  O  R 0 0 2 0 8  .................... 2 7  
4. 5. 1  
T h e   B -c ell   Diff er e nti ati o n   A nti g e n   C  D 1 9 i n  L y  m p h o  m a  .................................... 2 7  
4. 5. 2  
M  O  R 0 0 2 0 8   B a c k gr o u n d  a n d  Pr e cli ni c al   D at a  ..................................................... 2 7  
4. 5. 3  
Cli ni c al  E x p eri e n c e   wit h   M  O  R 0 0 2 0 8  .................................................................. 2 9  
4. 5. 3. 1  
Pr ot o c ol   X  m  A b 5 5 7 4 -0 1  ....................................................................................... 2 9  
4. 5. 3. 2  
O n g oi n g  St u di es  ................................................................................................... 3 0  
4. 5. 4  
S af et y  of   M  O  R 0 0 2 0 8  ........................................................................................... 3 1  
5  
S  T  U  D  Y  P  U  R P  O S  E/  R  A  TI  O  N  A  L  E  ............................................................................................... 3 2  
6  
O  B J  E  C  TI  V  E S ................................................................................................................................ 3 4  
6. 1  
P ri  m a r y   O bj e cti v es  .............................................................................................................. 3 4  
6. 2  
S e c o n d a r y   O bj e cti v es  ........................................................................................................... 3 4  
6. 3  
E x pl o r at o r y   O bj e cti v es  ........................................................................................................ 3 4  
7  
S  T  U  D  Y   E  N  D P  OI  N  T S  .................................................................................................................... 3 5  
7. 1  
C o -P ri  m a r y   E n d p oi nts  ........................................................................................................ 3 5  
7. 2  
S e c o n d a r y   E n d p oi nts  ........................................................................................................... 3 5  
8  
I  N  V  E S  TI  G  A  TIO  N  A  L  P  L  A  N  ........................................................................................................ 3 5  
8. 1  
P r ot o c ol -S p e cifi c   D efi niti o ns  ............................................................................................... 3 5  
8. 2  
St u d y   D esi g n  ......................................................................................................................... 3 6  
8. 3  
St u d y   C o n d u ct  ...................................................................................................................... 3 9  
8. 4  
E n d  of  St u d y  ......................................................................................................................... 3 9  
8. 5  
P ati e nt  S el e cti o n   C rit e ri a  .................................................................................................... 3 9  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 5  of 1 3 1  
8. 5. 1  
I n cl usi o n   Crit eri a ................................................................................................. 3 9  
8. 5. 2  
E x cl usi o n   Crit eri a  ................................................................................................ 4 1  
8. 6  
A d diti o n al   E x pl a n at o r y I nf o r  m ati o n  o n I n cl usi o n  a n d   E x cl usi o n   C rit e ri a .................... 4 2  
8. 7  
R a n d o  mis ati o n  ...................................................................................................................... 4 5  
8. 8  
R e -s c r e e ni n g  P r o c e d u r es ..................................................................................................... 4 6  
8. 9  
D efi niti o n  of  F e  m al e  of   C hil d b e a ri n g  P ot e nti al  ................................................................ 4 7  
9  
T  R  E  A  T  M  E  N  T S .............................................................................................................................. 4 7  
9. 1  
St u d y   T r e at  m e nts  ................................................................................................................. 4 7  
9. 1. 1  
M  O  R 0 0 2 0 8  .......................................................................................................... 4 8  
9. 1. 2  
R T  X ...................................................................................................................... 4 9  
9. 1. 3  
B E  N ...................................................................................................................... 4 9  
9. 2  
P r e  m e di c ati o n f o r  St u d y   D r u g I nf usi o ns ........................................................................... 5 0  
9. 3  
P ati e nt   M o nit o ri n g   D u ri n g  St u d y   D r u g I nf usi o ns  ............................................................ 5 0  
9. 4  
C rit e ri a f o r   D os e   M o difi c ati o ns  a n d  St u d y   D r u g   Dis c o nti n u ati o n  .................................. 5 0  
9. 4. 1  
M a n a g e  m e nt  of  St u d y   Dr u g I nf usi o n -R el at e d   R e a cti o ns  .................................... 5 0  
9. 4. 1. 1  
Gr a d e  2 I  R  Rs f or  p ati e nts r e c ei vi n g   M  O  R 0 0 2 0 8  ................................................. 5 1  
9. 4. 1. 2  
Gr a d e  3 I  R  Rs f or  p ati e nts r e c ei vi n g   M  O  R 0 0 2 0 8  ................................................. 5 2  
9. 4. 1. 3  
Gr a d e  4 I  R  Rs f or  p ati e nts r e c ei vi n g   M  O  R 0 0 2 0 8  ................................................. 5 2  
9. 4. 2  
M a n a g e  m e nt  of  Tr e at  m e nt -R el at e d  T o xi citi es  ..................................................... 5 2  
9. 4. 2. 1  
S af et y -r el at e d   Crit eri a f or   B E  N  Tr e at  m e nt  a n d   B E  N  Tr e at  m e nt 
P ost p o n e  m e nt  ....................................................................................................... 5 3  
9. 4. 2. 2  
A nti b o d y  Tr e at  m e nt   D os e   O  missi o ns/ P ost p o n e  m e nts  ......................................... 5 5  
9. 4. 2. 3  
Tr e at  m e nt   Dis c o nti n u ati o n  ................................................................................... 5 6  
9. 5  
P ri o r  a n d   C o n c o  mit a nt   T h e r a p y  ........................................................................................ 5 7  
9. 5. 1  
Gr o  wt h  F a ct ors  a n d  Tr a nsf usi o n  S u p p ort  ............................................................ 5 8  
9. 5. 2  
I nf e cti o n  Pr o p h yl a xis ........................................................................................... 5 8  
9. 5. 3  
A nti c a n c er  T h er a pi es  ........................................................................................... 5 8  
9. 5. 4  
S yst e  mi c   Gl u c o c orti c ost er oi ds  ............................................................................. 5 8  
9. 5. 5  
M a n a g e  m e nt  of  T u  m o ur  L ysis  S y n dr o  m e  ............................................................ 5 9  
9. 5. 6  
M a n a g e  m e nt  of  P ati e nts   w it h   Hist or y  or  Pr e vi o us  E v e nts  of  F e bril e 
N e utr o p e ni a  .......................................................................................................... 5 9  
9. 5. 7  
A nti  mi cr o bi als/  A nti vir als/  A ntif u n g als  ................................................................. 5 9  
9. 6  
T r e at  m e nt   C o  m pli a n c e  ........................................................................................................ 6 0  
9. 7  
O v e r d os e  of  St u d y   D r u gs  ..................................................................................................... 6 0  
9. 8  
Wit h d r a  w al f r o  m  St u d y   T r e at  m e nt  o r  St u d y/ Sit e   T e r  mi n ati o n  ...................................... 6 0  
9. 8. 1  
Wit h dr a  w al   Crit eri a .............................................................................................. 6 0  
9. 8. 2  
St u d y  or  Sit e  T er  mi n ati o n  .................................................................................... 6 1  
1 0  S  T  U  D  Y  P  R  O  C  E  D  U  R  E S  ................................................................................................................ 6 3  
1 0. 1  S c h e d ul e  of   Visits  a n d  P r o c e d u r es  ...................................................................................... 6 3  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 6  of 1 3 1  
1 0. 2  P r o c e d u r es  ............................................................................................................................ 7 2  
1 0. 2. 1  
Di a g n osti c   Bi o ps y  ................................................................................................ 7 2  
1 0. 2. 2  
D e  m o gr a p hi c   D at a/  R el e v a nt   M e di c al   Hist or y  a n d   C urr e nt   M e di c al 
C o n diti o ns/  B as eli n e,  St a g e  a n d  Pr o g n osti c   Cl assifi c ati o n  ................................... 7 3  
1 0. 2. 3  
Q u alit y  of  Lif e  ...................................................................................................... 7 3  
1 0. 3  S af et y   Ass ess  m e nts  ............................................................................................................... 7 3  
1 0. 3. 1  
Vit al  Si g ns  ............................................................................................................ 7 4  
1 0. 3. 2  
P h ysi c al  E x a  mi n ati o n  ........................................................................................... 7 4  
1 0. 3. 2. 1  
F ull  P h ysi c al  E x a  mi n ati o ns  .................................................................................. 7 4  
1 0. 3. 2. 2  
Li  mit e d  P h ysi c al  E x a  mi n ati o ns  ........................................................................... 7 5  
1 0. 3. 2. 3  
B o d y   M ass,   B o d y S urf a c e   Ar e a (  B S  A)  a n d   H ei g ht   M e as ur e  m e nts  ..................... 7 5  
1 0. 3. 3  
B- S y  m pt o  ms  ........................................................................................................ 7 5  
1 0. 3. 4  
El e ctr o c ar di o gr a  m  ................................................................................................ 7 6  
1 0. 3. 5  
A d v ers e  E v e nt   M o nit ori n g  ................................................................................... 7 6  
1 0. 3. 6  
M o nit ori n g  of  S e c o n d  Pri  m ar y   M ali g n a n ci es  ...................................................... 7 6  
1 0. 3. 7  
L a b or at or y   Ass ess  m e nts  ...................................................................................... 7 6  
1 0. 3. 7. 1  
L a b or at or y  T esti n g  ............................................................................................... 7 6  
1 0. 3. 7. 2  
H e p atitis   Vir us  S er ol o g y  ...................................................................................... 7 9  
1 0. 3. 7. 3  
Pr e g n a n c y  T esti n g  ................................................................................................ 8 0  
1 0. 3. 7. 4  
P  K   Ass ess  m e nts  ................................................................................................... 8 0  
1 0. 3. 7. 5  
I  m  m u n o g e ni cit y ................................................................................................... 8 0  
1 0. 3. 8  
Effi c a c y   Ass ess  m e nts  ........................................................................................... 8 1  
1 0. 3. 8. 1  
T u  m o ur I  m a gi n g  .................................................................................................. 8 1  
1 0. 3. 9  
B o n e   M arr o  w  ....................................................................................................... 8 2  
1 1  S  A F  E  T  Y   M  O  NI  T  O  RI  N  G  .............................................................................................................. 8 3  
1 1. 1  D efi niti o n  of   A d v e rs e   E v e nts,  S e ri o us   A d v e rs e   E v e nts,   A d v e rs e   E v e nts  of  S p e ci al I nt e r est
 ............................................................................................................................................... 8 3  
1 1. 2  A d v e rs e   E v e nt  a n d  S e ri o us   A d v e rs e   E v e nt   R e c o r di n g  a n d   R e p o rti n g  ........................... 8 5  
1 1. 3  P r e g n a n ci es  ........................................................................................................................... 8 6  
1 2  D  A  T  A   H  A  N  D  LI  N  G   A  N  D   A  R  C  HI  VI  N  G  ..................................................................................... 8 8  
1 2. 1  C o  m pl eti n g  a n d  Si g ni n g   C a se   R e p o rt  F o r  ms  .................................................................... 8 8  
1 2. 2  Cli ni c al   D at a   M a n a g e  m e nt  .................................................................................................. 8 8  
1 2. 3  A r c hi vi n g  a n d  Fili n g  ............................................................................................................ 8 8  
1 3  S  T  A  TI S  TI  C  A  L   M  E  T  H  O  D S   A  N  D  P  L  A  N  N  E  D   A  N  A  L  Y S  E S  ..................................................... 8 9  
1 3. 1  P o p ul ati o ns f o r A n al ysis  ...................................................................................................... 8 9  
1 3. 2  G e n e r al  St atisti c al   M et h o ds  ................................................................................................ 9 0  
1 3. 3  P ati e nt   Dis p ositi o n,   B as eli n e  a n d   T r e at  m e nt   C h a r a ct e risti cs  .......................................... 9 0  
1 3. 4  A n al ysis  of   Effi c a c y   D at a  ..................................................................................................... 9 1  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 7  of 1 3 1  
1 3. 4. 1  
Ass ess  m e nt  of  Effi c a c y   V ari a bl es:   C o -Pri  m ar y  E n d p oi nts  .................................. 9 3  
1 3. 4. 2  
A n al ys es  of t h e  S e c o n d ar y  Effi c a c y  E n d p oi nts  ................................................... 9 4  
1 3. 4. 2. 1  
B est   O bj e cti v e   R es p o ns e   R at e  ............................................................................. 9 5  
1 3. 4. 2. 2  
D ur ati o n  of   R es p o ns e  ........................................................................................... 9 6  
1 3. 4. 2. 3  
Dis e as e   C o ntr ol   R at e  ............................................................................................ 9 6  
1 3. 4. 2. 4  
Ti  m e t o  Pr o gr essi o n  ............................................................................................. 9 6  
1 3. 4. 2. 5  
O v er all  S ur vi v al  ................................................................................................... 9 7  
1 3. 4. 2. 6  
Ti  m e t o   N e xt  Tr e at  m e nt  ....................................................................................... 9 7  
1 3. 5  Q u alit y  of   Lif e   Q u esti o n n ai r es   E  O  R  T  C   Q  L  Q -C 3 0  a n d E  Q- 5  D -5  L  ................................ 9 7  
1 3. 6  I  m  m u n o g e ni cit y   A n al ysis .................................................................................................... 9 8  
1 3. 7  P h a r  m a c o ki n eti c   A n al ysis  ................................................................................................... 9 8  
1 3. 8  A n al ysis  of  S af et y   D at a  ........................................................................................................ 9 8  
1 3. 8. 1  
A d v ers e  E v e nts  .................................................................................................... 9 8  
1 3. 8. 2  
Cli ni c al  L a b or at or y  E v al u ati o ns  .......................................................................... 9 9  
1 3. 8. 3  
P h ysi c al  E x a  mi n ati o n  ......................................................................................... 1 0 0  
1 3. 8. 4  
Vit al  Si g ns  .......................................................................................................... 1 0 0  
1 3. 8. 5  
El e ctr o c ar di o gr a  ms ( 1 2 -l e a d  E  C  G) .................................................................... 1 0 0  
1 3. 9  Bi o  m a r k e rs  ......................................................................................................................... 1 0 1  
1 3. 1 0  Ot h e r   D at a  .......................................................................................................................... 1 0 1  
1 3. 1 1  S a  m pl e  Si z e   D et e r  mi n ati o n  ............................................................................................... 1 0 1  
1 3. 1 1. 1  
P ar a  m et ers  a n d   R es ults  of  S a  m pl e  Si z e   D et er  mi n ati o n  ..................................... 1 0 1  
1 3. 1 2  I nt e ri  m   A n al ysis ................................................................................................................. 1 0 5  
1 3. 1 3  P r o c e d u r es f o r   Missi n g,   U n us e d,  a n d  S p u ri o us   D at a  ..................................................... 1 0 5  
1 3. 1 4  R ul es f o r   E x cl u di n g  P ati e nts f r o  m   A n al ysis  .................................................................... 1 0 5  
1 3. 1 5  P r o c e d u r es f o r   R e p o rti n g   D e vi ati o ns f r o  m   O ri gi n al  St atisti c al  Pl a n ............................ 1 0 6  
1 4  S P  E  CI  A  L   R  E  Q  UI  R  E  M  E  N  T S   A  N  D  P  R  O  C  E  D  U  R  E S  ............................................................... 1 0 6  
1 4. 1  I n d e p e n d e nt   D at a   M on it o ri n g   C o  m  mitt e e (I  D  M  C) ........................................................ 1 0 6  
1 4. 2  I n d e p e n d e nt   R a di ol o g y/  Cli ni c al   R e vi e  w   C o  m  mitt e e (I  R  C)  ........................................... 1 0 7  
1 4. 3  P r ot o c ol   A  m e n d  m e nts  a n d   Ot h e r   C h a n g es i n  St u d y   C o n d u ct  ...................................... 1 0 8  
1 4. 4  R e g ul at o r y  a n d   Et hi c al   C o nsi d e r ati o ns, I n cl u di n g t h e I nf o r  m e d   C o ns e nt  P r o c ess ..... 1 0 8  
1 4. 5  Q u alit y   C o nt r ol ( St u d y   M o nit o ri n g)  ................................................................................ 1 0 9  
1 4. 6  Q u alit y   Ass u r a n c e  .............................................................................................................. 1 0 9  
1 4. 7  I ns u r a n c e ............................................................................................................................ 1 0 9  
1 4. 8  P u bli c ati o n  P oli c y  ............................................................................................................... 1 1 0  
1 5  R  E F  E  R  E  N  C  E S ............................................................................................................................. 1 1 1  
1 6  A P P  E  N  DI  C  E S  .............................................................................................................................. 1 1 8  
1 6. 1  A p p e n di x   A:   C o c k c r oft -G a ult  F o r  m ul a  ........................................................................... 1 1 8  
1 6. 2  A p p e n di x   B:   Hi g hl y   Eff e cti v e   C o nt r a c e pti o n  .................................................................. 1 1 9  
1 6. 3  A p p e n di x   C:   O v e r vi e  w  of  p u blis h e d  d at a  o n   N  K  C  C  as  a  p r o g n osti c f a ct o r 
i n D  L  B  C  L  a n d  F  L  .............................................................................................................. 1 2 0  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 8  of 1 3 1  
1 6. 4  A p p e n di x   D:   K a r n ofs k y  P e rf o r  m a n c e  St at us  S c al e  ........................................................ 1 2 2  
1 6. 5  A p p e n di x   E:   N e  w   Y o r k   H e a rt   Ass o ci ati o n  F u n cti o n al   Cl assifi c ati o n  ........................... 1 2 3  
1 6. 6  A p p e n di x  F: I nf o r  m ati o n  o n I n v esti g ati o n al  a n d   R e gist e r e d  P r o d u cts  ........................ 1 2 4  
1 6. 7  A p p e n di x   G:   E q ui v al e nt   D os es f o r   C o rti c ost e r oi ds  ........................................................ 1 2 5  
1 6. 8  A p p e n di x   H:   B o d y  S u rf a c e   A r e a (  B S  A)   C al c ul ati o n  ...................................................... 1 2 6  
1 6. 9  A p p e n di x I:   A n n   A r b o r  St a gi n g - C ots  w ol ds   R e c o  m  m e n d ati o ns  .................................. 1 2 7  
1 6. 1 0  A p p e n di x  J: I nt e r n ati o n al  P r o g n osti c I n d e x (I PI)  .......................................................... 1 2 8  
1 6. 1 1  A p p e n di x   K:   E  C  O  G  P e rf o r  m a n c e  St at us  ........................................................................ 1 2 9  
1 6. 1 2  A p p e n di x   L:   R es p o ns e   C rit e ri a  ........................................................................................ 1 3 0  
 
2. 2  List  of   T a bl es  
( E x cl u di n g t h os e i n t h e  a p p e n di x) 
 
T a bl e  1:  
D efi niti o n  of I nf usi o n-R el at e d   R e a cti o n  ...................................................................... 5 1  
T a bl e  2:  
Crit eri a   R e q uir e d f or t h e I niti ati o n  of   B E  N  Tr e at  m e nts  ............................................... 5 3  
T a bl e  3:  
B E  N   D os e   R e d u cti o n   Crit eri a  ...................................................................................... 5 4  
T a bl e  4:  
B E  N   D os e  L e v els  ......................................................................................................... 5 5  
T a bl e  5:  
S c h e d ul e  of   Ass ess  m e nts  ............................................................................................. 6 4  
T a bl e  6:  
L a b or at or y  E v al u ati o ns  ................................................................................................ 7 8  
T a bl e  7:  
A n al ysis  S ets  ................................................................................................................ 8 9  
T a bl e  8:  
Ass u  m pti o ns f or  S a  m pl e  Si z e  Esti m ati o n ( ori gi n al st u d y  d esi g n  a n d  ass u  m pti o ns)  .. 1 0 2  
T a bl e  9:  
P o  w er   C al c ul ati o n f or   O v er all  P o p ul a ti o n  a n d t h e   N  K  C  C-l o  w  S u b gr o u p ( as  a 
c o ns e q u e n c e  of  al p h a s plitti n g)  u n d er  diff er e nt s c e n ari os  ......................................... 1 0 3  
T a bl e  1 0:  
O p er ati n g   C h ar a ct eristi cs f or   O S  at t h e  Fi n al   A n al ysis .............................................. 1 0 4  
T a bl e  1 1:  
P o  w er   A n al ys es f or   O S  .............................................................................................. 1 0 4  
T a bl e  1 2:  
I  D  M  C   D e cisi o n   G ui d e   B as e d  o n   R es ults  of t h e I nt eri  m   A n al ysis ( n o n-bi n di n g)  ...... 1 0 5  
 
2. 3  List  of  Fi g u r es  
Fi g ur e  1:  
R e cr uit  m e nt  a n d  St u d y  Fl o  w  ........................................................................................ 3 7  
Fi g ur e  2:  
St u d y   D esi g n  ................................................................................................................ 3 8  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 9  of 1 3 1  
3  LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N S   A  N  D   D  E FI  NI  TI  O  N S   O F   T  E  R  M S  
A  B  C  
A cti v at e d   B -c ell 
A  D  C  C  
A nti b o d y -d e p e n d e nt c ell-m e di at e d  c yt ot o xi cit y 
A  D  C P  
A nti b o d y -d e p e n d e nt  c ell -m e di at e d  p h a g o c yt osis  
A E  
A d v ers e  e v e nt  
A E SI  
A d v ers e  e v e nt  of s p e ci al i nt er est  
A L L  
A c ut e l y  m p h o bl asti c l e u k a e  mi a  
A L T  
Al a ni n e tr a ns a  mi n as e  
A  N  C  
A bs ol ut e  n e utr o p hil  c o u nt  
a nti-H  B c  
H e p atitis   B vir us c or e  a nti b o d y  
a nti-H  C  V  
H e p atitis   C  vir us  a nti b o d y  
A S  C T  
A ut ol o g o us st e  m -c ell tr a ns pl a nt ati o n  
A S T  
As p art at e  a  mi n otr a nsf er as e  
A T  C  
A n at o  mi c al  T h er a p e uti c   C h e  mi c al ( cl ass)  
B  C L 2/ 6  
B- c ell   C L L/l y  m p h o  m a  2/ 6  
B  C  R 
B- c ell  a nti g e n r e c e pt or  
B E  N 
B e n d a  m usti n e  
b p  m  
B e ats  p er   mi n ut e ( h e art r at e)  
B S  A  
B o d y s urf a c e  ar e a  
B S  C 
B est s u p p orti v e  c ar e  
C 1  D 4  
C y cl e  1   D a y  4  
C  D  C  
C o  m pl e  m e nt  d e p e n d e nt  c yt ot o xi cit y  
C  D 1 6/ 1 9 / 2 0 
Cl ust er  of  diff er e nti ati o n 1 6/ 1 9 / 2 0 
C  H  O P  
C y cl o p h os p h a  mi d e,  h y dr o x y d a u n or u bi ci n ( als o r ef err e d t o  as  d o x or u bi ci n  or 
a dri a  m y ci n),  o n c o vi n ( vi n cristi n e)  a n d  pr e d nis o n e  or  pr e d nis ol o n e   
CI 
C o nfi d e n c e i nt er v al  
C L L 
C hr o ni c l y  m p h o c yti c l e u k a e  mi a  
C  N S  
C e ntr al  n er v o us s yst e  m  
C  O P  D  
C hr o ni c o bstr u cti v e  p ul  m o n ar y  dis e as e  
C P  H 
C o x  pr o p orti o n al  h a z ar ds  
C  R 
C o  m pl et e r es p o ns e /r e  missi o n 
C  R  O 
C o ntr a ct r es e ar c h o r g a nis ati o n 
C T 
C o  m p ut e d t o  m o gr a p h y  
C T  C  A E 
C o  m  m o n  T er  mi n ol o g y   Crit eri a f or   A d v ers e  E v e nts  
C T F  G  
Cli ni c al  Tri al  F a cilit ati o n   Gr o u p  
D  A -E P  O  C  H -R  
D os e -a dj ust e d  E P  O  C  H -R (et o p osi d e, p r e d nis o n e, o n c o vi n  [ vi n cristi n e], 
cy cl o p h os p h a  mi d e  a nd  h y dr o x y d a u n or u bi ci n  [d o x or u bi ci n ] pl us rit u xi  m a b ) 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 0  of 1 3 1  
D  C  R  
Dis e as e  c o ntr ol r at e  
D  H  A P  
Cis pl ati n,  c yt ar a bi n e,  d e x a  m et h as o n e  
D L  B  C L  
Diff us e l ar g e   B -c ell l y  m p h o  m a  
D L  C  O  
Diff usi o n  c a p a cit y  of t h e l u n g f or  c ar b o n   m o n o xi d e  
D  N  A  
D e o x yri b o n u cl ei c  a ci d  
D o  R  
D ur ati o n  of r es p o ns e  
D P  
Dr u g  pr o d u ct  
E  B  V  
E pst ei n -B arr  vir us  
E  C  G  
El e ctr o c ar di o gr a  m  
E  C  O  G  
E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p  
e  C  R F  
El e ctr o ni c  c as e r e p ort f or  m  
E  D T  A  
Et h yl e n e di a  mi n et etr a a c eti c  a ci d  
E  M  A  
E ur o p e a n M e di ci n es   A g e n c y  
E  O  R T  C   Q L  Q -C 3 0  
E ur o p e a n   Or g a nis ati o n f or   R es e ar c h  a n d  Tr e at  m e nt  of   C a n c er   Q u alit y  of  Lif e 
Q u esti o n n air e -C or e  3 0  
E  O T  
E n d  of tr e at  m e nt  
E  Q -5  D -5 L  
E ur o  Q ol  fi v e  di  m e nsi o ns  q u alit y  of lif e  q u esti o n n air e,  5 l e v els 
E S  H  A P  
Et o p osi d e,   m et h yl pr e d nis o n e,  c yt ar a bi n e,  cis pl ati n  
E u dr a  C T  
E ur o p e a n   U ni o n   Dr u g   R e g ul ati n g   A ut h oriti es   Cli ni c al  Tri als r e gist er  
F  A S  
F ull  a n al ysis s et  
F  C  B P  
F e  m al e  of  c hil d b e ari n g  p ot e nti al  
F c γ  R  
F c  g a  m  m a r e c e pt or  
F  D  A  
F o o d  a n d   Dr u g   A d  mi nistr ati o n  
F  D  G  
[1 8F]fl u or o d e o x y gl u c os e  
F E  V -1  
F or c e d  e x pir at or y  v ol u  m e i n  1 s e c o n d  
FI S  H  
Fl u or es c e n c e i n sit u h y bri dis ati o n  
F L  
F olli c ul ar l y  m p h o  m a  
F  N  A  
Fi n e  n e e dl e  as pir at e  
F  U  
F oll o  w -u p  
F  V  C  
F or c e d  vit al c a p a cit y 
G  C  B  
G er  mi n al  c e ntr e   B -c ell  
G  C P  
G o o d   Cli ni c al  Pr a cti c e  
G -C S F  
G r a n ul o c yt e  c ol o n y-sti  m ul ati n g f a ct or 
G  G T  
G a  m  m a -gl ut a  m yltr a nsf er as e  
G L P  
G o o d  L a b or at or y  Pr a ct ic e 
H  Bs  A b  
H e p atitis   B vir us s urf a c e  a nti bo d y  
H  Bs  A g  
H e p atitis   B vir us s urf a c e a nti g e n 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 1  of 1 3 1  
H  B  V  
H e p atitis   B  vir us  
H  C  V  
H e p atitis   C  vir us  
H  D  C  
Hi g h -d os e  c h e  m ot h er a p y  
HI  V  
H u  m a n i  m  m u n o d efi ci e n c y  vir us  
H  R  
H a z ar d r ati o  
I  A S 
I  m  m u n o g e ni cit y  a n al ysis s et 
I  B 
I n v esti g at or’s B r o c h ur e 
I  C E 
If osf a  mi d e,  c ar b o pl ati n,  et o p osi d e 
I  C F 
I nf or  m e d c o ns e nt f or  m  
I  C  H 
I nt er n ati o n al   C o nf er e n c e  o n   H ar  m o nis ati o n 
I  D  M  C 
I n d e p e n d e nt   D at a   M o nit ori n g   Co  m  mitt e e  
I E  C 
I n d e p e n d e nt  Et hi cs   C o  m  mitt e e 
I g 
I  m  m u n o gl o b uli n 
I  N  D 
I n v esti g ati o n al   N e  w   Dr u g  a p pli c ati o n 
I  N  N 
I nt er n ati o n al   N o n-pr o pri et ar y   N a  m e  
I PI 
I nt er n ati o n al P r o g n osti c In d e x  
I  R  B 
I nstit uti o n al   R e vi e  w   B o ar d 
I  R  C 
I n d e p e n d e nt   R a di ol o g y/  Cli ni c al   R e vi e  w   C o  m  mitt e e 
I  R  R 
I nf usi o n-r el at e d r e a cti o n 
I  R T 
I nt er a cti v e r es p o ns e t e c h n ol o g y 
I  V 
I ntr a v e n o us(l y) 
L  
Li  mit e d ( p h ysi c al  e x a  mi n ati o n)  
L  D  H  
L a ct at e  d e h y dr o g e n as e  
L E  N  
L e n ali d o  mi d e  
m  A b  
M o n o cl o n al  a nti b o d y  
M  C L  
M a ntl e   C ell  L y  m p h o  m a  
M e d  D  R  A  
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es  
M  RI  
M a g n eti c r es o n a n c e i  m a gi n g  
M  Y  C  
v -m y c  a vi a n   m y el o c yt o  m at osis  vir al  o n c o g e n e  h o  m o lo g  
N  A b  
N e utr alisi n g  a nti b o d y  
N  CI  
N ati o n al   C a n c er I nstit ut e  
N  H L  
N o n -H o d g ki n l y  m p h o  m a  
N  K  
N at ur al  kill er  
N  K  C  C  
N at ur al  kill er  c ell  c o u nt  
N  K  C  C -hi g h  
Hi g h  b as eli n e  n at ur al  kill er  c ell  c o u nt  
N  K  C  C -l o  w 
L o  w  b as eli n e  n at ur al  kill er  c ell  c o u nt  
N  O S  
N ot  ot h er  wis e s p e cifi e d  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 2  of 1 3 1  
N S  AI  D  
N o nst er oi d al  a nti -i nfl a  m  m at or y  dr u g 
N  Y  H  A  
N e  w   Y or k   H e art   Ass o ci ati o n  
O  R  R  
O bj e cti v e r es p o ns e r at e ( c o  m pl et e r es p o ns e  +  p arti al r es p o ns e) 
O S  
O v er all s ur vi v al  
P  B  M  Cs  
P eri p h er al  bl o o d   m o n o n u cl e ar  c ells  
P  D  
P h ar  m a c o d y n a  mi c (s) 
P E  
P h ysi c al  e x a  mi n ati o n  
P E T  
P ositr o n  e  missi o n t o  m o gr a p h y  
P F S  
Pr o gr essi o n -fr e e s ur vi v al 
P  K  
P h ar  m a c o ki n eti c (s) 
P  K  A S  
P  K  a n al ysis s et  
P L T  
Pl at el et  
P  M  B L  
P ri  m ar y   m e di asti n al l ar g e   B-c ell l y  m p h o  m a 
p. o.  
p er  os ,  by   m o ut h  
P P S  
P er -pr ot o c ol s et  
P  R  
P arti al r es p o ns e /r e  missi o n 
P  R ( E  C  G)  
P  R i nt er v al  
Q o L  
Q u alit y  of lif e  
Q  R S  
Q  R S i nt er v al  
Q T  
Q T i nt er v al  
Q T c  
C orr e ct e d Q T i nt er v al  
Q T c  B  
B a z ett’s Q T i nt er v al c orr e cti o n  
Q T c F  
Fri d eri ci a’s   Q T i nt er v al c orr e cti o n  
R  
R a n d o  mi z ati o n  
R  B  C  
R e d  bl o o d  c ell  
R -C  H  O P  
Rit u xi  m a b  pl us c y cl o p h os p h a  mi d e,  h y dr o x y d a u n or u bi ci n ( als o r ef err e d t o  as 
d o x or u bi ci n  or  a dri a  m y ci n),  o n c o vi n ( vi n cristi n e)  a n d  pr e d nis o n e  or 
pr e d nis ol o n e   
R  N  A  
Ri b o n u cl ei c  a ci d  
rp  m  
R es pir ati o ns  p er   mi n ut e (r es pir ati o n r at e)  
R  R ( E  C  G)  
R el ati v e r at e  
R -R   C L L  
R el a ps e d  or r efr a ct or y  c hr o ni c l y  m p h o c yti c l e u k a e  mi a 
R -R   D L  B  C L  
R el a ps e d  or r efr a ct or y  diff us e l ar g e   B -c ell l y  m p h o  m a  
R -R   N  H L  
R el a ps e d  or r efr a ct or y  n o n -H o d g ki n l y  m p h o  m a  
R T  X  
Rit u xi  m a b  
S  A E  
S eri o us  a d v ers e  e v e nt  
S  A F  
S af et y  a n al ysis s et  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 3  of 1 3 1  
S  A P  
St atisti c al A n al ysis  Pl a n  
S  CI  D  
S e v er e  c o  m bi n e d i  m  m u n o d efi ci e n c y  
S  D  
St a bl e  dis e as e  
S L L  
S  m all l y  m p h o c yti c l y  m p h o  m a  
S  m P  C  
S u  m  m ar y  of  Pr o d u ct   C h ar a ct eristi cs  
S  O  C  
S yst e  m   Or g a n   Cl ass  
S  O P  
St a n d ar d  o p er ati n g  pr o c e d ur e  
S P  D  
S u  m  of t h e  pr o d u ct  of t h e  di a  m et ers  
S P  M  
S e c o n d  pri  m ar y   m ali g n a n c y  
T  B  
T u b er c ul osis  
T E  A E  
Tr e at  m e nt -e  m er g e nt  a d v ers e  e v e nt  
T E  N  
T o xi c  e pi d er  m al  n e cr ol ysis  
T  H  R L  B  C L  
T  c ell/ histi o c yt e ri c h l ar g e   B -c ell l y  m p h o  m a  
T L S  
T u  m o ur l ysis s y n dr o  m e  
T  N  M  
T u  m o ur/  N o d e/  M et ast asis  
T T P  
Ti  m e t o pr o gr essi o n  
T T  N T  
Ti  m e t o  n e xt tr e at  m e nt  
U L  N  
U p p er li  mit  of  n or  m al  
U S  
U nit e d  St at es  
U S  A  N  
U nit e d  St at es   A d o pt e d   N a  m e  
V  A S  
Vis u al a n al o g u e s c al e 
VI  M  
Et o p osi d e, if osf a  mi d e,   m et h otr e x at e  or   mit o x a ntr o n e  
W  B  C  
W hit e  bl o o d  c ell  
W FI  
W at er f or i nj e cti o n 
W  H  O  
W orl d   H e alt h   Or g a ni z ati o n  
β -H  C  G  
B et a -h u  m a n  c h ori o ni c  g o n a d otr o pi n  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 4  of 1 3 1  
4  B  A  C  K  G  R  O  U  N  D  
4. 1  O v e r vi e  w  of   N o n -H o d g ki n   L y  m p h o  m a s 
N o n -  H o d g ki n l y  m p h o  m as (N  H Ls )  a c c o u nt f or  a p pr o xi  m at el y  5  %  of  all  n e  w  c a n c er  c as es  a n d 
c o  m pris e  a  h et er o g e n e o us  gr o u p  of l y  m p h o pr olif er ati v e   m ali g n a n ci es,   w hi c h i n  9 0  %  of  c as es  ar e 
d eri v e d fr o  m   B -c ells. 
 
Diff us e l ar g e   B - c ell l y  m p h o  m a (  D L  B  C L), t h e   m ost  c o  m  m o n   N  H L,  a c c o u nts f or  a p pr o xi  mat el y 
3 0  %  of   N  H Ls (Ar  mit a g e  a n d   W eis e n b ur g er  1 9 9 8 , S  w er dl o  w  et  al.  2 0 0 8 ) a n d  c o  m pris es  6 0  %  of 
all  n e  w l y  m p h o  m as i n t h e  el d erl y (T hi e bl e  m o nt  a n d   C oiffi er  2 0 0 7 ). T h er e is  a sli g ht 
pr e d o  mi n a n c e  of t h e   m al e  g e n d er ( 5 5  %) (M ort o n  et  al.  2 0 0 6 ).   D L  B  C L i n ci d e n c e i n cr e as es   wit h 
a g e, wit h  a   m e di a n  a g e  at  di a g n osis  of  6 4  y e ars (S h e n o y  et  al.  2 0 1 1 ). 
 
At  pr es e nt, D L  B  C L  n ot  ot h er  wis e s p e cifi e d (  N  O S)  c a n  b e f urt h er s u b di vi d e d i nt o  at l e ast 
t  w o   m ol e c ul ar  gr o u ps  b y  g e n e  e x pr essi o n  pr ofili n g:  g er  mi n al  c e ntr e   B-c ell (  G  C  B)  a n d  a cti v at e d 
B- c ell (  A  B  C)  s u bt y p es (R os e n  w al d  et  al.  2 0 0 2 , L e n z  et  al.  2 0 0 8 ). 
 
4. 2  T r e at  m e nt  of   D  L  B  C  L  
First -li n e tr e at  m e nt  e ns ui n g im  m e di at el y  aft er  di a g n osis  a n d st a gi n g  of   D L  B  C L  a n d  c o  m prisi n g 
rit u xi  m a b (  R T  X)  c o  m bi n e d   wit h C  H  O P  c h e  m ot h er a p y  (  R-C  H  O P:   R T  X pl us  c y cl o p h os p h a  mi d e, 
d o x or u bi ci n,  vi n cristi n e,  a n d  pr e d nis o n e ) is  c urr e ntl y t h e st a n d ar d  of  c ar e (C oiffi er  et  al.  2 0 0 2 , 
F e u gi er  et  al.  2 0 0 5 , H a b er  m a n n  et  al.  2 0 0 6).  Th e   R- C  H  O P r e gi  m e n is  a  “ pl atf or  m ”  c o  m bi n ati o n 
t h er a p y,   w hi c h   m a y  b e   m o difi e d i n  or d er t o i n cr e as e its t h er a p e uti c  effi c a c y,  e. g.   D  A-E P  O  C  H -R 
( d os e- a dj ust e d  et o p osi d e,  pr e d nis o n e,  o n c o vi n,  c y cl o-p h os p h a  mi d e  a n d  h y dr o x y d a u n or u bi ci n 
pl us rit u xi  m a b;  Wils o n  et  al. ( 2 0 1 2) .   Ne v ert h el ess,  e v e n   wit h t h e  a v ail a bilit y  of   R -C  H  O P -li k e 
tr e at  m e nt r e gi  m e ns,  a p pr o xi  m at el y  4 0– 5 0  %  of  p ati e nts   will  ulti  m at el y s u c c u  m b t o t h e  dis e as e, 
wit h  3 0 – 4 0  %  of p ati e nts r el a psi n g a n d  1 0  %  h a vi n g  a  di a g n osis  of  pri  m ar y  pr o gr essi v e  dis e as e  or 
b ei n g  n o n-r es p o n d ers (Pfr e u n ds c h u h  et  al.  2 0 0 8 , Pfr e u n ds c h u h  et  al.  2 0 1 1 ). 
 
P ati e nts  pr o gr essi n g  or r el a psi n g  aft er first -li n e tr e at  m e nt   will  b e  e v al u at e d f or t h eir  eli gi bilit y 
f or i nt e nsifi e d s al v a g e tr e at  m e nt str at e gi es   w hi c h  c a n l e a d t o l o n g-t er  m r e  missi o ns.  E x a  m pl es of 
s u c h s al v a g e  c h e  m ot h er a p y i n cl u d e   D  H  A P ( cis pl ati n,  c yt ar a bi n e,  d e x a  m et h as o n e),   VI  M 
( et o p osi d e, if osf a  mi d e,   m et h otr e x at e  or   mit o x a ntr o n e), I  C E (if osf a  mi d e,  c ar b o pl ati n,  et o p osi d e) 
a n d  E S  H  A P ( et o p osi d e,   m et h yl pr e d nis o n e,  c yt ar a bi n e,  cis pl ati n).  F or  p ati e nts   wit h 
c h e  m ot h er a p y- s e nsiti v e  dis e as e,  a ut ol o g o us st e  m-c ell tr a ns pl a nt ati o n  (  A S  C T)  as  c o ns oli d ati o n 
t h er a p y si g nifi c a ntl y i  m pr o v es t h e  o ut c o  m e  of s e c o n d-li n e t h er a p y.   A p pr o xi  m at el y  1 0 – 5 0  %  of 
p ati e nts tr e at e d   wit h a n i nt e nsifi e d r e gi  m e n i n s e c o n d-li n e  a c hi e v e  a l o n g-t er  m r e  missi o n  a n d 
c ur e (P hili p  et  al.  1 9 9 5 ). 
 
U nf ort u n at el y,  o nl y  a p pr o xi  m at el y  5 0  %  of  p ati e nts wit h r el a ps e d  or r efr a ct or y ( R-  R) D L  B  C L  ar e 
eli gi bl e f or a n i nt e nsifi e d tr e at  m e nt str at e g y, d u e   m ai nl y t o  c ar di a c  c o  m or bi diti es,  d e cr e as e d 
h a e  m at o po i eti c r es er v e, r e d u c e d  h e p ati c f u n cti o n or  a d v a n c e d  a g e, r estri cti n g t h e b e n efit  of t his 
a g gr essi v e  a p pr o a c h t o  a r el ati v el y s  m all s u bs et  of  p ati e nts (M orris o n  et  al.  2 0 1 4 ).  Si  mil arl y, 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 5  of 1 3 1  
o nl y  y o u n g er  a n d fit  p ati e nts  c a n  b e  e v al u at e d f or  all o g e n ei c st e  m c ell tr a ns pl a nt ati o n (Tr u el o v e 
et  al.  2 0 1 4). 
 
S e v er al tr e at  m e nt r e gi  m e ns  h a v e  b e e n d es cri b e d f or p ati e nts t h at r el a ps e  aft er i nt e nsifi e d 
s e c o n d-li n e tr e at  m e nt  or   w h o  ar e  n ot  eli gi bl e f or a n i nt e nsifi e d s e c o n d-li n e r e gi  m e n. D es pit e 
r e c e nt  a d v a n c es, t h e tr e at  m e nt  o pti o ns f or  p ati e nts   w h o  h a v e r el a ps e d  or  pr o gr ess e d  aft er 
s e c o n d-li n e tr e at  m e nt  of   D L  B  CL ,  or   w h o  ar e  n ot  eli gi bl e f or   A S  C T r e  m ai n li  mit e d.    
  
 
O n  3 1 J ul y  2 0 2 0, t h e   U. S.  F o o d  a n d   Dr u g   A d  mi nistr ati o n ( F  D  A)  a ut h ori z e d t af asit a  m a b-c xi x 
(  M o nj u vi  ®) i n  c o  m bi n ati o n   wit h l e n ali d o  mi d e f or   m ar k eti n g  u n d er t h e  pr o visi o n  of  ac c el er at e d 
a p pr o v al f or t h e tr e at  m e nt  of  a d ult  p ati e nts   wit h   R/  R   D L  B  C L. T af asit a  m a b -c xi x (  Mi nj u vi ® )  h as 
als o  b e e n  a p pr o v e d f or   m ar k eti n g ( c o n diti o n al  a p pr o v al) i n  E  U  ( 2 6   A u g ust  2 0 2 1), i n   U  K 
( 0 8 O ct o b er  2 0 2 1)   a n d i n   C a n a d a ( 1 9   A u g ust  2 0 2 1) i n  c o  m bi n ati o n   wit h l e n ali d o  mi d e f or t h e 
tr e at  m e nt  of  a d ult  p ati e nts   wit h   R/  R   D L  B  C L. 
 
Alt h o u g h   R T  X is   wi d el y  us e d i n t h e tr e at  m e nt  of   R- R   D L  B  C L f oll o  wi n g   R T  X -b as e d first -li n e 
t h er a p y,  cli ni c al st u di es  h a v e  d e  m o nstr at e d t h at  p ati e nts   w h o  h a v e r e c ei v e d  pri or   R T  X  ar e l ess 
li k el y t o r es p o n d t o   R T  X-c o nt ai ni n g s al v a g e t h er a pi es (M arti n  et  al.  2 0 0 8 , Giss el br e c ht  et  al. 
2 0 1 0 ).  Th er ef or e, t h e  d e v el o p  m e nt  of   m or e  eff e cti v e s al v a g e t h er a p y is  ess e nti al t o i  m pr o v e 
l o n g-t er  m  o ut c o  m es. 
 
M o n o cl o n al  a nti b o d y (  m  A b) t h er a p y   m a y h a v e t h e  p ot e nti al t o i  m pr o v e  o bj e cti v e r es p o ns e r at es 
(  O  R  Rs)  a n d o v er all s ur vi v al ( O S ) i n t his s etti n g wit h o ut i n cr e asi n g  h a e  m at ol o gi c al t o xi cit y.  T his 
p ossi bilit y is s u p p ort e d  b y  d at a fr o  m st u di es i n v esti g ati n g   C  D 1 9   m  A bs, i n cl u di n g   M  D  X- 1 3 4 2, 
S  A  R 3 4 1 9  a n d M E  DI - 5 5 1 (B ar g o u  et  al.  2 0 0 8 , Vi ar d ot  et  al.  2 0 1 1 , Y o u n es  et  al.  2 0 1 2 , 
M atl a  ws k a -  W as o  ws k a  et  al.  2 0 1 3, Ri br a g  et  al.  2 0 1 4 ). 
 
4. 3  B e n d a  m usti n e i n   D  L  B  C  L   T r e at  m e nt  
B e n d a  m usti n e (  B E  N ) is  a  c h e  m ot h er a p e uti c  a g e nt, s y nt h esis e d  as  a  h y bri d  of  a  p uri n e  a n al o g u e 
a n d  a n  al k yl at or. It h as  b e e n  d e  m o nstr at e d  i n  vitr o t h at   B E  N is  a cti v e i n c ell li n es   w hi c h  ar e 
r esist a nt t o s e v er al  ot h er  al k yl ati n g  a g e nts (B alf o u r  a n d   G o a  2 0 0 1, L e o ni  et  al.  2 0 0 8 ).  Th e 
m e c h a nis  m  of  a cti o n  of   B E  N is  n ot f ull y  el u ci d at e d  b ut i n v ol v es t  w o s e p ar at e   m et a b oli c 
p at h  w a ys,  o n e l e a di n g t o  d e o x yri b o n u cl ei c  a ci d (  D  N  A)  d a  m a g e,  pr o v o ki n g  a p o pt osis  a n d 
a n ot h er l e a di n g t o t h e  disr u pti o n  of  c ell  di visi o n.  T h e l att er   m e c h a nis  m is  k n o  w n  as   mit oti c 
c at astr o p h e.  T h e  d u al  eff e ct   m a y  b e  attri b ut a bl e t o t h e  c h e  mi c al str u ct ur e  of t h e   B E  N   m oi et y, 
w hi c h  c o  m pris es  a  2 -c hl or o et h yl a  mi n e  al k yl ati n g  gr o u p,  a  b e n zi  mi d a z ol e ri n g,  a n d  a  b ut yri c  a ci d 
si d e  c h ai n (L e o ni  et  al.  2 0 0 8 , L e o ni  2 0 1 1 ). 
 
B E  N is  a p pr o v e d i n s e v er al c o u ntri es   w orl d  wi d e f or t h e tr e at  m e nt  of  p ati e nts   wit h r el a ps e d 
r efr a ct or y i n d ol e nt l y  m p h o  m as,  c hr o ni c l y  m p h o c yti c l e u k a e  mi a (C L L )  a n d i n s o  m e  c o u ntri es, f or 
m ulti pl e   m y el o  m a.  
 
B E  N   w as  st u di e d  as   m o n ot h er a p y  a n d i n  c o  m bi n ati o n   wit h  ot h er  c h e  m ot h er a p e uti c  a n d/ or 
bi ol o gi c al  a g e nts ( e. g.   R T  X) i n   R-  R a g gr essi v e   N  H L,  yi el di n g O  R  R s fr o  m  3 2% t o  6 2. 7  %, wit h 
m e di a n pr o gr essi o n -fr e e s ur vi v al (P F S ) ti  m es  b et  w e e n  3. 6  a n d  6. 7   m o nt hs. Si  mil arl y , t h e 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 6  of 1 3 1  
c o  m bi n ati o n  of   B E  N  a n d   R T  X  us e d  as first- li n e tr e at  m e nt i n  p ati e nts n ot  eli gi bl e f or i nt e nsi v e 
c h e  m ot h er a p y r e gi  m e ns a c hi e v e d a n O  R  R  of 6 9  %, i n cl u di n g l o n g- l asti n g  c o  m pl et e r e  missi o ns, 
a n d  a   m e di a n  P F S  of  7. 7   m o nt hs (W ei d  m a n n  et  al.  2 0 0 2 , O g ur a  et  al.  2 0 1 1 , H or n  et  al.  2 0 1 2 , 
Ri g a c ci  et  al.  2 0 1 2 , W alt er  et  al.  2 0 1 2 , O h  m a c hi  et  al.  2 0 1 3 , V a cir c a  et  al.  2 0 1 4 ). 
T h er ef or e,  it   m a y  b e  c o n cl u d e d t h at R T  X wit h  B E  N c o  m p ar es f a v o ur a bl y i n t er  ms  of  effi c a c y 
wit h  ot h er r e gi  m e n s f or t his  diffi c ult-t o-tr e at  p ati e nt  p o p ul ati o n (C ol osi a  et  al.  2 0 1 4 ). It is 
es p e ci all y r el e v a nt gi v e n  t h at t h e  c o  m bi n ati o n  of R T  X wit h  B E  N  d e  m o nstr at es  a   m a n a g e a bl e 
t o xi cit y  pr ofil e  a n d c a n t h er ef or e  b e  us e d i n  el d erl y  p ati e nts  a n d/ or  p ati e nts   wit h  c o  m or bi diti es. 
I n t h e t  w o l ar g est  a n d   m ost r e c e ntl y  p u blis h e d st u di es i n   R-R   D L  B  C L , t h e  c o  m bi n ati o n  of R T  X 
wit h    B E  N  e v o k e d  pr e d o  mi n a ntl y  h ae  m at ol o gi cal t o xi citi es i n cl u di n g  n e utr o p e ni a, l e u k o p e ni a, 
t hr o  m b o c yt o p e ni a  a n d  a n ae  mi a.  T h e m y el os u p pr essi o n   w as l ar g el y r e v ersi bl e.   C o  m  m o n 
n o n- h a e  m at ol o gi c al a d v ers e  e v e n ts (A Es ) i n cl u d e d  g astr oi nt esti n al s y  m pt o  ms ( e. g., di arr h o e a, 
c o nsti p ati o n,  n a us e a), i nf e cti o ns  a n d f ati g u e (O h  m a c hi  et  al.  2 0 1 3 , V a cir c a  et  al.  2 0 1 4 ). 
 
D u e t o its f a v ou r a bl e  effi c a c y a n d  a d v a nt a g e o us t o xi cit y  pr ofil e t h e  c o  m bi n ati o n  of R T  X   wit h 
B E  N  b e c a  m e  a st a n d ar d  of  c ar e f or t h e tr e at  m e nt  of p ati e nts   wit h D L  B  C L  o v er r e c e nt y e ars.  
 
4. 4  O v e r vi e  w  of  n at u r al  k ill e r (  N  K) c ells i n l y  m p h o  m a , r el e v a n c e t o 
M  O  R 0 0 2 0 8   
S e v er al  p u blis h e d st u di es  h a v e  e v al u at e d  cli ni c al  o ut c o  m es i n r el ati o n t o  hi g h  or l o  w  b as eli n e 
N  K  C  C i n first -li n e  p ati e nts,  e. g.,  p ati e nts  n e  wl y  di a g n os e d wit h D L  B  C L (Ki  m  et  al.  2 0 1 4 , 
Kl a n o v a  et  al.  2 0 1 7 )  or  pr e vi o usl y  u ntr e at e d  pati e nts wit h f olli c ul ar l y  m p h o  m a ( F L)  (H e  et  al. 
2 0 1 6 , Kl a n o v a  et  al.  2 0 1 7 ).  
I n t h e   M  O  R 2 0 8  C 2 0 1 st u d y  a  c ut-off  1 0 0   N  K  c ells/ µ L   w as  pr o g n osti c f or t h e tr e at  m e nt  o ut c o  m e 
of M  O  R 0 0 2 0 8   m o n ot h er a p y i n   D L  B  C L  a n d  F L,   w hil e  ot h er  bl o o d  c ell  p o p ul ati o ns s u c h  as 
l y  m p h o c yt es  a n d  T  c ells s h o  w e d  n o  ass o ci ati o n   wit h t h e tr e at  m e nt  o ut c o  m e.  E v e n t h o u g h  a 
m ulti v ari at e  a n al ysis   w as  n ot  c o n d u ct e d  d u e t o t h e s  m all s a  m pl e si z e,  a str atifi e d  a n al ysis  di d  n ot 
r e v e al  a n y  o b vi o us  c o nf o u n di n g  of t h e   N  K  C  C s u b gr o u ps   wit h  a n y  ot h er  k e y  b as eli n e 
c h ar a ct eristi cs.  T h er ef or e,   N  K  C  C  p ot e nti all y is a n i n d e p e n d e nt f a ct or f or t h e tr e at  m e nt  o ut c o  m e 
of M  O  R 0 0 2 0 8. 
Si  mil ar t o t h e  o bs er v ati o n f or M  O  R 0 0 2 0 8, t h e   m aj orit y  of t h e  p u blis h e d st u di es f or  a nti- C  D 2 0 
a nti b o di es  als o r e p ort e d  a   N  K  C  C  c ut- off  of  1 0 0  c ells/ µ L,   w hi c h s h o  w e d i n d e p e n d e nt  pr o g n osti c 
v al u e.  T h e  c ut- off   w as  g e n er all y  b as e d  o n   m a xi  mi z e d  diff er e n c es i n  P F S  a n d/ or   O S  b et  w e e n 
p ati e nts   wit h  b as e li n e   N  K  C  C-l o  w  a n d   N  K  C  C- hi g h i n cl u d e d i n t h e r es p e cti v e st u di es (Ki  m  et  al. 
2 0 1 4 , H e  et  al.  2 0 1 6 , Kl a n o v a  et  al.  2 0 1 7 ).  
I n t  w o l ar g e  p h as e III tri als i n  p ati e nts   wit h   N  H L – t h e   G  O  Y  A tri al (  N  C T 0 1 2 8 7 7 4 1) i n  p ati e nts 
wit h  n e  wl y  di a g n os e d   D L  B  C L  a n d t h e   G  A L LI  U  M tri al (  N  C T 0 1 3 3 2 9 6 8) i n  p ati e nts   wit h 
pr e vi o usl y  u ntr e at e d  F L  – t h e  pr o g n osti c  c ut-off  of  1 0 0   N  K  c ells/ µ L   w as  als o  us ef ul t o  pr e di ct 
s u p eri orit y  of  a n  F c- e n h a n c e d  a nti-  C  D 2 0   m o n o cl o n al  a nti b o d y ( o bi n ut u z u  m a b)  v ers us  a 
n o n- e n h a n c e d  a nti   C  D 2 0   m o n o cl o n al  a nti b o d y (  R T  X).  T his  d e  m o nstr at es t h at  a   N  K  C  C  c ut- off 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 7  of 1 3 1  
i d e ntifi e d  vi a t h e  pr o g n osti c  eff e ct  c a n  b e  als o  us ef ul t o  pr e di ct s u p eri orit y  of  o n e   m o n o cl o n al 
a nti b o d y  o v er  a n ot h er. 
T h e s p o ns or  c o n d u ct e d  pr e- cli ni c al  e x p eri  m e nts t o i n v esti g at e t h e i n  vitr o   A  D  C  C  a cti vit y  of t h e 
F c - e n h a n c e d   C  D 1 9-s p e cifi c  a nti b o d y M  O  R 0 0 2 0 8 i n  c o  m p aris o n t o t h e   C  D 2 0-s p e cifi c  a nti b o d y 
rit u xi  m a b f or  a r a n g e  of  eff e ct or t o t ar g et ( E: T) r ati os  of   N  K  c ells  a n d   B-c ell t u  m o ur c ell li n es 
d eri v e d fr o  m   D L  B  C L,   m a ntl e  c ell l y  m p h o  m a (  M  C L)  a n d  c hr o ni c l y  m p h o c yti c l e u k a e  mi a (  C L L). 
T h e r es ults  of t h es e i n  vitr o  e x p eri  m e nts s u g g est t h at M  O  R 0 0 2 0 8 l e a ds t o str o n g er 
A  D  C  C --m e di at e d t ar g et  c ell l ysis i n  c o  m p aris o n t o   R T  X   u n d er  c o n diti o ns i n   w hi c h   N  K  c ells  ar e 
li  mit e d.   B as e d  o n t h e  ass u  m pti o n t h at i n  p ati e nts   wit h l o  w  b as eli n e   N  K  C  C,   N  K  c ell  n u  m b ers  at 
t h e t u  m o ur sit e   will  n ot  o ut- n u  m b er t h e  n u  m b er  of t u  m o ur c ells, t h es e  d at a s u p p ort t h e 
h y p ot h esis t h at M  O  R 0 0 2 0 8  c o ul d  h a v e  hi g h er t u  m o ur  killi n g  c a p a cit y  c o  m p ar e d t o rit u xi  m a b i n 
p ati e nts   wit h  a  p eri p h er al   N  K  c ell  c o u nt  of  1 0 0  or l ess   N  K  c ells/ µ L.  
 
4. 5  O v e r vi e  w  of   C  D 1 9  e x p r essi o n i n   D  L  B  C  L  a n d t r e at  m e nt   wit h   M  O  R 0 0 2 0 8  
4. 5. 1  T h e   B -c ell D iff e r e nti ati o n A nti g e n   C  D 1 9 i n L y  m p h o  m a  
T h e  diff er e nt i ati o n  a nti g e n   C  D 1 9 is  a  5 5 6-a  mi n o a ci d, t y p e I tr a ns  m e  m br a n e  c ell-s urf a c e  pr ot ei n 
wit h  a n i  m p ort a nt r ol e i n  b ot h  n or  m al  a n d   m ali g n a nt   B- c ell  p h ysi ol o g y.   C  D 1 9  b el o n gs t o t h e 
i  m  m u n o gl o b uli n (I g) s u p erf a  mil y  a n d is t h e  d o  mi n a nt si g n al tr a ns d u ci n g   m e  m b er  of t h e   B-c ell 
a nti g e n r e c e pt or (  B  C  R)  c o -r e c e pt or  c o  m pl e x,   w hi c h  als o i n cl u d es  c o  m pl e  m e nt r e c e pt or,   C  D 2 1, 
t h e t etr as p a ni n f a  mil y  pr ot ei n, C  D 8 1 , a n d t h e i nt erf er o n -i n d u c e d tr a ns  m e  m br a n e  pr ot ei n,   C  D 2 2 5 
(C art er  et  al.  2 0 0 2 ). 
 
C  D 1 9 is  e x pr ess e d  e arl y i n   B- c ell  d e v el o p  m e nt at t h e l at e  pr o-B  or  e arl y  pr e -B st a g e , j ust  b ef or e 
t h e I g  h e a v y  c h ai n  g e n e r e arr a n g e  m e nt,  a n d is  pr es e nt t hr o u g h o ut   B-c ell   m at ur ati o n  u ntil 
t er  mi n al  diff er e nti ati o n i nt o  pl as  m a  c ells (A n d ers o n  et  al.  1 9 8 4 ).   As  a l o  w-affi nit y  a nti g e n 
r e c e pt or,   C  D 1 9 f u n cti o ns t o  d e cr e as e t h e  a nti g e n  c o n c e ntr ati o n t hr es h ol d  n e c ess ar y t o tri g g er 
B- c ell  di visi o n  a n d  diff er e nti ati o n.  P ati e nts   wit h  a  h o  m o z y g o us   m ut ati o n i n t h e   C  D 1 9  g e n e 
(C  D 1 9 )  e x hi bit  d e cr e as e d   B- c ell  a cti v ati o n i n r es p o ns e t o   mit o g e n sti  m ul ati o n  a n d  ar e 
h y p o g a  m  m a gl o b uli n a e  mi c,   wit h  n or  m al  n u  m b ers  of  b o n e   m arr o  w  a n d  c ir c ul ati n g 
B -l y  m p h o c yt es (v a n  Z el  m  et  al.  2 0 0 6 ).   CD 1 9 r e g ul at es   B- c ell  pr olif er ati o n  a n d  d e v el o p  m e nt 
t hr o u g h   B  C  R- d e p e n d e nt  a n d i n d e p e n d e nt   m e c h a nis  ms (L esli e  a n d   Y o u n es  2 0 1 3 ). T h er e  ar e  
e  m er gi n g  d at a t h at s u g g est t h at C  D 1 9  pl a ys  a   B  C  R -i n d e p e n d e nt r ol e i n m ali g n a nt   B -c ell 
pr olif er ati o n  b y st a bili si n g  c o n c e ntr ati o ns  of t h e M  Y  C   o n c o pr ot ei n (P o e  et  al.  2 0 1 2 ). 
I  m p ort a ntl y,   C  D 1 9  e x pr essi o n is   m ai nt ai n e d i n l y  m p h o  m as   w hi c h s h o  w a  d o  w n-r e g ul ati o n  of 
C  D 2 0  e x pr essi o n f oll o  wi n g  a nti-  C  D 2 0 t h er a p y (C h u  et  al.  2 0 0 2 ). 
 
4. 5. 2  M  O  R 0 0 2 0 8   B a c k g r o u n d  a n d P r e cli ni c al D at a 
M  O  R 0 0 2 0 8 (s y n o n y  m s:   X  m  A b® 5 5 7 4,   M  O  R 2 0 8 ) is  a n  F c-e n h a n c e d    m  A b t h at  bi n ds t o t h e 
h u  m a n   B- c ell s urf a c e  a nti g e n   C  D 1 9.   M  O  R 0 0 2 0 8  p oss ess es si g nifi c a ntl y i n cr e as e d t u  m o ur 
c yt ot o xi cit y   w h e n  c o  m p ar e d   wit h t h e  p ar e nt al,  n o n -e n h a n c e d ,   m uri n e  4  G 7   C  D 1 9  a nti b o d y.  T h e 
i n cr e as e d  bi n di n g  of   M  O  R 0 0 2 0 8 t o  F c  g a  m  m a r e c e pt ors ( F cγR),  d u e t o t h e  e n gi n e er e d 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 8  of 1 3 1  
m ut ati o ns, si g nifi c a ntl y  e n h a n c es i n  vitr o a nti b o d y-d e p e n d e nt  c ell -m e di at e d  c yt ot o xi cit y 
(A  D  C  C ),  a nti b o d y- d e p e n d e nt  c ell-  m e di at e d  p h a g o c yt osis (A  D  C P),  a n d  dir e ct  c yt ot o xi c  eff e cts 
( a p o pt osis)  o n t h e t u  m o ur  c ells  c o  m p ar e d   wit h t h e  n o n- e n h a nc e d  p ar e nt al   m uri n e  a nti b o d y. 
M  O  R 0 0 2 0 8  h as  n ot  b e e n s h o  w n t o   m e di at e  c o  m pl e  m e nt- d e p e n d e nt  c yt ot o xi cit y (  C  D  C). 
 
M or e s p e cifi c all y, i n  pr e cli ni c al st u di es,   M  O  R 0 0 2 0 8  h as  b e e n s h o  w n t o si g nifi c a ntl y  e n h a n c e 
i n vitr o   A  D  C  C,   A  D  C P,  a n d  dir e ct  c yt ot o xi c  eff e cts ( a p o pt osis)  o n   C  D 1 9 + t u  m o ur  c ell li n es 
s p a n ni n g  a  br o a d r a n g e  of  h u  m a n l y  m p h o  m as  a n d l e u k a e  mi as (  B ur kitt’s l y  m p h o  m a,   C L L,  h air y 
c ell l e u k a e  mi a,   C  D 1 9 +  c hr o ni c   m y el oi d l e u k a e  mi a,   D L  B  C L,  a n d a c ut e l y  m p h o bl asti c l e u k a e  mi a 
[A L L ])  e x pr essi n g l e v els  of   C  D 1 9  a nti g e n r a n gi n g fr o  m  1 5, 0 0 0 t o  1 0 5, 0 0 0   m ol e c ul es/ c ell. 
Si  mil ar  eff e cts   w er e  als o  n ot e d i n r el ati o n t o fr es hl y is ol at e d p ati e nt   C L L  or   A L L  c ells  a n d  ar e 
als o  e x p e ct e d t o tr a nsl at e t o  pri  m ar y   N  H L  c ells , si n c e t h e  e x pr essi o n r a n g e r e p ort e d f or   A L L  a n d 
C L L   B -c ells  c o v ers t h e r a n g e  o bs er v e d f or   N  H L   B -c ells (Gi n al di  et  al.  1 9 9 8 , Ol ej ni c z a k  et  al. 
2 0 0 6 ).   MO  R 0 0 2 0 8  h as  als o s h o  w n s u p eri or  effi c a c y t o its  n o n- e n h a n c e d   p ar e nt al  a nti b o d y i n 
r el ati o n t o its  a bilit y t o i n d u c e  a   m ar k e d r e d u cti o n i n t u  m o ur  gr o  wt h, i n hi bit t u  m o ur  gr o  wt h r at e 
a n d i n cr e as e s ur vi v al i n  vi v o i n  x e n o gr aft   m o d els  of  h u  m a n l y  m p h o  m a i n s e v er e  c o  m bi n e d 
i  m  m u n o d efi ci e n c y ( S  CI  D)   mi c e. ( S e e r el e v a nt s e ctio ns  of I n v esti g at or’s   Br o c h ur e [I  B] .) 
 
T h e  p h ar  m a c o d y n a  mi c ( P  D) i nt er a cti o ns  of   M  O  R 0 0 2 0 8 i n  c o  m bi n ati o n   wit h fl u d ar a bi n e, B E  N, 
a n d l e n ali d o  mi d e (L E  N ) us e d i n t h e tr e at  m e nt  of  p ati e nts   wit h   C L L  a n d   N  H L,   w er e i n v esti g at e d 
i n  a  h u  m a n i ntr a v e n o us (I  V) l y  m p h o  m a   m o d el i n  S  CI  D   mi c e (se e r el e v a nt s e cti o ns  of I  B). I n t his 
ort h ot o pi c   m o d el f or  diss e  mi n at e d   B -c ell   m ali g n a n ci es, t h e   m e di a n s ur vi v al   w as s u p eri or f or  all 
of t h e  gr o u ps r e c ei vi n g   M  O  R 0 0 2 0 8  c o  m bi n ati o n t h er a p y (  wit h fl u d ar a bi n e,   B E  N  or L E  N )   w h e n 
c o  m p ar e d   wit h t h e  gr o u ps r e c ei vi n g   M  O  R 0 0 2 0 8   m o n ot h er a p y.   M or e s p e cifi c all y,   M  O  R 0 0 2 0 8 
( 3. 0   m g/ k g) i n  c o  m bi n ati o n   wit h   B E  N ( 1 3. 0,  1 6. 0   m g/ k g)   w as s u p eri or t o  eit h er t h er a p y  al o n e i n 
t er  ms  of i n cr e as ed m e di a n lif es p a n ( 2 6  %  v ers us  5 7  %).  T h e  eff e ct   w as  cl assifi e d  as  p ot e nti ati o n 
of t h e  effi c a c y  of   M  O  R 0 0 2 0 8,  as   M  O  R 0 0 2 0 8   w as t h e  o nl y  dr u g  a  m o n gst t h e  c o  m bi n ati o n 
p art n ers t est e d t h at  d e  m o nstr at e d  a si g nifi c a nt  eff e ct  o n s ur vi v al  as  a si n gl e  a g e nt.  
 
Tiss u e  cr oss -r ea cti vit y st u di es  h a v e s h o  w n t h at t h e  p att er n  a n d  distri b uti o n  of   M  O  R 0 0 2 0 8 
bi n di n g t o  c y n o  m ol g us   m o n k e y tiss u es  cl os el y  p ar all els t h os e  of  h u  m a n tiss u es.  Fl o  w  c yt o  m etr y 
e x p eri  m e nts s h o  w   M  O  R 0 0 2 0 8  bi n di n g t o  h u  m a n  a n d  c y n o  m ol g us   m o n k e y   B- c ells,  b ut  n ot t o t h e 
B- c ells  of  ot h er  c o  m  m o n l a b or at or y s p e ci es (s u c h  as r at,   m o us e, r a b bit  a n d  d o g).  T h er ef or e, 
p h ar  m a c ol o g y st u di es   w er e r estri ct e d t o  h u  m a n  a n d  c y n o  m ol g us   m o n k e y  c ell- b as e d i n  vitr o 
s yst e  ms,   C  D 1 9 +  h u  m a n   B- c ell t u  m o ur  x e n o gr aft   m o d els i n  S  CI  D   mi c e,  a n d  c y n o  m ol g us 
m o n k e ys i n  vi v o. I n i n  vi v o st u di es i n  c y n o  m ol g us   m o n k e ys,   M  O  R 0 0 2 0 8   w as s h o  w n t o i n d u c e 
B-l y  m p h o c yt e  d e pl eti o n i n  p eri p h er al  bl o o d,  b o n e   m arr o  w, s pl e e n  a n d i n g ui n al l y  m p h  n o d es. 
C y n o  m ol g us   m o n k e ys   w er e  als o j u d g e d t o  b e t h e  o nl y r el e v a nt  c o  m  m o n l a b or at or y s p e ci es f or 
t o xi cit y st u di es. 
 
T h e r es ults  of st u di es  e v al u ati n g t h e  p h ar  m a c o ki n eti cs ( P  K),  P  D  a n d t o xi cit y  of   M  O  R 0 0 2 0 8 i n 
c y n o  m ol g us   m o n k e ys,  ar e  pr o vi d e d i n t h e r el e v a nt s e cti o ns  of t h e I  B.  T h e fi n di n gs i n fi v e 
pr e cli ni c al st u di es   w er e li  mit e d t o t h e  e x p e ct e d  p h ar  m a c ol o gi c al  eff e cts  of   M  O  R 0 0 2 0 8,   wit h  n o 
r e p orts  of  u n a nti ci p at e d t o xi cit y. T h e f i v e st u di es,  all  c o n d u ct e d i n  c y n o  m ol g us   m o n k e ys 
i n cl u d e d:  a  2 6-  w e e k si n gl e  1 0. 0   m g/ k g  d os e,  P  K,  P  D  a n d t o xi cit y st u d y;  a  2 8- d a y si n gl e I  V  d os e, 
d os e- r a n gi n g (0. 3,  1. 0  a n d  3. 0   m g/ k g)  P  K/ P  D st u d y;  a  2 9- d a y, si n gl e- d os e ( 3. 0   m g/ k g) st u d y 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 2 9  of 1 3 1  
c o  m p ari n g   M  O  R 0 0 2 0 8   wit h t  w o  ot h er   C  D 1 9  a nti b o di es   wit h  diff er e nt  F c r e gi o ns;  a n  8- w e e k 
t o xi cit y st u d y i n   w hi c h   M  O  R 0 0 2 0 8   w as  a d  mi nist er e d I  V e v er y  2   w e e ks  at  a  d os e  of  2,  1 0  or 
5 0 m g/ k g f or  8  c o ns e c uti v e   w e e ks   wit h  a  9 0 -d a y r e c o v er y  p eri o d ;  a n d  a  1 3-  w e e k t o xi cit y st u d y 
i n   w hi c h   M  O  R 0 0 2 0 8   w as  a d  mi nist er e d I  V   w e e kl y t o s e x u all y   m at ur e  c y n o  m ol g us   m o n k e ys  at 
d os es  of  1 0,  3 0  or  1 0 0   m g/ k g f or  1 3  c o ns e c uti v e   w e e ks   wit h  a  1 3 2- d a y r e c o v er y p eri o d .  T h e  ai  m 
of t h e l att er   G o o d  L a b or at or y  Pr a cti c e (  G L P) -c o  m pli a nt,   m ulti pl e -d os e t o xi c ol o g y st u d i es w as t o 
s u p p ort t h e  us e  of   M  O  R 0 0 2 0 8 i n  h u  m a n  cli ni c al st u di es. As a n e x p e ct e d  p h ar  m a c ol o gi c al  eff e ct, 
a r e v ersi bl e l a c k  of  g er  mi n al  c e nt r es i n l y  m p h oi d  or g a ns  a n d   m ar k e dl y r e d u c e d  p eri p h er al 
C  D 2 0 +   B  c ell  c o u nts   w er e  o bs er v e d,   w hi c h   w er e  c o nsist e nt   wit h l o  w er e d I g  G l e v els i n s er u  m  as 
w ell  as  a r e v ersi bl e r e d u cti o n i n t h e  T - c ell  d e p e n d e nt  a nti b o d y r es p o ns e.  T h er e   w er e  n o 
M  O  R 0 0 2 0 8-r el at e d  eff e cts  o n  b o d y   w ei g ht,  cli ni c al si g ns, f o o d  c o ns u  m pti o n,  bl o o d  pr ess ur e, 
el e ctr o c ar di o gr a p h y, r es pir at or y r at e,  o p ht h al  m ol o g y,  n e ur o b e h a vi o ur al  o bs er v ati o ns, 
h a e  m at ol o g y,  c o a g ul ati o n,  uri n e  or  c yt o ki n e  a n al ysis.   M  O  R 0 0 2 0 8  h a d  n o  eff e cts  o n   m e nstr u al 
c y cl e l e n gt h i n f e  m al es a n d  n o  hist o p at h ol o g y/  mi cr os c o pi c  c h a n g es t o   m al e  a n d f e  m al e 
r e pr o d u cti v e  or g a ns.   O v er all,   M  O  R 0 0 2 0 8  a d  mi nistr ati o n t o t h e  c y n o  m ol g us   m o n k e y   w as  v er y 
w ell t ol er at e d  at  d os es  u p t o  1 0 0   m g/ k g. I n  a d diti o n,   G L P- c o  m pli a nt tiss u e  cr oss -r e a cti vit y 
st u di es   w er e  p erf or  m e d  o n  n or  m al tiss u e  p a n els fr o  m  h u  m a n  a n d  c y n o  m ol g us   m o n k e y  d o n ors. 
N o s p e cifi c st ai ni n g t o str u ct ur es  ot h er t h a n t h e  e x p e ct e d   m o n o n u cl e ar l e u k o c yt es, l y  m p h o c yt es 
a n d  h a e  m at o p oi eti c  pr e c urs or  c ells   w as  o bs er v e d.  
 
4. 5. 3  Cli ni c al   E x p e ri e n c e   wit h   M  O  R 0 0 2 0 8  
4. 5. 3. 1  P r ot o c ol   X  m  A b 5 5 7 4- 0 1 
A  P h as e   1 St u d y  of   X  m  A b ® 5 5 7 4 t o   E v al u at e t h e  S af et y,   T ol e r a bilit y,  a n d 
P h a r  m a c o ki n eti cs i n  P ati e nts   wit h   R el a ps e d  o r   R ef r a ct o r y   C h r o ni c   L y  m p h o c yti c 
L e u k a e  mi a 
T h e first st u d y i n  h u  m a ns   w as  a  p h as e I tri al e x pl ori n g t h e  us e  of   M  O  R 0 0 2 0 8 ( als o  k n o  w n  as 
X  m  A b ® 5 5 7 4  or M  O  R 0 0 2 0 8) i n  a d ult  p ati e nts  di a g n os e d  a c c or di n g t o I nt er n ati o n al   W or ks h o p  o n 
C L L  g ui d eli n es (H all e k  et  al.  2 0 0 8 ) wit h  a cti v e, tr e at  m e nt -r e q uiri n g   R-R   C L L/ s  m all l y  m p h o c yti c 
l y  m p h o  m a (S L L ).   R es ults  of t h e st u d y   w er e r e p ort e d  b y (W o y a c h  et  al.  2 0 1 4 ). 
 
T  w e nt y -s e v e n  p ati e nts   w er e  e nr oll e d t o  6  es c al ati n g  d os e l e v els,   wit h  e x p a nsi o n  at t h e  hi g h est 
d os e l e v el  of  1 2   m g/ k g.   Ni n e  d os es  of   M  O  R 0 0 2 0 8   w er e i nf us e d  o v er  8   w e e ks.   N o   m a xi  m al 
t ol er at e d  d os e w as r e a c h e d,  a n d t h e  dr u g   w as  g e n er all y   w ell t ol er at e d,   wit h i nf usi o n-r el at e d 
r e a cti o ns (I  R  Rs)  of  gr a d e  1  or  2  b ei n g t h e   m ost  c o  m  m o n t o xi citi es. Tr e at  m e nt -r el at e d  gr a d e  3  or 
4 A Es   o c c urr e d i n fi v e  p ati e nts  a n d i n cl u d e d  n e utr o p e ni a, t hr o  m b o c yt o p e ni a, i n cr e as e d  as p art at e 
a  mi n otr a nsf er as e  (  A S T), f e bril e  n e utr o p e ni a,  a nd t u  m o u r l ysis s y n dr o  m e ( T L S).   M  O  R 0 0 2 0 8 
s h o  w e d  pr eli  mi n ar y  effi c a c y,   wit h  1 8  p ati e nts ( 6 6. 7  %) r es p o n di n g  b y  p h ysi c al  e x a  mi n ati o n 
crit eri a  a n d l a b or at or y st u di es,  a n d  8  p ati e nts ( 2 9. 6  %) r es p o n di n g  b y  c o  m p ut e d t o  m o gr a p h y (  C T) 
crit eri a. M  O  R 0 0 2 0 8 s h o  w e d  a t er  mi n al  eli  mi n ati o n  h alf-lif e  of  a p pr o xi  m at el y  1 4  d a ys. A  d os e of 
1 2   m g/ k g   w as r e c o  m  m e n d e d f or  us e i n s u bs e q u e nt st u di es. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 3 0  of 1 3 1  
4. 5. 3. 2  O n g oi n g  St u di es  
T h e f oll o  wi n g ot h er st u di es  ar e  o n g oi n g. D et ails  of s af et y  a n d  effi c a c y  d at a ar e r e p ort e d i n t h e 
I  B: 
 
P r ot o c ol M  O  R 2 0 8  C 2 0 1  
A  P h as e II a,   O p e n -L a b el,   M ulti c e nt er  St u d y  of  Si n gl e -A g e nt   M  O  R 0 0 2 0 8,  a n  F c -O pti  mis e d 
A nti -C  D 1 9   A nti b o d y, i n  P ati e nts   wit h   R el a ps e d  or   R efr a ct or y   B -C ell   N o n -H o d g ki n’s 
L y  m p h o  m a  
 
P r ot o c ol   M  O  R 2 0 8  C 2 0 3  (  L-MI  N  D)  
A  P h as e II,  Si n gl e -Ar  m,   O p e n -L a b el,   M ult i c e ntr e  St u d y t o  E v al u at e  S af et y  a n d  Effi c a c y  of 
L e n ali d o  mi d e   C o  m bi n e d   wit h   M  O  R 0 0 2 0 8 i n  P ati e nts   wit h   R el a ps e d  or   R efr a ct or y (  R-R) Diff us e 
L ar g e   B -C ell  L y  m p h o  m a  
 
P r ot o c ol   M  O  R 2 0 8  C 2 0 5  (  C  O S  M  O S) 
A  P h as e II,  T  w o -C o h ort,   O p e n -L a b el,   M ulti c e nt er  St u d y t o  E v al u at e t h e  Effi c a c y  a n d  S af et y  of 
M  O  R 0 0 2 0 8   C o  m bi n e d   wit h I d el alisi b  or   V e n et o cl a x i n  P ati e nts   wit h   R el a ps e d  or   R efr a ct or y 
C L L/ S L L  Pr e vi o usl y  Tr e at e d   wit h   Br ut o n’s  T yr osi n e   Ki n as e I n hi bit or  
 
P r ot o c o l   M  O  R 2 0 8  C 1 0 7 ( Fi rst-MI  N  D)  
A  P h as e I b,  o p e n -l a b el, r a n d o  mi z e d st u d y t o  ass ess s af et y  a n d  pr eli  mi n ar y  effi c a c y  of 
T af asit a  m a b i n  a d diti o n t o   R -C  H  O P  or  T af asit a  m a b  pl us  L e n ali d o  mi d e i n  a d diti o n t o   R -C  H  O P i n 
p ati e nts   wit h  n e  wl y  di a g n os e d   Diff us e  L ar g e B -C ell  L y  m p h o  m a (  D L  B  C L)  
 
P r ot o c ol   M  O  R 2 0 8  C 3 1 0 ( F r o nt  MI  N  D)  
A P h as e III,   m ulti c e nt er, r a n d o  mi z e d,  d o u bl e -bli n d,  pl a c e b o -c o ntr oll e d tri al  c o  m p ari n g t h e 
effi c a c y  a n d s af et y  of t af asit a  m a b  pl us l e n ali d o  mi d e i n  a d diti o n t o   R -C  H  O P  v ers us   R -C  H  O P i n 
pr e vi o usl y  u ntr e at e d,  hi g h-i nt er  m e di at e  a n d  hi g h-ris k  p ati e nts   wit h  n e  wl y  di a g n os e d  diff us e 
l ar g e   B-c ell l y  m p h o  m a  
 
P r ot o c ol   M  O  R 2 0 8  C 4 1 4 (  R  E  A  L  MI  N  D)  
A  P h as e I  V,   m ulti c e nt er,  o bs er v ati o n al st u d y t h at   will  c oll e ct  d at a  o n tr e at  m e nts  a n d  o ut c o  m es 
f or  p ati e nts i n t h e   U S   wit h r ela ps e d  or r efr a ct or y  diff us e l ar g e   B -c ell l y  m p h o  m a   w h o  ar e st arti n g 
s e c o n d- or t hir d -li n e t h er a p y  a n d  ar e  n ot r e c ei vi n g  a ut ol o g o us st e  m  c ell tr a ns pl a nt. 
 
P r ot o c ol   M  O  R 2 0 8  C 1 1 5 (  MI  N  D  w a y)  
A  P h as e  1 b/ 2,   O p e n -L a b el,   M ulti c e nt er  St u d y t o  E v al u at e t h e  S af et y  a n d  P h ar  m a c o ki n eti cs  of  a 
M o difi e d  T af asit a  m a b I  V   D osi n g   R e gi  m e n   C o  m bi n e d   wit h  L e n ali d o  mi d e ( L E  N) i n  P ati e nts   wit h 
R el a ps e d  or   R efr a ct or y   Diff us e  L ar g e   B -C ell  L y  m p h o  m a  
 
P r ot o c ol I  N  C  M  O  R 0 2 0 8 -1 0 1 (t o p  MI  N  D)  
A  P h as e  1 b/ 2 a  b as k et st u d y t o  e v al u at e t h e s af et y, t ol er a bi lit y,  p h ar  m a c o ki n eti cs,  a n d  effi c a c y  of 
c o  m bi n ati o n t h er a p y   wit h t h e  a nti -C  D 1 9   m o n o cl o n al  a nti b o d y t af asit a  m a b  a n d t h e  PI 3  K d 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 3 1  of 1 3 1  
i n hi bit or  p ars a clisi b i n  a d ult  p arti ci p a nts   wit h r el a ps e d/r efr a ct or y (  R/  R)  n o n-  H o d g ki n l y  m p h o  m a 
or  c hr o ni c l y  m p h o c yti c l e u k e  mi a 
 
P r ot o c ol I  N  C  M  O  R 0 2 0 8- 1 0 2 ( J- MI  N  D)  
A P h as e  1 b  St u d y  of t af asit a  m a b, t af asit a  m a b  pl us l e n ali d o  mi d e, t af asit a  m a b  pl us  p ars a clisi b, 
a n d t af asit a  m a b  pl us l e n ali d o  mi d e i n  c o  m bi n ati o n   wit h   R -C  H  O P i n J a p a n es e  p arti ci p a nts   wit h 
n o n-  H o d g ki n l y  m p h o  m a.  
 
P r ot o c ol I  N  C  M  O  R 0 2 0 8- 3 0 1 (i n  MI  N  D) 
A  P h as e  3, r a n d o  mi z e d,  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d,   m ulti c e nt er st u d y t o  e v al u at e t h e 
effi c a c y  a n d s af et y  of t af asit a  m a b  pl us l e n ali d o  mi d e i n  a d diti o n t o rit u xi  m a b  v ers us l e n ali d o  mi d e 
i n  a d diti o n t o rit u xi  m a b i n  p ati e nts   wit h r el a ps e d/r efr a ct or y (  R/  R) f olli c ul ar l y  m p h o  m a  gr a d e  1 t o 
3 a  or   R/  R   m ar gi n al  z o n e l y  m p h o  m a 
 
P r ot o c ol   M  O  R 0 0 2 0 8 II  T   O S  U- 1 3 0 3 1 
P h as e II  St u d y  of  T af asit a  m a b i n   C o  m bi n ati o n   wit h  L e n ali d o  mi d e f or  P ati e nts   wit h   R el a ps e d  or 
R efr a ct or y   C hr o ni c  L y  m p h o c yti c  L e u k e  mi a (  C L L)/ S  m all  L y  m p h o c yti c  L y  m p h o  m a 
( S L L)/ Pr ol y  m p h o c yti c  L e u k e  mi a ( P L L), I n cl u di n g t h os e   w h o  h a v e   R el a ps e d  o n I br uti ni b,  or 
P ati e nts   wit h   U ntr e at e d   C L L/ S L L/ P L L  
 
P r ot o c ol II  R _I  N  T _  D  E _  H ess _  G  O  A  LII  
A  pr os p e cti v e,   m ulti c e nt er  r a n d o  mi z e d  p h as e II tri al i n v esti g ati n g 
G e  m cit a bi n e/  O x ali pl ati n/  Rit u xi  m a b   wit h  or   wit h o ut  T af asit a  m a b (  M  O  R 2 0 8) f or  p ati e nts   wit h 
r el a ps e d/r efr a ct or y   A g gr essi v e  L y  m p h o  m a (  G  O  A L II) 
 
4. 5. 4  S af et y  of   M  O  R 0 0 2 0 8 
M  O  R 0 0 2 0 8  off ers  a  n o v el   m e c h a nis  m  of  a cti o n t h at   m a y  a d d t o t h e  c ar e  of  p ati e nts   wit h   N  H L. 
B as e d  o n t h e  a v ail a bl e  d at a fr o  m t h e  c o  m pl et e d  cli ni c al st u d i es  of   M  O  R 0 0 2 0 8 ( Pr ot o c ol 
X  m  A b ® 5 5 7 4- 0 1  a n d   M  O  R 2 0 8  C 2 0 2),  pr eli  mi n ar y  d at a fr o  m t h e  o n g oi n g cli ni c al st u di es 
M  O  R 2 0 8  C 2 0 1 (J ur c z a k  et  al.  2 0 1 8), M  O  R 2 0 8  C 2 0 3,   M  O  R 2 0 8  C 2 0 4  a n d   M  O  R 2 0 8  C 2 0 5, 
n o n cli ni c al st u di es  a n d  e x p eri  m e nts,  a n d lit er at ur e  d at a  o n   C  D 1 9, t h e s p o ns or is  of t h e  o pi ni o n 
t h at t h e  p ot e nti al  b e n efit  of   M  O  R 0 0 2 0 8  o ut  w ei g hs t h e  p ot e nti al ris ks. It is  e x p e ct e d t h at t h e 
p ot e nti al ris ks   will  b e  a d e q u at el y  c o ntr oll e d  b y t h e  d esi g n  of t his tri al ( e. g.  b y t h e i n cl usi o n  a n d 
e x cl usi o n  crit eri a)  a n d  b y fr e q u e nt   m o nit ori n g  of  p ot e nti al  a d v ers e  dr u g r e a cti o ns t hr o u g h o ut t h e 
e ntir e st u d y.  
 
B as e d  o n t h e s af et y  d at a fr o  m t h e  cli ni c al st u di es list e d  a b o v e t h e  a nti ci p at e d  p ossi bl e ris ks 
ass o ci at e d   wit h   M  O  R 0 0 2 0 8   m o n ot h er a p y i n cl u d e t h e f oll ow i n g A Es  wit h  a s us p e ct e d 
r el ati o ns hi p t o   M  O  R 0 0 2 0 8 tr e at  m e nt (i n ci d e n c e  ≥  3   %): 
•  I  R  Rs (  m ostl y   Gr a d e  1/ 2) 
•  F e bril e  n e utr o p e ni a 
•  N e utr o p e ni a 
•  T hr o  m b o c yt o p e ni a 
•  T u  m o u r lysis s y n dr o  m e 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 3 2  of 1 3 1  
•  U p p er r es pir at or y tr a ct i nf e cti o ns 
•  L o  w er r es pir at or y tr a ct i nf e cti o n  (i n cl u di n g  p n e u  m o ni a  a n d  br o n c hitis) 
•  F ati g u e 
•  C hills  
•  P yr e xi a 
•  N a us e a  
•  Di arr h o e a 
•  H e a d a c h e  
•  R as h  
•  A S T  a n d   A L T i n cr e as es.  
 
Si n c e  a   m aj or  p h ar  m a c ol o gi c al  eff e ct  of   M  O  R 0 0 2 0 8 is   B- c ell  d e pl eti o n, t h e ris ks  ass o ci at e d   wit h 
t h e  us e  of  a p pr o v e d   B- c ell  d e pl eti n g t h er a p e uti cs  b as e d  o n t h e l a b elli n g  of  ot h er  a g e nts   wit h 
si  mil ar  eff e cts s h o ul d  b e  c o nsi d er e d. T h es e   m a y i n cl u d e:   B-c ell  d epl eti o n, l y  m p h o p e ni a, 
n e utr o p e ni a,  h e p atitis   B r e a cti v ati o n,  pr o gr essi v e   m ultif o c al l e u k o e n c e p h al o p at h y, 
m u c o c ut a n e o us r e a cti o ns  a n d i nf e cti o ns. 
 
T h e  a nti ci p at e d ris ks  ass o ci at e d   wit h t h e  a d  mi nistr ati o n  of   M  O  R 0 0 2 0 8  ar e  d es cri b e d i n  d et ail i n 
t h e   M  O  R 0 0 2 0 8 I  B. 
 
 
5  S  T  U  D  Y  P  U  R P  O S  E/  R  A  TI  O  N  A  L  E  
D es pit e r e c e nt i  m pr o v e  m e nts i n t h e   m a n a g e  m e nt  of   D L  B  C L,  a p pr o xi  m at el y  3 0 – 4 0  %  of  p ati e nts 
wit h   D L  B  C L tr e at e d   wit h   R -C  H  O P r el a ps e f oll o  wi n g i niti al i  m  m u n o c h e  m ot h er a p y (C oiffi er  et 
al.  2 0 0 2, F e u gi er  et  al.  2 0 0 5 , S e h n  et  al.  2 0 0 5 , H a b er  m a n n  et  al.  2 0 0 6 , Pfr e u n ds c h u h  et  al.  2 0 0 6 , 
Pfr e u n ds c h u h  et  al.  2 0 1 1 ).   Alt h o u g h  a si g nifi c a nt  n u  m b er  of  p ati e nts  c a n  b e s al v a g e d   wit h 
hi g h- d os e  c h e  m ot h er a p y ( H  D  C ) a n d s u bs e q u e nt   A S  C T, t h e   m aj orit y   will s u c c u  m b t o t h e  dis e as e. 
I n  p arti c ul ar, el d erl y   a n d/ or fr ail  p ati e nts a n d t h os e  wit h   m ulti pl e  c o  m or bi diti es  ar e i n  n e e d  of 
n o v el t h er a p e uti c  a p pr o a c h es as t h e i nt e nsifi e d tr e at  m e nt r e gi  m e ns  c a n n ot  b e  us e d i n t his 
p o p ul ati o n. I  m pr o vi n g t h e t h er a p e uti c  o pti o ns f or t his  gr o u p  of  p ati e nts is  a n i  m p ort a nt  u n  m et 
m e di c al  n e e d . 
 
As   R T  X -b as e d r e gi  m e ns  h a v e  b e c o  m e st a n d ar d first -li n e tr e at  m e nt i n   D L  B  C L, t h e  effi c a c y  of 
R T  X  c o  m bi n e d   wit h  c h e  m ot h er a p y i n t h e s e c o n d- li n e s etti n g  h as  d e cr e as e d  a n d t h er e is  a  n e e d 
f or  n e  w t h er a pi es i n  p ati e nts  pr o gr essi n g  or r el a psi n g aft er first - or s e c o n d -li n e   R T  X-b as e d 
tr e at  m e nt. T h e   C  D 1 9  a nti g e n is  a n  attr a cti v e t ar g et i n   D L  B  C L  as   C  D 1 9 is t y pi c all y  e x pr ess e d i n 
D L  B  C L  c ells,  h as  a si g n alli n g f u n cti o n t h at  c o ntri b ut es t o t h e   m ali g n a nt  p h e n ot y p e  a n d is  n ot 
d o  w n-r e g ul at e d i n p ati e nts   pr e-tr e at e d   wit h   C  D 2 0-t ar g et e d  a g e nts.  T h us, it   mi g ht  b e  p ossi bl e t o 
o v er c o  m e t h e  a bs ol ut e  or r el ati v e   R T  X r esist a n c e i n   R -R   N  H L b y  usi n g   M  O  R 0 0 2 0 8 i nst e a d  of 
R T  X  a n d t h er e b y t o i  m pr o ve  cli ni c al  o ut c o  m e i n t h e   R-  R   N  H L  p ati e nt  p o p ul ati o n. 
 
T h e  eff e cts  of   M  O  R 0 0 2 0 8  a p p e ar t o i n v ol v e   A  D  C  C,   A  D  C P,  a n d  dir e ct  c yt ot o xi c  a cti vit y 
( a p o pt osis).   M  O  R 0 0 2 0 8  a n d   B E  N ar e  a cti v e as si n gl e  a g e nts  a n d i n  c o  m bi n ati o n s h o  w 
s y n er gisti c  a ntil e u k a e  mi c  a n d  a ntil y  m p h o  m a  a cti vit y in  vi v o   a n d i n  vitr o.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 3 3  of 1 3 1  
M O R 0 0 2 0 8 de m o ns trate d si n gle-a ge nt acti vit y i n R -R  C L L/ S L L,  DL B C L,  f ollic ular ly m p h o ma 
a n d ot her i n d ole nt N H L s ( W o yach et al. 2 0 1 4, J urcza k et al. 2 0 1 5,  J urcza k et al. 2 0 1 6). 
M O R 0 0 2 0 8 elicits  o nl y mil d  h ae mat ol o gic al AEs an d ha s a mana gea ble  t o xicit y pr ofile . The  
pre d o mi na nt A Es are  IR R s, a class effect of ma n y  t hera pe utic anti b o dies, w hic h t y picall y occ ur 
d uri n g t he  first to  t hir d a p plicati o n.  Overall , M O R 0 0 2 0 8 is theref ore co nsi dere d t o be a g o o d 
ca n di date for c o m bi na ti on  wit h  esta blis he d  treat me nts, suc h  as B E N , in  D L B C L.  
B E N ha s o n e of the h i g hest anti -l y m p h o ma acti vities of si n gle age nts us e d t o treat R -R D L B C L  
a n d is w ell t olerate d  i n patie nts  wit h D L B C L  wit h a mana gea ble,  mai nl y hae mat ol o gical t o xicit y  
pr ofile  (O h mac hi et al. 2 0 1 3, C ol osia et al. 2 0 1 4, Vacirca et  al. 2 0 1 4 ). As a res ult , t he c urre nt 
o pe n-la bel, ra n d o mise d st u d y w as devel o pe d t o e val uate t he efficac y  an d safet y of M O R 0 0 2 0 8 
wit h  BE N  vers us R T X wit h  B EN i n  ad ult patie nts  wit h R-R D L B C L.  T he  mai n g o al of t his  st u d y 
is t o offer s uc h patie nts  a n o vel treat me nt o pti o n ta ki n g i nt o co nsi derati o n  t hat ma n y  patie nts  are 
frail, of a d va nce d a ge an d/ or ha ve  m ulti ple co m or bi dities.  
A n I nter nati o nal C o nse ns us Pa nel  has rec o m me n de d that  BE N  s h o uld  be a d mi nistere d at a d ose 
of 9 0 m g/ m 2, w he n c o m bi ne d with R T X in t he treat me nt o f a g gressi ve N H L ( C hes o n et al. 2 0 1 0, 
C hes o n et al. 2 0 1 6). The p u bl is he d st u dies in dicate d a co nsiste nt, ma na gea ble an d c o m para ble 
(bet wee n  st u dies) t o xicit y profile  f or patie nts  wit h DL B C L.  Walter  et al. (2 0 1 2) ha ve 
i n vesti gated B E N d os e ra n ges fr o m 6 0 t hr o u g h 1 2 0 m g/ m 2 an d ca me t o t he c o ncl usi o n t hat 
9 0 m g/ m 2 is t he ma xi m u m d os e t hat  ca n  be ac hie ve d  in  the  maj orit y  of p atie nts.  Se veral  stu dies 
ha ve co nfir me d t hat R T X wit h  B E N 9 0 m g/ m 2 is a hig hl y acti ve co m bi nati o n t hera p y a n d a n A E  
pr ofile co m paris o n bet wee n t he 1 2 0 m g/ m 2 an d 9 0 m g/ m 2 d ose le vel s clearl y fa v o ur e d the 
9 0 m g/ m 2 d ose. T heref ore, t he co m bi nati o ns of R T X or M O R 0 0 2 0 8 wit h B E N ( at 9 0 m g/ m 2) 
were  selecte d as t he  m ost  a p pro priate  c o mparat or  a n d e x peri me ntal re gi me ns for this st u d y. 
Si nce M O R 0 0 2 0 8 has n ot be e n pre vi o usl y st u die d i n c o m bi nati o n wit h B E N s yste maticall y in  a 
cli nical trial,  an  I nitial Safet y E v al uati o n  will prece de t he mai n  recr uit me n t i n t his cli nical trial. 
Acc u m ulati n g data (as descri be d  in  Secti o n  4. 4) after  t he st u d y was i nitiate d i ndicate  t hat N K C C 
is an i m p orta nt pr o g n ostic fact or i n D L B C L an d ma y als o affect t he anti-t u m o ur acti vit y  of 
m o n ocl o nal a nti b o dies d irecte d at C D 2 0 a n d/ or C D 1 9 di ffere ntiall y. Acc or di n gl y, t he pr ot oc ol 
was a me n de d  to  e nable t he efficac y  of  M OR 0 0 2 0 8 pl us B E N to be co m pare d wit h t he efficacy of 
R T X pl us B E N in t he  N K C C-l o w su b gr o u p of pa tie nts (defi ne d a t baseli ne ), as well  as i n the 
o verall p o p u lati o n. 






I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 3 6  of 1 3 1  
F or t h e  p ur p os e  of t h e  pr ot o c ol,  m aj o r s u r g e r y is  d efi n e d  as  a n y s ur gi c al  pr o c e d ur e t h at 
i n v ol v es i n its  c o urs e  g e n er al a naest h esi a  or r es pir at or y assist a n c e.  I ntr a v as c ul ar  a c c ess 
pr o c e d ur es  e. g.  c e ntr al li n e  pl a c e  m e nt  or s u b c ut a n e o us  p ort  pl a c e  m e nt,  ar e  n ot  c o nsi d er e d   m aj or 
s ur g er y. 
8. 2  S t u d y D esi g n 
T hi s is a ra n d o mise d, tw o- ar m, m ultice ntre , o pen -la bel, p hase II/III efficac y a n d safet y st u d y of 
M O R 0 0 2 0 8 in c o m bi nati o n wit h B E N  vers us RT X i n c o m bi nati o n wit h B E N . T he st u d y will 
e nr ol a d ult patie nts  wit h D L B C L  wh o  ha ve rela pse d after, or are refract or y  to , at least  o ne b ut n o 
m ore  t ha n t hree pri or s yste mic t hera p y  li nes (f or f urt her details see Secti o n  8. 6 an d  9. 5) a n d 
ha ve faile d or are n ot ca n di dates f or H D C a n d A S C T, a n d ha ve t h us e x ha uste d t heir t hera pe utic 
o pti o ns  of de m o nstrate d cli nical be nefit. At  least  o ne pr i or t hera p y li ne m ust ha ve i ncl u de d a 
C D 2 0 -tar gete d t hera p y (e. g. R T X). 
Patie nts  wit h pri mar y refract or y  DL B C L  (f or defi niti o n, see Secti o n 8. 1), patie nts wit h k n o w n 
" d o u ble/tri ple hit" D L B C L ge netics o r w h o ha ve u n de r g o ne p re vi o us all o ge neic ste m cell 
tra ns pla ntati o n are n ot eli gi ble  f or st u d y partici pati o n. Ad diti o nall y, patie nts  wit h a hist or y of 
A S C T  wit hi n a  perio d ≤3  m o nt hs pr i or to si g ni n g the inf or me d c o nse nt f or m (I C F) ca n n ot be 
i ncl u ded i n t he st u d y. 
T he  co m bi nati o n  o f M O R 0 0 2 0 8 an d  BE N  will be syste maticall y  eval uate d  f or t he first ti me i n a 
cli nical trial. Theref ore,  the trial  i ncl u des a n Initial  S afet y  E val uati o n, w hic h will e na ble t he 
I n de pe n de nt Data M o nit ori n g C o m mittee (I D M C) t o c o ncl u de w het her t he c o m bi nati o n 
treat me nt(s) are safe  (see Fi g ure 1 ). F urt her details  are pro vi de d  i n Secti o n  1 4. 1 an d t he I D M C 
C harter.  
T he  MO R 2 0 8 C 2 0 4  trial will e m pl o y  a parallel - gr o u p desi g n, w here b y patie nts will be ra n d o ml y 
assi g ne d t o t he t w o parallel treat me nt gr o u ps i n a rati o of 1: 1 (see Fi g ure 2 ). The st u d y will be 
perf or me d a cc or di n g t o a gr o u p- se q ue ntial, a dapti ve desi g n  wit h  p ossi ble sa m ple size a dj ust me nt 
after o ne pl a n ne d i nteri m anal ysis. T he interi m anal ysis w ill b e carrie d o ut w he n 1 2 8 P F S eve nts 
( 5 0 % of t he pla n ne d 2 5 6 eve nts) h a ve be e n o bser ve d. If the st u d y is co nti n ue d u ntil co m pleti o n 
a n d n o a da ptati o n is ma de  at i nteri m a nal ysis,  t he sam ple  size will be ap pr o xi matel y  
3 3 0 pa tie nts.  
I n N o ve m ber 2 0 1 9, the  ID M C r ec o mme n de d  to  i ncrease t he sa m ple size t o 4 5 0 patie nts. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 3 7  of 1 3 1  
 
Fi g u r e 1 :  
R e c r uit  m e nt  a n d  St u d y  Fl o  w  
Af ter s cr e e ni n g, eli gi bl e  p ati e nts   will  b e r a n d o  mi z e d i nt o  o n e  of t  w o st u d y  ar  ms.  P ati e nts   will  eit h er r e c ei v e 
M  O  R 0 0 2 0 8  +   B e n d a  m usti n e  or   Rit u xi  m a b  +   B e n d a  m usti n e fr o  m  c y cl e  1 t o  c y cl e  6.  Fr o  m  c y cl e  7  o n  w ar ds, t h e y 
m a y r e c ei v e   M  O  R 0 0 2 0 8  or   Rit u xi  m a b  o nl y.  
D uri n g t h e i niti al s af et y  e v al u ati o n  p h as e  of t h e tri al t h e first  3  p ati e nts i n  b ot h  ar  ms   will  b e  d os e d s e q u e nti all y   wit h 
a  4 8-h o ur l a g  p eri o d  b et  w e e n t h e  e nr ol  m e nts  of  2  c o ns e c uti v e  p ati e nts ( c o u nt e d fr o  m   C 1  D 4).  F oll o  wi n g  a  p ositi v e 
r e c o  m  m e n d ati o n  of t h e I  D  M  C, s e v e n  a d diti o n al  p ati e nts i n  e a c h  ar  m   m a y  b e  d os e d i n  p ar all el.   A n  a d diti o n al I  D  M  C 
r e vi e  w   will t a k e  pl a c e  aft er t h e l ast  of  1 0  p ati e nts i n  e a c h  ar  m  h a v e  c o  m pl et e d   C 3  D 1  visit i n t h eir r es p e cti v e 
tr e at  m e nt  all o c ati o n  ar  m.  S h o ul d t h e I  D  M  C   m ai nt ai n t h eir i niti al r e c o  m  m en d ati o n t h at t h e  c o  m bi n ati o n tr e at  m e nts 
ar e s af e, t h e tri al   m a y  pr o c e e d f urt h er   wit h r e cr uit  m e nt ( P h as e III  p art  of t h e tri al).  
 
A n i nt eri  m  a n al ysis   will  b e  p erf or  m e d  aft er  1 2 8  P F S  e v e nts  h a v e  b e e n  o bs er v e d.  T h e fi n al s a  m pl e si z e w as  a dj ust e d 
aft er t h e i nteri  m  a n al ysis  t o   N = 4 5 0.  T h e fi n al  a n al ysis i n cl u di n g  b ut  n ot li  mit e d t o  pri  m ar y  a n d s e c o n d ar y  e n d  p oi nt 
a n al ys es   will  b e  c o n d u ct e d  at t h e  e n d  of t h e tri al.  
   
A b br e vi ati o ns:   B E  N  =  b e n d a  m usti n e;   C  =   C y cl e ; I  D  M  C  = I n d e p e n d e nt   D at a   M o nit ori n g   C o  m  mitt e e;   M  O  R = 
M  O  R 0 0 2 0 8;   R  = r a n d o  mis ati o n ( 1: 1);   R T  X  = rit u xi  m a b.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


I n c yt e   C or p or ati o n    
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B-  MI  N  D) 
D at e:  1 0-  A pr- 2 0 2 4    
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt   N o.  8,   V ersi o n  1 1. 0     
E u dr a  C T   N u  m b er:  2 0 1 4- 0 0 4 6 8 9- 1 1 
 
V  V-  C LI  N- 0 1 9 4 2 9     
C o nfi d e nti al    
P a g e  3 8  of  1 3 1 
 
 
Fi g u r e  2:    
St u d y   D esi g n 
* S u bs e q u e nt t o t h e  c o  m pl eti o n  of   C o  m bi n ati o n  Tr e at  m e nt,  p ati e nts   wit h  a n  o n g oi n g r es p o ns e  of  at l e ast  P  R  at t h e 
e n d  of   C y cl e  6,  as  ass ess e d l o c all y,   will  c o nti n u e  a nti b o d y   m o n ot h er a p y tr e at  m e nt  u ntil  dis e as e  pr o gr essi o n i n 
a c c or d a n c e   wit h t h e i niti a l tr e at  m e nt  all o c ati o n (  R T  X  or   M  O  R 0 0 2 0 8). 
#B E  N is t o  b e  a d  mi nist er e d  o n   D a ys  2 + 3  of   C y cl e  1.  S u bs e q u e ntl y,   B E  N  c a n  b e  a d  mi nist er e d  o n   D a ys  1 + 2  or 
D a ys  2 + 3  a c c or di n g t o i nstit uti o n al/ p ati e nt/ p h ysi ci a n  c h oi c e. 
N ot e:  Str atifi c ati o n   will  n ot  b e  a p pli e d t o  p ati e nts r a n d o  mis e d  d uri n g I niti al  S af et y  E v al u ati o n (s e e Fi g ur e  1 ). 
A b br e vi ati o ns:   B E  N  =  b e n d a  m usti n e;  E  C  O  G  =  E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p;   O S  =  o v er all s ur vi v al;  P F S  = 
pr o gr essi o n-fr e e s ur vi v al;   R-  R   D L  B  C L  = r el a ps e d  or r efr a ct or y  diff us e l ar g e   B- c ell l y  m p h o  m a;   R  = r a n d o  mis ati o n 
( 1: 1);   R T  X  = rit u xi  m a b. 
   
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 3 9  of 1 3 1  
8. 3  St u d y    Co n d u ct  
T he  trial will be  co n d ucte d  at a p pr o xi matel y 1 8 0 sites w orl d wi de. 
T he total st u d y d urati o n is ex pecte d t o be ap pr o xi matel y 4 ye ars pl us F oll o w - U p (ass u mi n g n o 
sa m ple size a dj ust me nt  b y  the I D M C) . T he st u d y d urati o n f or an i n di vi d ual patie nt incl u de s 
Scree ni n g ( u p t o 2 8 da ys fr o m t he si g nin g of  t he IC F) , C o m bi nati o n Treat me nt (ma xi m u m 
6 m o nt hs) f oll o we d b y A nti b o d y M o n ot hera p y T reat me nt (u ntil  disease pr o gressi o n). After s t u d y 
treat me nt e n ds , eac h patie nt e nters Foll o w- U p  of a n i n di vi d uall y va r yi n g d urati o n. 
F oll o w- U p  be gi ns  wit h t he E n d  of Treat me nt ( E O T) visit. P atie nts  will als o ha ve a n o n- site 
3 0- da y p ost- treat me nt safet y  eval uati o n  visit ( 3 0-Da y  Safet y  F oll o w- U p visit). F oll o w -U p  f or t he 
pri mar y st u d y e n d p oi nt, i.e. P F S, s h o ul d be pe rf or me d ever y  3 m o nt hs u ntil d isease pr o gressi o n,  
wit h dra wal  of  c o nse nt or deat h, whic he ver  c omes first.  After c o nfir me d  pr o gressi o n,  patie nts 
s h o ul d be foll o we d u p f or O S.
F oll o w- U p  f or O S will be perfor me d  e ver y 3 m o nt hs fr o m t he date  of E O T or  t he last F oll o w-U p  
Visit f or t he pri mar y st u d y e n d p oi nt (i.e. P F S ), as a p plica ble . T he  first F oll o w-U p  f or O S  will be 
a cli nic visit.  S u bse q ue nt F oll o w- U p  for  O S  visits  ma y be p h o ne co ntacts. F or F oll o w- u p of a 
p atie nt w h o bec o mes eli gi ble f or “ F urt her or C o nti n ue d A nti b o d y Treat me nt,”  please refer t o 
Secti o n 1 0. 5.  
8. 4  E n d of St u d y  
T he en d of the st u d y is defi ne d as 3  years after  t he last patie nt w as ra n d o mize d  or after  
a p pr o xi matel y 7 5 %  of p atie nts ha ve  die d, w hic he ver occ urs f irst. U p o n st u d y cl os ure, t he 
s p o ns or will  n otif y t he a p plica ble re g ulat or y a ge nci es i n accor da nce wit h  local  re q uire me nts. 
8. 5  P atie nt Selecti o n Criteri a  
8. 5. 1  Incl usi o n  C riteri a  
Eli gi ble  patie nts m ust meet t he f oll o wi n g criteria t o be enr olle d  i n t he st u d y: 
Di a g n osis/ T ri al Po p ul ati o n 
1.
A g e ≥1 8  y e ars
•
F or  Si n g a p or e  o nl y:  a g e  ≥ 2 1  y e ars
2.
Hist ol o gi c all y   c o nfir  m e d  di a g n osis,  a c c or di n g t o t h e   W orl d   H e alt h   Or g a ni z ati o n (  W  H  O,
2 0 0 8)  cl assifi c ati o n,  of:
a)
Diff us e l ar g e   B -c ell l y  m p h o  m a  n ot  ot h er  wis e s p e cifi e d (  D L  B  C L   N  O S)
b)
T  c ell/ histi o c yt e ri c h l ar g e   B -c ell l y  m p h o  m a ( T  H  R L  B  C L)
c)    E pst ei n -B arr  vir us ( E  B  V)  p ositi v e   D L  B  C L  of t h e  el d erl y ( E  B  V -p ositi v e   D L  B  C L)
d)    C o  m p osit e l y  m p h o  m a   wit h  a   D L  B  C L  c o  m p o n e nt   wit h  a s u bs e q u e nt   D L  B  C L r el a ps e
e)    Dis e as e tr a nsf or  m e d fr o  m  a n  e arli er  di a g n osis  of l o  w- gr a d e l y  m p h o  m a (i. e.  a n i n d ol e nt
p at h ol o g y s u c h  as f olli c ul ar l y  m p h o  m a,   m ar gi n al  z o n e l y  m p h o  m a) i nt o   D L  B  C L   wit h  a
D L  B  C L r el a ps e s u bs e q u e nt t o   D L  B  C L tr e at  m e nt .


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 4 0  of 1 3 1  
3.
Fres h t u m o ur tiss ue f or ce ntral pat h ol o g y re vie w m ust be pr o vi de d as a n a dj u nct t o
partici pati o n i n t his st u d y. S h o ul d it n ot be p ossi ble t o o btai n a fres h t u m o ur tiss ue sa m ple,
arc hi val  paraffi n e m be d de d t u m o ur tiss ue ac q uire d ≤3 years pri or t o scree ni n g f or t his
p ro t oc ol m ust be availa ble  f or t his pur p ose .
4.
Patie nts m ust  ha ve:
a)
R- R  D L B C L (fo r defi niti o ns,  see Secti o n 8. 1 o f t he pr ot oc ol)
b)
at least  on e bi di me nsi o nall y  meas ura ble disease site.  Th e lesi o n must  ha ve a greatest
tra ns verse dia meter of  ≥1. 5  cm  a nd  greatest per pe n dic ular dia meter of ≥1. 0 c m at
baseli ne . T he lesi o n m ust be p ositi ve o n P E T sca n (f or defi niti o n, see Ju wei d  et al.
( 2 0 0 7)).
c)
recei ve d at least one , b ut n o m ore t ha n t hree pre vi o us s yste mic t hera py  li nes f or t he
treat me nt of D L B C L (for  f urt her details see Secti o ns  8. 6 an d  9. 5). At least  one p re vi o us
t hera p y li ne m ust ha ve i ncl u de d a C D 2 0-tar gete d  the ra p y (e. g. R T X).
d)
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 of 0 t o 2
5.
Patie nts a fter fail ure of A S C T  or patie nts c o nsi dere d  i n t he o pi ni o n of t he i n vesti gat or
c urre ntl y  n ot eli gi ble f or H D C wit h s u bse q ue nt A S C T . D oc u me ntati o n of t he reas o n f or
i neli gi bilit y f or A S C T m ust be prese nt i n t he patie nt’s  so urce  data  (f or details, see
Secti o n  8. 6 ).
L a b o r at o r y   V al u es  
6.
Patie nts  m ust meet t he f oll o wi n g la b orat or y  criteria at Scree ni n g:
a)
abs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 ×  1 09/ L ( u nless sec o n dar y t o b o ne marr o w 
i n v ol ve me nt b y D L B C L as de m o nstrate d b y b o ne marr o w as pirati o n a n d b o ne marr o w  
bi o ps y r e q uir e d f or Scree ni n g)
b ) p latelet c o u n t ≥9 0  ×  1 09/ L ( u nless sec o n dar y t o b o ne marr o w i n v ol ve me nt b y D L B C L as 
de m o nstrate d b y b o ne marr o w as pirati o n a n d b o ne marr o w bi o ps y re q uire d f or  
Scree ni n g ) a n d a bse nce of acti ve blee di n g
c)
total ser u m bilir u bi n ≤2. 5 ×  u pper li mit of n or mal ( U L N) u nless sec o n dar y t o Gil bert’s  
s y n dr o me (o r patter n co nsiste nt wit h  Gil bert’s)  or d oc u me nte d li ver i n v ol ve me nt b y 
l y m p h o ma. Patie nts wit h Gil bert's s y n dr o me or d oc u me nte d li ver i n v ol ve me nt b y 
l y m p h o ma ma y be i ncl u de d if t heir t otal bilir u bi n is ≤5 x  UL N  (see e xcl usi o n criteri o n 
6e )
d ) A L T, A S T a n d al kali ne p h os p hatase ≤3 ×  U L N or < 5 ×  UL N  in  cases of  doc u me nte d  
li ver i n v ol ve me nt b y l y m p h o ma
e)
ser u m creati ni ne ≤ 2. 0 U L N  or creati ni ne cleara n ce m ust b e ≥4 0  m L/ mi n,  calc ulate d  
usi n g a sta n dar d C oc kcr oft- G a ult f or m ula ( Coc kr o ft & Ga ult, 1 9 7 6;  see A p pe n di x A)
7.
F or  a fe male of c hil d beari n g po te ntial ( FC B P; f or defi niti o n  see Secti o n  8. 9 ), a ne gati ve 
pre g na nc y test m ust be c o nfir me d bef ore e nr ol me nt. A n F C B P  m ust  c om mi t to  take  hi g hl y  
effecti ve  c o ntrace pti ve preca uti o ns (see A p pe n di x B) wit h o ut i nterr u pti o n d uri n g t he st u d y 
a n d f or 3, 6 or 1 2 m o n t hs after t he last d ose of M O R 0 0 2 0 8, B E N or R T X res pecti vel y, 
w h ic he ver is later. A n FC B P  must  refrai n fro m b reastfee di n g an d  d o nati n g bl o o d or o oc ytes  
d uri n g t he c o urse of t he st u d y a n d f or 3, 6 or 1 2 m o n t hs after t he last d ose of M O R 0 0 2 0 8, 
B E N or  R T X r es pecti vel y,  wh ic he ver is later. (A p plic a ble  i n Re p u blic  of K ore a: a n FC B P  
m u st co m mit  to  ta ke h i ghl y  effecti ve c ontrace pti ve preca uti o ns (see  A p pe n di x B) wit h o ut 
i nterr u pti o n a n d refrai n fr o m breastfee di n g a n d d o nati n g bl o o d or o oc ytes d uri n g t he c o urse


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 4 1  of 1 3 1  
of t h e st u d y  a n d f or  6   m o nt hs  aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8, 6   m o nt hs  aft er t h e l ast  d os e 
of B E  N  or 1 2   m o nt hs  aft er t h e l ast  d os e  of   R T  X,   w hi c h e v er is l at er.) . 
8.
M al e  p ati e nts   m ust  us e   a n eff e cti v e  b arri er   m et h o d  of  c o ntr a c e pti o n wit h o ut i nt err u pti o n
d uri n g t h e st u d y  a n d f or  3,  6  or  1 2   m o nt hs  aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8,   B E  N  or   R T  X
r es p e cti v el y,   w hi c h e v er is l at er, if t h e  p ati e nt is s e x u all y  a cti v e   wit h  an F  C  B P .   M al es   m ust
r efr ai n fr o  m  d o n ati n g  bl o o d  or s p er  m  d uri n g t h e st u d y  p arti ci p ati o n  a n d f or  3,  6  or  1 2   m o nt hs
aft er t h e l ast  d os e  of M  O  R 0 0 2 0 8,   B E  N  or   R T  X r es p e cti v el y,   w hi c h e v er is l at er. ( A p pli c a bl e
i n   R e p u bli c of   K o r e a : m al es   m ust r efr ai n fr o  m  d o n ati n g  bl o o d  or s p er  m,  a n d if t h e  p ati e nt is
s e x u all y  a cti v e   wit h  a  F  C  B P,   m ust  us e  a n  eff e cti v e  b arri er   m et h o d  of  c o ntr a c e pti o n   wit h o ut
i nt err u pti o n  d uri n g t h e st u d y  a n d f or  6   m o nt hs  aft er t h e l ast  d os e  of   M  O  R 0 0 2 0 8,  6   m o nt hs
aft er t h e l ast  d os e  of B E  N  or 1 2   m o nt hs  aft er t h e l ast  d os e  of R T  X,   w hi c h e v er is l at er) .
9.   I n t h e  o pi ni o n  of t h e i n v esti g at or, t h e  p ati e nts m ust :
a)
b e  a bl e t o  c o  m pl y   wit h  all st u d y -r el at e d  pr o c e dur es,   m e di c ati o n  us e,  a n d  e v al u ati o ns
b)   b e  a bl e t o  u n d erst a n d  a n d  gi v e i nf or  m e d  c o ns e nt
c)
n ot  b e  c o nsi d er e d t o  b e p ot e nti all y  u nr eli a bl e  a n d/ or  n ot  c o o p er ati v e.
8. 5. 2  E x cl usi o n   C rit e ri a  
Eli gi bl e  p ati e nts   m ust  n ot  h a v e  a n y  of t h e f oll o  wi n g t o  b e  e nr oll e d i n t h e st u d y: 
E x cl usi o n a r y   Di a g n osis C rit e ri a  
1.
Patie nts w h o  ha ve:
a)
a n y ot her hist ol o gical t y pe of l y m p h o ma i ncl u di n g, e. g., pri mar y med iasti nal (t h y mic) 
lar ge B-cell ( P M B L ) or B ur kitt’s l ym p h o ma
b ) p ri mar y refract or y  DL B C L  (f or defi niti o n, s ee Secti o n 8. 1)
c)
p atie nts  wit h kn o w n  " do u ble/tri ple  hit" D L B C L  ge netics c h aracterise d by  sim ulta ne o us  
detecti o n of M Y C  wit h  B C L 2  a n d/ or B C L 6  tra nsl ocati o n, as d efi ne d b y  fl u oresce nce i n 
sit u h y bri disati o n (FI S H) . M Y C , B C L 2 , B C L 6  testi n g pri or t o st u d y e nr ol me nt is n ot  
re q uire d.
d ) ce ntral ner v o us s yste m ( C N S) l y m p h o ma i n vol ve me n t i n prese nt or past me dical 
h ist or y
E x cl usi o n a r y P r e vi o us  a n d C u r r e nt T r e at  m e nt C rit e ri a  
2.
Patie nts w h o ha d a maj or s ur ger y (for  defi niti o n, see Secti o n  8. 1 ) less t ha n 3 0 da ys pri or t o 
Da y 1 d osi n g
3.
Patie nt s w h o ha ve, wit hi n 1 4 da ys pri or t o Da y 1 d osi n g:
a)
n ot disc o nti n ue d C D 2 0-tar gete d t hera p y, c he m ot hera p y, ra di ot hera p y, i n vesti gati o nal 
a ntica nce r t hera p y or ot her l y m p h o ma-s pecific t hera p y  (f or e xce p ti o ns see Secti o n 9. 5. 3 )
b ) recei ve d  li ve vacci nes (for defi niti o n,  see Secti o n 8. 6 )
c)
req u ire d pare nteral a nti micr o bial t hera p y  f or acti ve, i nterc urre nt sy ste mic i nfecti o ns
4.
Patie nts w h o:
a)
i n t he o pi ni o n of t he i n vesti gat or, ha ve n ot rec o vere d s ufficie ntl y fr o m t he a d verse t o xic  
effects  of pri or t hera pies, maj or s ur geries (f or defi niti on,  see Secti o n 8. 1 ) or si g nifica nt 
tra u matic  i nj uries
b)
were pre vi o usl y  treate d wit h  CD 1 9 -tar gete d t hera p y or B E N


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 4 2  of 1 3 1  
c)
ha ve a hist or y of pre vi o us se vere aller gic reacti o ns t o c o m p o u n ds of si milar bi ol o gical or
c he mical c o m p ositi o n t o M O R 0 0 2 0 8, R T X, m uri ne pr otei ns or B E N , or the e xci pie nts
c o ntai ne d i n t he st u d y dr u g f or m ulati o ns
d)
ha ve u n der g o ne A S C T w it hi n a peri o d of ≤3 m o nt hs pri or t o si g ni n g t he I C F . Patie nts
w h o  ha ve  a m ore dista nt hist or y of A S C T m ust e x hi bit f ull hae mat ol o gical rec o ver y
bef ore e nr ol me nt i nt o t he st u d y.
e)
ha ve u n der g o ne pre vi o us all o ge nei c ste m  cell tra ns pla ntati o n
f) c o nc urre ntl y  use ot her a ntica ncer  or ex peri me ntal treat me nts  (f or e xce pti o ns see
Secti o n  9. 5. 3 )
E x c l usi o n a r y   Me di c al H ist o r y C rit e ri a  
5.
Pri or hist or y  of mali g na ncies ot her t ha n DL B C L,  u n less t he patie nt has  bee n  free of t he 
disease f or ≥3 years pri or t o S cree ni n g. E xce pti o ns t o t he ≥3 - year ti me  li mit i ncl ude  hist or y 
o f t he f oll o wi n g:
a)
ba sal cell carci n o ma of  t he s ki n
b)
s q ua m o us cell carci n o ma of  t he ski n
c)
carci n o ma  i n sit u of t he  cer vi x
d)
carci no ma  i n sit u of  the breast
e)
carci n o ma  i n sit u of t he bla d der
f) i nci de ntal  hist ol og ical fi n di n g of pr ostate ca ncer (T u m o ur/ N o de/ Metastasis [ T N M]  sta ge 
of T 1a or T 1 b)
6.
Patie nts  wit h:
a)
p o siti ve he patitis  B a n d/ or C ser ol o g y (for  defi niti o ns, see Secti o n  8. 6 )
b ) k n o w n s er o p o siti vit y for or hist or y  of acti ve  viral i nfecti o n wit h  hu ma n  
i m m u n o deficie nc y vir us (HI V)
c)
e vi de nce of  acti ve,  se vere u nc o ntr olle d s yste mi c i nfecti o ns (e. g., t u berc ul osis [ T B], 
o p p ort u nistic i nfecti o ns) or se psis
d ) a hist or y or e vi de nce of se verel y i m m u n oc o m pr o mise d state
e)
a hist or y or e vi de nce  of se vere he patic  im p airme nt (t ota l ser u m bilir u bi n >3  m g/ d L),  
ja u n dice u nless sec o n dar y t o Gil bert’s s y n dr o me or d oc u me nte d l i ver i n v ol ve me nt b y 
l y m p h o ma (see in cl usi o n criteri o n 6c)
f) a hist or y or e vi de nce of cli nicall y  sig nifica nt  car di o v asc ular,  cere br o vasc ular,  CN S  a n d/ or 
o t her disease t hat, i n t he i n vesti gat or’s o pi ni o n, w o ul d precl u de partici pati o n i n t he st u d y 
or c o m pr o mise t he patie nt’s a bilit y t o gi ve i nf or me d c o nse nt (f or a d diti o nal e x pla nati o ns, 
see Secti o n 8. 6 ).
8. 6  A d diti o n al   E x pl a n at o r y I nf o r  m ati o n  o n I n cl usi o n  a n d E x cl usi o n   C rit e ri a  
I n cl usi o n C rit e ri a:   Di a g n osis/  T ri al  P o p ul ati o n  
I n cl usi o n “ 2.   Hist ol o gi c all y  c o nfir  m e d  di a g n osis,  a c c or di n g t o t h e   W orl d   H e alt h   Or g a niz ati o n 
(  W  H  O,  2 0 0 8)  cl assifi c ati o n,  of: 
e)    Dis e as e tr a nsf or  m e d fr o  m  a n  e arli er  di a g n osis  of l o  w- gr a d e l y  m p h o  m a (i. e.  a n
i n d ol e nt  p at h ol o g y s u c h  as f olli c ul ar l y  m p h o  m a,   m ar gi n al z o n e l y  m p h o  m a) i nt o
D L B  C L   wit h  a   D L B  C L r el a ps e s u bs e q u e nt t o   D L B  C L tr e at  m e nt ”


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 4 3  of 1 3 1  
P ati e nts   wit h   Ri c ht er's tr a nsf or  m ati o n  or   Ri c ht er's s y n dr o  m e  ar e  n ot  eli gi bl e f or st u d y 
p arti ci p ati o n.  
In cl usi o n “ 5. P ati e nts  aft er f ail ur e  of  A S  C T   or  p ati e nts  c o nsi d er e d i n t h e  o pi ni o n  of t h e 
i n v esti g at or c urr e ntl y n ot  eli gi bl e f or H  D  C    wit h s u bs e q u e nt  A S  C T.   D o c u  m e nt ati o n  of t h e r e as o n 
f or i n eli gi bilit y f or  A S  C T   m ust  b e  pr es e nt i n t h e  p ati e nt’s s o ur c e  d at a. ” 
A s f or t h e   A SC T, t h e i n d u cti o n,  c o ns oli d a ti o n, st e  m  c ell  c oll e cti o n,  pr e p ar ati v e r e gi  m e n 
i n cl u di n g tr a ns pl a nt ati o n,  a n d   m ai nt e n a n c e   will  b e  c o nsi d er e d  a si n gl e li n e  of t h er a p y. 
F or t h e  p ur p os e  of t his  pr ot o c ol,  p ati e nts   w h o  ar e  n ot  c a n di d at es f or   H  D  C   wit h   A S  C T  ar e 
d efi n e d  b y   m e eti n g  a n y  of t h e f oll o  wi n g  crit eri a  as  e vi d e n c e d i n t h e  p ati e nt’s s o ur c e  d at a : 
1)
I n a d e q u at e  p erf or  m a n c e st at us (  K ar n ofs k y  P erf or  m a n c e  St at us  ≤  8 0  %; s e e A p p e n di x   D )
2)
Dis e as e  n ot r es p o nsi v e t o s al v a g e  c h e  m ot h er a p y.   R es p o nsi v e n ess is  d efi n e d  as  a t u  m ou r
d e  m o nstr ati n g  eit h er C  R  or  P  R t o s al v a g e  c h e  m ot h er a p y.
3)
I n a d e q u at e   m aj or  or g a n f u n cti o n:
a)
S y  m pt o  m ati c  c o n g esti v e  h e art f ail ur e
b)    L u n g f u n cti o n-f or c e d  vit al  c a p a cit y ( F  V  C), f or c e d  e x pir at or y  v ol u  m e i n  1 s e c o n d
( F E  V- 1),  a n d  c orr e ct e d  diff usi o n  c a p a cit y  of t h e l u n g f or  c ar b o n   m o n o xi d e (  D L  C  O)
≤  6 0  %
c)
R e n al f u n cti o n- c r e ati ni n e  cl e ar a n c e  <  6 0   mL /  mi n
d)
Li v er f u n cti o n-t ot al s er u  m  bilir u bi n  a n d tr a ns a  mi n as es  >  2  x   U L  N
e)
S eri o us  a cti v e  or  u n c o ntr oll e d   mi cr o bi al i nf e cti o ns ( e. g.  T  B)
4)    Hist or y  or  e vi d e n c e  of si g nifi c a nt  c o- m or bi d   m e di c al  or  ps y c hi atri c ill n ess   w hi c h   w o ul d
si g nifi c a ntl y  c o  m pr o  mis e t h e  p ati e nt's  cli ni c al c ar e  a n d  c h a n c es  of s ur vi v al
5)
I n a bilit y t o  c oll e ct  a d e q u at e st e  m  c ell  gr aft ( e. g.  <  1- 2  x  1 06 C  D 3 4 +  c ells fr e e  of t u  m o u r
c o nt a  mi n ati o n/ k g r e ci pi e nt  b o d y   w ei g ht)
In cl usi o n   C rit e ri a:   L a b o r at o r y  v al u es 
I ncl usi o n   “ 6.  P ati e nts   m ust   m e et t h e f oll o  wi n g l a b or at or y  crit eri a  at  S cr e e ni n g: 
e)
s er u  m  cr e ati ni n e  ≤ 2. 0 x   U L  N  or cr e ati ni n e  cl e ar a n c e   m ust  b e  ≥ 4 0   m L/  mi n  c al c ul at e d
usi n g  a st a n d ar d   C o c k cr oft-  G a ult f or  m ul a (C o c k cr oft  a n d   G a ult ( 1 9 7 6) ; se e
A p p e n di x  A  to t h e  pr ot o c ol)
G l o  m er ul ar filtr ati o n r at e  c a n  als o  b e  us e d i n  pl a c e  of  cr e ati ni n e  or  cr e ati ni n e  cl e ar a n c e (Cr  Cl).  
E x cl usi o n  c rit e ri a: E x cl usi o n a r y   Di a g n osis   C rit e ri a 
E x cl usi o n   “1. P ati e nts   w h o  h a v e:  
b) pri  m ar y r efr a ct or y   D L B  C L
P r ot o c ol   M  O  R 2 0 8  C 2 0 4  e x cl u d es  pri  m ar y r efr a ct or y  p ati e nts  d efi n e d  as  p ati e nts   w h o  pr o gr ess i n 
t h e  c o urs e  of first li n e tr e at  m e nt  or   wit hi n  6   m o nt hs  of  c o  m pl eti o n  of first li n e tr e at  m e nt.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 4  of 1 3 1  
T h e  pr ot o c ol  all o  ws t h e i n cl usi o n  of: 
1)   D L  B  C L  p ati e nts   wit h  a  hist or y  of  pri  m ar y r efr a ct or y  dis e as e   w h o   w er e r es p o nsi v e t o  a l at er 
tr e at  m e nt li n e,  
2) P ati e nts    wit h r el a ps e d   D L  B  C L  a n d r e  missi o n l asti n g   m or e t h a n  6   m o nt hs  of  pri or 
R T  X - c o nt ai ni n g t h er a p y 
3)   D L  B  C L  p ati e nts   w h o  ar e  n ot r es p o n di n g  or  pr o gr ess  e arl y   w h e n tr e at e d i n  2 n d  a n d  3r d li n e 
i n cl u di n g   R T  X- c o nt ai ni n g r e gi  m e ns. 
 
E x cl usi o n  c rit e ri a: E x cl usi o n a r y P r e vi o us  a n d C u r r e nt T r e at  m e nt  
E x cl usi o n   “3.  P ati e nts   w h o  h a v e,   wit hi n 1 4 d a ys  pri or t o   D a y  1  d osi n g: 
b ) R e c ei v e d li v e  v a c ci n es ” 
 
A d diti o n al i nf or  m ati o n: li v e  v a c ci n es ( e. g.  y ell o  w f e v er  v a c ci n ati o n) m ust n ot  b e  a d  mi nist er e d t o 
p ati e nts  i n t his st u d y.   V a c ci n ati o ns  a g ai nst i nfl u e n z a   wit h i n a cti v at e d  vir us  or  v a c ci n ati o n f or 
p n e u  m o c o c c al  dis e as es  ar e  all o  w e d . 
 
E x cl usi o n  c rit e ri a: E x cl u si o n a r y   Me di c al H ist o r y 
E x cl usi o n   “6. P ati e nts   wit h:  
a)  p ositi v e  h e p atitis  B  a n d/ or   C s er ol o g y ” 
 
I n t h e  c o nt e xt  of t h e  e x cl usi o n  crit eri a, s er o p ositi v e f or  or  a cti v e  vir al i nf e cti o n   wit h   H  B  V 
m e a ns:  
1)  H e p atitis   B  vir us s urf a c e  a nti g e n ( H  Bs  A g ) p ositi v e 
2)  H  Bs  A g n e g ati v e,  a nti -H  B c  p ositi v e  a n d  d et e ct a bl e  vir al   D  N  A (r e g ar dl ess  of   H  Bs  A b 
st at us). 
 
P ati e nts   w h o  e x hi bit t h e  cl assi c al  v a c ci n ati o n  pr ofil e  of   H  Bs  A b  p ositi v e,  a nti -H  B c  n e g ati v e  a n d 
H  Bs  A g  n e g ati v e  ar e  eli gi bl e.  
 
A  p ositi v e  h e p atitis   C t est is  d efi n e d  as  a  p o siti v e t est f or h e p atitis   C  vir us  a nti b o d y ( a nti-H  C  V ) 
a n d  a  p ositi v e t est f or   H  C  V   R  N  A.   T h us,  p ati e nts   wit h  p ositi v e s er ol o g y  b ut  n e g ati v e   H  C  V   R  N  A 
t est r es ults  ar e  eli gi bl e. 
 
Pl e as e r ef er t o S e cti o n 1 0. 3. 7. 2  f or f urt h er i nf or  m ati o n. 
 
b)  “ k n o  w n s er o p ositi vit y f or  or  hist or y  of  a cti v e  vir al i nf e cti o n   wit h  h u  m a n 
i  m  m u n o d efi ci e n c y  vir us (  HI V)” 
 
A d diti o n al i nf or  m ati o n: n o s af et y  d at a  o n t h e  us e  of C  D 1 9  a nti b o di es i n   HI  V  p ositi v e  p ati e nts 
ar e  c urr e ntl y  a v ail a bl e.  
 
c) “ e vi d e n c e  of  a cti v e, s e v er e s yst e  mi c,  u n c o ntr oll e d i nf e cti o ns ( e. g., 
t u b er c ul osis [ T B],  o p p ort u nisti c i nf e cti o ns)  or s e psis 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 5  of 1 3 1  
I nf e cti o ns  c o ntr oll e d  o n  c o n c urr e nt  a nti  mi cr o bi al  a g e nts  a n d/ or  a nti  mi cr o bi al  pr o p h yl a xis  p er 
i nstit uti o n al  g ui d eli n es  ar e  a c c e pt a bl e. 
 
f) “ a hist or y  or  e vi d e n c e  of  cli ni c all y si g nifi c a nt  c ar di o v as c ul ar, 
c er e br o v as c ul ar,   C  N S  a n d/ or  ot h er s yst e  mi c  dis e as e t h at   w o ul d i n t h e 
i n v esti g at or’s  o pi ni o n  pr e cl u d e  p arti ci p ati o n i n t h e st u d y  or  c o  m pr o  mis e t h e 
p ati e nt’s  a bilit y t o  gi v e i nf or  m e d  c o ns e nt. ” 
 
A d diti o n al i nf or  m ati o n:   cli ni c all y si g nifi c a nt  c ar di o v as c ul ar,  c er e br o v as c ul ar,   C  N S  a n d/ or  ot h er 
s yst e  mi c  dis e as e i n cl u d e,  b ut ar e n ot li  mit e d t o:  
1)  a m y o c ar di al i nf ar cti o n   wit hi n  6   m o nt hs  b ef or e  e nr ol  m e nt ,  u n c o ntr oll e d  a n gi n a  p e ct oris, 
el e ctr o c ar di o gr a p hi c  e vi d e n c e  of  a c ut e is c h a e  mi a  
2)  N e  w   Y or k   H e art   Ass o ci ati o n (  N  Y  H  A)  cl ass II  or  hi g h er  c o n g esti v e  h e art f ail ur e  (s e e 
A p p e n di x  E for   N  Y  H  A  cl assifi c ati o n)  
3)  s e v er e  u n c o ntr oll e d or  cli ni c all y si g nifi c a nt  c o n d u cti o n s yst e  m  a b n or  m aliti es  ( e. g. 
v e ntri c ul ar t a c h y c ar di a,  hi g h -gr a d e atri o v e ntri c ul ar - bl o c k). P ati e nts   wit h st a bl e, 
as y  m pt o  m ati c  atri al fi brill ati o n  ar e  all o  w e d i n t h e st u d y  pr o vi d e d t h e y  d o  n ot   m e et t h e 
ot h er  e x cl usi o n  crit eri a  
4)  s e v er e,  u n c o ntr oll e d  c ar di a c  dis e as e i n cl u di n g cli ni c all y si g nifi c a nt  p eri c ar di al  d is e as e 
5)  C  N S l esi o ns /c er e br o v as c ul ar  e v e nt(s)   wit h  cli ni c all y si g nifi c a nt s e q u el a e  
6)  C  N S,   m e ni n g e al  or  e pi d ur al   m ali g n a n ci es ( e. g.,  br ai n   m et ast as es,  k n o  w n   m e ni n g e osis 
l e u k a e  mi a) 
7)  c er e br o v as c ul ar  e v e nt(s)   wit h  cli ni c all y si g nifi c a nt s e q u el a e.  
 
S cr e e ni n g f or  c er e br os pi n al fl ui d   C  N S i n v ol v e  m e nt is  n ot  r e q uir e d  b ut   m a y  b e  p erf or  m e d  at t h e 
dis cr eti o n  of t h e i n v esti g at or.  
 
8. 7  R a n d o  mis ati o n  
D uri n g  S cr e e ni n g,  e a c h  p ati e nt   w h o si g ns t h e I  C F   will  b e  all o c at e d  a  u ni q u e i d e ntifi c ati o n 
n u  m b er.  
 
All  p ati e nts   w h o f ulfil  all i n cl usi o n  crit eri a  a n d   w h o  ar e  n ot  b arr e d  b y  a n y  of t h e  e x cl usi o n 
crit eri a   will  b e r a n d o  ml y  assi g n e d t o tr e at  m e nt  c o  m prisi n g    M  O  R 0 0 2 0 8 wit h B E  N  or   R T  X wit h 
B E  N i n  a  1: 1 r ati o.   R a n d o  mis ati o n   will  b e  d o n e t hr o u g h i nt er a cti v e r es p o ns e t e c h n ol o g y (I  RT ) 
b ef or e t h e  p ati e nt r e c ei v es  a n y st u d y   m e di c ati o n. W hil e  all i n cl usi o n  a n d  e x cl usi o n  crit eri a  n e e d 
t o  b e r e vi e  w e d  a g ai n  pri or t o r a n d o  misati o n, f or  all  crit eri a t h at r ef er t o l a b or at or y  p ar a  m e t ers, 
c e ntr al l a b or at or y r es ults  o bt ai n e d  d uri n g t h e s cr e e ni n g  p eri o d   will  b e  us e d f or  d et er  mi ni n g 
p ati e nt  eli gi bilit y f or st u d y r a n d o  mis ati o n. 
 
R es cr e e ni n g  of  p ati e nts   w h o   w er e  n ot  eli gi bl e f or st u d y  e nr ol  m e nt   will  b e  all o  w e d  u n d er t h e 
c o n diti o ns  d es cri b e d i n S e cti o n  8. 8 . P ati e nts   w h o  ar e r es cr e e n e d   will r e c ei v e  a  n e  w  u ni q u e 
i d e ntifi c ati o n  n u  m b er. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 6  of 1 3 1  
B ef or e r a n d o  mi sati o n,  e nr oll e d  p ati e nts   will  b e str atifi e d  a c c or di n g t o t h e f oll o  wi n g f a ct ors: 
a) Dis e as e r el a ps e/r e c urr e n c e:  e arl y ( ≤ 1 2   m o nt hs)  v ers us l at e ( > 1 2   m o nt hs ) fr o  m t h e 
c o  m pl eti o n  of t h e l ast tr e at  m e nt 
b)  A g e  ≤ 6 5  v ers us  > 6 5  y e ars  
c) E  C  O  G  p erf or  m a n c e st at us  0 -1  v ers us  2  
d)  Pri or s yst e  mi c t h er a p y li n es  ≤ 2 v ers us  > 2.  
 
R a n d o  mis ati o n  d uri n g I niti al S af et y   E v al u ati o n:  D uri n g I niti al  Saf et y E v al u ati o n , p ati e nts   will 
b e  all o c at e d t o tr e at  m e nt  c o  m prisi n g   M  O  R 0 0 2 0 8   wit h   B E  N  or   R T  X   wit h   B E  N vi a si  m pl e 
r a n d o  mis ati o n i n  a  1: 1 r ati o.  T h e i nf or  m ati o n  a b o ut str atifi c ati o n f a ct ors   will  n e v ert h el ess  b e 
c oll e ct e d f or t h es e  p ati e nts  as   w ell t o  b e  us e d i n t h e  a n al ysis  of t h e st u d y  d at a.  
 
8. 8  R e -s c r e e ni n g  P r o c e d u r es 
A  p ati e nt  c a n  b e r e -s cr e e n e d  at t h e  dis cr eti o n  of t h e i n v esti g at or  u n d er  c ert ai n  cir c u  mst a n c es. 
R e -s cr e e ni n g is r estri ct e d t o  o n e  att e  m pt  p er  p ati e nt  a n d  c a n  o nl y  b e  p erf or  m e d if  o n e  of t h e 
f oll o  wi n g  crit eri a is   m et: 
1.  T h e  p ati e nt  h as  alr e a d y  c o ns e nt e d  a n d   m et  all  of t h e i n cl usi o n  a n d  n o n e  of t h e  e x cl usi o n 
crit eri a  a n d  hi s  or  h er  e nr ol  m e nt   w as  d el a y e d  d u e t o  a n  u n e x p e ct e d  c h a n g e i n t h e 
p ati e nt’s  p ers o n al sit u ati o n ( e. g. f a  mil y iss u es) . 
2.  T h e  p ati e nt  pr e vi o usl y f ail e d t o  b e  eli gi bl e  d u e t o  a n y  e v e nt ( e. g.,  pl a n n e d s ur g er y, 
l a b or at or y t est r es ult) or a n y t e c h ni c al/l o gisti c r e as o n ( e. g. s cr e e ni n g  p eri o d  el a ps e d  d u e 
t o u n e x p e ct e d l e a v e  o r a bs e n c e  of  p ati e nt) t h at  h as  b e e n r es ol v e d. 
3.  T h e  p ati e nt f ail e d s cr e e ni n g pr e vi o usl y a n d  b e c o  m es  eli gi bl e f or t h e st u d y  b as e d  o n  a 
c h a n g e i n t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  as t h e r es ult  of  a  pr ot o c ol  a  m e n d  m e nt. 
4.  T h e p ati e nt f ail e d s cr e e ni n g  d u e t o  n o n -pr o gr ess e d/ n o n -r el a ps e d  dis e as e  at t h e ti  m e  of 
s cr e e ni n g  a n d l at er is  cli ni c all y  di a g n os e d  as  h a vi n g  pr o gr ess e d/r el a ps e d.  
N ot e:   A  p ati e nt s h o ul d  o nl y  b e r e -s cr e e n e d if t h er e is  a  cl e ar i n di c ati o n t h at t h e  p ati e nt   m a y  b e 
eli gi bl e  a c c or di n g t o t h e  c urr e ntl y  v ali d st u d y  pr ot o c ol.  
 
I n t h es e  c as es, if  pr e vi o us s cr e e ni n g  a cti viti es   w er e  dis c o nti n u e d  a n d  e nr ol  m e nt  di d  n ot  o c c ur, 
t h e f oll o  wi n g  pr o c e d ur es s h o ul d  b e i  m pl e  m e nt e d: 
1.  T h e  p ati e nt   m ust si g n  a n d  d at e  a  n e  w I  C F  as  p art  of t h e r e-s cr e e ni n g  pr o c e d ur e 
2.  T h e  eli gi bl e  p ati e nt   will r e c ei v e  a  n e  w  u ni q u e i d e ntifi c ati o n  n u  m b er  vi a t h e I R T  
3.  A  n e  w el e ctr o ni c  c as e r e p ort f or  m ( e  C  R F) will  b e  c o  m pl et e d  
4.  T h e  p ati e nt   will  b e  d o c u  m e nt e d  as r e -s cr e e n e d i n t h e so ur c e  d o c u  m e nts.  
 
A r e -s cr e e n e d  p ati e nt  c a n  b e  e nr oll e d, if  all  of t h e  c urr e nt i n cl usi o n  crit eri a  ar e   m et  a n d  n o n e  of 
t h e  e x cl usi o n  crit eri a  ar e   m et. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 7  of 1 3 1  
8. 9  D efi niti o n  of F e  m al e of   C hil d b e a ri n g P ot e nti al  
A s e x u all y   m at ur e f e  m al e p ati e nt or  a s e x u all y   m at ur e f e  m al e  p art n er  of  a   m al e p ati e nt is 
c o nsi d er e d t o  h a v e  c hil d b e ari n g  p ot e nti al  u nl ess s h e   m e ets  at l e ast o n e  of t h e f oll o  wi n g  crit eri a:  
1.  A g e ≥5 0  y e ars  a n d  n at ur all y a  m e n orr h o ei c f or ≥2 4   m o nt hs (i.e.,  h as n ot h a d   m e ns es  at  
a n y ti  m e i n t h e  pr e c e di n g  2 4  c o ns e c uti v e   m o nt hs).   A m e n orr h o e a f oll o  wi n g  c a n c er 
t h er a p y  d o es  n ot r ul e  o ut  c hil d b e ari n g  p ot e nti al 
2.  Pr e  m at ur e  o v ari a n f ail ur e  c o nfir  m e d  b y  a  g y n a e c ol o gist  
3.  Pr e vi o us  bil at er al s al pi n g o -o o p h or e ct o  m y,  or  h yst er e ct o  m y  
4.  X  Y  g e n ot y p e,  T ur n er s y n dr o  m e,  ut eri n e  a g e n esis . 
 
9  T  R  E  A  T  M  E  N  T S  
9. 1  S t u d y T r e at  m e nts  
T his is  a n  o p e n -l a b el st u d y.  Th e  c o  m bi n ati o n t r e at  m e nt  c o nsisti n g  of M  O  R 0 0 2 0 8 wit h B E  N  or 
R T  X  wit h B E  N will  b e  a d  mi nist er e d  at s p e cifi e d ti  m e p oi nts  at  pr ot o c ol -pr es cri b e d d os e l e v els 
f or  a   m a xi  m u  m  of si x c y cl es . 
 
S u bs e q u e nt t o t h e  c o  m pl eti o n  of t h e C o  m bi n ati o n T r e at  m e nt, p ati e nts wit h  a n  o n g oi n g r es p o ns e 
of  at l e ast  P  R,  as  p er l o c al  dis e as e r es p o ns e  ass ess  m e nt,  at t h e  e n d  of   C y cl e  6   will e nt er   A nti b o d y 
M o n ot h er a p y  Tr e at  m e nt i n  a c c or d a nc e   wit h t h eir  ori gi n al tr e at  m e nt  all o c ati o n u ntil  dis e as e 
pr o gr essi o n .  T h er ef or e, th e d ur ati o n  of   A nti b o d y M o n ot h er a p y T r e at  m e nt   m a y v ar y i n di vi d u all y . 
Tr e at  m e nt   m a y  b e st o p p e d  d u e t o  dis e as e r e c urr e n c e / pr o gr essi o n,   wit h dr a  w al  d u e t o 
u n a c c e pt a bl e t o xi cit y,  dis c o nti n u ati o n f or  a n y  ot h er r e as o n  or  d e at h,   w hi c h e v er  c o  m es first.   
 
I n t h e  c as e  of  dis e as e r e c urr e n c e/ pr o gr essi o n,  as  ass ess e d l o c all y, t h e i n v esti g at or will ,  b as e d  o n 
t h e  p ati e nt`s i n di vi d u al ris k/ b e n efit r ati o,  ali g n wit h t h e  S p o ns or a n d d e ci d e if t h e  p ati e nt s h o ul d 
r e c ei v e “ Furt h er  or C o nti n u e d  tr e at  m e nt   wit h a nti b o d y” i n  a c c or d a n c e   wit h t h e  ori gi n al tr e at  m e nt 
all o c ati o n (  R T  X  3 7 5   m g/  m2 at 2 8 -d a y  i nt er v als  or   M  O  R 0 0 2 0 8 1 2   m g/ k g  at 1 4 -d a y  i nt er v als) f or 
u p t o  2 4  m o nt hs i n t ot al .   M  O  R 0 0 2 0 8   will  b e  pr o vi d e d  b y t h e s p o ns or i n t h e  c o urs e  of t h e tri al. 
H o  w e v er , R T  X i n t hi s  p arti c ul ar  cli ni c al sit u ati o n will  n ot  b e  pr o vi d e d  b y t h e s p o ns or  a n d h as t o 
b e  pr es cri b e d  b y t h e tr e ati n g  p h ysi ci a n  a n d o bt ai n e d fr o  m c o  m  m er ci al s o ur c es. F or  p ati e nts 
r e c ei vi n g  a nti b o d y tr e at  m e nt  d es pit e  dis e as e r e c urr e n c e/ pr o gr essi o n,  b ef or e t h e  a d  mi nistr ati o n  of 
a nti b o di es,  bl o o d  p ar a  m et ers ( h ae  m at ol o g y, s er u  m  c h e  mistr y) s h o ul d  b e  e v al u at e d i n t h e l o c al 
l a b  a c c or di n g t o l o c al  g ui d eli n es/st a n d ar ds  of l o c al   m e di c al  pr a cti c e f or t h e  a d  mi nistr ati o n  of 
m A b s. A  uri n e  pr e g n a n c y t est s h o ul d  b e  p erf or  m e d f or an  F  C  B P . Vit al si g ns s h o ul d  b e   m e as ur e d 
a c c or di n g t o l o c al  pr a cti c e f or t h e  a d  mi nistr ati o n  of   mA b s.  
 
E a c h i n v esti g at or is r es p o nsi bl e f or  e ns uri n g t h at  d eli v eri es  of st u d y  dr u gs  a n d  ot h er st u d y 
m at eri als fr o  m t h e s p o ns or  a n d  ot h er  dr u gs fr o  m t h e  a p pr o pri at e s u p pli ers  ar e  c orr e ctl y r e c ei v e d, 
r e c or d e d, h a n dl e d  a n d st or e d s af el y  a n d  pr o p erl y i n  a c c or d a n c e   wit h  all  a p pli c a bl e r e g ul at or y 
g ui d eli n es,  a n d  us e d i n  a c c or d a n c e   wit h t his  pr ot o c ol.  T h e i n v esti g at or m a y  d el e g at e t h es e t as ks 
t o  a n ot h er  p ers o n ( a c c or di n g t o t h e l o c al l a  ws  a n d r e g ul ati o ns).   Dr u g  a c c ou nt a bilit y f or  ms   will 
b e  k e pt  b y  e a c h sit e  p arti ci p ati n g i n t h e st u d y  a n d   will  b e  c h e c k e d  d uri n g   m o nit ori n g  visits.  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 8  of 1 3 1  
St u d y  dr u g   m ust  b e  h a n dl e d, pr e p ar e d a n d  a d  mi nist er e d as  d es cri b e d i n t h e   Dr u g H a n dli n g 
M a n u al, t h e I  B f or   M  O  R 0 0 2 0 8,  a n d  ot h er s af et y- r el e va nt  d o c u  m e nts ( e. g. , S u  m  m ar y  of  Pr o d u ct 
C h ar a ct eristi cs ( [ S  mP  C ] f or t h e  E ur o p e a n   M e di ci n es   A g e n c y [ E  M  A]  or t h e  Pr es cri bi n g 
I nf or  m ati o n [  U S  Fo o d  a n d   Dr u g   A d  mi nistr ati o n ( F D  A )] f or   B E  N  a n d   R T  X). Pl e as e s e e 
A p p e n di x  F  f or  a d diti o n al i nf or  m ati o n. 
 
T h e i nf usi o n r at es  a n d ti  m es f or st u d y  dr u gs s p e cifi e d i n t h e  pr ot o c ol  a n d t h e   Dr u g   H a n dli n g 
M a n u al ar e r e c o  m  m e n d ati o ns f or t h e i n v esti g ati v e sit es’  us e. If r e q uir e d, t h e i n v esti g at or s h o ul d 
us e  cli ni c al j u d g e  m e nt  a n d i nstit uti o n al  g ui d el i n es t o  o pti  mis e  p ati e nt s af et y  b y  a dj usti n g t h e r at e 
of i nf usi o n  a c c or di n g t o t h e   m e di c al  c o n diti o n  of t h e  p ati e nt.  
 
M  O  R 0 0 2 0 8 will  b e s u p pli e d  b y t h e s p o ns or. B E  N  a n d   R T  X   will  b e a v ail a bl e fr o  m  c o  m  m er ci al 
s o ur c e.   C o n c o  mit a nt   m e di c ati o ns   will  b e  pr o vi d e d  b y t h e i n v esti g ati v e sit e  a n d  n ot  b y t h e 
s p o ns or. 
 
9. 1. 1  M  O  R 0 0 2 0 8 
M  O  R 0 0 2 0 8   D P ( dr u g  pr o d u ct)   m ust  b e st or e d  u n d er r efri g er ati o n  at  2°  C t o  8°  C i n its  ori gi n al 
p a c k a g e i n  a n  a p pr o pri at e st or a g e f a cilit y  e q ui p p e d   wit h t e  m p er at ur e  c o ntr ol, a c c essi bl e  o nl y t o 
t h e  p h ar  m a cist(s), t h e i n v esti g at or,  or  a  d ul y  d esi g n at e d  p ers o n. 
 
M  O  R 0 0 2 0 8   D P  is  a l y o p hilis at e s u p pli e d i n si n gl e- us e  2 0   m L  gl ass  vi als.  E a c h  vi al  c o nt ai ns 
2 0 0   m g  of   M  O  R 0 0 2 0 8 f or r e c o nstit uti o n   wit h  5 m L   w at er f or i nj e cti o n (  W FI).   R e c o nstit uti o n 
yi el ds  4 0   m g/  m L   M  O  R 0 0 2 0 8 i n  2 5 m  M  s o di u  m  citr at e,  2 0 0   m  M tr e h al os e  a n d  0. 0 2  % (  w/ v) 
p ol ys or b at e  2 0  at  p  H  6. 0.  E a c h  pr o d u ct  vi al is i nt e n d e d t o  d eli v er  2 0 0   m g  of   M  O  R 0 0 2 0 8 i n  5   m L 
of r e c o nstit ut e d s ol uti o n.  T h e s ol uti o n  aft er r e c o nstit uti o n is  c ol o url ess t o sli g htl y  y ell o  w  a n d 
ess e nti all y fr e e  of f or ei g n  p arti cl es; it   m a y  c o nt ai n  a f e  w   w hit e t o   w hitis h  pr o d u ct -r el at e d 
p arti cl es.  
 
F or  a d  mi nistr ati o n,   M  O  R 0 0 2 0 8   will  b e  dil ut e d i nt o  a  c o  m  m er ci all y  a v ail a bl e  2 5 0 m L i nf usi o n 
c o nt ai n er   wit h  0. 9  % (  w/ v) s o di u  m  c hl ori d e f or i nj e cti o n. 
 
T h e i n di vi d u al   M  O  R 0 0 2 0 8 i nf usi o n   will  b e  pr e p ar e d  u n d er  as e pti c  c o n diti o ns  a n d  a d  mi nist er e d 
at t h e st u d y sit e,  a c c or di n g t o t h e  dir e cti o ns  of t h e s p o ns or,   w hi c h   will  b e  pr o vi d e d i n  a   Dr u g 
H a n dli n g   M a n u al. I n  g e n er al,  a  vi al  of   M  O  R 0 0 2 0 8   m ust  b e  us e d  as s o o n  as  p ossi bl e  aft er 
r e c o nstit uti o n   wit h   W FI;  a n y s ol uti o n r e  m ai ni n g i n t h e  vi al  h as t o  b e  dis c ar d e d.   Aft er  dil uti o n f or 
i nf usi o n,  a d  mi nistr ati o n  of   M  O  R 0 0 2 0 8 s h o ul d t a k e  pl a c e  as s o o n  as  p ossi bl e.   M a xi  m u  m  all o  w e d 
st or a g e ti  m es  a n d  c o n diti o ns   will  b e  d et ail e d i n t h e   Dr u g   H a n dli n g M a n u al.  
 
M  O  R 0 0 2 0 8    will  b e  a d  mi nist er e d  at  a  d os e  of  1 2. 0   m g/ k g I  V.   D os e r e d u cti o ns  of   M  O  R 0 0 2 0 8  ar e 
n ot  all o  w e d  d uri n g t h e  c o urs e  of t h e st u d y. 
 
F or t h e first t hr e e   m o nt hs (  C y cl e  1 - 3)  of t h e st u d y,  e a c h  c y cl e   will  c o nsist  of  a   M  O  R 0 0 2 0 8 
i nf usi o n  o n   D a y  1,   D a y  8,   D a y  1 5  a n d   D a y  2 2  of t h e  c y cl e.   A d diti o n all y,  a l o a di n g  d os e   will  b e 
a d  mi nist er e d  o n   D a y  4  of   C y cl e  1. T h er e aft er  (  C y cl e  4-u ntil  dis e as e  pr o gr essi o n),  e a c h  c y cl e   will 
c o nsist  of  a   M  O  R 0 0 2 0 8 i nf usi o n  o n   D a y  1  a n d   D a y  1 5. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 4 9  of 1 3 1  
F or t h e first i nf usi o n, t h e I  V i nf usi o n r at e s h o u l d  b e  7 0   m L/ h f or t h e first  3 0   mi n ut es  a n d 
s u bs e q u e ntl y i n cr e as e d t o  a r at e  of  1 2 5   m L/ h; t h e t ot al i nf usi o n  d ur ati o n s h o ul d i d e all y  n ot 
e x c e e d  2. 5  h o urs.   All s u bs e q u e nt   M  O  R 0 0 2 0 8 i nf usi o ns   will  b e  a d  mi nist er e d I  V  at  a  c o nst a nt r at e 
of  1 2 5   m L/ h  o v er  a  2 -h o ur  p eri o d.   M  O  R 0 0 2 0 8 s h o ul d   N  O T  b e  a d  mi nist er e d  as  a n I  V  p us h  or 
b ol us.  
 
U nl ess  c o ntr ai n di c at e d t h e M  O  R 0 0 2 0 8  tr e at  m e nt s h o ul d  c o nti n u e,  e v e n if t h e  p ati e nt 
dis c o nti n u es   B E  N tr e at  m e nt.  
 
9. 1. 2  R  T  X  
S p e cifi c i nf or  m ati o n a b o ut t h e  c h e  mi c al str u ct ur e , pr o p erti es , f or  m ulati o n, st or a g e,  dis p os al a n d 
a d  mi ni str ati o n  of   R T  X ar e  pr o vi d e d i n t h e S  m P  C  ( E  M  A)  a n d  Pr es cri bi n g I nf or  m ati o n (  U S 
F  D  A ). 
 
R T  X s h o ul d  b e  a d  mi nist er e d  o nl y  as  a n  I  V i nf usi o n t hr o u g h  a  d e di c at e d li n e  a n d  n ot  as  a n I  V 
p us h  or  b ol us.  
 
R T  X   will  b e  a d  mi nist er e d  at  a  d os e  of  3 7 5   m g/  m 2 I  V o n   D a y  1  wit h  a  pr e -pl a n n e d tr e at  m e nt 
i nt er v al  of at l e ast 2 8  d a ys t o t h e s u bs e q u e nt   R T  X  a d  mi nistr ati o n.   D os e r e d u cti o ns  of   R T  X  ar e 
n ot  a ll o  w e d  d uri n g t h e  c o urs e  of t h e st u d y. 
 
R T  X   will  b e  a v ail a bl e fr o  m  c o  m  m er ci al  dr u g s u p pli es ( e. g.   M a b T h er a ® /  Rit u x a n® ). 
 
U nl ess  c o ntr ai n di c at e d t h e R T  X  tr e at  m e nt s h o ul d  c o nti n u e,  e v e n if t h e  p ati e nt  dis c o nti n u es   B E  N 
tr e at  m e nt.  
 
9. 1. 3  B  E  N  
S p e cifi c i nf or  m ati o n  a b o ut t h e  c h e  mi c al str u ct ur e,  pr o p erti es, f or  m ul ati o n, st or a g e ,  dis p os al a n d 
a d  mi nistr ati o n  of   B E  N  ar e  pr o vi d e d i n t h e S  m P  C ( E  M  A)  a n d  Pr es cri bi n g I nf or  m ati o n (  U S 
F  D  A) . 
 
B E  N   will  b e  a d  mi nist er e d  at  a  d os e  of  9 0   m g/  m 2 o n   D a y s 2 + 3  of C y cl e  1 . B E  N a d  mi nistr ati o n  
will  b e r e p e at e d  o n D a ys  1 + 2  or  2 + 3  of t h e s u bs e q u e nt  c y cl es,   wit h a  pr e-pl a n n e d  tr e at  m e nt 
i nt er v al  of at l e ast 2 8  d a y s  b et  w e e n t h e  c o  m  m e n cem e nt s of t  w o s u c c e e di n g  c y cl es ,  a c c or di n g t o 
i nstit uti o n al/ p ati e nt/ p h ysi ci a n  c h oi c e. A n  e x c e pti o n t o t his r ul e   m a y  o c c ur i n  c as e t h e B E  N 
a d  mi nistr ati o n s c h e  m e c h a n g es fr o  m   D a ys  2 + 3 t o   D a ys  1 + 2 , or  vi c e  v ers a , i n s u bs e q u e nt  c y cl es.  
 
It is s u g g est e d t h at  d uri n g C o  m bi n ati o n T r e at  m e nt,   B E  N tr e at  m e nt s h o ul d  b e  ali g n e d   wit h t h e 
a d  mi nistr ati o n  of m  A b  o n   D a y  1  o f t h e  c y cl e. W h e n a p pli c a bl e ,   B E  N s h o ul d  b e a d  mi nist er e d 
aft er t h e M  O  R 0 0 2 0 8  or   R T  X  i nf usi o n. 
 
B E  N d os e m a y  b e   m o difi e d i n  a  d e -es c al ati n g f as hi o n  or  dis c o nti n u e d  b as e d  u p o n  cli ni c al  a n d 
l a b or at or y fi n di n gs. I n t h e c as e  of  e arl y B E  N  dis c o nti n u ati o n , t h e  a nti b o d y tr e at  m e nt s h o ul d 
c o nti n u e u nl ess  c o ntr ai n di c at e d .  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 5 0  of 1 3 1  
D et ail e d  g ui d a n c e  o n  h o  w t o   m a n a g e  h a e  m at ol o gi c al a n d/ or  ot h er t o xi citi es is pr o vi d e d i n 
S e cti o n  9. 4. 2 . T h e r e c o  m  m e n d e d i nf usi o n ti  m e is  3 0 t o  6 0   mi n ut es.  T h e  pr e p ar e d   B E  N s ol uti o n 
s h o ul d  b e  a d  mi nist er e d  as  a n I  V i nf usi o n  a n d  n ot  as  a n I  V  p us h  or  b ol us. 
 
B E  N   will  b e  a v ail a bl e fr o  m  c o  m  m er ci al  d r u g s u p pli es ( e. g. L e v a ct ® / Tr e a n d a® ). 
 
9. 2  P r e m e di c ati o n f o r  St u d y   D r u g  I nf usi o ns 
A n y  pr e  m e di c ati o n  gi v e n s h o ul d  b e r e p ort e d i n t h e  e  C  R F. 
 
Pr e  m e di c ati o n f or   R T  X  a n d   B E  N i nf usi o ns s h o ul d f oll o  w i nstit uti o n al  g ui d eli n es  a n d/ or 
pr e  m e di c ati o n  a n d a d  mi nistr ati o n/i nf usi o ns s e cti o ns  of t h e  S  m P  C ( E  M  A)  or  Pr es cri bi n g 
I nf or  m ati o n (U S  F  D  A).  
 
I  R  Rs  h a v e  b e e n r e p ort e d i n  cli ni c al tri als   wit h   M  O  R 0 0 2 0 8.  T h er ef or e,  a r e c o  m  m e n d e d 
pr e  m e di c ati o n r e gi  m e n i n cl u d es  a  hist a  mi n e   H 1 r e c e pt or  bl o c k er ( e. g.,  di p h e n h y dr a  mi n e  5 0   m g 
p er  d os e I  V  or  e q ui v al e nt),  a n  a nti p yr eti c ( e. g.  a c et a  mi n o p h e n [ p ar a c et a  m ol]  1 0 0 0   m g  p er  d os e 
b y   m o ut h [ p. o.]  or I  V  or  e q ui v al e nt)  a n d  gl u c o c orti c ost er oi ds ( e. g.   m et h yl pr e d nis ol o n e  8 0 t o 
1 2 0 m g  p er  d os e I  V  or  e q ui v al e nt).  F or t h e  e q ui v al e nt  c orti c ost er oi d  d os es  pl e as e r ef er t o  
A p p e n di x   G . If r e q uir e d, t h e i n v esti g at or   m a y r e p e at  d os es  of i n di vi d u al  a g e nts  a n d  us e  ot h er 
a g e nts,  d os es  a n d/ or f or  m ul ati o ns i n  a c c or d a n c e   wit h i nstit uti o n al  g ui d eli n es. 
 
Pr e  m e di c ati o n is  m a n d at e d f or t h e first t hr e e   M  O  R 0 0 2 0 8 i nf usi o ns. Pr e  m e di c ati o n f or  p ati e nts 
w h o  d o  n ot  e x p eri e n c e  a n y I  R  Rs t o   M  O  R 0 0 2 0 8  d uri n g t h e first t hr e e i nf usi o ns ( d os es)   will  b e 
o pti o n al f or s u bs e q u e nt   M  O  R 0 0 2 0 8 i nf usi o ns  at t h e  dis cr eti o n  of t h e i n v esti g at or.   Ot h er  wis e, t h e 
pr e  m e di c ati o n s h o ul d  b e  c o nti n u e d f or s u bs e q u e nt  a d  mi nistr ati o ns.  
 
9. 3  P ati e nt   M o nit o ri n g   D u ri n g  St u d y   D r u g I nf usi o ns  
Vit al si g ns s h o ul d b e   m e as ur e d  as  o utli n e d i n  S e cti o n  1 3. 8. 4 . If   m  A b  a n d   B E  N  ar e  b ei n g 
a d  mi nist er e d  o n t h e s a  m e  d a y,  vit al si g ns s h o ul d  b e r e c or d e d i n  e  C  R F f or   m  A b i n f usi o n(s)  o nl y. 
All s u p p orti v e   m e as ur es  c o nsist e nt   wit h  o pti  m al  p ati e nt  c ar e s h o ul d  b e  pr o vi d e d t hr o u g h o ut t h e 
st u d y  a c c or di n g t o i nstit uti o nal st a n d ar ds.  
 
Pr e c a uti o ns f or  a n a p h yl a xis s h o ul d  b e  o bs er v e d  d uri n g st u d y  dr u g  a d  mi nistr ati o n.  E  m er g e n c y 
r es us cit ati o n  e q ui p  m e nt  a n d   m e di c ati o ns s h o ul d  b e r e a dil y  a v ail a bl e. 
 
9. 4  C rit e ri a f o r   D os e   M o difi c ati o ns  a n d St u d y D r u g   Dis c o nti n u ati o n  
9. 4. 1  M a n a g e  m e nt  of  St u d y   D r u g  I nf usi on- R el at e d   R e a cti o ns  
F or I  R  Rs r el at e d t o   B E  N  a n d/ or   R T  X, t h e i n v esti g at or s h o ul d f oll o  w t h e i nstr u cti o ns  c o nt ai n e d 
i n t h e  S  m P  C ( E  M  A)  or  Pr es cri bi n g I nf or  m ati o n (  U S  F  D  A)  of t h e s p e cifi c  pr o d u ct. 
 




I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 2  of 1 3 1  
If  a  p ati e nt   w h o  d e v el o p e d  a  gr a d e 2 I  R  R r e c ei v es f urt h er i nf usi o ns, t h e n  pr e  m e di c ati o n 
a c c or di n g t o t h e i nstit uti o n al  g ui d eli n es s h o ul d  b e  gi v e n  b ef or e  all s u bs e q u e nt i nf usi o ns. 
9. 4. 1. 2  G r a d e  3 I  R  Rs  f o r  p ati e nts  r e c ei vi n g   M  O  R 0 0 2 0 8 
If  a  p ati e nt  pr es e nts   wit h  a  gr a d e 3 I  R  R:  
•
T h e i nf usi o n s h o ul d  b e st o p p e d i  m  m e di at el y.
•
T h e  p ati e nt   m ust r e c ei v e  a p pr o pri at e tr e at  m e nt   wit h  a n a nti hist a  mi n e  a n d/ or
a c et a  mi n o p h e n ( p ar a c et a  m ol)  or   m et h yl pr e d nis ol o n e ( or  e q ui v al e nt)  a n d, if  n e c ess ar y,
f urt h er   m e di c ati o ns (i. e.  e pi n e p hri n e,  br o n c h o dil at or).
•
O nl y  aft er t h e  c o  m pl et e r es ol uti o n  of  all s y  m pt o  ms (t o  gr a d e ≤1),  a n d  aft er  h a vi n g
r e c ei v e d  a ppr o pri at e  pr o p h yl a cti c   m e di c ati o n(s)  as  d es cri b e d  a b o v e, t h e i nf usi o n   m a y  b e
r es u  m e d  at  a n i nf usi o n r at e  of  2 5  %. If,  aft er  1  h o ur, t h e  p ati e nt’s s y  m pt o  ms  d o  n ot r et ur n
a n d  vit al si g ns  ar e st a bl e, t h e i nf usi o n r at e   m a y  b e i n cr e as e d t o  a   m a xi  m u  m  of  5 0  % .
•
If,  aft er t h e r es u  m pti o n  of i nf usi o n, s y  m pt o  ms r et ur n (irr es p e cti v e  of  gr a d e), t h e i nf usi o n
m ust  b e st o p p e d i  m  m e di at el y  a n d t h e i nf usi o n t u bi n g s h o ul d  b e  dis c o n n e ct e d fr o  m t h e
p ati e nt. B as e d  o n t h e i n v esti g at or’s  d e cisi o n t h e  p ati e nt   m a y r e c ei v e f urt h er st u d y dr u g(s) ,
pr o vi d e d  cli ni c all y  a p pr o pri at e  pr e c a uti o ns  a r e  u n d ert a k e n. If t h e i n v esti g at or  d e ci d es t o
c o nti n u e   wit h f urt h er st u d y  dr u g(s)  a d  mi nistr ati o n, t h e n  pr e  m e di c ati o n  a c c or di n g t o t h e
i nstit uti o n al  g ui d eli n es s h o ul d  b e  gi v e n  b ef or e  all s u bs e q u e nt i nf usi o ns.
9. 4. 1. 3  G r a d e  4 I  R  Rs  f o r  p ati e nts  r e c ei vi n g   M  O  R 0 0 2 0 8 
If  a  p ati e nt  pr es e nts   wit h  a  gr a d e 4 I  R  R:  
•
T h e i nf usi o n s h o ul d  b e st o p p e d i  m  m e di at el y  a n d t h e i nf usi o n t u bi n g s h o ul d  b e
dis c o n n e ct e d fr o  m t h e  p ati e nt .
•
T h e  p ati e nt m ust r e c ei v e  a p pr o pri at e tr e at  m e nt   wit h  a n  a nti hist a  mi n e  a n d/ or
a c et a  mi n o p h e n ( p ar a c et a  m ol) a n d/or   m et h yl pr e d nis ol o n e ( or  e q ui v al e nt)  a n d, if
n e c ess ar y, f urt h er   m e di c ati o ns (i. e.  e pi n e p hri n e,  br o n c h o dil at or) .
•
T h e  p ati e nt   m ust  n ot r e c ei v e f urt h er i nf usi o ns  of t h e st u d y  dr u g t h at is j u d g e d  b y t h e
i n v esti g at or t o  b e t h e  c a us e  of t h e I  R  R,  b ut s h o ul d c o nti n u e tr e at  m e nt   wit h t h e  ot h er st u d y
dr u g  as  p er  pr ot o c ol.
9. 4. 2  M a n a ge me nt of T re at me nt- Rel ate d  To xicities  
T he  f oll o wi n g i nfor mati o n  will s u p p ort t he mana ge me nt of treat m e nt-relate d t o xicities whic h  
ma y res ult i n st u d y dr u g(s) d os e re d ucti o n or p o st p o ne me nt, eit her a t t he start of a ne w cycle  of 
t hera p y or d uri n g a cycle. 
G ui da nce f or d ose p ost p o ne me nt f or B E N a n d d ose re d ucti o n f or B E N is pr o vi de d i n 
Secti o n  9. 4. 2. 1 , gui da nce f or d ose o missi o n/ dela y / p ost p o ne me nt o f MO R 0 0 2 0 8 a n d R T X i n 
Secti o n  9. 4. 2. 2 , an d g ui da nce f or st u d y dr u g(s) treat me nt disc o nti n uati o n i n Secti o n  9. 4. 2. 3.  
All s ce nari os ma y  re q uire t he i m ple me n tati o n of th e p ri nci ples of best s up p orti ve car e ( B S C) 
acc or di n g  t o t he l ocal me dical practice  an d  t he i nstit uti o nal g ui deli nes. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 3  of 1 3 1  
9. 4. 2. 1  S af et y -r el at e d   C rit e ri a f o r   B  E  N   T r e at  m e nt  a n d   B  E  N   T r e at  m e nt  P ost p o n e  m e nt  
P ati e nts  c a n b e gi n  c h e  m ot h er a p y   wit h B E  N   o nl y if t h e  pr e-d os e l o c al l a b or at or y  p ar a  m et ers 
m e as ur e d l o c all y r e  m ai n i n t h e r a n g es s p e cifi e d b el o  w.  F urt h er  m or e,  p ati e nts  c a n r e c ei v e 
s u bs e q u e nt B E  N i nf usi o ns if t h e y  h a v e  p ass e d t h e  n e utr o p hils  a n d  pl at el ets  n a dir  a n d r e c o v er e d 
fr o  m  p ot e nti al B E  N -i n d u c e d  n o n- h ae  m at ol o gi c al t o xi citi es as  d es cri b e d i n T a bl e   2. 
T a bl e   2: 
C rit e ri a   R e q ui r e d f o r t h e I niti ati o n  of   B  E  N   T r e at  m e nts  
P a r a  m et e r  
P ati e nt s h o ul d  o nl y  b e  d os e d if:  
A  N  C  
≥ 1 0 0 0/  m  m 3 ( u nl ess  n e utr o p e ni a is j u d g e d t o  b e s e c o n d ar y t o l y  m p h o  m a 
i nfiltr ati o n  of  b o n e   m arr o  w).  P ati e nt   m a y  h a v e r e c ei v e d  gr o  wt h f a ct or s u p p ort. 
Pl at el ets  
≥ 7 5 0 0 0/  m  m 3 ( u nl ess t hr o  m b o c yt o p e ni a is j u d g e d t o  b e s e c o n d ar y t o l y  m p h o  m a 
i nfiltr ati o n  of  b o n e   m arr o  w). P ati e nt   m a y  h a v e r e c ei v e d tr a nsf usi o n s u p p ort i n 
eit h er sit u ati o n.  
T ot al  bilir u bi n;   A S T;   A L T  
≤  3  x   U L  N ( u nl ess  d u e t o   Gil b ert’s s y n dr o  m e  or  d o c u  m e nt e d li v er i n v ol v e  m e nt 
b y l y  m p h o  m a)  
Ot h er  cli ni c all y si g nifi c a nt  n o n -
h a e  m at ol o gi c al t o xi cit y  
N o  a cti v e  a n d u n c o ntr oll e d i nf e cti o n  
C y cl e  2 -6:  cli ni c all y r el e v a nt,  n o n -h a e  m at ol o gi c al   B E  N -i n d u c e d t o xi cit y  h as 
di  mi nis h e d i n s e v erit y t o  gr a d e  ≤2 or r e c o v er e d t o  b as eli n e l e v el (if t h e  c o n diti o n 
w as  pr e -e xisti n g)  
A b br e vi ati o ns:   A L T  =  al a ni n e tr a ns a  mi n as e;   A  N  C  =  a bs ol ut e  n e utr o p hil  c o u nt;   A S T  =  as p art at e  a  mi n otr a nsf er as e;   B E  N  = 
b e n d a  m usti n e;   U L  N  =  u p p er li  mit  of  n or  m al.  L a b or at or y  p ar a  m et ers  ar e  ass ess e d l o c all y.  
1.
If t he criteria  f or t he i nitiati o n of B E N treat me n t are n o t met,  t he su bse q ue nt B E N  
treat me nt is t o be p ost p o ne d. It is rec o m me n de d t hat t he A E gra de a n d t he hae mat ol o g y  
val ues are s u bse q ue ntl y i n vesti gate d at a ppr o xi matel y  3- da y inter vals.
2.
T here m ust  al wa y s be at least a 2 8- d a y inter val  bet wee n  t he c o m me nce m e nt of
t w o c o nsec uti ve B E N  treat me nt c ycles  (f or a d diti o nal i nf or mati o n  see Secti o n  9. 1. 3 ).
3.
M O R 0 0 2 0 8 or R T X ma y be c o nti n ue d ( please n ote Secti o n  9. 4. 2. 2) wh ile criteria  f or 
B E N  treat me nt are n ot  fulfille d.  For  t hese patie nts,  BE N  treat me nt will occ ur  as s o o n  as 
t he criteria f or re-treat me nt wit h BE N  are f ulfille d.
4.
If base d o n me dical j u d ge me nt, t he treati n g p h ysicia n c o nsi ders cli nical a n d/ or la b orat or y  
para meter c ha n ges n ot t o be st u d y dr u g-relate d t o xicit y, b ut t o re prese nt disease hist or y,  
nat ural fl uct uati o n or pr o gressi o n of t he u n derl yi n g disease, it is at t he p h ysicia n’s  
discreti o n, i n a cc o rda nce  wit h assess me nt of t he i ndi vi d ual r is k/ be nefit r ati o, t o deter mi ne  
w het her  th e n e w BE N  treat me nt s ho ul d  be i nitiate d (see Ta ble 2) or  B EN d o se mai ntai ne d 
(see Ta ble 3) wit h o ut meeti n g t he criteria f or s u bse q ue nt c ycles of  c he m ot hera p y. T he 
decisi o n a n d rati o nale be hi n d t he decisi o n s h o ul d be d oc u me nte d i n t he s o urce data.


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 4  of 1 3 1  
T a bl e   3: 
B  E  N   D os e   R e d u cti o n   C rit e ri a 
N  CI   C  T  C  A  E  c at e g o r y  S e v e rit y  
D os e   m o difi c ati o n  
H a e  m at ol o gi c 
A N  C <  1 0 0 0/ µl (  Gr a d e  ≥ 3)  o n   D a y  1  of 
C y cl es  2 - 6 
B E  N  c y cl e i niti ati o n (  D a y  1)  of   C y cl es  2 
−6 s h o ul d  b e  d el a y e d  u ntil t h e   A  N  C is
≥1 0 0 0/ µl  a n d t h e  P L Ts is  ≥ 7 5 0 0 0/ µl  or
c ell  c o u nts r et ur n t o  b as eli n e l e v el
o bt ai n e d  at s cr e e ni n g r es p e cti v el y *.
If Da y 1 is dela ye d  b y m ore  t ha n 
2 wee ks,  the n  B E N  s h o uld  be  res u me d 
at th e ne xt  lo wer  d o se le vel (see 
Ta ble  4 ). 
Gr o wt h  fact or (e. g. G -C S F)  a n d 
tra nsf usi o n su p p ort  s h o ul d be  c o nsi dere d  
acc or di n g to th e pri nci ples  of  me dical  
practice  a n d t he instit uti o nal  g ui deli nes  
d uri n g t his  a n d  su bse q ue nt  c ycles.   
P L Ts <  7 5 0 0 0/ µl (  Gr a d e  ≥ 2)  o n   D a y  1  of 
C y cl es  2 - 6 
A  N  C <  5 0 0/ µl (  Gr a d e  4)  of  a n y  d ur ati o n 
a c c o  m p a ni e d  b y  b o d y t e  m p er at ur e  of 
≥ 3 8. 3º  C  o n  a si n gl e  o c c asi o n  or  > 3 8º  C  o n 
t  w o  o c c asi o ns   m e as ur e d   wit hi n  1 2 
c o ns e c uti v e  h o urs  or  > 3 8º  C   m ai nt ai n e d 
≥ 1  h o ur  
B E N  c ycle  i nitiati o n ( Da y 1)  of  
C ycles  2- 6  s h o uld be  dela ye d  u ntil t he  
A N C is ≥1 0 0 0/ µl  wit h o u t e vi de nce  of  
fe ver or  i nfecti o n a nd P L Ts is 
≥7 5 0 0 0/ µl *. 
B E N s h o uld t hen b e res ume d  at t he ne xt 
l o wer d ose  le vel (see Ta ble  4 ) 
Gr o wt h  fact or (e. g. G -C S F)  a n d 
tra nsf usi o n su p p ort  s h o ul d be  c o nsi dere d  
acc or di n g to t he pri nc i ples of  me dical  
practice  a n d t he instit uti o nal  g ui deli nes  
d uri n g t his  a n d  su bse q ue nt  c ycles.  
A  N  C <  1 0 0 0/ µl (  Gr a d e  3) l asti n g  ≥  7  d a ys  
P L Ts <  2 5 0 0 0/ µl (  Gr a d e  4) l asti n g  ≥ 7  d a ys 
or  of  a n y  d ur ati o n if  a c c o  m p a ni e d  b y 
cli ni c all y si g nifi c a nt  bl e e di n g  
P L Ts <  1 0 0 0 0/ µl  at  a n y ti  m e  
N a us e a,  e  m esis  or 
di arr h o e a i n t h e 
a bs e n c e  of   m a xi  m u  m 
pr o p h yl a xis  
G r a d e  3 
C o nti n u e B E  N at t h e s a  m e  d os e,  b ut 
i nstit ut e t h e   m a xi  m u  m  pr o p h yl a cti c 
t h er a p y, i n cl u di n g e. g. a  5-H T 3 
a nt a g o nist f or  n a us e a  a n d  e  m esis,  a n d 
l o p er a  mi d e, or  a  c o  m p ar a bl e 
a nti di arr h o e al  a g e nt. 
Gr a d e  4  
Wit h h ol d   B E  N  u ntil r es ol uti o n  of 
t o xi cit y t o   Gr a d e  ≤  2   w hil e  o n   m a xi  m u  m 
pr o p h yl a cti c t h er a p y.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 5  of 1 3 1  
N  CI   C  T  C  A  E  c at e g o r y  S e v e rit y  
D os e   m o difi c ati o n  
N a us e a,  e  m esis  or 
di arr h o e a i n t h e 
pr es e n c e of m a xi  m u  m 
pr o p h yl a xis  
Gr a d e  ≥  3  
Wit h h ol d  B E N  until  t he t o xicit y ret ur ns 
t o Gra de  ≤ 2  or  baseli ne  le vel if t he 
c o n diti o n  was  pre -ex isti n g, a nd  restart 
B E N  at t he ne xt  l o wer d ose  (see    
Ta ble  4 ).  
All  ot h er cli ni c all y 
si g nifi c a nt t o xi citi es 
r el at e d t o   B E  N  
Gr a d e  ≥  3  
A b br e vi ati o ns:   A Es   = a d v ers e  e v e nts;   A  N  C  =  a bs ol ut e  n e utr o p hil  c o u nt; B E  N  = b e n d a  m usti n e;   G -C S F   = gr a n ul o c yt e  c ol o n y -
sti  m ul ati n g f a ct or;  P L Ts =  pl at el ets ( pl at el et  c o u nt) . 
*If  p ati e nts  h a v e f or i nst a n c e  a dis e as e -r el at e d s pl e n o  m e g al y  or   m ar k e d  b o n e   m arr o  w i n v ol v e  m e nt  b y l y  m p h o  m a  as  a  c a us ati v e
f a ct or of  c yt o p e ni as  at s cr e e ni n g, tr e at  m e nt   m a y  c o nti n u e   wit h o ut   m e eti n g t h e  h ae  m at ol o gi c crit eri a f or s u bs e q u e nt  c y cl es  of
c h e  m ot h er a p y. I n s u c h  c as es t h e  d e cisi o n t o  c o nti n u e   B E  N  d osi n g  at t h e  c urr e nt  d os e is  at t h e i n v esti g at or’s  dis cr eti o n.
P ri n ci pl es  of   B  E  N D os e   R e d u cti o n  
T h e  d os e  of   B E  N   m a y  b e r e d u c e d s u c c essi v el y fr o  m t h e st arti n g  d os e of  9 0   m g/  m 2  d ail y 
(T a bl e   4).  F or  a d diti o n al i nf or  m ati o n  pl e as e s e e  S e cti o n 9. 1. 3 . 
T h e   B E  N  d os e   m a y  o nl y  b e  a dj ust e d  o n c e  p er  c y cl e  a n d  b y  o n e  d os e l e v el.   O n c e  a  p ati e nt’s   B E  N 
d os e  h as  b e e n r e d u c e d,  n o  d os e r e- es c al ati o n is  p er  mitt e d.  
T a bl e   4: 
B  E  N D os e   L e v els  
St arti n g  d os e  
9 0   m g/  m 2 d ail y  o n   D a ys  1 + 2  or  2 + 3  e v er y  at l e ast 2 8  d a ys  
D os e  L e v el -  1 
6 0  m g/  m 2 d ail y  o n   D a ys  1 + 2  or  2 + 3 e v er y  at l e ast 2 8  d a ys  
D os e  L e v el -  2 
3 0   m g/  m 2 d ail y  o n   D a ys  1 + 2  or  2 + 3  e v er y at l e ast 2 8  d a ys  
Patie nts w h o  ca n n ot tolerate D ose Le vel  - 2  d ue t o to xiciti es descri be d  in  Ta ble  2 an d  Ta ble  3 
sh o ul d disc o nti n ue B E N treat me nt an d s h o ul d c o nti n ue anti b o d y t hera p y acc or di n g t o t heir i nitial 
treat me nt all ocati o n. 
9. 4. 2. 2  A nti b o d y  Tre at me nt  Dose O missi o ns/ P ost p o ne me nts  
D ose re d ucti o ns of M O R 0 0 2 0 8 or R T X are n ot all o we d d uri n g the co urse o f the st u d y. 
Treat me nt wit h M O R 0 0 2 0 8 or R T X ma y c o nti n ue i n case criteria f or B E N treat me n t are  not 
fu lfille d (see Ta ble  2). 
I n t he case  of cli nicall y si g nifica nt, g ra de 4  t o xicities j u d ge d n ot t o  be rel ate d  t o R T X or  
M O R 0 0 2 0 8: 
1.
R T  X  d os es s h o ul d  b e  p ost p o n e d  u ntil t o xi cit y  di  mi nis h es i n s e v erit y t o ≤g r a d e  3.


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 6  of 1 3 1  
2.
M  O  R 0 0 2 0 8  d os es s h o ul d b e  o  mitt e d  u ntil t o xi cit y  di  mi nis h es i n s e v erit y t o ≤gr a d e  3.
O n e   mi ss e d M  O  R 0 0 2 0 8  d os e s h o ul d  n ot  b e   m a d e  u p f or. If t h e  p ati e nt   miss es  a
s u bs e q u e nt   M  O  R 0 0 2 0 8  d os e, t h e s e c o n d   miss e d  d os e s h o ul d  b e  a d  mi nist er e d
i  m  m e di at el y  aft er t h e t o xi cit y r es ol v es.
In t h e c as e  of  cli ni c all y si g nifi c a nt  gr a d e  ≥ 3 t o xi citi es j u d g e d t o  b e  r el at e d t o R T  X  or 
M  O  R 0 0 2 0 8: 
1.
R T  X  d os es s h o ul d  b e  p ost p o n e d  u ntil t h e t o xi cit y  di  mi nis h es i n s e v erit y t o  gr a d e ≤1  or
r et ur ns t o  a  b as eli n e  gr a d e,  pr o vi d e d t h e  c o n diti o n   w as  pr e-e xisti n g  at  b as eli n e .
2.
M O  R 0 0 2 0 8  d os es s h o ul d b e  o  mitt e d  u ntil t h e t o xi cit y  di  mi nis h es i n s e v erit y t o g r a d e ≤1
or r et ur ns t o  a  b as eli n e  gr a d e,  pr o vi d e d t h e  c o n diti o n   w as  pr e- e xisti n g  at  b as eli n e . O n e
miss e d   M  O  R 0 0 2 0 8  d os e s h o ul d  n ot  b e   m a d e  u p f or. If t h e  p a ti e nt   miss es  a s u bs e q u e nt
M  O  R 0 0 2 0 8  d os e, t h e s e c o n d   miss e d  d os e s h o ul d  b e  a d  mi nist er e d i  m  m e di at el y  aft er t h e
t o xi cit y r es ol v es.
If ba se d o n me dical ju d g me nt , t he treati n g p h ysicia n c o nsi ders a cli nical A E  an d/ or la b orat or y 
para meter  cha n ge n ot  to  be a st ud y dr u g- relate d to xicit y  b ut t o represe nt  nat ural fl uct uati o n  or 
pr o gressi o n of the u n de rl yi n g disease, t he n it is at the p h ys icia n’s di screti o n a n d assess me nt o f 
t he in di vi d ual ris k/ be nefit ratio t o deter mi ne w het her t he pa tie nt sh o ul d be d os e d. T he de cisi o n 
a n d rati o nale be hi n d t he de cisi o n s h o ul d be d oc u me nte d i n t he so urce d ata. 
9. 4. 2. 3  Tre at me nt  Disc o nti n u ati o n  
If t he sa me st u d y dr u g  relate d t o xicit y persists f or m ore tha n 2 8 da ys , the  a d mi nistrati o n  of t his 
partic ular st u d y dr u g s h o ul d be di sc o nti n ue d an d  the pa tie nt sh o ul d c o nti n ue to be d ose d wit h t he 
ot her st u d y dr u g (i.e. t he res pecti ve co m bi nati o n part ner i n t hat treat me nt arm ). 
If t he sa me t o xicit y relate d t o b ot h st u d y dr u gs persists f or m ore t ha n 2 8 da ys, t he n treat me nt 
wit h  b ot h st u d y dr u gs s h o ul d per ma ne ntl y be disc o nti n ue d (see Secti o n  9. 8 ). 
If treat me nt is  i nterr u pte d f or more tha n 2 8 da ys d ue to a n A E an d/ or la b orat or y para meter 
c ha n ge t hat is n ot a st u d y dr u g- relate d t o xicit y, t he ad mi nistrati o n  of t his partic ular st u d y  dru g  
s h o ul d be di sc o nti n ue d a n d t he pa tie nt sh o ul d c o nti n ue t o be d ose d wit h t he ot her st u d y dr u g (i.e. 
t he res pecti ve co m bi nati o n  part ner i n t hat treat me nt ar m).  
If b ot h st u d y dr u gs are te m p oraril y wit h hel d f or m ore t ha n 2 8 da ys d ue t o t he sa me p ersisti n g 
cli nica l AE  an d/ or la b orat or y  para meter c ha n ge  the n treat me nt w it h b oth st u d y dr u gs s h o ul d 
per ma ne nt l y be di sc o nti n ue d.  
All sce nari os  may  req uire  t he im ple me ntati o n  of t he pri nci ples of t he BS C  acc or di n g  t o t he l ocal 
me dical pr actice an d t he instit uti o nal g ui deli nes . T he de cisi o n a n d rati o nale be hi n d t he de cisi o n 
s h o ul d be d o c u me nte d i n the so urce d ata. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 7  of 1 3 1  
9. 5  P ri o r  a n d   C o n c o  mit a nt   T h e r a p y  
A n y pri or, c o nc o mita nt , or pr oce d ural m e dicati o ns or thera p y gi ve n t o or ta ke n b y t he patie nt 
wit hi n  1 m o nt h  pri or t o co m m e nceme n t of t he st u d y an d u p t o  the  En d of  T re at me nt  vi sit 
( E O T) m ust  be rec or de d in  the s o urce d oc u me nts an d t he eC R F al o n g wit h t he i n dicati o n, wa y 
of a d mi nistrati o n/f or m ula  an d d osa ge. S uc h me dicati o ns (i ncl u di n g o ver-t he-c o u nter a ge nts) 
m ust be  liste d o n t he co nc o mita nt  me dicati o ns  f or m i n t he eC R F , wit h t he exce pti o n of [1 8 F] 
fl u or o de o x y gl uc ose (F D G) a n d/ or C T/ M RI c o ntrast a ge nts . 
F or a  patie nt t o be c o me  eli gi ble f or “ F urt her  or C o nti n ue d A nti b o d y  Tre at me nt ”  (if gi ve n 
des pite pr o gressi o n  of disease/rela pse), a n E O T Visit  incl u di n g  all pr ot oc ol prescri be d 
pr oce d ures ne ed t o be perf or me d i n or der t o ca pt ure t he  e ve nt  (i.e. disease pr o gressi o n/rela pse)  
f or the treat me nt t o c o nti n ue furt her. In s uc h cases the 3 0- D a y S afet y F oll o w- U p  will  n ot ta ke 
place as l o n g as anti b o d y t reat me nt c o nti n ues  f urt her. I nstea d, t he 3 0- D a y S afet y F oll o w- U p  
will ta ke  place 3 0 da ys after t he peri o d of “ F urt her  or Co nti n ue d A nti b o d y  Tre atm e nt ”  (if 
g i ve n des pite p ro gressi o n  of disease/rela pse) h as e n de d  (see Secti o n 1 1. 2 ). 
Fr o m t he  3 0- D a y S afet y F oll o w- U p  v isit, a ntica ncer  treat me nts a n d, in  t he case of  a n SA E/
A E SI  assesse d  as relate d  (see Secti o n 1 1. 2 ), ot her rele va nt i nf or mati o n, e. g. c o nc o mita nt 
me dicati o ns s h o ul d be d oc u me nte d. 
T he in vesti gat or sh o ul d i nstr uct the p atie nt n ot to ta ke an y a d diti o nal m e dicati o ns (i ncl u di n g 
o ver the- co u nter-- pr o d ucts) d u rin g t he st u d y wit h o ut pr i or co ns ultati o n. 
I nf or matio n s h o ul d be pr o vi de d o n a n y pre vi o us N H L- s pecific t hera pies si nce t he ti me p oi nt o f 
t he first di a g n osis of N H L. T he ge neric or t he tra de na me ma y be rec or de d. Patie nts sh o ul d n ot 
recei ve a n y D L B C L  s pecific- t hera p y ot her t han st u d y dr u gs ( M O R 0 0 2 0 8, R T X an d B E N) 
d uri n g C o m bi nati o n Treat me nt, d uri n g A nti b o d y M o n ot hera p y Treat me nt an d d uri n g f oll o w u p 
f or P F S .  
Patie nts ma y  c o nti n ue t he me dicati o ns t he y were recei vi n g  at baseli ne. Patie nts ma y  recei ve 
c o nc o mita nt  me dicati o ns  t hat are me dicall y  i n dicate d as sta n dar d care f or t he treat me nt of 
s y m pt o ms a n d interc urre nt  ill nesses. Me dicati o ns t o  treat c o nc o mita nt  d iseases suc h  as dia betes, 
h y perte nsi o n, br o nc hial ast h ma, c hr o nic o bs tr ucti ve p ul m o nar y di sease etc., are all o we d.  Patie nts 
will als o  recei ve  t hera p y t o mi ti gate si de effects of t he  st u d y me dicati o n  as cli nicall y i n dicate d, 
as well as  BS C  as pe r i nstit uti o nal g ui deli nes. This  may  i ncl u de, b ut is n ot li mite d  t o antie metics,  
a nti- diarr h oeals,  a ntic h oli ner gics,  a ntis pas m o dics, a nti p yretics,  a nti hista mi nes,  a nal gesics, 
a nti bi otics, a n d ot her me dicati o ns inte n de d t o treat sy m pt o ms. 
C o ncer ni n g B E N an d R T X, t he S m P C  ( EM A) or Prescri bi n g  I nfor mati o n  ( US  FD A)  sh o ul d  be  
referre d  t o f or i nf or mati o n o n the  ad mi nistrati o n  of c o nc o mita nt me dicati o ns  an d  p ote ntial 
dr u g- dr u g  i nteracti o ns.


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 5 8  of 1 3 1  
9. 5. 1  G r o  wt h  F a ct o rs  a n d   T r a nsf usi o n  S u p p o rt  
Gr o  wt h f a ct ors   m a y  b e  pr es cri b e d  at t h e i n v esti g at or’s  dis cr eti o n,  a c c or di n g t o  t h e pri n ci pl es  of 
m e di c al  pr a cti c e  a n d t h e i nstit uti o n al st a n d ar ds.   Gr o  wt h f a ct ors  or tr a nsf usi o n su p p ort  s h o ul d  n ot 
b e  a d  mi nist er e d  d uri n g S cr e e ni n g s ol el y f or t h e  p ur p os e  of i  m pr o vi n g  a  p ati e nt’s  bl o o d  v al u es i n 
or d er t o   m e et  eli gi bilit y  crit eri a.  
 
9. 5. 2  I nf e cti o n  P r o p h yl a xis 
I n v esti g at ors s h o ul d f oll o  w i nstit uti o n al  g ui d eli n es  c o n c er ni n g i nf e cti o n  c h e  m o pr o p h yl a xis f or 
p ati e nts r e g ar d e d t o  b e  at  hi g h ris k f or i nf e cti o n.  
 
9. 5. 3  A nti c a n c e r   T h e r a pi es  
T h e  us e  of  c o n c urr e nt  a nti n e o pl asti c t h er a pi es  ot h er t h a n st u d y  d r u gs, i n cl u di n g,  b ut  n ot li  mit e d 
t o  c h e  m ot h er a pi es,  h or  m o n al t h er a p y, i  m  m u n ot h er a p y,  bi ol o gi c al r es p o ns e   m o difi ers,   m  A bs   wit h 
or   wit h o ut  c o nj u g ati o n, r a di o -is ot o pi c t h er a pi es,  a n d t ar g et e d s  m all   m ol e c ul es  ar e  n ot  p er  mitt e d 
t hr o u g h o ut C o  m bi n ati o n  T r e at  m e nt, A nti b o d y   M o n ot h er a p y  T re at  m e nt  a n d  d uri n g f oll o  w  u p f or 
P F S . A ll o g e n ei c st e  m c ell tr a ns pl a nt ati o n is  c o nsi d er e d t o  b e a  pr ot o c ol  pr o hi bit e d  a nti c a n c er 
t h er a p y. 
 
Li  mit e d fi el d r a di ot h er a p y f or r e d u ci n g s y  m pt o  m s r el at e d t o t u  m ou r   m ass  eff e ct is  all o  w e d 
d uri n g  S cr e e ni n g.  
 
Pr o vi d e d  all t h e i n cl usi o n  a n d  n o n e  of t h e  e x cl usi o n  crit eri a  a p pl y , at t h e  dis cr eti o n  of t h e 
i n v esti g at or, t h e i ntr at h e c al  pr o p h yl a xis of   C  N S  dis e as e ( e. g.   m et h otr e x at e  a n d  c yt ar a bi n e) is 
all o  w e d i n t h e  c o urs e  of t h e tri al.  T h e s e c o n c o  mit a nt m e di c ati o ns   will  b e  pr o vi d e d  b y t h e 
i n v esti g ati v e sit e  a n d  n ot  b y t h e s p o ns or. 
 
9. 5. 4  S yst e  mi c   Gl u c o c o rti c ost e r oi ds  
Si n gl e -d os e, t o pi c al, i ntr a n as al, i n h al e d c orti c ost er oi ds,  as   w ell  as e y e  dr o ps  or l o c al i nj e cti o ns 
( e. g., i ntr a-arti c ul ar)  c o nt ai ni n g  c orti c ost er oi ds  or  p h ysi ol o gi c r e pl a c e  m e nt  of 
gl u c o c orti c ost er oi ds  ar e  p er  mitt e d  d uri n g st u d y  p arti ci p ati o n.  
 
S yst e  mi c gl u c o c orti c ost er oi ds  i n  d os es  u p t o  2 0   m g/ d a y  pr e d nis o n e  or  e q ui v al e nt (i. e. e q ui p ot e nt 
c orti c ost er oi d)  ar e  p er  mitt e d  b ut  o nl y f or t h e tr e at  m e nt  of  n o n-n e o pl asti c  c o  m or bi d i n di c ati o ns 
( e. g., r h e u  m at oi d  art hritis). 
 
S yst e  mi c gl u c o c orti c ost er oi ds  i n  d os es  a b o v e  2 0   m g/ d a y  pr e d nis o n e  or  e q ui v al e nt (i. e. 
e q ui p ot e nt  c orti c ost er oi d)  ar e  p er  mitt e d f or  a li  mit e d  p eri o d  of ti  m e  u n d er f oll o  wi n g 
cir c u  mst a n c es:  
a) us e  as pr e  m e di c ati o n  
b)  e x a c er b ati o n s of  c hr o ni c  n o n -n e o pl asti c  c o n diti o n s s u c h  as c hr o ni c  o bstr u cti v e 
p ul  m o n ar y  dis e as e (  C  O P  D),  br o n c hi al  ast h  m a  or r h e u  m at oi d  art hritis ,  et c. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 5 9  of 1 3 1  
c)
se vere a n d/ or life-th reate n i n g c o n diti o ns s uc h as a dre nal i n s ufficie nc y, 
c yt o ki ne release s y n dr o me, etc.
d )
a ntie metic pr o p h yla xis f or u p t o 2 4 h o urs
e)
t o ma na ge se ver e D L B C L  ma nifestati o ns (e. g.  c om p ressi ve disease,  ra pi dl y  
pr o gressi n g s y m pt o matic a de n o pat h y) bef ore C ycle 1 Da y 1 as per  
i nstit uti o nal sta n dar ds. The  gl uc ortic oster oi ds d o se nee ds t o  be ta pere d t o 
2 0 m g or less of pre d nis o ne or e q ui vale nt per da y pri or t o st u d y dr u g(s) 
a d mi nistrati o n o n C ycle 1 Da y 1. W here ver p ossi ble , the  fresh t u m o ur  
tiss ue ( Secti on  1 0. 2. 1 ) s ho ul d  be c ollecte d  bef ore st arti n g  the  
a d mi nistr ati o n of gl uc oc ortic oster oi ds i n d oses a b o ve 2 0 m g/ d a y
(pre d nis o ne  or e q ui v ale nt,  ple ase refer t o A p pe n di x  G).
T h e gl u c o c orti c ost er oi d   d os a g e  a n d t h e  all o  w a bl e tr e at  m e nt  p eri o d   will  b e  d et er  mi n e d  b y t h e 
i n v esti g at or  o n  a  c as e- b y-c as e  b asis . T h e i n v esti g at or s h o ul d  dis c uss t h e s yst e  mi c  us a g e  of 
gl u c o c orti c ost er oi ds i n  d os es  a b o v e  2 0   m g/ d a y ( pr e d nis o n e  or  e q ui v al e nt)   wit h t h e   m e di c al 
m o nit or  of t h e st u d y  pri or t o t h e i  m pl e  m e nt ati o n ,   w h e n e v er f e asi bl e. T h e s p e cifi e d s yst e  mi c 
gl u c o c orti c ost er oi d s  us e, if s h ort i n  d ur ati o n, is  n ot li k el y t o  c o nf o u n d t h e tr e at  m e nt eff e ct  a n d 
effi c a c y  a n al ysis.  
Im  m u n os u p pr essi v e t h er a pi es  ot h er t h a n s yst e  mi c  gl u c o c orti c ost er oi ds  as  d es cri b e d  ar e  n ot 
p er  mitt e d.   
9. 5. 5  M a n a g e  m e nt  of   T u  m o u r   L ysis  S y n d r o  m e 
Pr e v e nti o n  a n d t h er a p y  of T L S  s h o ul d  b e  c o n d u ct e d  a c c or di n g t o t h e  dis cr eti o n  of t h e 
i n v esti g at or f oll o  wi n g t h e  pri n ci pl es  of   m e di c al  pr a cti c e  a n d t h e i nstit uti o n al  g ui d eli n es. 
All o p u ri n ol s h o ul d  n ot  b e  gi v e n  o n  d a ys   w h e n   B  E  N is i nf us e d b e c a us e  a n i n c r e as e d  ris k  of 
St e v e n  J o h ns o n s y n d r o  m e  a n d to xi c epi d e r  m al n e c r ol ysis (  T  E  N)  h as  b e e n  r e p o rt e d.  
9. 5. 6  M a n a g e  m e nt  of  P ati e nts   wit h Hist o r y  o r  P r e vi o us E v e nts  of  F e b ril e   N e ut r o p e ni a  
P ati e nts   wit h  a  p ositi v e   m e di c al  hist or y of,  or  pr e vi o us i n ci d e n c es of f e bril e  n e utr o p e ni a    w hil e  o n 
st u d y,  or t h os e wit h  a n i n di vi d u al ris k f or f e bril e  n e utr o p e ni a  > 2 0  %, s h o ul d r e c ei v e  pr o p h yl a cti c 
gr a n ul o c yt e  c ol o n y- sti  m ul ati n g f a ct or (  G-C S F)  a c c or di n g t o t h e  pri n ci pl es  of   m e di c al  pr a cti c e 
a n d t h e i nstit uti o n al  g ui d eli n es.  
9. 5. 7  A nti  mi c r o bi als/ A nti vi r als/ A ntif u n g als  
A nti  mi cr o bi als/ a nti vir als/ a ntif u n g als  s h o ul d  als o  b e  a d  mi nist er e d f or  pr o p h yl a xis  a n d/ or f or 
tr e at  m e nt  a c c or di n g t o t h e  pri n ci pl es  of   m e di c al  pr a cti c e  a n d t h e i nstit uti o n al  g ui d eli n es. 
S yst e  mi c  a ntif u n g al  c o v er a g e is  g e n er all y  n ot r e c o  m  m e n d e d.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 6 0  of 1 3 1  
9. 6  T r e at  m e nt   C o  m pli a n c e  
D osi n g m o dificati o ns d u e to t o xicit y are de scri be d i n Secti o n 9. 4. 2 an d are n ot co vere d here. 
Patie nts will recei ve M O R 0 0 2 0 8, R T X a n d B E N u n der t he direct s u per visi o n of st u d y pers o n nel. 
Eac h a d mi nistrati o n v ol u me or d ose will be c hec ke d a n d t he vial/ o uter pac ka ge c o de a n d v ol u me 
or d ose per a d mi nistrati o n will be rec or de d i n eac h patie nt’s e C R F as well as i n t he s o urce data.  
A pa tie nt w ill be co nsi dere d c o m plia nt w it h t he p r ot oc ol if t he M O R 0 0 2 0 8, R T X an d B E N d os e 
a d mi nistere d is ≥8 0 % t o ≤1 2 0 % of t he assi g ned d osa ge pe r si n gle i nf usi o n. 
Dr u g acc o u nta bilit y will be chec ke d b y t he field m o nit or d ur i n g site v isits an d at the co m pleti o n 
of the st u d y. 
9. 7  O ver d o se of St u d y Dr u gs  
A n o ver d ose of M O R 0 0 2 0 8, R T X or B E N is defi ne d as a d ose e xcee di n g t he pla n ne d d ose b y 
m ore t ha n 2 0 % (for f urt her i nf or mati o n  see Secti o n  1 1. 1 ). For e xact a d vice o n ha n dli n g a B E N 
a n d/ or R T X o ve r d ose please  refer t o Sm P C  (E M A ) or Prescri bi n g In f or mati o n (U S  F D A).  N o 
s pecific treat me nt is rec o m me n de d f or o ver d ose of M O R 0 0 2 0 8. T reat me nt re mai ns at t he 
discreti o n  o f t he i n vesti gat or. 
9. 8  Wit h dr a w a l fro m  St u d y Tre at me nt or  St u d y/Site  Ter mi n ati o n  
9. 8. 1  Wit h dr a w al Criteri a  
Patie nts  may  v ol u ntar il y wit h dra w fr o m t he st u d y or treatme nt. Patie nts ma y be di sc o nti n ue d 
fr o m treat me nt a t t he discreti o n of t he i n vesti gat or at a n y ti me.  
At a  mi ni m u m, all patie nts wh o  disc o nti n ue st u d y treat me nt,  incl u di n g  t h ose wh o  ref use t o ret ur n 
for a  fi nal visit, will be co ntacte d  f or safet y e val uati o ns at t he 3 0- Da y  Safet y  F oll o w- U p  vi sit. 
If s uc h wit h dra wal occ urs, or if t he patie nt fails  t o ret ur n f or visits,  t he i n vesti gat or m ust 
deter mi ne  t he pri mar y reas o n f or a p atie nt´s  pre mat ure wit h dra wal fr o m t he st u d y a n d  rec or d  t he 
i nf or matio n o n t he eC R F.  If t he reas o n f or wit h dra wal is an  A E,  m o nit ori n g sh o ul d  co nti n ue  
u ntil  t he o utc o me is e vi de nt. The s pecific e ve nt  or test res ult(s)  must  be rec or de d i n the e C R F.  At  
t he di screti o n of the sp o ns or, patie nts m a y als o be re m o ve d fr o m the st u d y, f or i nsta nce i n a case 
w he n  it is retr os pecti vel y esta blis he d t hat patie nts d o not f ul fil all i ncl usi o n or meet certai n 
e xcl usi o n  criter ia (e. g., tu m o ur tiss ue  is not  a vaila ble  f or ce ntral pat h ol o g y revie w ). 
It sh o ul d be clearl y d oc u me nte d i n t he so urce d ata, w het he r patie nts wit h dre w t heir co nse nt an d 
w ill n ot e nter Foll o w- U p  or if t he pa tie nt wit h dre w t heir co nse nt for st u d y dr u g treat me nt, b ut 
will c o nti n ue  f urt her partici pati o n i n t he st u d y. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 6 1  of 1 3 1  
E x a  m pl es f or   wit h dr a  w al  crit eri a i n cl u d e  b ut  ar e  n ot li  mit e d t o: 
•
A E (s)
•
A b n or mal la b orat or y val ue(s)
•
A b n or ma l test pr oce d ure res ult(s)
•
U n ma na gea ble t o xicit y relate d t o st u d y dr u g(s) (i ncl u di n g but  not li mite d  t o medical  
e ve nts descri be d i n Secti o ns  9. 4 an d  9. 8. 2)
•
Pr o t oc ol vi olati o n
•
Pa tie nt wit h dra wal of c o nse nt
•
Pre g na nc y o r breast-fee di n g
•
L oss t o f oll o w- u p
•
I na bilit y of t he patie nt t o  co m pl y  wit h st u d y req uire me n ts
•
C o n diti o ns re q uiri n g t hera pe utic i nter ve nti o n n ot per mitte d b y t he pr ot oc ol
•
A d mi nistrati ve  pr o ble ms
•
Ra di ol o gicall y c o nfir me d disease pr o gressi o n
•
Wit h dra wal  of  a patie nt  f or a ny  reas o n  at th e discreti o n of t he i nvesti gat or
P ati e nts   w h o  ar e   wit h dr a  w n f or  a n y r e as o n m ust n ot r e- e nt er t his  cli ni c al st u d y  at  a n y ti  m e.  
F or  p ati e nts   w h o  ar e l ost t o f oll o  w- u p  at l e ast t hr e e  att e  m pts  of  c o nt a ct  b y t h e sit e s h o ul d  b e 
m a d e  a n d  d o c u  m e nt e d i n t h e s o ur c e d at a.  
9. 8. 2  St u d y  o r  Sit e   T e r  mi n ati o n  
T h e i n v esti g at or  a n d t h e s p o ns or  b ot h r es er v e t h e ri g ht t o t er  mi n at e t h e st u d y  at  a n y ti  m e  at  a 
gi v e n  cli ni c al st u d y  c e ntr e.  T h e s p o ns or  als o r es er v es t h e ri g ht t o t er  mi n at e t h e  e ntir e st u d y  or 
t e  m p or aril y i nt err u pt  e nr ol  m ent  a n d/ or  d osi n g  of  alr e a d y  e nr oll e d  p ati e nts f or f urt h er  e v al u ati o n.  
S t o p pi n g  crit eri a f or t his st u d y   will i n cl u d e,  b ut  ar e  n ot li  mit e d t o: 
1.
F or t h e first  1 0  p ati e nts  e nr oll e d i n  c o h ort M  O  R 0 0 2 0 8  +   B E  N  d uri n g t h e s af et y r u n-i n
p h as e:
•
T o xi citi es w hi c h  o c c u r i n t h r e e  o r   m o r e  p ati e nts  (t o xi cit y   m e a ns  a n  a d v ers e  dr u g
r e a cti o n   wit h  a s us p e ct e d  c a us al r el ati o ns hi p t o tri al   m e di c ati o ns  as  ass ess e d  b y t h e
i n v esti g at or  or t h e s p o ns or):

Li v er:   A c ut e  h e p ati c f ail ur e > Gr a d e  4

All er gi c r e a cti o n,  a n a p h yl a xis,  c yt o ki n e r el e as e s y n dr o  m e > Gr a d e  4

A n y  c ar di a c  e v e nt > Gr a d e  4

E  C  G:   Q T c  pr ol o n g ati o n ( T ors a d e  d e  p oi nt es)  > Gr a d e  4

G astr oi nt esti n al:   Di arr h o e a,  n a us e a,  v o  miti n g > Gr a d e  4

A c ut e  ki d n e y i nj ur y  > Gr a d e  4


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 6 2  of 1 3 1  
 
M ulti o r g a n fail ur e  >   Gr a d e  3  
 
P ul  m o n ar y  h a e  m orr h a g e  >   Gr a d e  3  
 
P n e u  m o ni a >  Gr a d e  4  
 
S e psis  ≥   Gr a d e  4  
 
T u  m o u r l ysis s y n dr o  m e >  Gr a d e  4  
• 
A n y  ot h er  u n e x p e ct e d, s us p e ct e d  a d v ers e  dr u g r e a cti o n  of t h e s a  m e  n at ur e   w hi c h is 
≥ Gr a d e  4  a n d   w hi c h  o c c urs i n t hr e e  or   m or e  p ati e nts.  
• 
H a e  m at ol o gi c t o xi cit y   w hi c h  o c c urs i n f o ur  or   m or e  p ati e nts  a n d   w hi c h  h as  n ot 
di  mi nis h e d i n s e v erit y t o  gr a d e  ≤ 2  or r e c o v er e d t o  b as eli n e l e v e l (if t h e  c o n diti o n   w as 
pr e -e xisti n g)   wit hi n  2 8  d a ys (t o xi cit y   m e a ns  a n  a d v ers e  dr u g r e a cti o n   wit h  a 
s us p e ct e d  c a us al r el ati o ns hi p  as  ass ess e d  b y t h e i n v esti g at or  or t h e s p o ns or):  
 
F e bril e  n e utr o p e ni a >  Gr a d e  4  
 
N e utr o p e ni a >  Gr a d e  4  
 
A n ae  mi a >  Gr a d e  4  
 
T hr o  m b o c yt o p e ni a >  Gr a d e  4  
2.  T h er e aft er f or  all  p ati e nts  e nr oll e d i n  c o h ort M  O  R 0 0 2 0 8  +   B E  N:  
• 
≥ 3 0  %  of  p ati e nts  e x p eri e n ci n g  u n e x p e ct e d   Gr a d e  ≥ 4  a d v ers e  dr u g r e a cti o ns  as 
d es cri b e d  a b o v e.  
3.  S p o ns or  d e cisi o n f oll o  wi n g t h e r e c o  m  m e n d ati o n  of I  D  M  C  or t h e  o ut c o  m e  of t h e i nt eri  m 
a n al ysis 
 
S h o ul d  a t er  mi n ati o n  of  a  gi v e n  cli ni c al st u d y  c e ntr e  or t h e   w h ol e st u d y  b e c o  m e  n e c ess ar y, t h e n 
a d e q u at e  pr o c e d ur es   will  b e  arr a n g e d  aft er  c ar ef ul  c o nsi d er ati o n  a n d  c o  m  m u ni c at e d t o  all 
i n v ol v e d  p arti es. I n t er  mi n ati n g  a st u d y  c e ntr e,  or th e  e ntir e st u d y, t h e s p o ns or  a n d t h e 
i n v esti g at ors   will  e ns ur e t h at  a d e q u at e  c o nsi d er ati o n is  gi v e n t o t h e  pr ot e cti o n  of t h e  p ati e nts’ 
i nt er ests. I nstit uti o n al   R e vi e  w   B o ar ds (I  R  Bs)/I n d e p e n d e nt  Et hi cs   C o  m  mitt e es (I E  Cs)  a n d 
c o  m p et e nt  a ut h oriti es   will  b e  n oti fi e d  of  pr e  m at ur e t er  mi n ati o n i n  a c c or d a n c e   wit h  a p pli c a bl e 
r e g ul at or y r e q uir e  m e nts.  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 6 3  of 1 3 1  
1 0  S  T  U  D  Y  P  R  O  C  E  D  U  R  E S  
1 0. 1  S c h e d ul e  of   Visits  a n d  P r o c e d u r es  
T a bl e   5 lists  all s c h e d ul e d ass ess  m e nts,  a n d i n di c at es   wit h  a n  “  X ” t h e  visits  at   w hi c h t h es e 
ass ess  m e nts  ar e  p erf or  m e d. P ati e nts i n  b ot h tr e at  m e nt  ar  ms  ar e s u p p os e d t o f oll o  w t h e s a  m e 
s c h e d ul e  of  visits irres p e cti v e  of tr e at  m e nt  all o c ati o n.  All  d at a  o bt ai n e d fr o  m t h es e  ass ess  m e nts 
m ust  b e s u p p ort e d i n t h e  p ati e nt´s s o ur c e  d o c u  m e nt ati o n. 
 
Visit s c h e d uli n g  c al c ul ati o n:  
E a c h   Visit fr o  m   C y cl e  1   D a y  1  u ntil  a n d i n cl u di n g   C y cl e  7   D a y  1 s h all  b e s c h e d ul e d  b as e d  o n 
t h e  d at e  of t h e   C y cl e  1   D a y  1  visit  a n d i n li n e   wit h t h e  gi v e n  visit   wi n d o  w ( e. g., t h e   C y cl e  2 
D a y   1  visit s h all  b e s c h e d ul e d  2 8  d a ys  aft er t h e  d at e  of   C y cl e  1   D a y  1 ± 3  d a ys; t h e   C y cl e  3   D a y  1 
visit s h all  b e s c h e d ul e d  5 6  d a ys  aft er t h e  d at e  of   C y cl e 1   D a y  1  ± 3  d a ys;   C y cl e  3   D a y  1 5 s h all  b e 
s c h e d ul e d  7 0  d a ys  aft er t h e  d at e  of   C y cl e  1   D a y  1  ± 1  d a ys,  et c.).  
E a c h   Visit fr o  m   C y cl e 7   D a y  1 5  o n  w ar ds s h all  b e s c h e d ul e d  b as e d  o n t h e  d at e  of t h e C y cl e  7  
D a y   1  visit  a n d i n li n e   wit h t h e  gi v e n  visit   wi n d o  w  a n d  n ot  b as e d  o n t h e  d at e  of   C y cl e  1   D a y  1. 
 
















I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 1  of 1 3 1  
4Pr e g n a n c y t ests: f or  F  C  B P:   A s er u  m  pr e g n a n c y t est   m ust  b e  p erf or  m e d  d uri n g S cr e e ni n g. O n C 1  D 1 , a s e c o n d,   m e di c all y s u p er vis e d  uri n e  pr e g n a n c y t est   m ust  b e  p erf or  m e d  pri or 
t o t h e st art  of st u d y  dr u g.  T h e r es ults  of  b ot h t ests   m ust  b e  n e g ati v e i n  or d er t o r e c ei v e C 1  D 1  d osi n g. A β -H  C  G  s er u  m pr e g n a n c y t est s h o ul d  als o  b e  p erf or  m e d at t h e E  O T   visit. At 
all  ot h er i n di c at e d ti  m e  p oi nts,  a  uri n e  pr e g n a n c y t est f or  F  C  B P s h o ul d b e  p erf or  m e d l o c all y  a n d t h e r es ult   m ust  b e  n e g ati v e f or  d osi n g.  
5S a  m pl e t o  b e  c oll e ct e d  a n d  e v al u at e d  i n t h e l o c al l a b or at or y   wit hi n  2 4  h o urs  pri or t o t h e  a d  mi nistr ati o n  of t h e st u d y  dr u g(s) a n d r e vi e  w e d  b y st u d y tr e ati n g  p h ysi ci a n  b ef or e st u d y 
dr u g  a d  mi nistr ati o n.  T h e l o c al  l a b or at or y s a  m pl es   will  als o  b e  c oll e ct e d f or t h e   R T  X +  B E  N  p ati e nts,  d es pit e t h e f a ct t h at t h e y m a y  n ot r e c ei v e st u d y  dr u gs  at  a  p arti c ul ar  visit. 
U n d er s u c h  cir c u  mst a n c es, t h e s a  m pl e  c oll e cti o n ti  m e  p oi nt  o n s u c h  visits is  at t h e i n v esti g at or’s  dis cr eti o n.  
6A nti -  M  O  R 0 0 2 0 8 a nti b o d y s a  m pl es  a n d   M  O  R 0 0 2 0 8  P  K s a  m pl es   will  b e  c oll e ct e d i n t h e   M  O  R 0 0 2 0 8-tr e a t  m e nt  ar  m  o nl y a n d s a  m pl e  c oll e cti o n s h all  b e st o p p e d  aft er   C y cl e  2 3 . 
7S e e  S e cti o n  1 0. 3. 9  f or  d et ails. R e p e at b o n e m arr o  w  bi o ps y  a n d  as pir ati o n t o c o nfir  m  a   C  R a n d o nl y i n t h os e  p ati e nts   w h o  h a d k n o  w n  b o n e   m arr o  w i n v ol v e  m e nt  pri or t o 
r a n d o  mis ati o n. B o n e   m arr o  w  bi o ps y  a n d  as pir ati o n will  o nl y  b e r e p e at e d if r es p o ns e i n  pri or  c y cl es w as  n ot   C  R.  
8M  O  R 0 0 2 0 8  P  K s a  m pl e  (t o  b e  c oll e ct e d i n t h e   M  O  R 0 0 2 0 8 tr e at  m e nt  ar  m  o nl y) t o b e t a k e n  pr e -d os e  a n d  1  h o ur  ± 1 0   mi n  aft er t h e  e n d  of   M  O  R 0 0 2 0 8 i nf usi o n.  
9M  O  R 0 0 2 0 8  P  K s a  m pl es  (t o  b e  c oll e ct e d i n t h e   M  O  R 0 0 2 0 8 tr e at  m e nt  ar  m  o nl y) s h o ul d o pti  m all y  b e  c oll e ct e d  b ef or e   B E  N  a d  mi nistr ati o n  (  w h e n  a p pli c a bl e).  
1 0A nti -M  O  R 0 0 2 0 8  a nti b o d y s a  m pl e  a n d   M  O  R 0 0 2 0 8  P  K s a  m pl e   will  b e  c oll e ct e d pr e- d os e  o nl y i n  o d d  n u  m b er e d A nti b o d y   M o n ot h er a p y Tr e at  m e nt c y cl es of t h e M  O  R 0 0 2 0 8 
tr e at  m e nt  ar  m o nl y (i. e. tr e at  m e nt   C y cl es  7,  9,  1 1 ,  et c. u ntil  a n d i n cl u di n g   C y cl e  2 3 ). N o s a  m pl es t o  b e  c oll e ct e d  aft er   C y cl e  2 3.  
1 1R el e v a nt f or t h e  c o nfir  m ati o n  of   C  R  at   C 6  D 2 8  a n d d uri n g s u bs e q u e nt  dis e as e r es p o ns e  ass ess  m e nts. 
1 2Wit h t h e  e x c e pti o n  of   C 7 D 1 ,  d uri n g   A nti b o d y   M o n ot h er a p y Tr e at  m e nt  a n d F oll o  w -U p f or  P F S,  dis e as e  ass ess  m e nt  usi n g   C T   will  b e  p erf or  m e d  e v er y  3   m o nt hs  ±  2   w e e ks fr o  m 
t h e  pr e vi o us s c a n  u ntil  dis e as e  pr o gr essi o n,  d e at h  or st u d y  dis c o nti n u ati o n (  w hi c h e v er  o c c urs first). Dis e as e r es p o ns e  ass ess  m e nt   m a y  als o i n cl u d e st a n d ar d  of  c ar e  pr o c e d ur es t o 
d et er  mi n e t h e  dis e as e st at us  p er   C h es o n 2 0 0 7 crit eri a ( e. g.  c o nfir  m at or y  bi o ps y, l u  m b ar  p u n ct ur e,  et c f or  P  D)  
1 3I n c as e t h at t h e  p ati e nt is   wit h dr a  w n fr o  m tr e at  m e nt  b ef or e t h e  e n d  of   C y cl e  6  f or r e as o ns  ot h er t h a n  P  D. C T  o nl y   m a y  b e  p erf or  m e d i n li e u  of  P E T/  C T if  E  O T t a k es  pl a c e   wit hi n 
C y cl e  1.  P E T/  C T is  o nl y r e q uir e d  at t h e  E  O T  visit if it   w as  n ot  p erf or  m e d i n t h e  c y cl e  b ef or e t h e  e n d  of tr e at  m e nt.  
1 4F or  a  p ati e nt t o  b e c o  m e  eli gi bl e f or “ F u rt h e r  o r   C o nti n u e d   A nti b o d y   T r e at  m e nt ”  t h e 3 0- D a y  S af et y  F oll o  w -U p  will  n ot t a k e  pl a c e  as l o n g  as  a nti b o d y tr e at  m e nt  c o nti n u es. 
I nst e a d, t h e 3 0- D a y  S af et y  F oll o  w -U p  will t a k e  pl a c e  3 0  d a ys  aft er t h e  p eri o d  of “ F u rt h e r  o r   C o nti n u e d   A nti b o d y   T r e at  m e nt ”  (if  gi v e n  d es pit e  pr o gr essi o n  of  dis e as e/r el a ps e) 
h as  e n d e d. St arti n g f r o  m t h e  3 0-D a y  S af et y  F oll o  w -U p  visit, a nti c a n c er tr e at  m e nts  a n d  S  A E s/  A E SIs ass ess e d  as r el at e d  (s e e  S e cti o n 1 1. 2 ) sh o ul d  b e d o c u  m e nt e d. F or  a n  E  O T  visit 
t a ki n g  pl a c e  b ef or e t h e  e n d  of   C y cl e  6, a n y c o n c o  mit a nt   m e di c ati o n  n e e ds t o  b e r e c or d e d.  
1 5F or  p ati e nts r e c ei vi n g  “ F urt h er  or   C o nti n u e d   A nti b o d y  Tr e at  m e nt ” (if  gi v e n  d es pit e  pr o gr essi o n  of  dis e as e/r el a ps e) f or  u p t o  2 4   m o nt hs i n t ot al :   Bef or e t h e  a d  mi nistr ati o n  of 
a nti b o di es,  bl o o d  p ar a  m et ers ( h a e  m at ol o g y, s er u  m  c h e  mistr y) s h o ul d  b e ass ess e d i n t h e l o c al l a b  a c c or di n g t o l o c al  g ui d eli n es/st a n d ar ds a p pli c a bl e  f or  a d  mi nistr ati o n  of 
m o n o cl o n al  a nti b o di es.   A  uri n e  pr e g n a n c y t est s h o ul d  b e  p erf or  m e d i n  F  C  B P.   Vit al si g ns s h o ul d  b e   m e as ur e d  pri or t o tr e at  m e nt  a n d  a c c or di n g t o l o c al  pr a cti c e a p pli c a bl e f or t h e 
a d  mi nistr ati o n  o f   m o n o cl o n al  a nti b o di es.   Ot h er  pr o c e d ur es  d es cri b e d i n t h e  c ol u  m n   A nti b o d y   M o n ot h er a p y  Tr e at  m e nt   will  n ot  a p pl y f or t his  p ati e nt  p o p ul ati o n. 
1 6H  B  V -D  N  A t o  b e r e-  m e as ur e d  o nl y if  a nti-H  B c   w as p ositi v e d uri n g s cr e e ni n g ( pl e as e s e e  S e cti o n  1 0. 3. 7. 2 ). 
1 7E  O  R T  C   Q L  Q -C 3 0  a n d  E  Q - 5  D-5 L t o  b e  a d  mi nist er e d  o n   D 1  of t h e  o d d -n u  m b er e d   A nti b o d y   M o n ot h er a p y  Tr e at  m e nt  c y cl es  ( e. g.,   C 7  D 1, C 9  D 1,   C 1 1  D 1 , et c). 
1 8First  F  U  visit f or   O S t o  b e p erf or  m e d  as  a  cli ni c  visit.  
1 9D is e as e  ass ess  m e nts a n d t u  m o ur   m e as ur e  m e nts   will  b e   m a d e  b y  p ositr o n  e  missi o n t o  m o gr a p h y ( P E T)  a n d  c o  m p ut e d t o  m o gr a p h y (  C T) or   C T  al o n e wit h  c o ntr ast.  F or  all  p ati e nts , 
n e c k/ c h est/ a b d o  m e n/ p el vis   C T is r e q uir e d.  T h e   C T  p orti o n  of  a  c o  m bi n e d [ 1 8 F]fl u or o d e o x y gl u c os e ( F  D  G) -P E T/  C T s c a n s h o ul d  b e  p erf or  m e d   wit h  c o ntr ast  a n d  c oll e ct e d   wit h 
r es ol uti o n s uffi ci e nt t o  all o  w  a c c ur at e  a n d  c o nsist e nt  c o  m p aris o n  of t ar g et l esi o n   m e as ur e  m e nts   wit h s u bs e q u e nt   C T s c a ns. If a v ail a bl e  a n d  of  a c c e pt a bl e  q u alit y ( e. g.,   C T  p orti o n 
of  P E T/  C T s c a n   w as  p erf or  m e d   wit h  c o ntr ast),  pr e vi o usl y  p erf or  m e d  P E T/  C T  e x a  mi n ati o ns, i n  a c c or d a n c e   wit h t h e st a n d ar d  of  c ar e, t h at   w er e  d o n e  u p t o  4   w e e ks  pri or t o 
S cr e e ni n g   m a y  b e  e  m pl o y e d.  Dis e as e r es p o ns e  ass ess  m e nt   m a y  als o i n cl u d e st a n d ar d  of  c ar e  pr o c e d ur es t o  d et er  mi n e t h e  dis e as e st at us  p er   C h es o n  crit eri a ( e. g.  c o nfir  m at or y 
bi o ps y, l u  m b ar  p u n ct ur e,  et c f or  P  D).  F or f urt h er  d et ails  pl e as e r ef er t o  S e cti o n  1 0. 3. 8. 1 . 
2 0I n t h e  c o urs e  of  F  U f or   O S, Q o L  q u esti o n n air es   will  b e  a p pli e d  o nl y  d uri n g t h e first  F  U f or   O S  visit,   w hi c h   will  b e  a  cli ni c  visit.  
2 1D uri n g   A nti b o d y   M o n ot h er a p y  Tr e at  m e nt,  a li  mit e d  P E   will  b e  p erf or  m e d  o n   D a y  1  of   C y cl es 7, 1 0,  1 3,  1 6,  et c.  
2 2Pr e  m e di c ati o n t o  b e  a d  mi nist er e d  as  o u tli n e d i n S e cti o n  9. 2 . 
2 3 D at a  c oll e cti o n 
   w as st o p p e d  as  of  2 2-J  U  N-2 0 2 0,  b e c a us e s uffi ci e nt  d at a   w as  alr e a d y  c oll e ct e d f or t h e  e x pl or at or y  p ur p os e.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 2  of 1 3 1  
1 0. 2  P r o c e d u r es  
All st u d y -r e q uir e d  pr o c e d ur es s h o ul d  o c c ur  as  o utli n e d i n T a bl e  5. D e vi ati o ns fr o  m t h e ti  mi n g  of 
ass ess  m e nts   will  b e  c o nsi d er e d  pr ot o c ol n o n- c o  m pli a n c es   a n d s h o ul d  b e r e c or d e d i n t h e s o ur c e 
d o c u  m e nts  al o n g   wit h t h e r e as o n f or t h e  e x c ursi o n. 
 
S cr e e ni n g  b e gi ns  o n t h e  d at e t h at t h e I  C F is si g n e d  a n d   will l ast f or  u p t o  2 8  d a ys. I n  e x c e pti o n al 
c as es, t h e s cr e e ni n g  p eri o d   m a y  b e  e xt e n d e d  at t h e  dis cr eti o n  of t h e i n v esti g at or f or  a t ot al  of  u p 
t o  4 2  d a ys  d u e t o  a n y t e c h ni c al/l o gisti c r e as o ns ( e. g.,  e xt e n d e d i  m a gi n g  e q ui p  m e nt  br e a k d o  w n 
a n d/ or s er vi ci n g,  d el a ys i n t h e  d eli v er y  of  c e ntr al l a b or at or y r es ults).  T h e r e as o n f or s u c h 
e xt e nsi o n  al o n g   wit h  a n  e v al u ati o n  b y t h e i n v esti g at or  e ns uri n g t h at s u c h e xt e nsi o n  d o es  n ot  p os e 
a n y  h e alt h ris k f or t h e  p atie nt s h o ul d  b e  d o c u  m e nt e d i n t h e  p ati e nt’s s o ur c e  d at a. T h e I  C F   m ust 
b e si g n e d  pri or t o t h e  c o n d u ct  of  a n y  ass ess  m e nts s ol el y f or t h e  p ur p os e  of t his st u d y.  St a n d ar d 
of  c ar e  ass ess  m e nts  d o n e  o n t h e  d a y  of  c o ns e nt ( b ut  pri or t o si g ni n g t h e I  C F)  d o  n ot  n e e d t o  b e 
r e p e at e d s ol el y f or t h e  p ur p os e  of s cr e e ni n g  a n d   m a y  b e  us e d  as st u d y  d at a, if t h e y  a n d t h eir 
r es ults m e et t h e  pr ot o c ol r e q uir e  m e nts.  
 
O n   C y cl e  1   D a y  1,  p ati e nt  eli gi bilit y   m ust  b e  c o nfir  m e d  b ef or e  dr u g  a d  mi nistr ati o n. 
 
1 0. 2. 1  Di a g n osti c   Bi o ps y  
P ati e nts s h o ul d  b e  eli gi bl e  a n d   willi n g t o  u n d er g o  a  bi o ps y or s ur gi c al  e x cisi o n of  a l y  m p h  n o d e 
a n d/ or  ot h er  p at h ol o gi c al tiss u e,  pr o vi di n g  e n o u g h t u  m o ur tiss u e f or c e ntr al  hist ol o gi c al r e vi e  w 
a n d c orr el ati v e st u di es,  as  a pr er e q uisit e f or   p arti ci p ati o n i n t his st u d y.  S h o ul d it  n ot  b e  p ossi bl e 
t o  o bt ai n  a fr es h t u  m o ur tiss u e s a  m pl e,  ar c hi v al  p ar affi n  e  m b e d d e d t u  m o ur tiss u e  a c q uir e d 
≤ 3  y e ars  pri or t o s cr e e ni n g f or t his  pr ot o c ol   m ust  b e  a v ail a bl e f or t his  p ur p os e.  
 
I n  a d diti o n,  p ati e nts   will  h a v e t h e  o pti o n t o  c o ns e nt f or st or a g e  a n d  us e  of t h eir s u b  mitt e d t u  m o ur 
tiss u e f or f ut ur e l y  m p h o  m a r es e ar c h. 
 
Hist ol o gi c al  c o nfir  m ati o n  of t h e  di a g n osis  of   D L  B  C L   will  b e  p erf or  m e d  b y  a  c e ntr al  p at h ol o gist.  
S ur gi c all y  a c q uir e d tiss u e s a  m pl es  ar e  pr ef err e d,  b ut  c or e  bi o psi es  ar e  p er  mitt e d.  Fi n e  n e e dl e 
as pir at es ( F  N  A)   will  n ot  b e  a c c e pt e d f or  hist ol o gi c al  c o nfir  m ati o n.  
 
C e nt r al  p at h ol o g y  r e vi e  w is   m a n d at o r y ,  b ut r etr os p e cti v e i n  n at ur e.   A n  eff ort s h o ul d  b e   m a d e 
t o s u b  mit tiss u e s a  m pl e(s)   wit hi n  3 0  da ys  of r a n d o  mis ati o n.  P ati e nts  c a n  b e r a n d o  mis e d  pri or t o 
s u b  missi o n  of tiss u e s a  m pl e(s).  T h e l o c al  p at h ol o g y r e p ort i n di c ati n g  a   D L  B  C L  or D L  B  C L   N  O S  
di a g n osis is  a c c e pt a bl e f or  d et er  mi ni n g  a  p ati e nt’s  eli gi bilit y.    O n r e q u est  of t h e i n v esti g at or, t h e 
s p o ns or   m a y f a cilit at e  a n i nt er a cti o n  b et  w e e n t h e i n v esti g at or  a n d t h e  c e ntr al  p at h ol o gist t o 
dis c uss iss u es  c o n n e ct e d t o t h e i niti al  di a g n osis  est a blis h e d l o c all y.  If t h e  q u alit y  of t h e tiss u e 
s a  m pl e  d o es  n ot  all o  w  c e ntr al  p at h ol o g y  a n al ysis,  a n ot h er  ar c hi v al sa  m pl e  of t h e  a p pr o pri at e 
q u alit y   m a y  b e r e q u est e d  b y t h e  S p o ns or. 
 
I n t h e  c as e  of  dis cr e p a n ci es  b et  w e e n t h e  ass ess  m e nts  of t h e l o c al  a n d t h e  c e ntr al  p at h ol o gists, t h e 
ass ess  m e nt  of t h e  c e ntr al  p at h ol o gists   will  b e r el e v a nt f or s e nsiti vit y  a n al ys es  of t h e  pri  m ar y  
effi c a c y   e n d p oi nt  a n al ysis. If t h e   D L  B  C L  di a g n osis  of t h e l o c al  p at h ol o gist  c a n n ot  b e  c o nfir  m e d 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 7 3  of 1 3 1  
b y t he ce ntral pa t h ol o gists, a n d a pa tie nt’s treat me nt ha s alrea d y c o m me nce d, t he pa tie nt ma y 
re mai n  i n t he st u d y at t he  discreti o n of t he  treati n g p h ysicia n. 
B o ne marr o w bi o ps y a n d b o ne marr o w as pirati o n are n ot c o nsi dere d  a de q uate f or t he p ur p ose of 
dia g n ostic bi o ps y i n t his trial (als o see Secti o n  1 0. 3. 9 ). 
1 0. 2. 2  De m o gr a p hic D at a/ Rele v a nt  Me dic al H ist or y a n d  Curre nt  Me dic al 
C o n diti o ns/ B aseli ne, St a ge a n d  Pr o g n ostic Cl assific ati o n  
De m o gra p hic va ria bles t o be rec or de d will incl u de: age, ge n der, r ace , b o d y hei g ht, a n d b o d y 
wei g ht. Wei g ht an d hei g ht sh o ul d be m eas ure d w hile t he pa tie nt is w it h o ut sh oes, b ut dr esse d. 
At the ti me of si g ni n g of the IC F, rele va nt m e dical hi st or y a n d c urre nt m e dical c o n diti o ns sh o ul d 
be  rec or de d.  T he  medical hist or y  of N H L  s h o ul d be d oc u me nte d i n detail, incl u di n g baseli ne 
s y m pt o ms as well as a detaile d  hi st or y of pr i or ca ncer  t hera pies f or NH L , wit h start a n d st o p 
dates,  n u m ber of t hera p y  li ne(s), disease pr o gressi o n d uri n g or after t hera p y, as w ell as 
disc o nti n uati o ns d ue t o i nt olera bilit y or an y ot her cli nicall y si g nifica nt ill ness. A n y pre vi o us 
t hera p y (e. g., c he m ot hera p y, i m m u n ot hera p y, or ra diatio n t hera p y) for D L B C L sh o ul d be 
rec or de d i n t he eC R F. Als o, e xa mi nati o ns lea di n g t o t he d ia g n osis of t he latest p r o gressi o n of 
D L B C L  sh o ul d be d oc u me nte d i n t he pa tie nt’s so urce d oc u me nts. T his ma y i ncl u de, e. g., r es ults  
of la b orat or y  exa mi nati o ns,  i magi n g  res ults or  cli nica l s y m pt o ms relate d  t o DL B C L.  The  
assess me nt of the l y m p h o ma sh o ul d i ncl u de sta gi n g. I n or der t o reflect the patie nt’s  stat us at t he 
ti me of e nr ol me nt, t he sta n dar d sta gi n g s yste m u se d f or D L B C L reflecti n g t he n u m ber of s ites o f 
i n v ol ve me nt an d t heir relatio n t o t he dia p hra g m, t he existe nce of B -s y m pt o ms, a n d the  prese nce 
of extra n o dal di sease, will be d oc u me nte d ( see Ap pe n di x I  for A n n Ar b or S ta gi n g). 
A d d iti o nall y, th e dis ease ris k assess me nt as p er t he I nter nati o nal Pr o g n ostic I n de x (IPI ; see 
A p pe n di x J ) an d  patie nt  stat us as per  EC O G  perf or ma nce stat us criteria ( see A p pe n di x K ) will 
be rec or de d. 
1 0. 2. 3  Q u alit y  of Life  
I n t he co urse of the st u d y, t w o Q o L q uesti o n naires w ill b e us e d: 
a)
th e s t a n d ar dis e d E ur o p e a n   Or g a nis ati o n f or   R es e ar c h  a n d Tr e at  m e nt  of   C a n c er   Q u alit y  of
Lif e   Q u esti o n n air e -C or e  3 0 ( E  O  R T  C  Q L  Q -C 3 0 ).
b)   t h e  E ur o  Q ol fi v e  di  m e nsi o ns  q u alit y  of lif e  q u esti o n n air e wit h 5 l e v els ( E  Q- 5  D- 5 L).
Res ults of  t he c o m plete d Q o L q ue sti o n naires w ill be entere d b y t he site int o t he eC R F. 
1 0 . 3 S afet y Assess me nts  
Saf et y m o nit ori n g  for all  patie nts enr olle d  i n t he st u d y will i ncl u de  la b orat or y  safet y assess me nts  
(e. g., hae mat ol o g y, bl o o d c he mistr y, ur i nal ysis a n d c oa g ulati o n) an d cli nical eval uati o ns (e. g., 
p h ysical e xa mi nati o ns, vital si g ns, 1 2-l ea d electr ocar di o gra m [ EC G ], a n d m o nit ori n g of sec o n d 
pri mar y mali g na nc y [ S P M ] o cc urre nce)  as detaile d  in  the Sc h e d ule of  Assess me nts (Ta ble  5). 
All  A E s an d  S A Es  s h o ul d be rec or de d in t he eC R F. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 4  of 1 3 1  
L a b or at or y  a n d   A E t o xi citi es   will  b e  gr a d e d  a c c or di n g t o   N  CI-  C T  C  A E,  v ersi o n  4. 0 ( or  hi g h er). 
P ati e nts   w h o  e x p eri e n c e  a n y t o xi cit y s h o ul d  b e f oll o  w e d  u ntil t h e t o xi cit y  h as st a bilis e d, t h e 
t o xi cit y  h as r et ur n e d t o t h e  b as eli n e l e v el,  or  a  n e  w tr e at  m e nt  h as  c o  m  m e n c e d. 
S af et y   m o nit ori n g is  d et ail e d i n   S e cti o n 1 1 . 
 
1 0. 3. 1  Vit a l  Si g ns 
Vit al si g ns   will  b e   m e as ur e d  at t h e ti  m e  p oi nts  d es cri b e d i n t h e  S c h e d ul e  of   Ass ess  m e nts  
(T a bl e   5). If   m  A b  a n d   B E  N  ar e  b ei n g  a d  mi nist er e d  o n t h e s a  m e  d a y,  vit al si g ns s h o ul d  b e 
r e c or d e d i n  e  C  R F f or   m  A b i nf usi o n(s)  o nl y.  T h es e  ass ess  m e nts i n cl u d e  b o d y t e  m p er at ur e, 
s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e r e a di n gs (  m  m  H g),  h e art r at e ( b e ats  p er   mi n ut e [ b p  m]),  a n d 
r es pir at or y r at e (r es pir ati o ns  p er   mi n ut e [r p  m]).   Vit al si g ns   will  be   m e as ur e d  wit hi n  1 5 mi n ut es 
pri or t o i nf usi o n, 1 5  ±  5   mi n ut es  aft er t h e st art  of i nf usi o n,  a n d  3 0  ±  1 0   mi n ut es  aft er t h e st art  of 
i nf usi o n.   Aft er t h e  3 0-mi n ut e  ass ess  m e nt,  vit al si g ns  n e e d t o  b e   m e as ur e d o n c e  e v er y  3 0 t o 
6 0  ± 1 5   mi n ut es  d uri n g t h e i nf usi o n  a n d  at t h e  e n d  of i nf usi o n ( ±  2 0   mi n).  T h e  a ct ual ti  m e  of  vit al 
si g n   m e as ur e  m e nts s h o ul d  b e  a c c ur at el y  d o c u  m e nt e d. If t h e i nf usi o n is i nt err u pt e d  a n d/ or 
s u bs e q u e ntl y r est art e d,  vit al si g ns s h o ul d  b e  ass ess e d  e v er y  6 0  ±  1 5   mi n ut es  aft er t h e first  h o ur. 
D uri n g  visits   w h e n st u d y  dr u g i nf usi o ns  d o  n ot t a k e  pl a c e,  vit al si g ns  n e e d t o  b e   m e as ur e d  o nl y 
o n c e,  at  all  visits  a c c or di n g t o  T a bl e   5. 
 
F or t h e s af et y  of t h e  p ati e nt, i n t h e  c o urs e  of   C y cl e  1   D a y  1 (first   M  O  R 0 0 2 0 8 i nf usi o n)  a n d 
C y cl e  1   D a y  2 (first i nf usi o n  of   B E  N) t h e  p ati e nt   will st a y  at t h e st u d y sit e f or  a p pr o xi  m at el y 
2  h o urs  aft er t h e  e n d  of st u d y  dr u g  a d  mi nistr ati o n f or t h e   m o nit ori n g  of t h e  o c c urr e n c e  of  a c ut e 
t o xi citi es.  
 
T h e fr e q u e n c y  or  d ur ati o n  of   m o nit ori n g   m a y  b e  a d a pt e d as cli ni c all y i n di c at e d,  e. g., if i n t h e 
o pi ni o n  of t h e i n v esti g at or, t h e  vit al si g n r es ults  at t h e ti  m e  of  e v e nt  o ns et  ar e  cli ni c all y 
si g nifi c a nt. I n s u c h  a  c as e, t h e  p ati e nt’s  vit al si g n   m e as ur e  m e nts s h o ul d  c o nti n u e t o  b e r e c or d e d 
u ntil t h e y  h a v e r et ur n e d t o  n or  m al  or  pr e- i nf usi o n l e v els.  S u bs e q u e ntl y, a n   A E s h o ul d  b e 
r e c or d e d. If  p ossi bl e,  b ef or e  vit al si g ns  ar e   m e as ur e d, t h e  p ati e nt s h o ul d  b e r esti n g f or  at l e ast 
5 mi n ut es.  T h e s a  m e  p ositi o n s h o ul d  b e  us e d  e a c h ti  m e  vit al si g ns  ar e   m e as ur e d i n  a  gi v e n 
p ati e nt,  a n d  bl o o d  pr ess ur e s h o ul d  b e   m e as ur e d fr o  m t h e  ar  m  c o ntr al at e r al t o t h e sit e  of st u d y 
dr u g  a d  mi nistr ati o n.   B o d y t e  m p er at ur e s h o ul d  b e   m e as ur e d  a c c or di n g t o  n or  m al i nstit uti o n al 
pr a cti c e.  
 
1 0. 3. 2  P h ysi c al   E x a  mi n ati o n  
1 0. 3. 2. 1  F ull  P h ysi c al   E x a  mi n ati o ns  
A f ull  p h ysi c al  e x a  mi n ati o n ( P E)   will  b e  p erf or  m e d  b y t h e I n v esti g at or  or  a  q u al ifi e d  d esi g n e e 
d uri n g  S cr e e ni n g  a n d  at t h e  E  O T  v isit. 
 
F ull  P E   m ust  b e  p erf or  m e d  a c c or di n g t o t h e  b est st a n d ar ds  of l o c al   m e di c al  pr a cti c e ,  b ut s h o ul d 
i n cl u d e  at l e ast m e as ur e  m e nt  of  vit al si g ns,  p al p a bl e t u  m o ur  ass ess  m e nt  (if  a p pli c a bl e),  g e n er al 
a p p e ar a nc e, s ki n,  h e a d,  e y es,  e ars,  n os e, t hr o at i n cl u di n g   W al d e y er l y  m p h ati c str u ct ur es, l u n gs, 
br e asts  a n d  a xill a e,  c ar di o v as c ul ar s yst e  m,  b a c k  a n d s pi n e,  a b d o  m e n ,  e xtr e  miti es, l y  m p h  n o d es, 
a n d  n e ur ol o gi c al  e x a  mi n ati o n.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 7 5  of 1 3 1  
1 0. 3. 2. 2  Li  mit e d  P h ysi c al   E x a  mi n ati o ns  
Li mite d  P Es ma y be foc use d o n t u m o ur res p o nse assess me nt (l y m p h n o des, li ver, s plee n, etc.) 
a n d A Es at t he i n vesti gat or discreti o n. S uc h li mite d P Es will be  perf or me d as i n dicate d  i n the 
Sc he d ule of  Assess me nts  (Ta ble  5). D uri n g A nti b o d y M o n ot hera p y T reat me nt, a li mite d PE  will 
be pe rf or me d o n Da y 1 of C ycles 7, 1 0, 1 3, 1 6 etc. 
S y m pt o m- dri ve n f ull P Es m a y be pe rf or med as cli nically i n dicate d at an y st u d y visit. Si milarl y, 
t he in vesti gat or m a y e xte n d t he sc o pe of P E at an y visit if c o nsi der e d cli nicall y  rele va nt.  
1 0. 3. 2. 3  B o d y  M ass, Bo d y  Surf ace Are a  (B S A)  a nd  Hei g ht  Me asure me nts  
B o d y mass an d B S A w ill be us e d t o calc ulate t he d oses of M O R 0 0 2 0 8, a n d, R T X an d B E N, 
res pecti vel y.  
B o d y hei g ht w ill be meas ure d o n t he S cree ni n g visit o n l y. 
B o d y mass an d B S A w ill be m eas ure d at least d u ri n g t he S cree ni n g visit an d o n Da y 1 of eac h 
c ycle . T hese va ria bles sh o ul d be us e d to calc ulate t he st u d y dr u g d oses in t he co urse o f a gi ve n 
c ycle an d o n D a y 1 of the succee di n g c ycle, wit h t he exce pti o n of C 1 D 1. O n C 1 D 1, b o d y mass 
a n d B S A m eas ure d o n t hat da y will b e us e d t o calc ulate the d o ses of the st u d y dr u gs.  
B o d y  m ass a n d  BS A  meas ure me nt  ma y ta ke place pre - o r p os t- d ose, with t he exce pti o n of C 1 D 1 
w here t he y  nee d  to  be meas ure d  a nd  calc ulate d  pre - d ose. 
D uri n g t he c o urse of t his st u d y, th e M osteller’ s al g orit h m  s h o ul d be use d  for  BS A  calc ulati o ns 
(see A p pe n di x H). Pr o v i de d t he i nstit uti o nal sta n dar ds req uire  t he use o f a not her sta n dar d B SA 
for m ula , s p o ns or ap pr o v al ma y be o btai ne d  o n a case b y  case basis.  
1 0. 3. 3  B- S y m pt o ms  
T h e pr ot oc ol s pecific defi niti o n  of B-s y m pt o ms is base d o n t he C ots w ol ds Rec o m me n dati o ns 
(see A p pe n di x I). 
B -s y  m pt o  ms  ar e  d efi n e d as  a n y  o n e  or   m or e  of t h e f oll o  wi n g  dis e as e-r el at e d s y  m pt o  ms  or si g ns:
•
U ni nt e nti o n al   w ei g ht l oss  of ≥ 1 0  %   wit hi n t h e  pr e c e di n g  6   m o nt hs or l ess
•
Dr e n c hi n g  ni g ht s  w e ats   wit h o ut si g ns  of i nf e cti o n
•
R e c urr e nt,  u n e x pl ai n e d f e v er   wit h t e  m p er at ur es  a b o v e  3 8°  C   wit h o ut si g ns  of i nf e cti o n
A ss ess  m e nt  of t h e  pr es e n c e  or  a bs e n c e  of   B-s y  m pt o  ms   will  b e  p erf or  m e d  at  v ari o us ti  m e  p oi nts 
as i n di c at e d i n t h e  S c h e d ul e  of   Ass ess  m e nts (s e e  T a bl e   5). 
M e di c al  hist or y  of   B-s y  m pt o  ms s h o ul d  b e  d o c u  m e nt e d. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 6  of 1 3 1  
1 0. 3. 4  El e ct r o c a r di o g r a  m  
St a n d ar d  1 2- l e a d r esti n g  E  C  Gs s h o ul d  b e  o bt ai n e d  at t h e  v ari o us ti  m e  p oi nts  d es cri b e d i n t h e 
S c h e d ul e  of   Ass ess  m e nts (T a bl e   5). If  p ossi bl e, E  C  Gs s h o ul d b e r e c or d e d  aft er t h e  p ati e nt  h as 
r est e d i n  a s u pi n e  p ositi o n f or  at l e ast  5 mi n ut es. H e art r at e  a n d  P  R,   Q  R S ,   R  R  a n d   Q T i nt er v als 
s h o ul d  b e  d et er  mi n e d.   All  E  C  Gs s h o ul d  b e  p erf or  m e d  a n d i nt er pr et e d l o c all y. T h e i n v esti g at or 
s h o ul d e v al u at e t h e  cli ni c al si g nifi c a n c e  of  e a c h  v al u e  o utsi d e t h e r ef er e n c e r a n g es  a c c or di n g t o 
t h e  n at ur e  a n d  d e gr e e  of t h e  o bs er v e d  a b n or  m alit y.   A n y  n e  w  a b n or  m al  v al u es  c o nsi d er e d t o  b e 
cli ni c all y si g nifi c a nt s h o ul d  b e r e p ort e d  as   A Es.  
 
If  cli ni c all y si g nifi c a nt  a b n or  m aliti es  ar e  o bs er v e d  or  art ef a cts  ar e  pr es e nt t h at r es ult i n  a n 
i n a bilit y t o  a d e q u at el y i nt er pr et t h e r es ults, t h e  E  C  G s h o ul d b e r e p e at e d.   A n  a v er a g e  of  all 
i nt er v als   m e as ur e d i n  all  E  C  G tr a ci n gs r e c or d e d  at  a  gi v e n ti  m e  p oi nt   m a y  b e t a k e n if  n e c ess ar y. 
 
1 0. 3. 5  A d v e rs e   E v e nt   M o nit o ri n g  
A Es s h o ul d b e  ass ess e d  at  e a c h  visit  a n d r e p ort e d  as s p e cifi e d i n   S e cti o n 1 1 .  For s cr e e ni n g 
f ail ur e  p ati e nts,  o nly  S  A Es s h o ul d  b e r e c or d e d i n t h e  e  C  R F. 
 
1 0. 3. 6  M o nit o ri n g  of  S e c o n d  P ri  m a r y   M ali g n a n ci es 
S P  Ms   will  b e   m o nit or e d  as  e v e nts  of  s p e ci al i nt er est  a n d s h o ul d  b e i n cl u d e d  as  p art  of t h e 
ass ess  m e nt  of   A Es t hr o u g h o ut t h e  c o urs e  of t h e st u d y. I n v esti g at ors  ar e t o r e p ort  a n y  S P  Ms  as 
A d v ers e  E v e nts  of  S p e ci al I nt er est  (  A E SIs), r e g ar dl ess  of  c a us al r el ati o ns hi p t o t h e st u d y  dr u gs, 
o c c urri n g  at  a n y ti  m e, f or t h e  d ur ati o n  of t h e st u d y, fr o  m   C y cl e  1,   D a y  1  u p t o  a n d i n cl u di n g t h e 
F oll o  w- U p f or  P F S.  E v e nts  of  S P  M  ar e t o  b e r e p ort e d  usi n g t h e  S  A E r e p ort f or  m  a n d   m ust  b e 
c o nsi d er e d  a n i  m p ort a nt   m e di c al  e v e nt  e v e n if  n o  ot h er s eri o us  crit eri a  a p pl y; t h es e  e v e nts   m ust 
als o  b e  d o c u  m e nt e d i n t h e  a p pr o pri at e  p a g e(s)  of t h e  e  C  R F  a n d t h e  p ati e nt’s s o ur c e  d o c u  m e nts. 
 
D o c u  m e nt ati o n  c o n c er ni n g t h e  di a g n osis  of t h e  S P  M   m ust  b e  pr o vi d e d  at t h e ti m e  of r e p orti n g  as 
a n  S  A E ( e. g.,  a n y  c o nfir  m at or y  hist ol o g y  or  c yt ol o g y r es ults,   X- r a ys,   C T s c a ns). 
 
1 0. 3. 7  L a b o r at o r y   Ass ess  m e nts  
D et ail e d i nstr u cti o ns  a n d  a  m o u nts  of  bi ol o gi c al s a  m pl es  n e e d e d f or t h e r es p e cti v e l a b or at or y 
m e as ur e  m e nts   will  b e s u  m  m aris e d i n t h e l a b or at or y   m a n u al.   All s a  m pl es   will  b e  c oll e ct e d  as 
n o n- f asti n g s a  m pl es. 
 
1 0. 3. 7. 1  L a b o r at o r y   T esti n g 
Cli ni c al l a b or at or y p ar a  m et ers   m e as ur e d i n t h e  c o urs e  of t h e st u d y  ar e list e d i n  T a bl e   6.  Lo c al 
a n d  c e ntr al l a b or at ori es   will  b e us e d t hr o u g h o ut t h e st u d y . 
 
C e ntr al l a b or at or y r es ults  ar e r e q uir e d f or  d et er  mi ni n g  p ati e nt  eli gi bilit y f or st u d y  e nr ol  m e nt   a n d 
will  b e  us e d i n t h e   a n al ysis  of t h e st u d y r es ults.   D uri n g t h e  c o urs e  of t h e st u d y,  all s c h e d ul e d 
c e ntr al l a b or at or y r es ults s h o ul d  b e r e vi e  w e d  as s o o n  as  p ossi bl e  aft er   D a y  1  of  e a c h  c y cl e.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 7 7  of 1 3 1  
Patie nts  m ust neit her be q ua lifie d f or stu d y e li gi bility n or ra nd o mise d base d o n t he res ults of t he 
l ocal la b orat or y  assess me nts.  
It is per mitte d  t o re pe at t wice the  ce ntr al la b or at or y assess me nt  of bl o o d  cell c o u nts,  li ver 
e nz y mes,  ser u m electr ol ytes co nce ntrati o n (s o di u m, p otassi u m, calci u m) a n d/ or ser u m cr eati ni ne  
or creati ni ne  cleara nce/ gl o mer ular  filtrati o n rate duri n g Scree ni n g d ue  t o t he varia bilit y of t he  
para meter s an d t heir de pe n de nce o n a mul tit u de of fact ors  (e. g. h y drati o n, m uscle mass). Tha t is, 
pr o vi de d n o safet y c o ncer ns arise an d t hat su c h la b orat or y res ults m i g ht h a ve be e n ca use d b y a 
tra nsie nt , me dicall y pl a usi ble eve nt , whic h res ol ve d s p o nta ne o usl y or as res ult of a me dical 
i nter ve ntio n in t he m ea nti me (e. g. deh y drati o n, v o miti n g, i ma gi n g pr oce d ure w it h a c o ntrast) , or 
tec h nical iss ues. T his pr oce d ure an d t he rati o nale be hi n d it m ust be ex plicitl y d oc u me nte d i n 
s o urce data. 
L ocal la b orat or y  res ults will be  us e d for treat me nt or cli nicall y  relate d de cisi o ns,  or f or t he 
i m me diate safet y n ee ds  of a st u d y patie nt. Local  la b orat or y res ults s h o ul d be re vie we d as so o n as 
p ossi ble  after t heir recei pt a n d  bef ore d osi n g  so  t hat t he  a d mi nistrati o n  of t he i n vesti gati o nal 
me dici nal p r o d uct m a y be adj uste d or interr u pte d if ne cessar y. L oc al la b or at or y  assess me nts 
m a y  be perf or me d  u p t o  2 4  h o urs bef ore a dmi nistr ati o n  of  st u d y dru gs  a nd m a y f all 
o utsi de  of t he pla n ne d visit  wi n d o w. 
In  or de r t o kee p  t he ex peri me ntal c o n diti o ns  as si milar as possi ble , irres pecti ve o f treat me nt 
all ocati o n, t he l ocal la b orat or y sa m ples will als o  be c ollecte d  f or the R T X + B E N  patie nts at  t he 
res pecti ve st u d y visits (see Ta ble 5), des pite t he fact th at t he y ma y n ot necessaril y recei ve st u d y 
dr u gs at  a gi ve n  visit. In  s uc h case t he restricti o n t hat sa m ples  nee d to  be c ollecte d a n d e val uate d 
i n t he l ocal la b orat or y a n d re vie wed b y st u d y treati n g p h ysicia n bef ore st u d y dr u g a d mi nistrati o n 
will n ot ap pl y. 
T he  si g ne d an d  i nterprete d  lab orat or y  res ults ( b ot h l ocal a n d  ce ntral) are  t o be ke pt in t he 
patie nt’s s o urce d oc u me ntati o n. T he la b orat or y res ults s h o ul d be re vie we d, date d a n d si g ne d in a 
ti mel y m a n ner b y  t he i n vesti gat or. A n y  cli nicall y si g nifica nt discre pa ncies bet wee n  local  a n d 
ce ntral  la b orat or y  res ults  will be e val uate d o n a case - b y-case basis.  All b l o o d sa m ples sh o ul d be 
pr ocesse d a n d ha n dle d acc or di n g to sta n dard la b orat or y pr oce d ures. T he ti me of bl o o d c ollecti o n 
s h o ul d be d o c u me nte d i n the eC R F. 
A n y  ab n or mal la b orat or y  fi n din gs  (i de ntifie d eit her t hr o u g h l ocal or ce ntral la b orat or y  anal ysis) 
t hat co nstit ute an A E sh o ul d be re p orte d as s uc h a n d s h o ul d be foll o we d u p u ntil t he o utc o me is 
k n o w n. Als o, a d diti o nal dia g n ostic tests ma y  be i n dicate d  to  deter mi ne  a m ore precise dia g n osis 
of t he  pa tie nt’s co n diti o n  (e. g., orderi n g a w hite b l o o d cell [W B C ] diff ere ntia l co u nt t o  hel p 
c haracterise a hi g h or l o w W B C co u nt, or or deri n g a de ter mi nati o n of re d bl o o d cell [R B C ] 
i n dices t o hel p characterise  a l o w ha e mat ocrit).  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 8  of 1 3 1  
T a bl e   6:     
L a b o r at o r y   E v al u ati o ns 
E v al u ati o n  
A n al ysis  
L o c al  l a b o r at o r y (E  D T  A 
bl o o d  a n d s er u  m s a  m pl e)  
S er u  m  cr e ati ni n e,  h a e  m o gl o bi n,   W  B  Cs, i n cl u di n g   W  B  C  diff er e nti al 1, 
pl at el ets, s o di u  m,  p ot assi u  m,   A S T,   A L T, t ot al  bilir u bi n  
H a e  m at ol o g y  
( E  D T  A  bl o o d) 
W  B  C   wit h  diff er e nti al  c o u nt,  h a e  m at o crit,  h a e  m o gl o bi n,   m e a n 
c or p us c ul ar  v ol u  m e,   m e a n  c or p us c ul ar  h a e  m o gl o bi n, m e a n 
c or p us c ul ar  h a e  m o gl o bi n  c o n c e ntr ati o n,  pl at el et  c o u nt,   R  B  C  c o u nt, 
l y  m p h o c yt es,   m o n o c yt es,  n e utr o p hils,  b a n d  n e utr o p hils,  e osi n o p hils, 
b as o p hils  
S cr e e ni n g: s h o ul d i n cl u d e  a  p eri p h er al  bl o o d s  m e ar 
B a n d  n e utr o p hils  ar e  o nl y r e p ort e d   w h e n  a   m a n u al  diff er e nti al  c o u nt 
p erf or  m e d  a n d  b a n ds  ar e  pr es e nt  
S e r u  m  c h e  mist r y  
(s er u  m s a  m pl e) 
A L T, t ot al  al b u  mi n,  al k ali n e  p h os p h at as e,  a  m yl as e,   A S T,  bi c ar b o n at e, 
bilir u bi n (t ot al),  ur e a, t ot al  c al ci u  m,  c hl ori d e,  cr e ati ni n e,  cr e ati ni n e 
ki n as e, g a  m  m a -gl ut a  m yltr a nsf er as e ( G  G T ),  gl u c os e, l a ct at e 
d e h y dr o g e n as e ( L  D  H ), li p as e,  p h os p h at e,  p ot assi u  m,  pr ot ei n (t ot al), 
s o di u  m,  uri c  a ci d,  β 2-mi cr o gl o b uli n,   C -r e a cti v e  pr ot ei n 
C o a g ul ati o n  p a r a  m et e rs  
(s o di u  m  citr at e  bl o o d) 
A cti v at e d  p arti al t hr o  m b o pl asti n ti  m e,  pr ot hr o  m bi n ti  m e, i nt er n ati o n al 
n or  m alis ati o n r ati o  
I g  c o n c e nt r ati o ns 
(s er u  m s a  m pl e) 
I g  c o n c e ntr ati o ns (I g  G, I g  M, I g  A) 
S e r ol o g y  p a r a  m et e rs  
(s er u  m s a  m pl e) 
H e p atitis   B:   H  Bs  A g,  a nti -H  B c  a n d   H  Bs A b s.   H  B  V D  N  A if  a nti -H  B c 
p ositi v e,  o pti o n al   
H e p atitis   C:   H  C  V  a nti b o d y (  H  C  V   R  N  A  q u a ntifi c ati o n if  a nti -H  C  V  
p ositi v e)  
P r e g n a n c y t est  
(s er u  m or  uri n e s a  m pl es) 
 
β -H  C  G s er u  m  or  uri n e , f e  m al es  of  c hil d b e ari n g  p ot e nti al  o nl y. 
S er u  m s a  m pl es t est e d i n  c e ntr al l a b or at or y  a n d  uri n e s a  m pl es t est e d 
l o c all y 
U ri n al ysis  
A p p e ar a n c e,  c ol o ur,  uri n e  bilir u bi n,  gl u c os e, h a e  m o gl o bi n,  k et o n es, 
p  H,  pr ot ei n, s p e cifi c  gr a vit y,  ur o bili n o g e n .  
Mi cr os c o p y   will  o nl y  b e  p erf or  m e d if  cli ni c all y i n di c at e d . 
G e n ot y pi n g * 
(m u c os al  c h e e k s  w a b, 
o pti o n al)  
F c γ  RII a  a n d  F c γ  RIII a  p ol y  m or p his  m  
I  m  m u n o g e ni cit y 
(s er u  m s a  m pl e) 
 
A nti -M  O  R 0 0 2 0 8  a nti b o di es  
P  K 
(s er u  m s a  m pl e) 
 
M  O  R 0 0 2 0 8  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 7 9  of 1 3 1  
*   M a y  b e  p erf or  m e d  at  a n ot h er ti  m e  p oi nt t h a n   C 1 D 1 if it   w as i n a d v ert entl y    miss e d. 
A b br e vi ati o ns:   A  D  C  C   = a nti b o d y-d e p e n d e nt  c ell -m e di at e d  c yt ot o xi cit y;   A L T   = al a ni n e tr a ns a  mi n as e; a nti-H  B c   = 
h e p atitis   B  c or e  a nti b o d y; a nti-H  C  V  = h e p atitis   C  vir us  a nti b o d y; A S T   = as p art at e a  mi n otr a nsf er as e;  β -H  C  G   = 
b et a -h u  m a n  c h ori o ni c  g o n a d otr o pi n; E  D T  A   = et h yl e n e di a  mi n et etr a a c eti c  a ci d; G  G T   = g a  m  m a -gl ut a  m yltr a nsf er as e; 
H  Bs A b   = h e p atitis   B s urf a c e  a nti b o d y;   H B s  A g  = h e p atitis   B s urf a c e  a nti g e n;  H  B  V   = h e p atitis   B  vir us;  I g  = 
i  m  m u n o gl o b uli n; L D  H   = l a ct at e  d e h y dr o g e n as e;   N  K  = n at ur al  kill er;  P  B  M  Cs  =  p eri p h er al  bl o o d   m o n o n u cl e ar  c ells; 
P  K   = p h ar  m a c o ki n eti cs; R  B  C   = r e d  bl o o d  c ell;   W  B  C  = w hit e  bl o o d  c ells.  
1W  B  C  diff er e nti al  c a n  b e  a ut o  m at e d  or   m a n u al  as  p er i nstit uti o n al st a n d ar ds. R eti c ul o c yt es  (t est e d l o c all y) m a y  b e 
d et er  mi n e d  o nl y   w h e n  cli ni c all y i n di c at e d.  
 
D u e t o t h e  e x pl or at or y  n at ur e  of s o  m e  ass a ys, t h e s p o ns or   m a y  d e ci d e  at  a n y  p oi nt  d uri n g t h e 
st u d y t o t er  mi n at e t h es e  ass ess  m e nts, i n   w hi c h  c as e t h e sit es   will  b e i nf or  m e d  a c c or di n gl y.  
 
1 0. 3. 7. 2  H e p atitis Vi r us  S e r ol o g y  
P ati e nts    will  b e  e x a  mi n e d  a c c or di n g t o t h e s c h e d ul e i n T a bl e   5 f or  vir al  h e p atitis   B  a n d   C 
s er ol o g y. H e p atitis   B  bi o  m ar k ers i n cl u d e   H Bs  A g,  a nti-  H  B c  a n d   H  Bs  A b . P ati e nts   wit h  a  p ositi v e 
t est f or h e p atitis    B  vir us  c or e  a nti b o d y (a nti-H  B c ) c a n  o nl y  b e i n cl u d e d if   H B  V -D  N  A is  n ot 
d et e ct e d. I n t h es e  p ati e nts,   H  B  V -D  N  A s h o ul d  b e  ass ess e d  as  o utli n e d i n  T a bl e   5. 
 
I n t h e  c o nt e xt  of t h e  e x cl usi o n  crit eri a, s er o p ositi v e f or  or a cti v e  vir al i nf e cti o n   wit h   H  B  V  
m e a ns : 
a) H  Bs  A g   p ositi v e 
b)  H  Bs A g  n e g ati v e,  a nti- H  B c  p ositi v e  a n d  d et e ct a bl e  vir al   D  N  A  (r e g ar dl ess  of   H  Bs  A b 
st at us). 
 
P ati e nts   w h o  e x hi bit t h e  cl assi c al  v a c ci n ati o n  pr ofil e  of   H  Bs A b  p ositi v e,  a nti- H  B c  n e g ati v e  a n d 
H  Bs A g  n e g ati v e  a r e  eli gi bl e. 
 
If   H  B  V   D  N  A  b e c o  m es  d et e ct a bl e  d uri n g tr e at  m e nt,  p ati e nts s h o ul d  b e  pr o p h yl a cti c all y tr e at e d 
a n d f oll o  w e d- u p f or  p ot e nti al  h e p atitis   B r e a cti v ati o n  as  p er l o c al   m e di c al  pr a cti c e  or 
i nstit uti o n al  g ui d eli n es f or   C  D 2 0  a nti b o di es s u c h  as   R T  X. If th e   H  B  V  D  N  A  ass a y is  p ositi v e, 
t h e n  p ati e nts  c a n  o nl y st a y i n t h e st u d y if t h e y  ar e  ass ess e d  b y  a  p h ysi ci a n  e x p eri e n c e d i n t h e 
E v al u ati o n  
A n al ysis  
B- /  T-/  N  K  c ell  c o u nti n g 
( h e p ari nis e d bl o o d  a n d E  D T  A 
bl o o d )  
C ell  c o u nts  vi a fl o  w  c yt o  m etr y  
C  D 1 6  e x p r essi o n  o n 
p e ri p h e r al   N  K  c ells  
( h e p ari nis e d  bl o o d)  
C  D 1 6   m ol e c ul es  e x pr ess e d  p er  c ell (  C  D 1 6  a nti b o di es  b o u n d  p er  c ell)  
vi a fl o  w  c yt o  m etr y  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 8 0  of 1 3 1  
treat me nt o f he patitis  B an d  pre-em pti v e treat me nt is i nitiate d, if dee me d ap p r opr iate, an d/ or 
acc or di n g  t o l ocal practice/ g ui deli nes. 
He patitis C ser ol o g y is t o be d o ne at Sc ree ni n g onl y.  He patitis  C bi o mar kers i ncl u d e he patitis  C 
vir us a nti b o d y (a nti- H C V).  For patie nts  w h o  are positi ve  f or a nti- HC V,  H C V R N A s h o ul d be 
meas ure d. 
A p ositi ve he p atitis C  test is defi ne d  as a p o siti ve test f or a nti- HC V  a n d a p ositi ve  test f or H C V 
R N A.  T h us, p atie nts wit h  po siti ve ser ol og y  but  ne gati ve H C V  RN A  test res ults are eli gi ble. 
1 0. 3. 7. 3  Pre g n a nc y  Test i n g 
F or  an F C B P , a pre g na nc y  test will be  perf or me d  at vari o us pre - a n d p ost-treat me nt ti me poi nts 
eit her  b y a uri ne pre g na nc y test or a beta-h u ma n c h ori o nic g o na d otr o pi n ( β - HC G)  test of a  ser u m 
sa m ple (see Ta ble 6). The pre g na nc y test assa y s h o ul d ha ve a mi ni m u m se nsiti vit y of 2 5 I U/ m L. 
At  Scree ni n g a n d t he E O T  visit, a β- HC G ser u m pre g na nc y test s h o ul d be perf or me d f or a n 
F C B P. 
A n F C B P  m ust ha ve t w o ne gati ve pre g na nc y tests pri or t o starti n g t he st u d y dr u g ad mi nistr ati o n. 
T he first pre g na nc y test m ust be perf or me d d uri n g Scree ni n g a n d t he sec o n d pre g na nc y test m ust 
be perf or me d o n C ycle 1 Da y 1 pri or t o t he start of st u d y dr u g. T he patie n t m ust n ot recei ve st u d y 
dr u g u ntil t he st u d y d oct or has verifie d t hat t he res ults of t hese pre g na nc y tests are ne gati ve. 
S u bse q ue nt pre g na nc y tests will be c o n d ucte d as i n dicate d i n t he Sc he d ule of Assess me nts,   
Ta ble  5. 
1 0. 3. 7. 4  P K  Assess me nts 
C o nce ntrati o n-t i me pr ofiles a n d  PK  para meter s will  be assesse d  fo r M O R 0 0 2 0 8 acc or di n g t o t he 
sc he d ule i n Ta ble  5. P K s a m ples w ill not be  collecte d  fr o m patie nts treate d wit h RT X  a n d 
c o nce ntrati o n -ti me pr ofiles or PK  p ara meters will  n ot b e assesse d  for  BE N  or R T X.  P K  sa mple 
c ollecti o n s hall be st o p pe d after C ycle 2 3. 
Ser u m sa m ples f or P K a nal ysis of M O R 0 0 2 0 8 will be ha n dle d a n d st ore d as s pecifie d  in  the 
la borat or y  ma n ual at t he st u d y site u ntil s hi p me nt o n dr y ice t o a n e xter nal a nal ytical la b orat or y. 
At eac h sa m pli n g ti me p oi nt, t he o btai ne d ser u m sa m ple s h o ul d be s plit i nt o tw o  ali q u ots ( o ne 
pri mar y a n d o ne b ac k - up  sa mple). 
1 0. 3. 7. 5  I mm u n o ge nicit y 
Ser u m sa m ples  f or a nti- M O R 0 0 2 0 8 a nti b o d y a nal ysis will be c ollecte d acc or di n g t o t he sc he d ule 
i n Ta ble 5. Anti- dr u g a nti b o d y sa m ples will n o t b e collecte d  fr om patie nts  treate d  wit h R T X. 
Ser u m sa m ple  c ollecti o n  f or a nti- M O R 0 0 2 0 8 a nti b o d y a nal ysis s hall be st o p pe d  after C ycle 2 3. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 1  of 1 3 1  
S er u  m s a  m pl es f or  a nti -  M  O  R 0 0 2 0 8  a nti b o d y  a n al ysis   will  b e  h a n dl e d  a n d st or e d  as s p e cifi e d i n 
t h e l a b or at or y   m a n u al  at t h e st u d y sit e  u ntil s hi p  m e nt  o n  dr y i c e t o  a n  e xt er n al  a n al yti c al 
l a b or at or y.   At  e a c h s a  m pli n g ti  m e  p oi nt, t h e  o bt ai n e d s er u  m s a  m pl e s h o ul d  b e s plit i nt o t hr e e 
ali q u ots ( o n e  pri  m ar y  a n d  t  w o b a c k - u p s a  m pl es). 
 
1 0. 3. 8  Effi c a c y   Ass ess  m e nts  
T h e  pri  m ar y effi c a c y e n d p oi nt a n al ysis   will  b e e v al u at e d t hr o u g h c e ntr al r e vi e  w  b y a n 
I n d e p e n d e nt   R a di ol o g y/  Cli ni c al   R e vi e  w   C o  m  mitt e e (I  R  C) t h at   will  a p pl y   C h es o n  crit eri a (s e e 
A p p e n di x L ). T h e r e vi e  w pr o c ess will  b e  d efi n e d i n t h e I  R  C   C h art er.  
 
Effi c a c y   will  b e  e v al u at e d i n t er  ms  of  P F S  ( pri  m ar y  e n d p oi nt), b est O  R  R,   D  C R,   D o  R,   O S,  T T P 
a n d  T T  N T  (s e c o n d ar y  e n d p oi nts).  F or  d efi niti o ns, s e e  S e cti o n 1 3. 4 . 
 
L o c al  ass ess  m e nt  of  effi c a c y r es p o ns e (  C h es o n  crit eri a) will  b e r e q uir e d i n  a d diti o n t o  c e ntr al 
r e vi e  w  at t h e  b e gi n ni n g  of   C y cl e  3,   C y cl e  5  a n d  at t h e  E  O T  visit t o  d et er  mi n e   w h et h er t h e 
dis e as e  h as  pr o gr ess e d.  L o c al  effi c a c y  ass ess  m e nt   will  als o  b e  p erf or  m e d  at t h e  e n d  of   C y cl e  6 
f or t h e  d e cisi o n   w h et h er tr e at  m e nt   will  c o nti n u e  as   A nti b o d y   M o n ot h er a p y  Tr e at  m e nt fr o  m 
C y cl es  7 o n  w ar ds. Dis e as e r es p o ns e  ass ess  m e nt  as i n di c at e d i n  T a bl e   5 m a y  als o i n cl u d e 
st a n d ar d  of  c ar e  pr o c e d ur es t o  d et er  mi n e t h e  dis e as e st at us  p er   C h es o n  crit eri a ( e. g.  c o nfir  m at or y 
bi o ps y, l u  m b ar  p u n ct ur e,  et c f or  P  D) .   D at a fr o  m t h es e  pr o c e d ur es is  c oll e ct e d  a n d pr o vi d e d t o t h e 
I  R  C  as  d efi n e d i n t h e I  R  C   C h art er. 
 
1 0. 3. 8. 1  T u  m o u r I  m a gi n g  
D uri n g t h e  c o urs e  of t h e st u d y, dis e as e  a n d r es p o ns e  ass ess  m e nts  as   w ell  as t u  m o ur 
m e as ur e  m e nts   will  b e  p erf or  m e d.  
 
I niti al  dis e as e  a n d  dis e as e r es p o ns e  ass ess  m e nts will  b e   m a d e  b y p ositr o n  e  missi o n t o  m o gr a p h y 
(P E T )  a n d c o  m p ut e d t o  m o gr a p h y ( C T ) at S cr e e ni n g  a n d   D a y  2 8 ( ± 4  d a ys)  of   C y cl e  6  a n d  at t h e 
E  O T v isit, i n t h e  c as es   w h er e  a  p ati e nt is   wit h dr a  w n fr o  m tr e at  m e nt  b ef or e t h e  e n d  of   C y cl e  6 f or 
r e as o ns  ot h er t h a n  pr o gr essi v e  dis e as e. 
 
T h e   C T  p orti o n  of  a  c o  m bi n e d [ 1 8F]fl u or o d e o x y gl u c os e ( F  D  G )-P E T/  C T s c a n s h o ul d  b e 
p erf or  m e d   wit h  c o ntr ast  a n d  c oll e ct e d   wit h r es ol uti o n s uffi ci e nt t o  all o  w  a c c ur at e  a n d  c o nsist e nt 
c o  m p aris o n  of t ar g et l esi o n   m e as ur e  m e nts   wit h s u bs e q u e nt   C T s c a ns.  
 
T u  m o ur   m e as ur e  m e nts  a n d  dis e as e r es p o ns e  ass ess  m e nt  will als o  b e  p erf or  m e d  as i n di c at e d i n 
T a bl e   5 b y   C T  wit h  c o ntr ast . 
 
M a g n eti c r es o n a n c e i  m a gi n g (  M  RI)   m a y  b e  us e d i n li e u  of   C T,  a n d P E T/  M  RI i n li e u  of  P E T/  C T 
f or  p ati e nts   wit h  c o ntr ai n di c ati o ns t o t h e  a d  mi nistr ati o n  of  c o ntr ast  a g e nts,  or  d u e t o  ot h er 
m e di c al r e as o ns,  at t h e s a  m e ti  m e  p oi nts  as   C T,  or i n  a d diti o n t o   C T,  at t h e  dis cr eti o n  of t h e 
i n v esti g at or (i n t his  c as e,   M  RI   m a y  b e  p erf or  m e d  as/  w h e n  a p pr o pri ate).  T h e   m et h o d  us e d  at 
b as eli n e s h o ul d  b e  us e d t hr o u g h o ut t h e st u d y  u nl ess  ot h er  wis e   m e di c all y i n di c at e d. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 8 2  of 1 3 1  
If a vaila ble a n d of  acce pta ble q ualit y  (e. g., CT  p orti o n of P E T/ C T sca n  was perfor me d  wit h  
c o ntrast) , pre vi o usl y perf or me d PE T/ C T  exa mi nati o ns,  i n acc or da nce w it h t he sta n dar d of care, 
t hat w ere d o ne u p t o 4  wee ks pr i or t o Scree ni n g ma y  be use d for  a patie nt’s baseli ne  ce ntral  
ra di ol o g y assess me nt. A d diti o nal P E T/ C T  or C T/ M RI exa mi nati o ns ma y be pe rf or med b y t he 
i n vesti gat or d uri n g t h e co ur se of the st u d y, if d ee me d necessar y (e. g., t o c o nfir m the o cc urre nce 
of  a C R or  di sease pr o gressi o n or t o ma ke  i m p orta nt treat me nt-relate d decisi o ns).   
If t he p atie nt di sc o nti n ues fr o m treat me nt, a PE T/ C T  sca n  is o nl y  req uire d  at t he E O T  vi sit if 
s uc h sca n was n ot pe rf or me d in t he cycle pr i or t o the en d of treat me nt. C T m a y be pe rf or med i n 
lie u o f P E T/ C T if t he pa tie nt disc o nti n ues fr om treat me nt wit hi n  Cycle  1. 
T he sa me sca n  mo dalit y  s h o ul d be use d for  all assess me nts, a nd  all patie nts are re q uire d  t o have  
sca ns of the ne c k/c hest/a b d o me n/ pel vis. 
If it is i m p ossi ble f or t he patie nt t o  have  t heir P E T exa mi nati o n  i n faste d state, ade q uate  
pr oce d ures sh o ul d be in place t o meas ure an d c o ntr ol b l o o d gl uc ose le vel. 
I n a d diti o n t o t he Inter nati o nal W or ki n g Gr o u p 2 0 0 7 ( C hes o n et al. 2 0 0 7) e val uati o n 
c o m p o ne nts,  radi ol o gists  f ulfilli n g t he r oles of ce ntral re vie wers will rec ord  t he classificati o n of 
P E T/ C T  sca ns acc or di n g to  the 5 -p oi nt scale  q ualitati ve rati n g an d  meas ure me nt of t he  vertical 
le n gt h of the splee n. T hese as pects of the L u ga n o  Classificati o n ( C hes o n et al. 2 0 1 4) are n ot a 
dir ect c o m p o ne nt of  t he I nter nati o nal W or ki n g Gr o u p 2 0 0 7 re vie w an d are inte n de d as 
s u p ple me ntal i nf or mati o n o nly.  
1 0. 3. 9  B o ne M arr o w  
At t he Scree ni n g visit, a u ni- or  bilateral b o ne marr o w bio ps y a n d a s pirate s h o ul d be o btai ne d t o 
assess b o ne marr o w i n v ol ve me nt. Res ults fr o m a b o ne marr o w e xa mi nati o n d o ne u p t o 4 w ee ks 
pri or t o Scree ni n g a re acce pta ble pro vi de d t he patie nt’s disease has bee n sta ble si nce t he n . 
T he ac hie ve me nt  of C R  in  the c o urse  of M O R 2 0 8 C 2 0 4 st u d y m ust be c o nfir me d l ocall y, b y 
cli nical a n d ra di ol o gic eval uati o n al o n g wit h b o ne m arr o w co nfir mati o n.  The latter  a p plies o n l y 
i n case t he b o ne m arr o w w as in v ol ve d b y l y m p h o ma be f ore the ra n d o misati o n. If b o ne m arr o w 
was n ot in v ol ve d b y l y m p h o ma be f ore co m me nci n g t he st u d y treat me nt, t he n b o ne m arr o w 
c o nfir mati o n bi o ps y a n d as piratio n is n ot re q uire d. T he re peate d b o ne m arr o w exa mi nati o n is 
als o  n ot  re q uire d f or patie nts i n wh o m b o ne  ma rr o w ha s alrea d y bee n cleare d of  t he i nfiltrate at 
pre vi o us eval uati o n, i.e . t heir pr e vi o us b o ne m arr o w res p o nse was C R.  
Hist o l o gical exa mi nati o n  of t he bo ne  marr o w bi o ps y a n d as pirate s h o ul d be perf or me d l ocall y 
at t he pr ot o c ol s pecifie d time  p oi nts  (see Ta ble  5 ). 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 3  of 1 3 1  
1 1  S  A F  E  T  Y   M  O  NI  T  O  RI  N  G  
T h e  p ati e nts   will  b e  cl os el y  o bs er v e d  a n d  q u esti o n e d f or  a n y  ki n d  of   A E  d uri n g t h e st u d y 
pr o c e d ur es  a n d  at f oll o  w -u p  a p p oi nt  m e nts t hr o u g h o ut t h e st u d y  p eri o d   wit h  n o n -l e a di n g 
q u esti o ni n g ( e. g. , “  H o  w  d o  y o u f e el ? ”).   A Es  als o   m a y  b e  d et e ct e d   w h e n t h e y  ar e  v ol u nt e er e d  b y 
t h e  p ati e nt  d uri n g  or  b et  w e e n st u d y  visits  or t hr o u g h  p h ysi c al  e x a  mi n ati o n, l a b or at or y t ests,  or 
ot h er  ass ess  m e nts.  
 
St u d y  p ers o n n el   m ust r e  m ai n  vi gil a nt f or t h e  o c c urr e n c e  of   A Es,  p arti c ul arl y t h os e t h at   m a y  b e 
lif e-t hr e at e ni n g.  P ers o n n el   w h o  ar e tr ai n e d i n t h e  a c ut e   m a n a g e  m e nt  of I  R  Rs,  c yt o ki n e r el e as e 
s y n dr o  m e,  a n a p h yl a xis,  a n d  ot h er  e  m er g e n ci es,  a n d   w h o  h a v e  a c c ess t o  a p pr o pri at e  cli ni c al 
s u p pli es, s h o ul d  b e r e a dil y  a v ail a bl e. 
 
All   A Es s h o ul d  b e tr e at e d  a p pr o pri at el y.  S u c h tr e at  m e nt   m a y i n cl u d e  c h a n g es i n st u d y  dr u g 
tr e at  m e nt i n cl u di n g  p ossi bl e i nt err u pti o n  or  dis c o nti n u ati o n, st arti n g  or st o p pi n g  c o n c o  mit a nt 
tr e at  m e nts,  c h a n g es i n t h e fr e q u e n c y  or  n at ur e  of  ass ess  m e nts,  h os pit alis ati o n,  or  a n y  ot h er 
m e di c all y r e q uir e d i nt er v e nti o n.   O n c e  a n   A E is  d et e ct e d, it s h o ul d  b e f oll o  w e d  u p,  a n d  a n 
ass ess  m e nt s h o ul d  b e   m a d e  at  e a c h  visit ( or   m or e fr e q u e ntl y, if  n e c ess ar y)  of  a n y  c h a n g es i n its 
s e v erit y, its s eri o us n ess, its s us p e ct e d r el ati o ns hi p t o t h e st u d y  dr u g(s),  a n y  of t h e i nt er v e nti o ns 
r e q uir e d t o tr e at it,  a n d its  o ut c o  m e.  
 
1 1. 1  D efi niti o n  of   A d v e rs e   E v e nts,  S e ri o us   A d v e rs e  E v e nts,  A d v e rs e  E v e nts  of  
S p e ci a l Int e r est  
A n   A E is  d efi n e d  as  a n y  u nt o  w ar d   m e di c al  o c c urr e n c e i n  a  p ati e nt  a d  mi ni st er e d  a   m e di ci n al 
pr o d u ct,   w hi c h  d o es  n ot  n e c ess aril y  h a v e  a  c a us al r el ati o ns hi p t o t his tr e at  m e nt.  
 
A n   A E  c a n t h er ef or e  b e  a n y  u nf a v o ur a bl e  a n d  u ni nt e n d e d si g n (i n cl u di n g  a n  a b n or  m al l a b or at or y 
fi n di n g), s y  m pt o  m,  or  dis e as e t e  m p or all y  ass o ci at e d   wit h t h e us e  of  a st u d y  dr u g,   w h et h er  or  n ot 
it is  c o nsi d er e d r el at e d t o t h at st u d y  dr u g. 
 
A Es i n cl u d e  a n y  cli ni c all y si g nifi c a nt  d et eri or ati o n  of  a  p ati e nt’s   m e di c al st at us  aft er t h e si g ni n g 
of t h e I  C F.   Als o,  a n i n cr e as e i n t h e fr e q u e n c y  or i nt e nsit y  of  a  pr e -e xisti n g  e pis o di c  e v e nt  or 
c o n diti o ns  a n d  e v e nts r es ulti n g fr o  m  pr ot o c ol   m a n d at e d  pr o c e d ur es ( e. g. i n v asi v e  pr o c e d ur es) 
f all  u n d er t h e  d efi niti o n  of   A Es. I n  a d diti o n,  o v er d os es ( d efi n e d  as  e x c e e di n g t h e  pl a n n e d  d os e 
b y > 2 0 %) s h o ul d  b e r e c or d e d  as   A Es.  
 
As f ar  as  p ossi bl e,  e a c h   A E s h o ul d  b e  e v al u at e d t o  d et er  mi n e t h e f oll o  wi n g:  
•  R el ati o ns hi p t o t h e st u d y  dr u g (s us p e ct e d/ n ot s us p e ct e d)  
•  D ur ati o n (st art  a n d  e n d  d at e , or if  c o nti n ui n g  at  e n d  of st u d y)  
•  Int e nsit y: t h e i nt e nsit y  of  all   A Es   will  b e  gr a d e d  as   mil d,   m o d er at e,  or s e v er e  usi n g t h e 
f oll o  wi n g  d efi niti o ns: 
o  mil d:  
 t ol er a bl e 
o  m o d er at e:  
i nt erf er es   wit h  n or  m al  a cti vit y 
o  s e v er e:  
 i n c a p a cit ati n g ( c a us es i n a bilit y t o  p erf or  m  us u al  a cti viti es  or w or k)  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 4  of 1 3 1  
•  S e v erit y i. e. t o xi cit y  gr a d e:  d et er  mi n e d  a c c or di n g t o t h e   N  CI-C T  C  A E  v ersi o n  4. 0  of 
M a y  2 8,  2 0 0 9,  usi n g t h e f oll o  wi n g  d efi niti o ns:  
o  gr a d e  1:   mil d;  as y  m pt o  m ati c  or   mil d s y  m pt o  ms;  cli ni c al  or  di a g n osti c  
 
 o bs er v ati o ns  o nl y; i nt er v e nti o n  n ot i n di c at e d  
o  gr a d e  2:  m o d er at e;   mi ni  m al, l o c al  or n o n -i n v asi v e i nt er v e nti o n i n di c ate d;   
 li  miti n g  a g e-a p pr o pri at e i nstr u  m e nt al  a cti viti es  of  d ail y li vi n g  
 
 (r ef ers t o  pr e p ari n g   m e als, s h o p pi n g f or  gr o c eri es  or  cl ot h es,  
 
 usi n g t h e t el e p h o n e,   m a n a gi n g   m o n e y,  et c.)  
gr a d e  3:  s e v er e  or   m e di c all y si g nifi c a nt  b ut  n ot i  m  m e di at el y lif e-t hr e ate ni n g; 
h os pit alis ati o n  or  pr ol o n g ati o n  of  h os pit alis ati o n i n di c at e d;  dis a bli n g; li  miti n g 
s elf-c ar e  a cti viti es  of  d ail y li vi n g  
o  gr a d e  4:  lif e-t hr e at e ni n g  c o ns e q u e n c es;  ur g e nt i nt er v e nti o n i n di c at e d 
o  gr a d e  5:  d e at h r el at e d t o   A E  
•  O ut c o  m e  
•  A cti o n t a k e n ( n o  a cti o n t a k e n; st u d y  dr u g t e  m p or aril y i nt err u pt e d; st u d y  dr u g 
p er  m a n e ntl y  dis c o nti n u e d  d u e t o t his   A E;  c o n c o  mit a nt   m e di c ati o n t a k e n;  n o n -dr u g 
t h er a p y  gi v e n;  h os pit alis ati o n/ pr ol o n g e d  h os pit alis ati o n) 
•  S eri o us n ess:   w h et h er it is s eri o us,   w h er e  a  S  A E is  d efi n e d  as o n e t h at:  
o  r es ults i n  d e at h 
o  is lif e-t hr e at e ni n g 
o  r e q uir es i n-p ati e nt  h os pit alis ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit alis ati o n 
( h os pit alis ati o n si g nifi es t h at t h e  p ati e nt   w as  a n i n-p ati e nt f or  at l e ast  o n e 
o v er ni g ht st a y)  u nl ess  h os pit alis ati o n is f or:  
 r o uti n e tr e at  m e nt  or   m o nit ori n g  of t h e st u di e d i n di c ati o n,  n ot  ass o ci at e d   wit h 
d et eri or ati o n  of s y  m pt o  ms r el at e d t o   N  H L  
 el e cti v e  or  pr e -pl a n n e d tr e at  m e nt f or  a  pr e -e xisti n g  c o n diti o n t h at is  u nr el at e d 
t o   N  H L  a n d  h as  n ot   w ors e n e d si n c e si g ni n g  of t h e i nf or  me d  c o ns e nt 
 s o ci al r e as o n  a n d r es pit e  c ar e i n t h e  a bs e n c e  of  a n y  d et eri or ati o n i n t h e 
p ati e nt’s  g e n er al  c o n diti o n  
o  r es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y  or i n c a p a cit y 
o  is  a  c o n g e nit al  a n o  m al y  or  birt h  d ef e ct 
o  is   m e di c all y si g nifi c a nt, i. e.  d efi n e d  as a n  e v e nt t h at j e o p ar dis es t h e  p ati e nt  or   m a y 
r e q uir e   m e di c al i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  o ut c o  m es list e d  pr e vi o usl y. 
 
T h e t er  m  “lif e -t hr e at e ni n g ” r ef ers t o  a n  e v e nt i n   w hi c h t h e  p ati e nt   w as, i n t h e  vi e  w  of t h e 
r e p orti n g i n v esti g at or,  at i  m  m e di at e ris k  of  d e at h  at t h e ti  m e  of t h e  e v e nt; it  d o es  n ot r ef er t o  a n 
e v e nt t h at  h y p ot h eti c all y   mi g ht  h a v e  c a us e d  d e at h if it   w er e   m or e s e v er e.   M e di c al j u d g  m e nt 
s h o ul d  b e  e x er cis e d i n  d e ci di n g   w h et h er  a n   A E is s eri o us i n  ot h er sit u ati o ns: i  m p ort a nt   A Es t h at 
ar e  not i  m  m e di at el y lif e -t hr e at e ni n g  or  d o  n ot r es ult i n  d e at h  or  h os pit alis ati o n  b ut   m a y 
j e o p ar dis e t h e  p ati e nt  or   m a y r e q uir e i nt er v e nti o n t o  pr e v e nt  o n e  of t h e  ot h er  o ut c o  m es list e d i n 
t h e  pr e vi o us  d efi niti o ns s h o ul d  als o  b e  c o nsi d er e d  as s eri o us. 
 
A E SI s ar e T L S,  S P  M, I  R  Rs  a n d all er gi c r e a cti o ns t o st u d y  dr u g  ≥ gr a d e  3 ,  c yt o ki n e r el e as e 
s y n dr o  m e  a n d  o v er d os es. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 8 5  of 1 3 1  
U nli ke r o uti ne safet y  assess me nts,  SA Es a n d  A E SI s are m o nit ore d c o nti n u o usl y a n d ha ve s pecial 
re p orti n g re q uire me nts (see Secti o n  1 1. 2 ). 
T he  i n vesti gat or sh o ul d  de ter mi ne t he ca usalit y  (relati o nshi p t o t he stu d y dr u g) ba sed o n his/ her 
cli nica l e x perie nce  an d  o n  t he i nf or mati o n gi ve n in  t he I B. T he  ca usal relati o ns hi p  of all A Es t o 
t he st u d y d r u g will be j u d ge d as eit her  s uspecte d  or n ot s us pecte d.  A s uspecte d  ca usal  
relati o ns hi p  mea ns  at least a reas o na ble p os si bilit y t hat the eve nt is ca use d b y t he st u d y dr u g. If 
n o relati o ns hi p has be e n pr o vi de d b y the in vesti gat or , t he eve nt w ill b e co nsi dere d as relate d t o 
t he st u d y dr u g. 
I nf or matio n a b o ut ad verse dr u g reacti o ns alread y k n o w n a b o ut the i n vesti gati o nal st u d y dr u g ca n 
be fo u n d i n t he IB (M O R 0 0 2 0 8), S m P C an d/ or P rescri bin g I nf or matio n ( B E N, R T X), or will be  
c o m m u nicate d  i n t he f or m of I n vesti gat or N otificati o ns. This  i nfor mati o n  will be i ncl u de d i n t he 
patie nt IC F a n d s h o ul d be di sc ussed wit h t he pa tie nt d ur i n g t he st u d y, as n ee de d. 
1 1 . 2 A d ver se E v e nt a n d Seri o us A d vers e E ve nt Rec or di n g  an d Re p orti n g  
All  AEs (e xce pt  n o n-seri o us A Es  f or scree ni n g  fail ures) t hat occ ur after t he pr o visi o n of 
i nf or me d c o nse nt an d u p to 3 0 da ys after last dr u g ad mi nistrati o n  will be rec or de d i n t he eC R F  
a n d i n t he p atie nt’s me dical rec or ds, w het her or n ot the y are c o nsi dere d b y t he in vesti gat or t o be 
relate d to t he st u d y dr u g. T hereafter, o nl y S A Es / A E SIs assesse d  as relate d  t o a n y st u d y dr u g 
s h o ul d be rec or de d. All A Es sh o ul d be rec or de d usi n g acce pta ble di a g n oses, if p os si ble. F or 
scree ni n g fail ure pa tie nts, n o n-seri o us A Es w ill n ot be rec or de d i n t he e C R F b ut o nl y i n t he 
patie nt’s  medical rec or ds.   
I n a d diti o n, all S A Es an d A E SI s will be rec or de d o n t he S A E re p ort f or m. St u d y ce ntres a n d 
i n vesti gat ors are i nstr ucte d t o re p ort all S A Es a n d A ESI s t o t he s p o ns or ( or desi g nee) w it hi n 
2 4 h o urs, usi n g t he st u d y- s pecific S A E re p ort f or m. 
Ge nerall y, t he di a g n osis instea d of the in di vi d ual sy m pt o ms s h o ul d be re p orte d as t he eve nt ter m. 
If a di a g n osis ha s be e n re p orte d as an A E, it is n ot ne cessar y to re p ort eac h i n di vi d ual si g n a n d 
s y m pt o m of  t hat AE  as a  se parate A E. For  e xam ple,  if a fe brile ne utr o pe nia is re p orte d as a n  AE,  
t here is n o nee d t o re p ort ne utr o p hil co u nt de crease an d f e ver ab o ve 3 8° C , or ot her relate d si g ns, 
s y m pt o ms, or la b orat or y val ues as se parate A Es. H o we ver, if s uc h e ve nts occ ur in is olati o n, a n d 
fe brile ne utr o pe nia is n ot di a g n ose d, t he n eac h e ve nt sh o ul d be re p orte d as an A E. 
I RR s a n d aller gic reacti o ns to st u d y dr u gs gr a de 3 or hi g her, o r c yto ki ne release s y n dr o me,  
w hic h  are A ESI s in t his st u d y, s h o ul d be re p orte d as di a g n osis al o n g wit h t heir res pecti ve 
s y m pt o ms i n o ne eve nt  ter m  (e. g., ‘I R R w it h sy m pt o ms  of hi ves, c hills a n d fe ver’ f or IR R s). F or 
o ver d oses , t he di a g n osis an d if ap plica ble t he acc o m pa n yi n g sy m pt o ms ca use d b y t he o ve r d ose 
s h o ul d be re p orte d. 
All n o n- seri o us A Es m ust be foll o we d u p f or a fi nal o u tc o me. A n o utc o me of “u n k n o w n” is n ot 
c o nsi dere d t o be an acce pta ble fi nal o utc o me. A n o utc o me o f “n ot ye t res ol ve d” is an acce pta ble 
fi nal o ut c o me for n o n- seri o us A Es at t he e n d of a patie nt’s partici pa ti o n in t he st u d y. All S A Es 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 6  of 1 3 1  
m ust  b e f oll o  w e d  u p f or  a fi n al  o ut c o  m e  u ntil r es ol uti o n  or, if r es ol uti o n  b e c o  m es  u nli k el y,  u ntil 
st a bilis ati o n  or  d e at h.  
 
E v e nts t h at  ar e  cl e arl y  c a us e d  b y  pr o gr essi o n  of t h e  u n d erl yi n g  dis e as e ( e. g. tr a nsf or  m ati o n t o 
m or e  a g gr essi v e t u  m ou r hist ol o g y or   B -s y  m pt o  ms) s h o ul d  n ot  b e r e c or d e d  as   A Es  or  S  A Es. 
T h es e  d at a   will  b e  c a pt ur e d  as  effi c a c y  ass ess  m e nt  d at a  o nl y. If t h er e is  a n y  u n c ert ai nt y  as t o 
w h et h er  a n  e v e nt is  d u e t o  dis e as e  pr o gr essi o n, it s h o ul d  b e r e c or d e d  as  a n   A E or  S  A E . 
 
D e at hs t h at  o c c ur  d uri n g t h e  pr ot o c ol-s p e cifi e d  a d v ers e  e v e nt r e p orti n g  p eri o d t h at  ar e cl e arl y 
attri b ut e d t o  pr o gr essi o n  of t h e  u n d erl yi n g  dis e as e s h o ul d  n ot  b e r e c or d e d  as  S  A Es.   All  ot h er 
o n-st u d y  d e at hs, r e g ar dl ess  of r el ati o ns hi p t o st u d y  dr u g,   m ust  b e r e c or d e d  o n t h e   A d v ers e  E v e nt 
e  C  R F  a n d i  m  m e di at el y r e p ort e d  o n t h e  S  A E r e p ort f or  m t o t h e  S p o ns or.   D e at h s h o ul d  b e 
c o nsi d er e d  a n  o ut c o  m e  a n d  n ot  a  disti n ct  e v e nt.  T h e  e v e nt  or  c o n diti o n t h at  c a us e d t h e f at al 
o ut c o  m e s h o ul d  b e r e c or d e d  as t h e si n g l e   m e di c al  c o n c e pt  o n t h e   A d v ers e  E v e nt  e  C  R F. 
G e n er all y,  o nl y  o n e s u c h  e v e nt s h o ul d  b e r e p ort e d. 
 
D uri n g  F oll o  w- U p  f or   O v er all  S ur vi v al, t h e f oll o  wi n g s h o ul d  b e r e p ort e d: 
•  D e at hs  attri b ut e d t o  pr o gr essi o n  of t h e  u n d erl yi n g  dis e as e s h o ul d  b e r e p ort e d  vi a t h e 
e  C  R F . 
•  S  A Es/  A E SIs  t h e i n v esti g at or  b e c o  m es  a  w ar e  of  a n d  c o nsi d ers t o  b e r el at e d t o  a n y st u d y 
dr u g s h o ul d  b e r e p ort e d i n t h e  e  C  R F  a n d o n t h e  S  A E r e p ort f or  m vi a f a x t o t h e   C  R  O (s e e 
b el o  w). 
 
N otifi c ati o n  of i niti al  or f oll o  w - u p  S  A E/  A E SI i nf or  m ati o n ( b y  usi n g t h e st a n d ar d  S  A E f or  m 
pr o vi d e d  b y t h e s p o ns or)   m ust  b e s e nt  b y e  m ail  or f a x t o t h e s p o ns or ( or  d esi g n e e).  
 
1 1. 3  P r e g n a n ci es  
As  d et ail e d i n t h e  S c h e d ul e  of   Ass ess  m e nts (T a bl e   5) a n d  S e cti o n  1 0. 3. 7. 3 , s er u  m  pr e g n a n c y 
t esti n g   will  b e  c arri e d  o ut  at t h e  S cr e e ni n g  a n d E  O T  v isits.   D uri n g t h e tr e at  m e nt  p eri o d  of t h e 
st u d y,  uri n e  pr e g n a n c y t esti n g   will  b e  p erf or  m e d l o c all y  a n d  c a n  b e r e p e at e d if r e q uir e d.   A n y 
pr e g n a n c y t h at  o c c urs  d uri n g st u d y  p arti ci p ati o n ( aft er si g n at ur e  of t h e i nf or  m e d  c o ns e nt f or  m 
u ntil 3,  6  or  1 2   m o nt hs aft er l ast  d os e  of M  O  R 0 0 2 0 8,   B E  N  or   R T  X r es p e cti v el y,   w hi c h e v er is 
l at er) s h o ul d  b e r e p ort e d  usi n g  a   Cli ni c al  Tri al  Pr e g n a n c y  F or  m. Li k e  wis e, if  a f e  m al e s e x u al 
p art n er  of a p ati e nt  p arti ci p ati n g i n t his tri al b e c o  m es  pr e g n a nt   wit hi n  3,  6  or  1 2   m o nt hs  aft er l ast 
d os e  of   M  O  R 0 0 2 0 8,   B E  N  or   R T  X r es p e cti v el y,   w hi c h e v er is l at er, t his  pr e g n a n c y s h o ul d  b e 
r e p ort e d. (A p pli c a bl e i n   R e p u bli c  of   K o r e a : a n y  pr e g n a n c y t h at  o c c urs  d uri n g st u d y 
p arti ci p ati o n ( aft er si g n at ur e  of t h e i nf or  m e d  c o ns e nt f or  m  u ntil  6   m o nt hs  aft er l ast  d os e  of 
M  O  R 0 0 2 0 8, 6   m o nt hs  aft er t h e l ast  d os e  of   B E  N  or  1 2   m o nt hs  aft er t h e l ast  d os e  of R T  X) s h o ul d 
b e r e p ort e d  usi n g  a   Cli ni c al  Tri al  Pr e g n a n c y  F or  m.  Li k e  wis e, if  a f e  m al e s e x u al  p art n er  of  a 
p ati e nt  p arti ci p ati n g i n t his tri al  b e c o  m es  pr e g n a nt   wit hi n  6   m o nt hs  aft er l ast  d os e  of 
M  O  R 0 0 2 0 8,  6   m o nt hs  aft er t h e l ast  d os e  of B E  N  or  1 2   m o nt hs  aft er t h e l a st  d os e  of   R T  X, t his 
pr e g n a n c y s h o ul d  b e r e p ort e d.) 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 7  of 1 3 1  
T o  e ns ur e  p ati e nt s af et y,  e a c h  pr e g n a n c y  of  a st u d y  p ati e nt  or  a f e  m al e s e x u al p art n er  of  a st u d y 
p ati e nt   m ust  als o  b e r e p ort e d   wit hi n  2 4  h o urs  of l e ar ni n g  of its  o c c urr e n c e  b y e  m ail  or f a x t o 
s p o ns or ( or d esi g n e e).  
 
S t u d y  p ati e nts   w h o  b e c o  m e  pr e g n a nt   m ust  b e   wit h dr a  w n fr o  m t h e st u d y tr e at  m e nt. A   m al e 
p ati e nt   w h os e  s e x u al p art n er  b e c o  m es  pr e g n a nt   m a y  c o nti n u e st u d y  p arti ci p ati o n.  
 
A  n e  wl y  di a g n os e d  pr e g n a n c y i n  a  p ati e nt  or f e  m al e s e x u al p art n er  of  a st u d y  p ati e nt   w h o  h as 
r e c ei v e d st u d y   m e di c ati o n is  n ot  c o nsi d er e d  an  S  A E  u nl ess it   m e ets  a n y  crit eri a  of s eri o us n ess  or 
it is s us p e ct e d t h at t h e st u d y   m e di c ati o n i nt er a ct e d   wit h  a  c o ntr a c e pti v e   m et h o d  a n d l e d t o 
pr e g n a n c y.  
 
If t h e  pr e g n a n c y r es ults i n cli ni c al  c o ns e q u e n c es/ c o  m pli c ati o ns i n   m ot h er  or  c hil d,  e. g. if t h e 
c hil d is  b or n   wit h  a  birt h  d ef e ct, t his s h o ul d  b e r e p ort e d  as  a n  S  A E  of   m ot h er  or  c hil d  as 
a p pli c a bl e. 
 
T h e  pr e g n a n c y s h o ul d  b e f oll o  w e d  u p t o  d et er  mi n e  o ut c o  m e, i n cl u di n g s p o nt a n e o us  or  v ol u nt ar y 
t er  mi n ati o n,  d et ails  of  birt h,  a n d t h e  pr es e n c e  or  a bs e n c e  of  a n y  birt h  d ef e cts  or  c o n g e nit al 
a b n or  m aliti es  or   m at er n al  a n d  n e  w b or n  c o  m pli c ati o ns.  E v er y i nf a nt  h as t o  b e f oll o  w e d  u p f or 
2  m o nt hs  aft er  d eli v er y.  
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 8 8  of 1 3 1  
1 2  D  A  T  A   H  A  N  D  LI  N  G   A  N  D   A  R  C  HI  VI  N  G  
1 2. 1  C o  m pl e ti n g  a n d  Si g ni n g   C as e   R e p o rt  F o r  ms 
A n  e  C  R F  will  b e  us e d i n t his st u d y. T h e i n v esti g at or will  b e r es p o nsi bl e f or  a c c ur at e  a n d ti  m el y 
d at a  e ntr y a n d  d at a  cl arifi c ati o ns i n t h e  e  C  R F.   D at a  e ntr y   m a y  b e  d el e g at e d t o  a d e q u at el y tr ai n e d 
sit e  p ers o n n el. A n y  err ors s h o ul d  b e  c orr e ct e d   wit hi n t h e  el e ctr o ni c s yst e  m. I n t h e c as e  of 
missi n g  d at a,  a r e as o n s h o ul d  b e  gi v e n. T h e  a u dit tr ail   will r e c or d  all  c h a n g es   m a d e, t h e  d at e  a n d 
ti  m e  of t h e  c orr e cti o n,  a n d t h e  p ers o n  c orr e cti n g t h e  err or.  T h e  a p pr o pri at e  el e ctr o ni c si g n at ur e 
will  b e  pr o vi d e d.  T h e i n v esti g at or   will r e c ei v e  a  c o p y  of t h eir  e  C  R F i n  a r e a d a bl e f or  m at  aft er 
d at a b as e l o c k f or  ar c hi vi n g.  
 
1 2. 2  Cli ni c al   D at a   M a n a g e  m e nt  
T h e   C  R  O   will  b e r es p o nsi bl e f or t h e  pr o c essi n g  a n d  q u alit y  c o nt r ol  of t h e  d at a  a c c or di n g t o t h e 
C  R  O’s st a n d ar d  o p er ati n g  pr o c e d ur es ( S  O Ps).   D at a   m a n a g e  m e nt   will  b e  c arri e d  o ut  b y t h e C  R  O. 
T h e  h a n dli n g  of  d at a, i n cl u di n g  d at a  q u alit y  c o ntr ol,   will  c o  m pl y   wit h  all  a p pli c a bl e r e g ul at or y 
g ui d eli n es.  
 
D et ails f or  d at a  v ali d ati o n  a n d  e dit  c h e c ks   will  b e  d es cri b e d i n  a p pr o pri at e  d at a   m a n a g e  m e nt 
d o c u  m e nts.   Q u eri es   will  b e  h a n dl e d  vi a t h e  e  C  R F s yst e  m.   D at a  cl e a ni n g   will  c o nti n u e  u ntil  all 
q u eri es  ar e r es ol v e d.  
 
M e di c al  c o di n g   will  us e   M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti e s (  M e d  D  R  A),   V ersi o n  1 8.1 
(or  hi g h er ) f or   A Es  a n d   m e di c al  hist or y  a n d t h e   W  H  O D r u g D i cti o n ar y E n h a n c e d f or 
m e di c ati o n.  
 
1 2. 3  A r c hi vi n g  a n d  Fili n g  
All st u d y  d o c u  m e nt ati o n  at t h e i n v esti g at or sit e  a n d s p o ns or sit e   will  b e  ar c hi v e d i n  a c c or d a n c e 
wit h I nt er n ati o n al C o nf er e n c e  o n   H ar  m o nis ati o n (I  C  H)  E 6   G o o d   Cli ni c al  Pr a cti c e (  G  C P) 
g ui d a n c e  a n d t h e  cli ni c al tri al  a gr e e  m e nt.  
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 8 9  of 1 3 1  
1 3  S  T  A  TI S  TI  C  A  L   M  E  T  H  O  D S   A  N  D  P  L  A  N  N  E  D   A  N  A  L  Y S E S 
T h e  d at a   will  b e a n al ys e d   b y t h e s p o ns or a n d/ or  d esi g n e e.   A n y  d at a  a n al ysis  c arri e d  o ut 
i n d e p e n d e ntl y  b y t h e i n v esti g at or s h o ul d  b e s u b  mitt e d t o I n c yt e   C or p or ati o n  b ef or e  p u bli c ati o n 
or  pr es e nt ati o n. 
It is  pl a n n e d t h at t h e  d at a fr o  m  p arti ci p ati n g c e ntr es  i n t his  pr ot o c ol   will  b e  c o  m bi n e d, s o t h at  a n 
a d e q u at e  n u  m b er  of  p ati e nts   will  b e  a v ail a bl e f or  a n al ysis . 
T h e f oll o  wi n g  a n al ys es  ar e  pl a n n e d: 
•
I nteri m A n al ysis: pla n ne d t o ta ke place after a p pr o xi matel y 1 2 8 P F S e ve nts ( base d o n  
I R C assess me nt) ha ve bee n o bser ve d i n t he o verall p o p ulati o n ( F A S) .
Fi n a l A n al ysis: pla n ne d t o ta ke place at t he e n d of t he st u d y (f or defi niti o n see      
Secti o n  8. 4 ), i n de pe n de nt of h o w ma n y I R C P F S  e ve nts ha v e bee n  obser ve d  at that  poi nt  
i n time.  All e n d p oi nts as descri be d i n Secti o n  7 w ill b e a nal yze d .
A d diti o n al s af et y  a n al ys es   m a y  b e  p erf or  m e d t o s u p p ort i nt er a cti o ns   wit h r e g ul at or y  a ut h oriti es.  
1 3. 1  P o p ul ati o ns f o r   A n al ysis  
T a bl e   7 d et ails t h e  d efi n e d  a n al ysis  s ets. 
T a bl e   7: 
A n al ysis  S ets  
A n al ysis s et  
D es c ri pti o n  
F ull  a n al ysis s et ( F  A S)  
All  p ati e nts   w h o   w er e r a n d o  mis e d t o  eit h er tr e at  m e nt  ar  m.  
A n al ys es  usi n g t h e  F  A S   will  b e  b as e d  u p o n t h e tr e at  m e nt 
t o   w hi c h  e a c h  p ati e nt   w as r a n d o  mis e d. 
P er -pr ot o c ol s et ( P P S)  
All  p ati e nts i n t h e  F  A S,  h a vi n g  at l e ast  o n e  d os e  of 
M  O  R 0 0 2 0 8  or   R T  X,  a n d   B E  N.  
P ati e nts   wit h o ut  a n y  p ost -b as eli n e  ass ess  m e nt  of   D L  B  C L 
r es p o ns e  or   wit h s p e cifi c  k e y pr ot o c ol  d e vi ati o ns   will  b e 
e x cl u d e d fr o  m t h e  P P S.  
S af et y  a n al ysis s et ( S  A F)  
All  p ati e nts   w h o r e c ei v e d  at l e ast  o n e  d os e  of   M  O  R 0 0 2 0 8 
or   R T  X  or   B E  N.  
A n al ys es  usi n g t h e  S  A F   will  b e  b as e d  o n t h e a ct u al 
tr e at  m e nt r e c ei v e d. 
P  K  a n al ysis s et ( P  K  A S)  
T h e P  K   po p ul ati o n   will i n cl u d e  all  p ati e nts   w h o  h a v e  at 
l e ast  o n e  q u a ntifi a bl e s er u  m   M  O  R 0 0 2 0 8  c o n c e ntr ati o n 
( P  K  p ar a  m et ers   will  b e  c al c ul at e d  as  d at a  p er  mit.) 
I  m  m u n o g e ni cit y  a n al ysis s et (I  A S) 
All  p ati e nts   w h o  w er e r a n d o  mis e d  a n d h a v e  at l e ast  o n e 
a nti-M  O  R 0 0 2 0 8  a nti b o d y  ass ess  m e nt.  
A b br e vi ati o ns:   B E  N   = b e n d a  m usti n e;  P  K   = p h ar  m a c o ki n eti cs;   R T  X   = rit u xi  m a b. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 0  of 1 3 1  
1 3. 2  G e n e r al  St atisti c al   M et h o ds  
T a b ul ati o ns  of s u  m  m ar y st atisti cs,  gr a p hi c al  pr es e nt ati o ns,  a n d st atisti c al  a n al ys es   will  b e 
p erf or  m e d  usi n g  S  A S ®  s oft  w ar e  v ersi o n  9. 3  or  hi g h er. 
 
C o nti n u o us,  q u a ntit ati v e  v ari a bl e s u  m  m ari es   will i n cl u d e t h e  n u  m b er  of  p ati e nts (  N) (  wit h 
n o n -missi n g  v al u es/ v ali d  c as es),   m e a n, st a n d ar d  d e vi ati o n,   mi ni  m u  m,  2 5t h  q u artil e,   m e di a n,  7 5t h 
q u artil e  a n d   m a xi  m u  m,  e x c e pt f or  P  K   m etri cs,   w h er e  a d diti o n al st atisti cs m a y  b e  us e d.  
 
C at e g ori c al,  q u al it ati v e  v ari a bl e s u  m  m ari es   will i n cl u d e t h e fr e q u e n c y  a n d  p er c e nt a g e  of 
p ati e nts/ e ntri es i n t h e  p arti c ul ar  c at e g or y.  
 
D efi niti o n  of  b as eli n e  v al u e: t h e l ast  pr e -a d  mi nistr ati o n  o bs er v ati o n   will  b e  us e d  as t h e  b as eli n e 
v al u e f or  c al c ul ati n g  p ost -a d  mi nistr ati o n  c h a n g es fr o  m  b as eli n e.  
 
All  d at a  o bt ai n e d vi a  t h e  e  C  R F  a n d  e nt er e d i nt o t h e  d at a b as e   will  b e  pr o vi d e d i n s e p ar at e  d at a 
listi n gs s h o  wi n g i n di vi d u al  p ati e nt  v al u es.  T h e  pl a n ni n g  a n d r e p orti n g  of st atisti c al  a n al ys es   will 
b e  c arri e d  o ut  as  d es cri b e d i n t h e   C  R  O’s  S  O Ps.   A S t atisti c al A n al ysis P l a n ( S  A P)  det aili n g t h e 
st atisti c al  a n al ys es   will  b e  pr e p ar e d a n d si g n e d  off b ef or e t h e d at a b as e l o c k.  
 
1 3. 3  P ati e nt   Dis p ositi o n,   B as eli n e  a n d   T r e at  m e nt   C h a r a ct e risti cs  
T h e  n u  m b er  of  p ati e nts s cr e e n e d, r a n d o  mis e d,  a n d i n cl u d e d i n  e a c h  a n al ysis  p o p ul ati o n   will  b e 
s u  m  m arised. I n  a d diti o n , t h e  n u  m b er  of  p ati e nts t h at  dis c o nti n u e tr e at  m e nt  d uri n g t h e 
C o  m bi n ati o n T r e at  m e nt  or t h e A nti b o d y M o n ot h er a p y T r e at  m e nt  or F oll o  w -U p will  b e 
s u  m  m arise d, al o n g   wit h r e as o ns f or  dis c o nti n u ati o n.  
 
T h e  n u  m b er  of  p ati e nts  c o  m pl eti n g C o  m bi n ati o n T r e at  m e nt ( 1/ 2/ 3/ 4/ 5/ 6  c y cl es),  a n d t h e  n u  m b er 
of  p ati e nts i n cl u d e d i n A nti b o d y M o n ot h er a p y T r e at  m e nt (cy cl es  > 7)  a n d F oll o  w -U p will  b e 
s u  m  m arise d  a n d list e d. 
 
D e  m o gr a p hi c i nf or  m ati o n   will  b e s u  m  m aris e d f or t h e f ull  a n al ysis s et (F  A S ) a n d s af et y a n al ysis 
s et (S  A F ) p o p ul ati o ns  usi n g  d es cri pti v e st atisti cs. D e  m o gr a p hi c i nf or  m ati o n will  als o  b e 
s u  m  m aris e d f or t h e N  K  C  C -l o  w s u b gr o u p. G e n d er  a n d r a c e will  b e s u  m  m aris e d  b y  c o u nts  a n d 
p er c e nt a g es.  
 
M e di c al  hist or y  will  b e s u  m  m aris e d  b y  c o u nts  a n d  p er c e nt a g es  usi n g   M e d  D  R  A s yst e  m  or g a n 
cl ass ( S  O  C)  a n d  pr ef err e d t er  m  cl assifi c ati o ns.   C o n c o  mit a nt   m e di c ati o ns   will  b e r e c or d e d  a n d 
c o d e d  usi n g t h e   W  H  O   Dr u g   Di cti o n ar y  E n h a n c e d  a n d  gr o u p e d  b y   A n at o  mi c al  T h er a p e uti c 
C h e  mi c al (  A T  C) cl ass es.  T a b ul ati o ns   wit h  c o u nts/ p er c e nt a g es   will s h o  w t h e n u  m b er  of 
m e di c ati o ns/ p er c e nt a g e  us e d i n  e a c h  cl ass.  
 
T h e N  H L -s p e cifi c   m e di c al  hist or y   will  b e s u  m  m aris e d f or t h e  d ur ati o n  of  dis e as e si n c e i niti al 
di a g n osis,  n u  m b er  of  pr e vi o us t h er a pi es  (t h er a p y li n es), t y p e  of  pr e vi o us t h er a p y,  a n d  b est 
r es p o ns e f oll o  wi n g  pr e vi o us N  H L -s p e cifi c t h er a p y.   Dis e as e st a gi n g  a n d  dis e as e ris k  ass ess  m e nt 
will  b e  e v al u at e d  b y fr e q u e n c y t a b ul ati o ns  as   w ell.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 1  of 1 3 1  
1 3. 4  A n al ysis  of   Effi c a c y   D at a  
I n t his st u d y t  w o  c o- pri  m ar y  e n d p oi nts ( P F S i n F  A S  a n d  P F S i n   N  K  C  C -l o  w s u b gr o u p) a nd t  w o 
k e y s e c o n d ar y  e n d p oi nts (  O  R  R  a n d   O S) i n t h e F  A S  or   N  K  C  C -l o  w s u b gr o u p will  b e t est e d   wit h 
i nf er e nti al st atisti cs.  
 
T h e f oll o  wi n g s c h e  m e   will  b e f oll o  w e d t o t est t h e  c o - pri  m ar y  e n d p oi nts  a n d t h e s e c o n d ar y 
e n d p oi nts: 
 
1)  F or  c o nfir  m at or y  h y p ot h esis t esti n g  at t h e fi n al  a n al ysis , t h e  p-v al u es  of t h e st atisti c al t ests 
f or t h e  pri  m ar y  a n d  k e y s e c o n d ar y  e n d p oi nt will  b e c o  m bi n e d fr o  m st a g e I ( i nf or  m ati o n  u p t o 
t h e int eri  m an al ysis)  a n d st a g e II ( i nf or  m ati o n b et  w e e n t h e i nt er i  m an al ysis  a n d fi n al 
a n al ysis)  of t h e st u d y  usi n g t h e i n v ers e  n or  m al   m et h o d f or t h e  o v er all  p o p ul ati o n ( F  A S)  a n d 
t h e N  K  C  C -l o  w s u b gr o u p.  T his  pr o c e d ur e  pr es er v es t h e  o v er all ( e x p eri  m e nt- wis e) t y p e I  err or 
r at e  of  α  =  0. 0 5 (t  w o-si d e d) (W ass  m er  2 0 0 6 ). 
 
T h e  pr e-s p e cifi e d   w ei g hts t o  b e  us e d f or  c o  m bi ni n g t h e  p- v al u es fr o  m t h e t  w o st a g es s h o ul d 
s atisf y t h e  c o n diti o n t h at t h e s u  m  of t h e s q u ar e  of t h e w ei g hts  a d d  u p t o  1.   T h e s q u ar e  of t h e 
w ei g ht at st a g e I   will  b e  e q u al t o  0. 4  a n d  at st a g e II   will  b e  e q u al t o  0. 6. 
 
2)  T h e t ot al  T y p e I  err or i n t his st u d y  c o nsisti n g  of  4. 8  % will  b e  distri b ut e d  o v er t h e t  w o 
c o- pri  m ar y  e n d p oi nts  a n d t h e  k e y s e c o n d ar y  e n d p oi nts  a c c or di n g t o t h e f oll o  wi n g s c h e  m e: 
 
𝜶𝜶𝟐𝟐
∗ is s u c h t h at st u d y   wis e   T y p e I  e r r o r  r at e is   m ai nt ai n e d  at  4. 8  % 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 2  of 1 3 1  
T h e  al p h a (t  w o -si d e d) t o  b e s p e nt f or t h e t  w o  c o- pri  m ar y  e n d p oi nts   will  d e p e n d  o n t h e 
o ut c o  m e  of si  m ul ati o ns  d e  m o nstr ati n g t y p e I  err or  c o ntr ol f or  eit h er  of t h e t  w o s c e n ari os: 
a) C o ns er v ati v el y  all o c ati n g  al p h a f oll o  wi n g  a stri ct   B o nf err o ni -t y p e s plit  of  3. 4  % for t h e 
o v er all  p o p ul ati o n ( F  A S)  a n d  a   m a xi  m u  m  of  1. 4  % f or N  K C  C-l o  w . W ass  m er ( 2 0 1 1)  an d 
S u git a ni  et  al. ( 2 0 1 6) , c o ul d  d e  m o nstr at e t h at  c o  m bi ni n g i n v ers e  n or  m al   m et h o d  a n d 
B o nf err o ni t y p e  p artiti o n  of  al p h a i nt o   m ulti pl e  h y p ot h esis  c o ns er v es t h e t o t al st u d y   wis e 
T y p e I  err or r at e i n t h e str o n g s e ns e.  
 
b)  Al p h a  all o c at e d t o t h e N  K  C  C -l o  w s u b gr o u p  d e p e n di n g  o n t h e  c orr el ati o n  b et  w e e n t h e 
o v er all  p o p ul ati o n ( F  A S)  a n d t h e N  K  C  C -l o  w s u b gr o u p (S pi ess e ns  a n d   D e b ois  2 0 1 0 ).  Th e 
c orr el ati o n  d e p e n ds  o n t h e  pr o p orti o n  of  P F S  e v e nts  o bs er v e d i n t h e N  K  C  C -l o  w 
s u b gr o u p  v ers us t h e t ot al  n u  m b er  of  P F S  e v e nts  o bs er v e d i n t h e  o v er all  p o p ul ati o n 
( F  A S).  F or  e x a  m pl e, if t h e N  K  C  C -l o  w s u b gr o u p  c o nt ai ns  5 0  % ( or  5 5  %)  of t h e  e v e nts 
o bs er v e d i n t h e  o v er all  p o p ul ati o n ( F  A S),  al p h a   will  b e  a   m a xi  m u  m  of  2. 2  % ( or  2. 3  %) f or 
t h e   N  K  C  C-l o  w s u b gr o u p  a n d  3. 4  % f or t h e  o v er all  p o p ul ati o n ( F  A S).   
 
3)  If t h e  pri  m ar y  e n d p oi nt is   m et f or t h e  o v er all  p o p ul ati o n ( F  A S), t h e s e c o n d ar y  e n d p oi nts   will 
b e  hi er ar c hi c all y t est e d f or t h e o v er all  p o p ul ati o n ( F  A S)   wit h t h e  al p h a t h at   w as  pr o vi d e d f or 
F  A S  (i. e.,  3. 4  %). If  a n y  k e y-s e c o n d ar y  e n d p oi nt is  n ot   m et i n t h e F  A S, t h e c o-pri  m ar y 
e n d p oi nt  of  P F S  a n d t h e  k e y-s e c o n d ar y  e n d p oi nts   will  b e t est e d f oll o  wi n g t h e s a  m e 
hi er ar c hi c al  pl a n i n t h e   N  K  C  C -l o  w s u b gr o u p  at t h e  all o c at e d  al p h a. 
 
4)  If t h e  pri  m ar y  e n d p oi nt is  n ot   m et f or t h e  F  A S ,  b ut is   m et i n t h e N  K  C  C -l o  w s u b gr o u p, t h e 
s e c o n d ar y  e n d p oi nts   will  b e  hi er ar c hi c all y t est e d f or t h e N  K  C  C -l o  w s u b gr o u p  d e p e n di n g  o n 
t h e  o ut c o  m e  of t h e si  m ul ati o ns   m e nti o n e d  pr e vi o usl y, t h at is 
a) wit h t h e  al p h a t h at   w as  all o c at e d t o t h e N  K  C  C -l o  w s u b gr o u p   wit h t h e  c o ns er v ati v e 
B o nf err o ni-t y p e s plit ( 2 a),  or 
 
b)  t h e  al p h a  all o c at e d f or  e a c h  k e y s e c o n d ar y  e n d p oi nt   will  b e t h e   mi ni  m u  m  of t h e  al p h a 
( 2 b) 
i. t h at   w as  all o c at e d t o t h e N  K  C  C -l o  w s u b gr o u p  a n d  
ii. t h e  al p h a t h at   will  b e  c al c ul at e d  c o nsi d eri n g  c orr el ati o n  of t h e  gi v e n  e n d p oi nt 
b et  w e e n t h e N  K  C  C -l o  w s u b gr o u p  a n d t h e  o v er all  p o p ul ati o n ( F  A S).  
 
F or t h e  k e y- s e c o n d ar y  e n d p oi nts c orr el ati o n will  b e c al c ul at e d  a c c or di n g t o t h e  
f oll o  wi n g: 
o  F or   O  R  R:  b as e d  o n t h e  pr o p orti o n  of  p ati e nts i n   N  K  C  C- l o  w  vs  F  A S 
o  F or   O S:  b as e d  o n t h e  pr o p orti o n  of  e v e nts i n   N  K  C  C- l o  w  vs  F  A S 
 
T h e  a d e q u a c y  of t h e  c o  m bi n e d  us e  of t h e  
•  i n v ers e  n or  m al   m et h o d f or t h e  a d a pti v e d esi g n 
•  al p h a s p e n di n g f or t h e t  w o  c o- pri  m ar y  e n d p oi nts ( as st at e d  a b o v e) 
•  hi er ar c hi c al t esti n g  pr o c e d ur e  of s e c o n d ar y  e n d p oi nts i n t h e N  K  C  C -l o  w 
s u b gr o u p 
i n r es p e ct t o t h e t y p e I  err or  c o ntr ol   will  b e  pr o v e n  b y si  m ul ati o ns  a n d r e p ort e d i n t h e 
S  A P ,   w hic h   will b e fi n ali z e d  pri or t o t h e int eri  m an al ysis.   T h e  al p h a t o  b e  all o c at e d t o t h e 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 3  of 1 3 1  
N  K  C  C -lo  w s u b gr o u p   will  d e p e n d  o n t h e r es ult  of t h es e si  m ul ati o ns  a n d   will  b e  d e ci d e d 
f oll o  wi n g t h e  c o ns er v ati v e  a p pr o a c h  of  a d e q u at el y  c o ntr olli n g t h e st u d y-wis e ty p e I  err or 
r at e  of  4. 8  %.  
 
1 3. 4. 1  Ass ess  m e nt  of E ffi c a c y V a ri a bl es : C o -P ri  m a r y   E n d p oi nt s 
T h e  pri  m ar y  effi c a c y  e n d p oi nt   will  b e  P F S,  d efi n e d  as t h e ti  m e  el a ps e d  b et  w e e n r a n d o  mis ati o n 
a n d I  R  C -ass ess e d ti  m e  of t u  m o ur  pr o gr essi o n  or  d e at h fr o  m  a n y  c a us e.  T h e  d at e  of  pr o gr essi o n 
will  b e  d e e  m e d t o  b e t h e first  d at e w h e n  pr o gr essi v e  dis e as e   w as  di a g n os e d . P ati e nts w it h  n o 
dis e as e  pr o gr essi o n  as  of t h e  a n al ysis  c ut -off  d at e   will  b e  c e ns or e d  at t h e  d at e  of t h e l ast t u  m o ur 
ass ess  m e nt.  
 
P ati e nts l ost  t o f oll o  w-u p   will  b e  c e ns or e d  at t h e l ast  a v ail a bl e t u  m o ur  ass ess  m e nt.  P ati e nts   wit h 
n o  p ost -b as eli n e  ass ess  m e nt   will  b e  c e ns or e d  at t h e ti  m e  of r a n d o  misati o n. 
 
P ati e nts w h o r e c ei v e  n o n -st u d y a ntic a n c er tr e at  m e nt  b ef or e  dis e as e  pr o gr essi o n,  or p ati e nts wit h 
cli ni c al  b ut  n ot r a di ol o gi c al e vi d e n c e  of  pr o gr e ssio n   will  b e  c e ns or e d  at t h e  d at e  of t h e l ast 
e v al u a bl e t u  m o ur  ass ess  m e nt.   A d diti o n al  c e ns ori n g  d et ails   will  b e  o utli n e d i n t h e  S  A P.  
 
T h e fi n al a n al ysis   will  b e p erf or  m e d o n t h e  F  A S  a n d t h e   N  K  C  C -l o  w s u b gr o u p  of t h e  F  A S, t h e 
l att er d efi n e d  as p ati e nts  h a vi n g 1 0 0  or l ess   N  K  c ells  p er  µl  bl o o d  at  b as eli n e . 
 
P ati e nts t o  b e i n cl u d e d i n t h e   N  K  C  C -l o  w s u b gr o u p   m ust  h a v e  a n  e v al u a bl e  b as eli n e   N  K  C  C 
v al u e.  
 
P F S   will  b e  c o  m p ar e d  b et  w e e n tr e at  m e nt  gr o u ps i n t h e F  A S p o p ul ati o n  a n d   N  K  C  C -lo  w  
s u b gr o u p usi n g t h e str atifi e d l o g -r a n k t est.  T h e  esti  m at e  of t h e  h a z ar d r ati os (  HR s) a n d 
c orr es p o n di n g  9 5  % c o nfi d e n c e i nt er v al ( CI ) will  b e  pr o vi d e d  usi n g  a   C o x  pr o p orti o n al  h a z ar ds  
(  C P  H) m o d el i n cl u di n g tr e at  m e nt  a n d t h e str atifi c ati o n f a ct ors ( dis e as e r el a ps e/r e c urr e n c e: 
≤ 1 2  m o nt hs  v ers us  > 1 2   m o nt hs fr o  m l ast tr e at  m e nt,  E  C  O  G  p erf or  m a n c e st at us:  0 -1  v ers us  2 , 
a g e ≤  6 5  y e ars  v ers us > 6 5  y e ars  a n d t h e n u  m b er  of  pr e vi o us s yst e  mi c t h er a p y li n es  ≤ 2  v ers us  > 2) . 
T h e str atifi c ati o n f a ct ors   will  b e  d efi n e d  as  p er t h eir r a n d o  mi sati o n  assi g n  m e nt.  P F S f or  e a c h  ar  m  
a n d  a n al ysis  p o p ul ati o n  will  b e s u  m  m ari se d  usi n g t h e K a pl a n -M ei er  m et h o d . 
 
V ari o us s u p p orti v e  a n al ys es m a y  b e  p erf or  m e d  usi n g t h e  F  A S a n d   N  K  C  C -lo  w  s u b gr o u p ( u nl ess 
ot h er  wis e  n ot e d):  
 
1.  T h e  pri  m ar y  effi c a c y  e n d p oi nt  a n al ysis  as  o utli n e d  a b o v e   will  b e  c o n d u ct e d  usi n g t h e 
P P S . 
2.  A n  u n str atifi e d l o g-r a n k t est   will  b e  c al c ul at e d,  a n d  a   C P  H   m o d el fit, wit h  o nl y tr e at  m e nt 
i n t h e   m o d el. 
3.  M ulti v ari at e  a n al ysis   will  b e  p erf or  m e d i n cl u di n g t h e str atifi c ati o n f a ct ors,  b o n e   m arr o  w 
i n v ol v e  m e nt,  a n d t h e f oll o  wi n g s et  of p ot e nti al  pr o g n osti c /pr e di cti v e f a ct ors: r a c e,   G  C  B 
v ers u s  n o n-G  C B  D L  B  C L, I PI ,  pri or A S  C T ,  n u  m b er  of  pri or t h er a p y li n es: 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 9 4  of 1 3 1  
a)    A st e p -wis e s el e cti o n  pr o c ess   will  b e  us e d t o i d e ntif y  a fi n al s u bs et  of f a ct ors t o  b e
i n cl u d e d.   O n c e t h e s u bs et is est a blis h e d, t h e n tr e at  m e nt   will  b e  a d d e d t o t h e   m o d el t o
ass ess its  eff e ct .
b)
A n  e x pl or at or y  a n al ysis  of tr e at  m e nt  b y f a ct or i nt er a cti o ns  usi n g t h e   C P  H   m o d el   will
b e  c arri e d  o ut.  F urt h er  d et ails   will  b e  pr o vi d e d   wit hi n t h e  S  A P .
4.    A n al ys es   will  b e  d o n e f or t h e s u b gr o u ps  of t h e str atifi c ati o n f a ct ors  a n d  b o n e   m arr o  w
i n v ol v e  m e nt,  as   w ell  as  a n y  ot h er  pr o g n osti c f a ct ors i d e ntifi e d i n t h e  a b o v e   m ulti v ari at e
a n al ysis.  T h e H  R a n d  9 5  %   CI   will  b e  pr es e nt e d f or  e a c h s u b gr o u p.
V ari o us s e nsiti vit y  a n al ys es r e g ar di n g   missi n g  d at a   will  b e  p erf or  m e d  usi n g t h e  F  A S  a n d 
N  K  C  C -l o  w s u b gr o u p: 
1. P ati e nts l ost  t o f oll o  w- u p,  b ut  h a vi n g  a n  a v ail a bl e  d e at h  d at e,   will  b e i n cl u d e d i n t h e
ti  m e-t o-e v e nt  a n al ysis  as  a n  e v e nt.  T his   will  a c c o u nt f or  a  p ossi bl e i  m b al a n c e i n  d e at hs,
w hi c h  c o ul d  bi as t h e  P F S   m e as ur e  m e nt  b y  o v er esti  m ati n g t h e  P F S i n t h e tr e at  m e nt  ar  m
wit h l ess  d o c u  m e nt e d f oll o  w - u p.
2. I nt er v al  c e ns ori n g   will  b e  a p pli e d.   Diff er e nt  c o nsi d er ati o ns f or i nt er v al  c e ns ori n g   will  b e
c o nsi d er e d   wit h  d et ails s p e cifi e d  i n t h e  S  A P.
3. A n  a n al ysis   will  b e  d o n e  as  p er t h e  pri  m ar y effi c a c y  e n d p oi nt a n al ysis  b ut   wit h  c e ntr al
r e a d er  b as eli n e  di a g n osis r es ults.  T his is t o  as c ert ai n t h at l o c al  a n d  c e ntr al r e a d er
diff er e n c es  d o  n ot  aff e ct t h e r es ults.
4. T h e   m et h o d  of   m ulti pl e i  m p ut at i o n   m a y  b e  a p pli e d t o  a c c o u nt f or   N  K  C  C  v al u es   missi n g  at
b as eli n e.  T his   will  b e i  m pl e  m e nt e d i n  c as e  of   m or e t h a n  1 0  %   missi n g  b as eli n e   N  K  C  C
v al u es.
5. C o x  P  H   M o d el t o  esti  m at e t h e   H  R i n F  A S  a n d N  K  C  C -lo  w s u b gr o u p   m a y i n cl u d e t h e
a d diti o n al  c of a ct or  of   N  K  C  C -l o  w b as eli n e  st at us i n t h e   m o d el.
6. T o  a c c o u nt f or  a  p ossi bl e i  m b al a n c e  b et  w e e n tr e at  m e nt  ar  ms i n t h e   N  K  C  C -l o  w s u b gr o u p,
b al a n ci n g  of  c o v ari at es  vi a  Pr o p e nsit y  S c or e   w ei g hti n g   m et h o d ( Li  et  al.  2 0 1 8)   m a y  b e
a p pli e d.
F urt he r t y pes of a nal yses  o n P F S m a y be spe cifie d i n t he SA P.  
1 3. 4. 2  A n al ys es of  th e Sec o n d ar y  Effic ac y  En d p oi nts  
Hierarc hical testi n g will be em pl o ye d f or ke y sec o n dar y e n d p oi nts, w it h t he pri mar y e n d p oi nt 
P F S s er vi n g  as a  gate kee per. T he T y pe I err or rate w ill be a dj uste d acc or di n gl y t o s u p p ort 
la belli n g clai ms for ke y sec o n dary e n d p oi nts.  
S pecificall y,  t he f oll o wi n g proce d ures  will be i m ple me nte d to  ma i ntai n t he o ve rall T y pe I err or 
rate acr oss t h e pri mar y an d  t w o ke y sec o n dar y e n d p oi nts of t he st u d y at a n a dj uste d t w o -si de d 
si g nifica nce le vel al p ha fo r t he fi nal a nal ysis (for details  see Secti on  1 3. 1 1. 1 ). 
T he  pr i mar y efficac y  e nd p oi nt  a nal ysis will serve as t he gate kee per  f or the ke y s ec o n dar y  
e n d p oi nt a nal yses,  i.e., the  pr i mary  efficac y h y p ot hesis m us t be  rejecte d at t he t w o-si de d 
a dj uste d  si g nifica nce le vel al p ha bef ore t he efficac y  h y p otheses f or  the  sec o n dar y  efficac y 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 9 5  of 1 3 1  
e n d p oi nts  c a n  b e t est e d.  T h e k e y s e c o n d ar y  e n d p oi nts   will  b e t h e f oll o  wi n g (i n t h e or d er  of 
d es c e n di n g i  m p ort a n c e): 
•
K e y s e c o n d ar y  1: b est O  R  R
•
K e y s e c o n d ar y  2 :   O S
If t he pri mar y h y p othesis  is rejecte d, the  t w o key s ec o n dar y e n d p oi nts w ill be se q ue ntiall y teste d 
at the  t w o-si de d a dj uste d si g nifica nce le vel al p ha i n t he or der liste d ab o ve . If a n ul l h y p ot hesis is 
n ot rejecte d, for mal se q ue ntial testi n g  will be st op pe d  an d  o nly  n o m i nal si g nifica nce will be  
me nti o ne d f or the re mai ni n g sec o n dar y e n d p oi nts. A nal yses a n d p- val ues  will be re p orte d f or all 
t he efficac y e n d p oi nts, i ncl u di n g t he pri mar y e n d p oi nt, t he ke y s ec o n dar y e n d p oi nts, a n d a ll 
ot her sec o n dar y en d p oi nts liste d i n Secti o n  7. 2.  
N ot e t hat if t he primar y  en d p oi nt is  met f or  t he o verall (F A S)  p o p ulati o n, t he sec o n dar y 
e n d p oi nts  will be hierarc hicall y  teste d f or t he F A S p o p ul ati o n w it h t he al p ha that w as pr o vi de d 
for F A S .  
If t he pri mar y en d p oi nt  is n ot met f or t he F A S p o p ul ati o n, b ut is met i n t he NK C C -lo w 
s u b gr o u p, t he n t he sec o n dar y e n d p oi nts will be hierarc hicall y teste d f or t he N K C C -l o w s u b gr o u p 
wit h t he al p ha t hat was pr o vi de d f or t he N K C C -l o w s u b gr o u p (see Secti o n 1 3. 4. 1 ), ta ki n g i nt o 
acc o u nt t he c orrelati o n bet wee n t he s u b gr o u p a n d the o ve rall p o p ulati o n (F A S)  wit h  regar ds  t o 
t he sec o n dar y e n d p oi nt co nsi dere d. . 
If the p ri mar y e n d p oi nt is n ot m et in t he o ve rall p o p ulati o n 
 
, t here w ill n ot be an y al p ha left to carr y o ve r for t he sec o n dar y e n d p oi nt s. I n t his 
sit uati o n, a nal ysis o f the sec o n dar y e n d p oi nts w ill be pe rf or me d f or the 
 
 as e x pl orat ory a nal yses. T he p- val ues  will be prese nte d  f or ill ustrati ve 
p ur p oses o nl y. 
1 3. 4. 2. 1  Best  O bjecti ve  Res po nse R ate 
O bjecti ve res p o nse is defi ne d  whe n  a patie nt  is classifie d as ha vi n g  a C R  or PR  after D L B C L  
e val uati o n usi n g t he I nter nati o nal W or ki n g Gr o u p r es p o nse  criteria f or mali g na nt l y m p h o ma  
( C hes o n et al. ( 2 0 0 7); see A p pe n di x L ). 
F or eac h  visit a vaila ble, the n u m ber (c o u nts an d perce nta ges) of pa tie nts i n eac h of t he foll o wi n g 
cate g ories will  be pres e nte d  in  a ta ble: pr o gressi ve disease, S D,  PR , C R  a n d o bj ecti ve res p o nse 
( C R or P R ). Ta b ulati o n will  s h o w missi n g res p o nse e val uati o ns as well, i ncl u di n g these patie nts 
i n t he den o mi nat or f o r calc ulati n g  the  rates. DL B C L  res p o nse assess me nts of lo cal a n d I RC 
e val uati o ns will be ta b ulate d. 
T he  best  O R R is defi ne d as t he pr o p orti o n of pati e nts  wit h CR  or P R (see Secti o n 6. 2 ). 
T he de n o mi nat or for calc ulati n g t he rate s/ perce nta ges will be base d u p o n t he total n u m ber of 
patie nts in t he F A S p o p ulati o n (a n d i n t he N K C C-l o w su b gr o u p of the F A S). Patie nts w it h n o 
p ost- baseli ne assess me nt  of res p o nse  will be i ncl u de d as n o nres p o n ders.  Res p o nse rates will  be 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 6  of 1 3 1  
e v al u at e d  usi n g t h e l o c al  a n d t h e  c e ntr al  e v al u ati o n  of t h e I  R  C. F or t h e I  R  C  e v al u ati o ns t h e b est 
O  R  R  f or  e a c h tr e at  m e nt  ar  m   will  b e t h e r at e  of  p ati e nts   w h o   m et t h e o bj e cti v e r es p o ns e 
d efi niti o n  u p  u ntil t h e l ast  a v ail a bl e t u  m ou r  ass ess  m e nt.  T h e  n u  m b er  of  p ati e nts  cl assifi e d  as 
r es p o n d ers  a n d t h e r es p e cti v e r at es  as   w ell  as  9 5  % CI s (  Cl o p p er-P e ars o n)   will  b e  pr es e nt e d. T h e 
b est O  R  R s will  als o  b e  c o  m p ar e d  b et  w e e n tr e at  m e nts  usi n g t h e   C o chr a n -M a nt el -H a e ns z el t est 
str atifi e d  b y r a n d o  mis ati o n str at a. 
 
B est r es p o ns e   will  b e  d et er  mi n e d   wit h r es p e ct t o  all r es p o ns e  e v al u ati o ns  gi v e n  u ntil l ast 
a v ail a bl e t u  m o u r  ass ess  m e nt.   B est r es p o ns e r at es   will  b e  d es cri pti v el y t a b ul at e d  as t h e b est O  R  R, 
disti n g uis hi n g  b et  w e e n t h e l o c al  a n d t h e  c e ntr al r a di ol o gi c al  e v al u ati o n. 
 
T h e  b est O  R  Rs   m a y  als o  b e  e x pl or e d   wit hi n f urt h er s u b gr o u ps ot h er t h a n   N  K  C  C -l o  w.   D et ails 
will  b e  pr o vi d e d   wit hi n t h e  S  A P.  
 
1 3. 4. 2. 2  D u r ati o n  of R es p o ns e  
D o  R is d efi n e d  as t h e ti  m e el a ps e d b et  w e e n t h e i niti al ti  m e  p oi nt  of t u  m o ur r es p o ns e (  C  R  or  P  R) 
a n d t h e ti  m e  of d o c u  m e nt e d t u  m o ur  pr o gr essi o n.   R es p o ns e  d ur ati o n   will  b e t a b ul at e d f or r es ults 
gi v e n  b y t h e l o c al  ass ess  m e nt  as   w ell  as  b y t h e  c e ntr al  ass ess  m e nts  of t h e I  R  C. D es cri pti v e 
a n al ysis   will  b e  d o n e f or   D  O  R  a  m o n g  p ati e nts   w h o r es p o n d e d i n  e a c h  ar  m f or t h e  o v er all 
p o p ul ati o n  a n d f or t h e   N  K  C  C -l o  w s u b gr o u p. 
 
1 3. 4. 2. 3  Dis e as e C o nt r ol R at e  
D  C  R is  d efi n e d  as  h a vi n g  a r es p o ns e  of   C  R,  P  R  or  S  D (  D  C  R  =   O  R R  +  S  D).  T h e   D  C  R   will  b e 
e v al u at e d  as f or t h e  b est   O  R  R.  
 
1 3. 4. 2. 4  Ti  m e t o  P r o g r essi o n  
T T P is  d efi n e d  as t h e ti  m e fr o  m r a n d o  mi sati o n  u ntil  d o c u  m e nt e d   D L  B  C L  pr o gr essi o n  or  d e at h  as 
a r es ult  of l y  m p h o  m a.  T h e  e v e nt  of i nt er est is  o nl y  dis e as e  pr o gr essi o n  a n d  d e at h fr o  m 
l y  m p h o  m a;  d e at h fr o  m  ot h er  c a us es   will  n ot  b e  c o nsi d er e d i n r elati o n t o t h e  T T P  e v al u ati o n.  
 
P ati e nts  n ot  e x p eri e n ci n g  dis e as e  pr o gr essi o n   will  b e  c e ns or e d  at t h e l ast a v ail a bl e D L  B  C L 
ass ess  m e nt. P ati e nts  d yi n g fr o  m  ot h er  c a us es   will  b e  c e ns or e d  at t h e ti  m e  of  d e at h.  E arl y 
dr o p -o uts   wit h o ut  a n y  d o c u  m e nt e d  d at e  of  pr o gr essi o n   will  b e  c e ns or e d  at t h e l ast a v ail a bl e 
D L  B  C L  ass ess  m e nt.  
 
T T P   will  b e  a n al ys e d  usi n g t h e s a  m e  e v e nt  a n al ysis s ets  as f or t h e  pri  m ar y effi c a c y  e n d p oi nt 
a nal ysis  of  P F S.  St atisti cs t o  b e r e p ort e d  a n d  gr a p hi c al vis u alis ati o ns   will  b e t h e s a  m e  as f or t h e 
pri  m ar y  effi c a c y  p ar a  m et er.  
 
T T P o n -st u d y will  b e  c o  m p ar e d   wit h t h e T T P  o n  e a c h  p ati e nt’s   m ost r e c e nt pri or t h er a p y  vi a 
t a b ul ate d d es cri pti v e st atisti cs.   A d diti o n all y, T T P  o n t h e p ati e nt’s m ost r e c e nt  pri or t h er a p y  will 
b e t est e d  as  a f a ct or i n  a C P  H m o d el   wit h str at ifi c ati o n f a ct ors  a n d  b o n e   m arr o  w i n v ol v e  m e nt t o 
d et er  mi n e if t his si g nifi c a ntl y i nfl u e n c es t h e  T T P of  p ati e nts u n d er st u d y tr e at  m e nt.  
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 7  of 1 3 1  
1 3. 4. 2. 5  O v e r all S u r vi v al  
O S is  d efi n e d  as t h e ti  m e fr o  m r a n d o  mis ati o n t o t h e  d at e  of  d e at h.  P ati e nts   w h o  ar e  ali v e  or   w h o 
dr o p  o ut  e arl y   will  b e  c e ns or e d  at t h e l ast  a v ail a bl e st u d y  visit  ass ess  m e nt.   A n al ysis str at e gi es 
will f oll o  w t h os e  a p pli e d f or t h e  pri  m ar y  effi c a c y  p ar a  m et er.  
 
1 3. 4. 2. 6  Ti  m e t o N e xt T r e at  m e nt  
T T  N T is  d efi n e d  as t h e t i  m e fr o  m r a n d o  mis ati o n t o t h e ti  m e  of i nstit uti o n  of  n e xt t h er a p y f or  a n y 
r e as o n i n cl u di n g  dis e as e  pr o gr essi o n, tr e at  m e nt t o xi cit y  a n d  p ati e nt  pr ef er e n c e.  T T  N T   will  b e 
s u  m  m arise d  b y tr e at  m e nt  gr o u p  a n d  pr es e nt e d  usi n g   K a pl a n -M ei er  c ur v es.  T T  N T  will  als o  b e 
a n al ys e d i n  a si  mil ar   m a n n er t o t h e  pri  m ar y effi c a c y  e n d p oi nt a n al ysis  usi n g  a str atifi e d l o g -r a n k 
t est  a n d  a   C P  H   m o d el.  S e nsiti vit y  a n al ys es   m a y  b e  p erf or  m e d  a n d   w o ul d  b e  o utli n e d i n t h e  S  A P. 
 
1 3. 5  Q u alit y  of   Lif e   Q u esti o n n ai r e s E  O  R  T  C   Q  L  Q -C 3 0  a n d  E  Q -5  D -5  L  
T h e E  O  R T  C   Q L  Q -C 3 0 is  c o  m p os e d  of  b ot h   m ulti -it e  m s c al es  a n d si n gl e-it e  m   m e as ur es.  T h es e 
i n cl u d es fi v e f u n cti o n al s c al es ( p h ysi c al f u n cti o ni n g, r ol e f u n cti o ni n g,  e  m oti o n al f u n cti o ni n g, 
c o g niti v e f u n cti o ni n g, s o ci al f u n cti o ni n g), t hr e e s y  m pt o  m s c ales (f ati g u e,  n a us e a  a n d  v o  miti n g, 
p ai n),  a gl o b al  h e alt h st at us/  Q o  L s c al e  a n d si x si n gl e it e  ms ( d ys p n o e a, i ns o  m ni a, l oss  of 
a p p etit e,  c o nsti p ati o n,  di arr h o e a, fi n a n ci al  diffi c ulti es).  E a c h  of t h e   m ulti -it e  m s c al es i n cl u d es  a 
diff er e nt s et  of it e  ms –  n o it e m  o c c urs i n   m or e t h a n  o n e s c al e.   A  hi g h s c al e s c or e r e pr es e nts  a 
hi g h er r es p o ns e l e v el. T h us,  a  hi g h s c or e f or  a f u n cti o n al s c al e r e pr es e nts  a  hi g h  or  h e alt h y l e v el 
of f u n cti o ni n g,  a  hi g h s c or e f or t h e  gl o b al  h e alt h st at us r e pr es e nts  a  hi g h  q u alit y  of lif e ,  b ut  a 
hi g h s c or e f or  a s y  m pt o  m s c al e  or s y  m pt o  m it e  m r e pr es e nts  a  hi g h l e v el  of s y  m pt o  m at ol o g y  a n d 
f u n cti o n al i  m p air  m e nt. 
 
T h e  E  Q -5  D -5 L  q u esti o n n air e  c o  m pris es  a  d es cri pti v e s yst e  m  a n d  a  vis u al  a n al o g u e s c al e (  V  A S). 
T h e  E  Q -5  D -5 L  c o nt ai ns fi v e  q u esti o ns ( m o bilit y, s elf -c ar e,  us u al  a cti viti es,  p ai n/ dis c o  mf ort,  a n d 
a n xi et y/ d e pr essi o n).   R es p o n d e nts  c o ul d  c h o os e  o n e  of t h e fi v e l e v els t o  d es cri b e t h eir  h e alt h 
st at e  o n t h e  d a y  of s ur v e y.  T h es e fi v e l e v els i n cl u d e  “ n o  pr o bl e  m ”,  “sli g ht  pr o bl e  ms ”,  “  m o d er at e 
pr o bl e  ms ”  a n d  “s e v er e  pr o bl e  ms ” i n  all fi v e  di  m e nsi o ns,  a n d  “ u n a bl e ” i n   m o bilit y, s elf -c ar e  a n d 
us u al  a cti viti es  or  “ e xtr e  m e  pr o bl e  ms ” i n  p ai n/ dis c o  mf ort  a n d  a n xi et y/ d e pr essi o n. T h e  h e alt h  of 
t h e r es p o n d e nt is i n di c at e d  b y  a ti c k  or  a  cr oss i n t h e  b o x  a g ai nst th e   m ost  a p pr o pri at e st at e  m e nt 
i n  e a c h  of t h e  5  di  m e nsi o ns.  T his  d e cisi o n r es ults i n  a  1-di git  n u  m b er  e x pr essi n g t h e l e v el 
s el e ct e d f or t h at  di  m e nsi o n.  T h e  di gits f or  5  di  m e nsi o ns  c a n  b e  c o  m bi n e d i n  a  5 -di git  n u  m b er 
d es cri bi n g t h e r es p o n d e nt’s  h e alt h st at e.  E  Q -5  D -5 L  h e alt h st at es,  d efi n e d  b y t h e  E  Q -5  D -5 L 
d es cri pti v e s yst e  m,   m a y  b e  c o n v ert e d i nt o  a si n gl e i n d e x  v al u e.  
 
A  v erti c al,  h as h -m ar k e d  vis u al  a n al o g u e s c al e ( E  Q -V  A S) is  a n c h or e d  b y  0 (t h e   w orst i  m a gi n a bl e 
h e alt h st at e)  at t h e  b ott o  m  a n d  1 0 0 (t h e  b est i  m a gi n a bl e  h e alt h st at e)  o n t h e t o p f or r es p o n d e nts 
t o r at e t h eir  o v er all  h e alt h. A  cr oss i n t h e  E  Q -5  D -5 L   V  A S s c al e i n di c at es  h o  w t h e r es p o n d e nt 
h e alt h is t o d a y  a n d t h e n t h e  n u  m b er is tr a ns cri b e d i n a b o x.  
 
S c ori n g  of  e a c h s c al e   will  b e  c al c ul at e d, f oll o  wi n g t h e r es p e cti v e   m a n u als.  T h e  b as eli n e 
ass ess  m e nt is t h e l ast  a v ail a bl e  ass ess  m e nt  b ef or e first i nf usi o n  of st u d y   m e di c ati o n.   D es cri pti v e 
st atisti cs f or  e a c h  of t h e s c or es   will  b e t a b ul at e d.   Als o,  c h a n g es f r o  m  b as eli n e f or  e a c h s c or e,  a n d 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 8  of 1 3 1  
n u  m b ers  of  p ati e nts   wit h i  m pr o v e  m e nt  a n d  d et eri or ati o n   will  b e s u  m  m aris e d  b y  visit.  F urt h er 
d et ail   will  b e  pr o vi d e d i n t h e  S  A P.  
 
1 3. 6  I  m  m u n o g e ni cit y   A n al ysis 
O n e  of t h e s e c o n d ar y o bj e cti v es will  b e t o  e v al u at e t h e  p ot e nti al i  m  m u n o g e ni cit y  of M  O  R 0 0 2 0 8  
i n t h e i  m  m u n o g e ni cit y  a n al ysis s et (I  A S).  T h e  a n al ysis   will s h o  w  b ot h t h e a bs ol ut e  n u  m b er  a n d 
p er c e nt a g e  of  p ati e nts   w h o  d e v el o p  a nti -M  O  R 0 0 2 0 8  a nti b o di es.   R es ults  of s e  mi -q u a ntit ati v e 
a nti-M  O  R 0 0 2 0 8  a nti b o d y titr e  d et er  mi n ati o ns  of  c o nfir  m e d  p ositi v e s a  m pl es   will  b e t a b ul at e d , as 
w ell  as t h e n u  m b er  a n d  p er c e nt a g e  of  p ati e nts  h a vi n g  p ositi v e  ass ess  m e nts.  C o nfir  m e d  p ositi v e 
a nti-M  O  R 0 0 2 0 8  a nti b o d y s a  m pl es   will  b e  c h ar a ct eri se d   wit h r es p e ct t o  n e utr ali si n g  c a p a cit y i n  a 
n e utr ali si n g  a nti b od y (  N  A b)  ass a y. 
 
1 3. 7  P h a r  m a c o ki n eti c   A n al ysis  
O n e  of t h e s e c o n d ar y  o bj e cti v es   will  b e t o i n v esti g at e t h e  P  K  pr ofil e  of   M  O  R 0 0 2 0 8  usi n g t h e  P  K 
a n al ysis s et ( P  K  A S) . P  K  p ar a  m et ers f or   M  O  R 0 0 2 0 8   will  b e  c o  m p ut e d  b as e d  o n  n o n -
c o  m p art  m e nt al  d at a  a n al ysis  a n d s u  m  m aris e d  usi n g  d es cri pti v e st atisti cs ( s u c h  as n,   m e a n, 
g e o  m etri c   m e a n, st a n d ar d  d e vi ati o n,  c o effi ci e nt  of  v ari ati o n,   m e di a n,   mi ni  m u  m  a n d   m a xi  m u  m). 
M e a n c o n c e ntr ati o ns ( o n  ori gi n al  a n d  o n l o g -li n e ar s c al e)  of M  O  R 0 0 2 0 8  will  b e  vis u alis e d i n 
fi g ur es.  F urt h er  d et ails  of  P  K  a n al ysis   will  b e s p e cifi e d i n t h e  S  A P. 
 
I n  a d diti o n, a p o p ul ati o n P  K  a n al ysis of   M  O  R 0 0 2 0 8  will  b e c o n d u ct e d .  T h e  pl a n n e d m et a -
a n al ysis   will  e n c o  m p ass P  K  d at a fr o  m   M  O  R 2 0 8  C 2 0 4  a n d  ot h er  cli ni c al tri als   wi t h   M  O  R 0 0 2 0 8. 
T h e  a n al ysis will  pr o vi d e  a n  u n d erst a n di n g  of t h e  p o p ul ati o n P  K of   M  O  R 0 0 2 0 8 a n d  d et er  mi n e  
t h e i nfl u e n c e  of i ntri nsi c  a n d  e xtri nsi c f a ct ors (s u c h  as  b ut  n ot li  mit e d t o  a g e,  g e n d er, r a c e, l e v el 
of  h e p ati c  or r e n al f u n cti o n  a n d  pr es e n c e  of  a nti -d r u g  a nti b o di es) t h at   m a y i nfl u e n c e P  K 
v ari a bilit y.  D et ails  of t h e i nt e n d e d p o p ul ati o n P  K a n al ysis  will  b e  d es cri b e d i n  a s e p ar at e 
p o p ul ati o n  P  K pr ot o c ol  a n d t h e r es ults will  b e  d es cri b e d i n  a s e p ar at e p o p ul ati o n  P  K st u d y  
r e p ort. 
 
1 3. 8  A n al ysis  of  S af et y   D at a  
1 3. 8. 1  A d v e rs e   E v e nts  
O n e  of t h e s e c o n d ar y  e n d p oi nts is t h e  e v al u ati o n  of t h e fr e q u e n c y, i n ci d e n c e,  a n d s e v erit y  of 
A Es.  
 
A Es   will  b e  c o d e d  a c c or di n g t o   M e d  D  R  A  S  O  C  a n d  pr ef err e d t er  ms. I n ci d e n c e a n d fr e q u e n c y of 
all   A Es   will  b e s u  m  m aris e d  b y  S  O  C,  pr ef err e d t er  m, r e l ati o ns hi p t o tr e at  m e nt, s e v erit y  a n d 
s eri o us n ess. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 9 9  of 1 3 1  
A n   A E s u  m  m ar y t a bl e   will  b e  pr es e nt e d s h o  wi n g t h e  n u  m b er  of  e v e nts,  n u  m b er  of  p ati e nts  a n d 
t h e  p er c e nt a g e  of  p ati e nts  h a vi n g: 
 
•  T r e at  m e nt-e  m er g e nt  a d v ers e  e v e nts ( T E  A Es)  
•  S  A Es  
•  D r u g-r el at e d  T E  A Es (s plit  b y   B E  N-,   M  O  R 0 0 2 0 8- a n d   R T  X -r el at e d  a n d  o v er all) 
•  D r u g-r el at e d  T E  A Es i n  e a c h s e v erit y/t o xi cit y  gr a di n g ( a c c or di n g t o N  CI -C T  C  A E ) 
•  T E  A Es t h at l e d t o st u d y  dis c o nti n u ati o n  
•  I  R  Rs  b y  gr a d e. 
 
I n  a d diti o n, t h e i n ci d e n c e r at e  of   A Es i n  e a c h  of t h e a b o v e-m e nti o n e d  c at e g ori es   will  b e 
pr es e nt e d   wit h  9 5  % CI s  b as e d  o n t h e  n u  m b er  of  p ati e nts  a n d t h e  n u  m b er  of   A Es. 
 
T h e  n u  m b er  of   A Es, i n r el ati o n t o t h e  n u  m b er  a n d  p er c e nt a g e  of  p ati e nts   wit h  o n e  or   m or e 
T E  A E s, will  b e s u  m  m aris e d  b y   M e d  D  R  A  S  O  C  a n d  pr ef err e d t er  m f or  e a c h tr e at  m e nt  ar  m.  S u c h 
s u  m  m ari es   will  b e  dis pl a y e d f or  all  T E  A Es,  T E  A Es  b y   m a xi  m u  m s e v erit y/t o xi cit y,  a n d  T E  A Es 
b y r el ati o ns hi p t o st u d y  dr u gs,  S  A Es,  dr u g -r el at e d  T E  A Es  a n d  T E  A Es t h at l e d t o st u d y 
dis c o nti n u ati o n.  
 
T h e s p o ns or   will  d es cri b e   A E SI s, i n  a d diti o n t o t h os e r e p ort e d  as  S  A Es.   A E SI t a b ul ati o ns   will  b e 
a n al o g o us t o t h e t a b ul ati o n  of  T E  A Es.  
 
1 3. 8. 2  Cli ni c al   L a b o r at o r y   E v al u ati o ns  
T h e  a n al ysis  of c e ntr al l a b or at or y  p ar a  m et ers f or  e a c h tr e at  m e nt  ar  m   will  be  pr es e nt e d, s e p ar at e d 
i nt o  bl o o d  p ar a  m et ers (e. g., h a e  m at ol o g y, s er u  m  c h e  mistr y,  c o a g ul ati o n)  a n d  uri n e  p ar a  m et ers 
( uri n al ysis).   All  d at a c oll e ct e d i n t h e  c o u rs e  of t h e st u d y will  b e list e d.  
 
D es cri pti v e s u  m  m ari es  of  a ct u al ( a bs ol ut e)  v al u es  a n d  c h a n g e -fro  m -b as eli n e  v al u es   will  b e 
pr es e nt e d ,  e. g., f or h a e  m at ol o g y  a n d s er u  m  c h e  mistr y f or t h e S  A F  b y  visit . 
 
E a c h  a b n or  m al  v al u e  m e as ur e d i n t h e  c e ntr al l a b or at or y will  b e fl a g g e d t o s h o  w   w h et h er it is  a 
v al u e  b el o  w  or  a b o v e t h e r ef er e n c e r a n g e.  F or t h e  ass ess  m e nt  of l a b or at or y  v ari a bl es, t h e 
i n v esti g at or   will  n e e d t o j u d g e t h eir  cli ni c al si g nifi c a n c e. 
T h e  ass ess  m e nt  of t h e  cli ni c al r el e v a n c e of c e ntr al l a b or at or y  v ari a bl es will  b e t a b ul at e d  b y ti  m e 
p oi nt f or  e a c h  cli ni c al l a b or at or y  a n al yt e  usi n g fr e q u e n c y t a b ul ati o ns. A d diti o n all y, f or  e a c h 
l a b or at or y  p ar a  m et er, s hifts i n  ass ess  m e nts fr o  m  b as eli n e t o s el e ct e d  p ost-a d  mi nistr ati o n ti  m e 
p oi nts   will  b e  pr es e nt e d.  F urt h er  d et ail s   will  b e  pr o vi d e d i n t h e  S  A P. 
 
If   N  CI-C T  C  A E  gr a d es  ar e  a v ail a bl e f or  a  cli ni c al l a b or at or y  a n al yt e, t h e y   will  b e  d eri v e d 
a c c or di n g t o   N  CI -C T  C  A E,   V ersi o n  4. 0  ( or  hi g h er),  a n d us e d t o  pr es e nt  a d diti o n al fr e q u e n c y  a n d 
s hift t a bl es  b as e d  o n   N  CI-C T  C  A E  gr a d es.  
 
T h e  ass ess  m e nt  of  c at e g ori c al  uri n al ysis  v ari a bl es   will  b e t a b ul at e d  b y ti  m e  p oi nt f or  e a c h  uri n e 
p ar a  m et er f or t h e S  A F  (fr e q u e n c y t a bl es). A d diti o n all y, f or  e a c h  of t h es e , uri n e  p ar a  m et er s hifts 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 0  of  1 3 1  
i n  ass ess  m e nts fr o  m  b as eli n e t o s el e ct e d  p ost-a d  mi nistr ati o n ti  m e  p oi nts   will  b e  pr es e nt e d (s hift 
t a bl es). 
 
C e ntr al l a b or at or y  v al u es t h at  ar e  o utsi d e t h e r ef er e n c e r a n g e   will  als o  b e fl a g g e d i n t h e  d at a 
listi n gs,  al o n g   wit h t h e  c orr es p o n di n g r ef er e n c e r a n g es. 
 
1 3. 8. 3  P h ysi c al   E x a  mi n ati o n  
B as eli n e P Es will  b e s u  m  m aris e d b y  b o d y s yst e  m.   N e  w  a n d   w ors e ni n g  a b n or  m al P E  fi n di n gs 
d uri n g t h e st u d y   will  b e  e nt er e d  as   A E s  a n d  a n al ys e d   wit hi n t h e   A E t a bl es. 
 
1 3. 8. 4  Vit al  Si g ns  
D es cri pti v e s u  m  m ari es  of  a ct u al  v al u es  a n d  c h a n g es fr o  m  b as eli n e   will  b e  c al c ul at e d f or  vit al 
si g ns.  T h es e s u  m  m ari es   will  b e  pr es e nt e d f or t h e S  A F  at  all ti  m e  p oi nts.  E a c h  a b n or  m al  v al u e 
will  b e fl a g g e d t o s h o  w   w h et h er it is  a  v al u e  b el o  w  or  a b o v e t h e  n or  m al li  mit. 
 
1 3. 8. 5  El e ct r o c a r di o g r a  ms ( 1 2 -l e a d   E  C  G) 
S u  m  m ar y  E  C  G  ass ess  m e nt ( c at e g ori es: ‘ n or  m al ’; ‘ a b n or  m al, cli ni c all y si g nifi c a nt ’; ‘ a b n or  m al, 
n ot  cli ni c all y si g nifi c a nt ’)   will  b e t a b ul at e d  b y ti  m e  p oi nt  usi n g fr e q u e n c y t a b ul ati o ns. 
 
E a c h r es ult  of t h e  1 2 -l e a d  EC  G ( P  R,   Q  R S,   R  R  a n d   Q T  i nt er v al  v al u es)   will  b e fl a g g e d t o s h o  w 
w h et h er it is  a  v al u e  b el o  w  or  a b o v e t h e  n or  m al li  mit.  
 
S u  m  m ar y st atisti cs f or  all ti  m e  p oi nts   will  b e  dis pl a y e d f or   Q T  a n d  b ot h   Q T c  c orr e cti o n   m et h o ds. 
T h e   B a z ett’s  c orr e cti o n   m et h o d (B a z ett  1 9 2 0 ) f or   Q T c   will  b e  a p pli e d  as f oll o  ws: 
 
B a z ett’s   C orr e cti o n (  Q T c B) 
R R
Q T
Q T c B
m s e c
=
 
 
T h e  Fri d eri ci a  c orr e cti o n   m et h o d (Fri d eri ci a  1 9 2 0 ) f or   Q T c   will  b e  a p pli e d  as f oll o  ws: 
 
Fri d eri ci a’s   C orr e cti o n (  Q T c F)  
3
s e c
R R
Q T
Q T c F
m
=
 
 
W h er e  r el ati v e r at e (  R  R)  =  6 0/ h e art r at e 
 
Als o, t h e  n u  m b er  a n d  p er c e nt a g e  of  p ati e nts   wit h   Q T c  v al u es  a b o v e t h e  n or  m al li  mit ( > 4 5 0   ms, 
> 4 8 0   ms,  > 5 0 0   ms)  a n d t h e  n u  m b er  a n d  p er c e nt a g e  of  p ati e nts   w h o  e x p eri e n c e d  a  c h a n g e 
≥ 3 0  ms  or  a  c h a n g e  ≥ 6 0  ms   will  b e  pr es e nt e d  b y ti  m e  p oi nt.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 1  of  1 3 1  
1 3. 9  Bi o  m a r k e rs  
1 3. 1 0  O t h e r D at a  
All  ot h er  d at a  as  d o c u  m e nt e d i n t h e  e  C  R F   will  b e list e d  a n d/ or t a b ul at e d  usi n g  d es cri pti v e 
st atisti cs  or  c o u nts/ p er c e nt a g es,  d e p e n di n g  o n t h e  n at ur e  of  d at a. 
 
1 3. 1 1  S a  m pl e  Si z e   D et e r  mi n ati o n  
A p pr o xi  m at el y  3 3 0  p ati e nts   wit h   R-  R   D L  B  C L   w h o   m e et t h e i n cl usi o n  crit eri a  a n d  h a v e  n o n e  of 
t h e  e x cl usi o n  crit eri a   will  b e r a n d o  mis e d i nt o  o n e  of t h e t  w o  p ar all el tr e at  m e nt  gr o u ps i n  a r ati o 
of  1: 1.  T h e st u d y   will  b e  p erf or  m e d  a c c or di n g t o  a t  w o- st a g e,  gr o u p-s e q u e nti al,  a d a pti v e  d esi g n 
wit h  a  p ossi bl e s a  m pl e si z e  a dj ust  m e nt  aft er  a  pl a n n e d i nt eri  m  a n al ysis   wit h  a  c h e c k f or f utilit y.  
  
T h e t  w o -st a g e,  gr o u p-s e q u e nti al,  a d a pti v e  d esi g n   wit h  o n e i nt eri  m  a n al ysis  a n d  a si n gl e  pri  m ar y 
e n d p oi nt   w as  e v al u at e d  b y si  m ul ati o ns t o i n v esti g at e t h e  a p pr o pri at e n ess  of t his  a p pr o a c h f or t h e 
st u d y  o bj e cti v es,  at t h e ti  m e  of t h e  ori gi n al st u d y  d esi g n.   Det ails  of t h e s e si  m ul ati o ns   will  b e 
gi v e n i n t h e  S  A P.  Pri or t o t h e i nt eri  m  a n al ysis , t h e st u d y  d esi g n   w as   m o difi e d t o i n c or p or at e o n e  
a d diti o n al c o-pri  m ar y  e n d p oi nt  ( b as e d  o n t h e   N  K  C  C-l o  w s u b gr o u p). F urt h er si  m ul ati o ns   w er e 
c o n d u ct e d  a n d  d et ails  of t h es e   will  als o  b e  pr o vi d e d i n t h e  S  A P. 
 
1 3. 1 1. 1  
P a r a  m et e rs  a n d R es ults  of S a  m pl e S i z e D et e r  mi n ati o n  
St u d y s a  m pl e si z e  esti  m ati o ns  a n d  ass u  m pti o ns b as e d  o n t h e  ori gi n al st u d y  d esi g n (i. e., wit h  a 
si n gl e  pri  m ar y  e n d p oi nt) ar e s u  m  m aris e d i n  T a bl e   8. T h e  pri  m ar y  o bj e cti v e  of t h e st u d y is t o 
d et e ct  a st atisti c all y si g nifi c a nt  diff er e n c e i n  P F S f or t h e  e x p eri  m e nt al tr e at  m e nt  ar  m r el ati v e t o 
t h e  c o  m p ar at or  ar  m.   At t h e ti  m e  of t h e  ori gi n al st u d y  d esi g n, it w as ass u  m e d t h at t h e   m e di a n  P F S 
i n t h e   M  O  R 0 0 2 0 8 wit h   B E  N   gr o u p   w o ul d  e q u al  7. 0   m o nt hs  v ers us  4. 9   m o nt hs i n t h e  c o  m p ar at or 
st a n d ar d tr e at  m e nt   R T  X wit h   B E  N gr o u p ( H  R   of  0. 7 0),  b as e d  o n lit er at ur e  d at a (O h  m a c hi  et  al. 
2 0 1 3 , V a cir c a  et  al.  2 0 1 4 ). A t  w o -st a g e,  gr o u p-s e q u e nti al,  a d a pti v e  d esi g n   wit h  o n e i nt eri  m 
a n al ysis w as  pl a n n e d .  T esti n g  of t h e  n ull  h y p ot h esis  at t h e fi n al  a n al ysis w o ul d  b e  b as e d  o n t h e 
i n v ers e  n or  m al   m et h o d  a p pl yi n g   O’  Bri e n- Fl e  mi n g  b o u n d ar y (O'  Bri e n  a n d  Fl e  mi n g  1 9 7 9 , 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 2  of  1 3 1  
W ass  m er  2 0 0 6 ).  T his  pr o c e d ur e  pr es er v es t h e  o v er all ( e x p eri  m e nt-wis e) t y p e I  err or r at e  of  α = 
0. 0 5 i n  a str o n g s e ns e f or  d at a- dri v e n  c h a n g es i n  d esi g n  aft er i nt eri  m  a n al ysis  of s ur vi v al tri als.  
 
B as e d  o n t h e  ori gi n al st u d y  d esi g n  a n d  ass u  m pti o ns,  a t ot al  n u  m b er  of  2 5 6  P F S  e v e nts  ar e 
r e q uir e d  b as e d  o n  a   H  R  of  0. 7 0   wit h  8 0  %  p o  w er  at fi n al  a n al ysis, usi n g  a t  w o -si d e d l o g-r a n k t est 
at  a n  al p h a l e v el  of  4. 8  %  a n d  a  1: 1 r a n d o  mis ati o n r ati o  b et  w e e n t h e t  w o tr e at  m e nt gr o u ps.   B as e d 
o n  1 8   m o nt hs  of  e nr ol  m e nt  a n d  a  1 2-  m o nt h  F oll o  w-  U p,  2 8 6 e v al u a bl e  p ati e nts  n e e d t o  b e 
e nr oll e d.   A p pl yi n g  a  1 3  %  dr o p- o ut r at e   w o ul d r es ult i n  a t ot al  n u  m b er  of  p ati e nts  of 
a p pr o xi  m at el y  3 3 0. 
 
T a bl e   8: 
Ass u  m pti o ns  f o r  S a  m pl e  Si z e   Esti  m ati o n ( o ri gi n al st u d y  d esi g n  a n d 
ass u  m pti o ns)  
P ar a  m et er f or s a  m pl e siz e  esti  m ati o n  
 
M  O  R 0 0 2 0 8   wit h   B E  N tr e at  m e nt  ar  m: m e di a n P F S  
7. 0   m o nt hs  
R T  X   wit h   B E  N tr e at  m e nt  ar  m: m e di a n P F S  
4. 9   m o nt hs  
H a z ar d r ati o ( e x p eri  m e nt al/ c o  m p ar at or)  
0. 7 0  
O v er all si g nifi c a n c e l e v el ( o v er all t y p e I  err or r at e  of  α) 
5. 0  %  
A dj ust e d si g nifi c a n c e l e v el  at i nt eri  m  a n al ysis ( O’  Bri e n- Fl e  mi n g)  
0. 5 2  %  
A dj ust e d si g nifi c a n c e l e v el  at fi n al  a n al ysis ( O’  Bri e n- Fl e  mi n g)  
4. 8  %  
P o  w er  
8 0  %  
E nr ol  m e nt  d ur ati o n (  m o nt hs)  
1 8  
F oll o  w -u p  d ur ati o n (  m o nt hs)  
1 2  
A c cr u al r at e  
A b o ut  1 7  p ati e nts/  m o nt h  
E v e nts r e q uir e d  
2 5 6  
E v al u a bl e  p ati e nts t o  b e  e nr oll e d  
2 8 6  
O v e r all  p ati e nt  n u  m b e r (i n cl u di n g  1 3 %  d r o p - o ut) 
3 3 0  
 
Wit h  pr o p os e d i ntr o d u cti o n  of  c o- pri  m ar y  e n d p oi nt i n   N  K  C  C-l o  w s u b gr o u p,  a n d  a s plit  of t ot al 
al p h a  of  4. 8  % i n t h e  o v er all ( F  A S)  p o p ul ati o n  a n d t h e N  K  C  C -l o  w s u b gr o u p, t h er e   will  b e  a 
c h a n g e i n t h e  p o  w er  of t h e t  w o- si d e d l o g r a n k t est if t h e t ot al  n u  m b er  of  o v er all ( F  A S) P F S 
e v e nts is  k e pt  u n c h a n g e d  at  2 5 6.  T h e t a bl e  b el o  w  pr es e nts t h e  ass u  m pti o ns  a n d t h e  p o  w er  as  a 
c o ns e q u e n c e  of  al p h a-s plitti n g  a n d i ntr o d u cti o n  of t h e  c o- pri  m ar y  e n d p oi nt: 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 3  of  1 3 1  
T a bl e   9: 
P o  w e r C al c ul ati o n f o r O v e r all  P o p ul ati o n  a n d t h e N  K  C  C -lo  w  S u b g r o u p ( as  a 
c o ns e q u e n c e  of a l p h a splitti n g)  u n d e r  diff e r e nt s c e n a ri os  
O v er all  P o p ul ati o n 
Ass u  m pti o n  
N =  3 3 0  
N = 4 5 0  
M e di a n  P F S  =  7  m  vs.  4. 9  m  
M e di a n  P F S  =  7  m  vs.  4. 9  m  
H a z ar d r ati o  =  0. 7  
H a z ar d r ati o  =  0. 7  
E v e nts  =  2 5 6  
E v e nts  = 3 6 9  
Al p h a  =  3. 4  %  
Al p h a  =  3. 4  %  
P o  w er  =  7 7  %  
P o  w er  =  9 0  %  
P ossi bl e  S c e n ari os f or   N  K  C  C -l o  w  S u b gr o u p  
O v er all  P o p ul ati o n  S a  m pl e 
Si z e  
N =  3 3 0  
N = 4 5 0  
N  K  C  C -l o  w S a  m pl e  Si z e  
1 3 2 ( 4 0  %)  
1 4 8 ( 4 5  %)  
1 6 5 ( 5 0  %)  
1 8 0 ( 4 0  %)  
2 0 2 ( 4 5  %)  
2 2 5 ( 5 0  %)  
M e di a n  P F S  (  m o nt hs) 
5  vs.  3  
5  vs.  3  
5  vs.  3  
5  vs.  3  
5  vs.  3  
5  vs.  3  
H a z ar d   R ati o  
0. 6  
0. 6  
0. 6  
0. 6  
0. 6  
0. 6  
E v e nts  
1 0 9  
1 2 3  
1 3 7  
1 5 4  
1 7 1  
1 9 1  
Al p h a (t  w o -si d e d) 
1. 4  %  
1. 4  %  
1. 4  %  
1. 4  %  
1. 4  %  
1. 4  %  
P o  w er  
0. 5 8  
0. 6 5  
0. 7 0  
0. 7 6  
0. 8 1  
0. 8 6  
 
Pr o p orti o n  of t ot al ev e nts  
0. 4 3  
0. 4 8  
0. 5 4  
0. 4 2  
0. 4 6  
0. 5 2  
Al p h a  a dj ust e d (t  w o -si d e d) * 
2. 0  %  
2. 2  %  
2. 3  %  
2. 0  %  
2. 1  %  
2. 2  %  
P o  w er  a dj ust e d  
0. 6 3  
0. 7 1  
0. 7 6  
0. 8  
0. 8 5  
0. 8 9  
*   Ass u  mi n g  c orr el ati o n  b et  w e e n t h e s u b gr o u p  a n d t h e  o v er all  p o p ul ati o n (S pi ess e ns  a n d   D e b ois  2 0 1 0 ). 
 
As  o utli n e d i n  S e cti o n  1 3. 1 2 ,  at t h e ti  m e  of t h e i nt eri  m  a n al ysis, t h e I  D  M  C   will  h a v e t h e  o pti o n 
of r e c o  m  m e n di n g  a n i n cr e as e i n s a  m pl e si z e t o  4 5 0  p ati e nts.  T h e st atisti c al  d et ails f or  a s a  m pl e 
si z e i n cr e as e t o  4 5 0  p ati e nts,  b as e d  o n t h e r e vis e d st u d y  d esi g n (i. e.,   wit h t  w o c o-pri  m ar y 
e n d p oi nts  a n d  al p h a s p e n di n g )  ar e s u  m  m ari z e d i n t h e  S  A P.  
 
I n  a d diti o n t o  P F S,   O S is  c o nsi d er e d  a n i  m p ort a nt  e n d p oi nt t o i nf or  m  b ot h  effi c a c y  a n d s af et y.  
T a bl e 1 0  b e l o  w  pr o vi d es  d et ails  o n t h e  o p er ati n g  c h ar a ct eristi cs f or   O S at t h e ti  m e  of  Fi n al 
A n al ysis: 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 4  of  1 3 1  
T a bl e 1 0 :  
O p e r ati n g   C h a r a ct e risti cs f o r   O S  at t h e  Fi n al   A n al ysis  
S a  m pl e  Si z e   C o nsi d e r ati o ns  
D et ails  
S a  m pl e  Si z e  
4 5 0  
M e di a n   O S i n  c o ntr ol  ar  m (  R T  X   wit h   B E  N)  
F ull  p o p ul ati o n:  1 0   m o nt hs  
N  K  C  C -l o  w s u b gr o u p:  7   m o nt hs 
M e di a n   O S i n  e x p eri  m e nt al  ar  m ( M  O  R 0 0 2 0 8  wit h   B E  N)  
F ull  p o p ul ati o n:  1 4. 3   m o nt hs  
N  K  C  C -l o  w s u b gr o u p:  1 1. 7 m o nt hs  
Ass u  m e d   O S   H  R  
F ull  p o p ul ati o n:  0. 7  
N  K  C  C -l o  w s u b gr o u p:  0. 6 
T est 
2- si d e d str atifi e d l o g-r a n k t est 
Gl o b al si g nifi c a n c e l e v el  
t  w o-si d e d  5  % 
E x p e ct e d   O S  e v e nts 1  
F ull  p o p ul ati o n:  3 3 8 1 
N  K  C  C -l o  w s u b gr o u p:  1 3 52 
L o c al t  w o -si d e d si g nifi c a n c e l e v el 
F ull  p o p ul ati o n:  3. 4  %  
N  K  C  C -l o  w s u b gr o u p:  1. 4  % 
P o  w er  at t h e ti  m e  of  Fi n al   A n al ysis  
F ull  p o p ul ati o n:  8 8  %  
N  K  C  C -l o  w s u b gr o u p:  7 0  %  
1 T h es e  n u  m b ers  ar e  b as e d  o n t h e  ass u  m pti o n t h at  Fi n al   A n al ysis   will  o c c ur   w h e n  a p pr o xi  m at el y  7 5  %  of  p ati e nts  h a v e  di e d  b ut 
usi n g l o c al si g nifi c a n c e l e v els  as st at e d i n  Fi g ur e  9 -1  of t h e  S  A P.  
2 Ass u  mi n g  4 0  %  of  all  p ati e nts  b el o n g t o t h e   N  K  C  C -l o  w s u b gr o u p. 
 
I n  c o n n e cti o n   wit h t h e  a b o v e, T a bl e 1 1  pr o vi d es t h e  p o  w er  c al c ul ati o ns f or   O S  gi v e n t h e 
diff er e nt  n u  m b er  of  p ossi bl e   O S  e v e nts i n t h e  F  A S  a n d t h e   N  K  C  C -l o  w s u b gr o u p: 
 
T a bl e 1 1 :  
P o  w e r   A n al ys es f o r   O S  
F ull  p o p ul ati o n  
N  K  C  C -l o  w s u b g r o u p 
N u  m b e r  of   O S 
e v e nts 
Inf o r  m ati o n 
f r a cti o n 
P o  w e r  
N u  m b e r  of   O S 
e v e nts 
I nf o r  m ati o n 
f r a cti o n 
P o  w e r  
2 5 0  
9 1  %  
7 6  %  
1 0 0  
6 1  %  
5 4  %  
2 7 5  
1 0 0  %  
8 0  %  
1 2 5  
7 6  %  
6 6  %  
3 0 0  
1 0 9  %  
8 4  %  
1 3 6  
( pr oj e ct e d f or 
Fi n al   A n al ysis)  
8 2  %  
7 0  %  
3 2 5  
1 1 8  %  
8 7  %  
1 5 0  
9 1  %  
7 5  %  
3 4 0  
( pr oj e ct e d f or 
Fi n al   A n al ysis)  
1 2 0  %  
8 8  %  
1 6 5  
1 0 0  %  
8 0  %  
3 5 0  
1 2 7  %  
8 9  %  
1 7 5  
1 0 6  %  
8 3  %  
* at t  w o -si d e d  al p h a  of  3. 4  % f or t h e  F  A S,  a n d  1. 4  % f or t h e   N  K  C  C-l o  w s u b gr o u p.  T h e  c al c ul ati o ns  ar e  b as e d  o n f oll o  wi n g 
ass u  m pti o ns:   m e di a n   O S f or   B  R i n  F  A S:  1 0   m o nt hs, tr u e  h a z ar d r ati o  of  0. 7;   m e di a n   O S f or   B  R i n   N  K  C  C -l o  w:  7   m o nt hs, tr u e 
h a z ar d r ati o  of  0. 6 .   
 
T h e  i nf or  m ati o n fr a cti on i n t h e  a b o v e t a bl e r ef ers t o t h e  n u  m b er  of   O S  e v e nts t h at   mi g ht  b e 
o bs er v e d  c o  m p ar e d t o t h e  c al c ul at e d  b e n c h  m ar k  n u  m b er  of   O S  e v e nts  at  8 0  %  p o  w er. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 5  of  1 3 1  
1 3. 1 2  I nt e ri  m A n al ysis  
T h e i nt eri  m  a n al ysis is  pl a n n e d  aft er t h e  o bs er v ati o n  of  5 0  %  o f t h e r e q uir e d  e v e nts, i. e.,  aft er 
1 2 8 P F S e v e nts.  T h e   H  R   will  b e  c al c ul at e d  a n d t hr e e  o ut c o  m es   will  b e  p ossi bl e  b as e d  o n t h e 
i nt eri  m r es ult.  T h e st u d y   m a y  b e st o p p e d  d u e t o f utilit y, t h e st u d y   m a y  c o nti n u e   wit h t h e 
mi ni  m u  m  pl a n n e d  n u  m b er  of  3 3 0  p ati e nts ( 2 5 6 P F S e v e nts),  or t h e s a  m pl e si z e m a y b e i n cr e as e d  
t o  4 5 0  p ati e nts (t o  o bt ai n  3 6 9  P F S  e v e nts). E arl y st o p pi n g f or  effi c a c y is  n ot  all o  w e d.  
 
T h e  p ossi bl e s c e n ari os  of  c o  m bi n ati o n  of  o bs er v e d  P F S  h a z ar d r ati os (  M  O  R 0 0 2 0 8  pl us   B E  N 
v ers us   R T  X  pl us   B E  N) i n t h e  F  A S  a n d   N  K  C  C -l o  w s u b gr o u p  a n d  p ot e nti al I  D  M  C 
r e c o  m  m e n d ati o ns b as e d  o n t h e  m ar e s u  m  m ari z e d i n T a bl e  1 2 .  
 
T a bl e   1 2:  
I  D  M  C D e cisi o n G ui d e B as e d  o n R es ults  of t h e Int e ri  m A n al ysis ( n o n -
bi n di n g)  
S c e n a ri o  
O bs e r v e d  P F S  h a z a r d  r ati o  at i nt e ri  m 
a n al ysis  
( e x p e ri  m e nt al  vs  c o  m p a r at o r  a r  m) 
I  D  M  C  r e c o  m  m e n d ati o n 
 
O v e r all  p o p ul ati o n  
N  K  C  C -l o  w 
s u b g r o u p 
 
1 
≤ 0. 7 5  
≤ 0. 6 5  
C o nti n u e tri al   wit h o ut s a  m pl e si z e   m o difi c ati o n  
( S S  = 3 3 0) , if  b ot h  c o n diti o ns  ar e   m et. 
2 
> 0. 8 5  
> 0. 7 5  
St o p f or f utilit y , if  b ot h  c o n diti o ns  ar e   m et. 
3 
All  ot h er s c e n ari os  
I n cr e as e s a  m pl e si z e t o  4 5 0 
 
I n  a d diti o n, t h e I  D  M  C   will r e c o  m  m e n d t o  c o nti n u e  or  n ot c o nti n u e t h e  d e v el o p  m e nt  of  a 
c o  m p a ni o n  di a g n osti c.  G ui d a n c e f or I  D  M  C r e c o  m  m e n d ati o ns   will   b e  pr o vi d e d i n t h e I  D  M  C 
c h art er. 
F or  c o nfir  m at or y  h y p ot h esis t esti n g  at t h e fi n al  a n al ysis, t h e i n v ers e  n or  m al   m et h o d  of 
c o  m bi ni n g t h e  p- v al u es   will  b e  us e d.  T his  pr o c e d ur e  pr es er v es t h e  o v er all ( e x p eri  m e nt -wis e) 
t y p e I  err or r at e  of  α  =  0. 0 5 (t  w o-si d e d). 
 
1 3. 1 3  P r o c e d u r es f o r   Missi n g,   U n us e d,  a n d  S p u ri o us   D at a  
Missi n g  v al u es   will  n ot  b e s u bstit ut e d  b y  esti  m at e d  v al u es  b ut   will  b e tr e at e d  as   missi n g i n t h e 
st atisti c al  e v al uati o n.   All  d at a fr o  m  all  p ati e nts r a n d o  mis e d i n t h e st u d y   will  b e i n cl u d e d i n  all 
listi n gs,  pl ots, s u  m  m ar y t a bl es,  a n d st atisti c al  a n al ys es   wit h r es p e ct t o t h e  a n al ysis  p o p ul ati o ns 
assi g n e d t o t h e  v ari o us  o bj e cti v es.  
 
1 3. 1 4  R ul es f o r   E x cl u di n g  P ati e nts f r o  m A n al ysis  
All  d os e d  p ati e nts   will  b e i n cl u d e d i n t h e  a n al ys es  u nl ess  n ot  ot h er  wis e s p e cifi e d ( e. g. , wit h 
r es p e ct t o t h e  diff er e nt  a n al ysis  p o p ul ati o n  d efi niti o ns). 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 0 6  of  1 3 1  
1 3 . 15  Pr oce d ures  f or Re p orti n g De vi ati o ns fr o m  Ori gi n al  St atistic al Pl a n 
Details of  the a nal yses  t o be perfor me d  o n data fr o m t his st u d y will be pr o vi de d i n a se parate 
S A P. A n y de viati o ns fr o m the statistical anal ysis o utli ne d i n t his pr ot oc ol will be de scri be d, a n d 
reas o ns f or t he deviati o ns  liste d, i n t he fi nal cli nical st u d y re p ort. 
1 4  S P E CI A L  RE Q UI R E M E N T S  AN D  P R O C E D U R E S  
1 4 . 1 I n de pe n dent D at a M o nit ori n g C o m mittee  (I DM C)  
T he de sig n of the stu d y s pecifies t he esta blis h me nt of a n  I DM C  acc or di n g  t o t he I C H E 9  
g ui deli ne an d i n li ne w it h t he rec o m me n dati o ns of the U S  F D A G ui da nce o n “ Est a blis h me nt a n d 
O per ati o n  o f Cli nic al Tri al D at a M onit ori n g  Co m mittees ” (Marc h 2 0 0 6 ). The  ID M C  will be  
res p o nsi ble f or pe ri o dically m o nit ori n g st u d y e nr ol me nt statistics, c o m plia nce, a n d efficac y a n d 
safet y data fr o m the o n g oi n g trial a n d f or alerti n g t he sp o ns or of p os sible c o ncer ns relate d t o the 
c o n d uct of t he trial. 
T he sp o ns or w ill ap p oi nt the I D M C pri or to t he ra n d o mi sati o n of t he first patie nt i nt o  the  st u d y. 
As  t he co m bi nati o n  of M O R 0 0 2 0 8 an d  BE N  w ill be syste maticall y  e val uate d  f or t he first ti me i n 
a setti n g  of a cli nical trial, I DM C  revie w  will be ma n date d d uri n g I nitia l Sa fet y E val uati o n 
(P h ase  II of t he trial) t o c o ncl u de w het her t he c o m bi nati o n treat me nts  are safe (see Fi g ure 1 ). 
I n t he co urse of I nitial Safet y E val uati o n, t he  first t hree patie nts in b ot h i n vesti gati o nal ar ms 
( M O R 0 0 2 0 8 + B E N a n d R T X + B E N)  will be d ose d se q ue ntiall y wit h a 4 8- h o ur la g peri o d 
bet wee n t he enr ol me nt s of tw o c o nsec uti ve p atie nts (c o u nte d fr o m C 1 D 4). 
Af ter c o m pleti o n o f t he first treat me nt wee k ( C1 D 8) b y  t he thir d  co nsec uti ve  pa tie nt i n eac h  ar m 
(a p pr o xi matel y 6 patie nts in t otal) the safet y data w ill be re vie we d b y t he I D M C. 
F oll o wi n g a p ositi ve rec o m me n dati o n of the ID M C, se ve n a d diti o nal pa tie nts i n eac h  ar m  ma y 
be  d ose d i n paralle l (a p pr o xi matel y  14  pa tie nts i n t otal). A n  ad diti o nal I D M C  revie w  will ta ke  
place  after t he last of 1 0 pa tie nts i n eac h  ar m (a p pr o xi matel y 2 0  patie nts in  t otal) ha ve co m plete d  
C 3 D 1  visit i n t heir res pecti ve treat me nt all ocati o n ar m (c o m plete I nitial Safet y Eval uati o n).  
T he e xact n u m ber of patie nts eli gi ble f or e val uati o n de pe n ds o n t he treat me nt all ocati o n w it hi n 
t he ra n d o misati o n bl oc ks. Furt her m ore, f or e ver y patie nt w h o wit h dra ws or disc o nti n ues i n t he 
c o urse of I nitial Safet y E val uati o n bef ore ha vi n g recei ve d st u d y dr u g o n C ycle 3 Da y 1, a ne w 
patie nt ma y be ra n d o mise d. F or a  sc he matic prese ntati o n of t he st u d y o utli ne, see Fi g ure 1 an d 
Fi g ure 2. 
S h o ul d  t he ID M C  mai ntai n t heir i nitial rec o m me n dati o n t hat t he co m bi nati o n  treat me nts are 
safe, t he trial ma y procee d  fur t her wit h recr uit me nt  (P hase  III of the  trial). S u bse q ue nt ID M C 
meeti n gs w ill be calle d f or as o ut li ne d i n t he I D M C C harter t hr o u g h o ut t he entire trial. 
Recr uit me nt  w ill c o nti n ue sea mlessl y be t wee n meeti n gs u nles s s pecificall y re q ueste d b y I D M C. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 7  of  1 3 1  
E a c h I  D  M  C r e vi e  w   will  e n c o  m p ass t h e  n u  m b er , fr e q u e n c y, s e v erit y a n d t y p e  of   A Es,  as   w ell  as 
cli ni c al l a b or at or y  bi o c h e  mistr y  a n d  h ae  m at ol o g y  p ar a  m et ers  a n d  ot h er r el e v a nt s af et y  d at a.  T h e 
I  D  M  C   will  als o a d vis e t h e s p o ns or w h et h er t h e tri al  d esi g n r e q uir es   m o difi c ati o ns  or  h as   m et t h e 
pr e- d efi n e d tri al st o p pi n g r ul es . 
 
I n  a d diti o n, t h e I  D  M  C   will  b e  e ntr ust e d t o  c o n d u ct t h e tri al’s  pl a n n e d i nt eri  m  a n al ysis  as  a 
c o nfi d e nti al  pr o c ess.   Alt h o u g h t h e tri al   will  b e  c o n d u ct e d i n  a n  o p e n- l a b el f as hi o n,   w h er e 
i n v esti g at ors  a n d  p ati e nts  ar e  a  w ar e  of i n di vi d u al tr e at  m e nt  assi g n  m e nt  a n d  o ut c o  m e  at t h eir sit e, 
t h e r es ults  of t h e  c o  m p ar ati v e i nt eri  m  a n al ysis (tr e at  m e nt  ar  m  v ers us  c o  m p ar at or  ar  m)   will  o nl y 
b e  a v ail a bl e t o I  D  M  C   m e  m b ers. T his f ulfils t h e  n e e d  of r estri cti n g t h e  a n al ysis  c o n d u ct  a n d t h e 
dis cl os ur e  of  t h e i nt eri  m  a n al ysis r es ults t o  o nl y  a li  mit e d  a n d  pr e d et er  mi n e d  n u  m b er  of  p e o pl e 
f or t h e  p ur p os e  of   m ai nt ai ni n g t h e i nt e grit y  of t h e tri al. T h e ID  M  C   will  o p er at e  u n d er  a   C h art er 
t h at  d es cri b es t h e c o  m p ositi o n, r ol es  a n d r es p o nsi biliti es  of t h e  c o  m  mitt e e  a n d i d e ntifi es t h e 
m e  m b e rs  a n d t h e  c o nt a ct  p ers o ns r el e v a nt t o t h e tri al. All  ot h er  p ers o ns i n v ol v e d i n t h e tri al 
c o n d u ct   will r e  m ai n  bli n d e d t o t h e i nt eri  m  a n al ysis r es ults  u ntil t h e r e g ul ar  e n d  of t h e tri al  h as 
b e e n r e a c h e d ,  or  u ntil t h e tri al  h as  b e e n st o p p e d  e arli er ( d u e t o f utilit y,  or  b y  d e cisi o n  of t h e 
s p o ns or).   
 
T h e I  D  M  C   will  b e  a d vis or y t o t h e s p o ns or. T h e sp o ns or   will  b e r es p o nsi bl e f or r e vi e  wi n g t h e 
I  D  M  C r e c o  m  m e n d ati o ns, t o  d e ci d e   w h et h er t o  c o nti n u e  or t er  mi n at e t h e tri al  d u e t o f utilit y,  a n d 
t o  d et er  mi n e   w h et h er a n y  a  m e n d  m e nt t o t h e  pr ot o c ol  or  c h a n g es i n st u d y  c o n d u ct  ar e r e q uir e d. 
 
T h e i nf or  m ati o n  a b o ut f urt h er st u d y  c o n d u ct  aft er t h e i nt eri  m  a n al ysis   will  b e  us e d f or  a  p ossi bl e 
a  m e n d  m e nt  of t h e  e xisti n g tri al  pr ot o c ol  or  as  n e e d e d  b y t h e r e g ul at or y  a ut h oriti es. 
 
If t h e s p o ns or  d e ci d es t o st o p t h e tri al  d u e t o f utilit y,  dis cl os ur e  of t h e r es ults will  b e  p erf or  m e d 
as  us u al f oll o  wi n g t h e  d efi n e d  pri n ci pl es  at  a fi n al  a n al ysis. If t h e s p o ns or  d e ci d es t o  c o nti n u e t h e 
tri al  or t o  c o nti n u e t h e tri al   wit h   m o difi c ati o ns, th e i nt eri  m r es ults   will  b e  k e pt  c o nfi d e nti al. 
I n v esti g at ors   will  o nl y  b e i nf or  m e d  a b o ut t h e  d e cisi o n t o  c o nti n u e/t o  c o nti n u e   wit h 
m o difi c ati o ns/ or t o  dis c o nti n u e t h e tri al.  
 
1 4. 2  I n d e p e n d e nt   R a di ol o g y/  Cli ni c al   R e vi e  w   C o  m  mitt e e  (I  R  C) 
T h e  pri  m ar y  e n d p oi nt, P F S ,   will  b e e v al u at e d t hr o u g h c e ntr al r e vi e  w  b y t h e I  R  C.  T h e  pr o c ess 
will  b e  d efi n e d i n d et ails i n t h e t e xt  of t h e I  R  C   Ch art er . 
 
F or r a di ol o g y ass ess  m e nt, t  w o  pri  m ar y r e vi e  w ers (  R a di ol o g y   R e vi e  w ers   1  a n d  2)   will 
i n d e p e n d e ntl y r e vi e  w  e a c h  p ati e nt’s s c a ns  a c c or din g t o t h e I nt er n ati o n al   W or ki n g   Gr o u p 2 0 0 7 
r es p o ns e  crit eri a (C h es o n  et  al.  2 0 0 7 ).   A dj u di c ati o n   will  b e r e q uir e d if R a di ol o g y   R e vi e  w ers  1 
a n d  2  dis a gr e e  o n t h e  o ut c o  m es,  n a  m el y   D at e  of  Pr o gr essi o n,   B est   R es p o ns e,  a n d/ or   D at e  of 
I niti al   R es p o ns e. I n  or d er t o r es ol v e  dis cr e p a n ci es,   R e vi e  w er  3 (  A dj u di c at or)   will i n d e p e n d e ntl y 
e v al u at e t h e  c as e  i n  q u esti o n.   R e vi e  w er  3   will  h a v e si  m ult a n e o us a c c ess t o  all i  m a g es  a n d 
pr e vi o us  ass ess  m e nts (i . e., i  m a g es, i  m a g e  o v erl a ys, ti  m e  p oi nt  e v al u ati o ns,  a n d s u  m  m ar y 
fi n di n gs fr o  m  b ot h  pri  m ar y re vi e  w ers).   R e vi e  w er i d e ntit y   will  b e f ull y  bli n d e d.   R e vi e  w er  n a  m es 
will  n ot  b e a d d e d t o t h e i nf or  m ati o n  pr o vi d e d f or  a dj u di c ati o n,  a n d f urt h er  m or e, t h e  or d er i n 
w hi c h t h eir fi n di n gs  ar e  pr es e nt e d   will  b e r a n d o  mis e d  a cr oss  c as es t o  pr e v e nt  c o n diti o n e d  bi as. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 8  of 1 3 1  
R e vi e  w er  3   will  c h o os e t h e  ass ess  m e nt t h at  h e  or s h e  c o nsi d ers t o r e pr es e nt t h e   m or e  c orr e ct 
ass ess  m e nt  of t h e  o ut c o  m es i n t h e f oll o  wi n g  or d er  of  pr e c e d e n c e:   D at e  of  Pr o gr essi o n,   B est 
R es p o ns e,  a n d   D at e  of I niti al   R es p o ns e.  
 
F oll o  wi n g r a di o l o g y r e vi e  w, t h e fi n al r a di ol o g y  ass ess  m e nts  a n d  p ati e nt  cli ni c al  d at a   will  b e 
pr es e nt e d t o t h e  cli ni c al  o n c ol o gist   w h o   will d et er  mi n e t h e fi n al  o ut c o  m e f or  e a c h  p ati e nt  b as e d 
o n r e vi e  w  of  b ot h i  m a gi n g  a n d  cli ni c al  d at a.  
 
T h e  o ut c o  m e  of t his r e vi e  w is  eit h er t h e  P F S  d at e  or  a  c e ns or i n g d at e,   w hi c h is t h e  d at e  of l ast 
f oll o  w-u p   wit h o ut  e vi d e n c e  of  dis e as e  pr o gr essi o n f or  all  p ati e nts s u b  mitt e d f or r e vi e  w.  
 
1 4. 3  P r ot o c ol   A  m e n d  m e nts  a n d   Ot h e r   C h a n g es i n  St u d y   C o n d u ct  
A n y  c h a n g es t o t h e  pr ot o c ol   will  b e   m a d e i n t h e f or  m  of  a n  a  m e n d  m e nt. 
 
C h a n g es t o t h e  c o n d u ct  of t h e st u d y  ar e  n ot  p er  mitt e d.   A n y  u nf or es e e n  c h a n g es i n t h e st u d y 
c o n d u ct   will  b e r e c or d e d i n t h e  cli ni c al st u d y r e p ort.  
 
1 4. 4  R e g ul at o r y  a n d   Et hi c al   C o nsi d e r ati o ns, I n cl u di n g t h e I nf o r  m e d   C o ns e nt 
P r o c ess  
Pri o r t o i niti ati o n  of  a st u d y sit e, I n c yt e   C or p or ati o n will  o bt ai n f a v o ur a bl e  o pi ni o n/ a p pr o v al 
fr o  m t h e  a p pr o pri at e r e g ul at or y  b o di es/l o c al  h e alt h  a ut h oriti es (i n  a c c or d a n c e   wit h l o c al 
r e g ul ati o ns)  a n d t h e I  R  B/I E  C t o  c o n d u ct t h e st u d y i n  a c c or d a n c e   wit h I  C  H   GC P  a n d  a p pli c a bl e 
c o u ntr y -s p e cifi c r e g ul at or y r e q uir e  m e nts. 
 
N o s u bst a nti al  c h a n g es t o t h e fi n al  a p pr o v e d  pr ot o c ol   will  b e i niti at e d   wit h o ut t h e I  R  B’s/I E  C’s 
pri or   writt e n  a p pr o v al  or f a v o ur a bl e  o pi ni o n  a n d  a p pr o v al  b y t h e r e g ul at or y  b o di es/l o c al  h e alt h 
a uth oriti es,  e x c e pt   w h e n  n e c ess ar y t o  eli  mi n at e i  m  m e di at e  h a z ar ds t o t h e  p ati e nts  or   w h e n t h e 
c h a n g e i n v ol v es  o nl y l o gisti cs  or  a d  mi nistr ati o n.  
 
T his  cli ni c al st u d y   w as  d esi g n e d  a n d s h all  b e  c o n d u ct e d  a n d r e p ort e d i n  a c c or d a n c e   wit h t h e 
pr ot o c ol,   wit h I  C  H E 6   G  C P  g ui d eli n es,   wit h  a p pli c a bl e l o c al r e g ul ati o ns,  a n d   wit h t h e  et hi c al 
pri n ci pl es l ai d  d o  w n i n t h e   D e cl ar ati o n  of   H elsi n ki, i n cl u di n g,  b ut  n ot li  mit e d t o:  
•  I  R  B/I E  C r e vi e  w  a n d f a v o ur a bl e  o pi ni o n/ a p pr o v al  of t h e st u d y  pr ot o c ol  a n d  a n y 
s u bs e q u e nt  a  m e n d  m e nts 
•  P ati e nt i nf or  m e d  c o ns e nt  
•  In v esti g at or r e p orti n g r e q uir e  m e nts . 
 
T h e i n v esti g at or   will  o bt ai n fr e el y  gi v e n   writt e n  c o ns e nt fr o  m  e a c h  p ati e nt  aft er  a n  a p pr o pri at e 
e x pl a n ati o n  of t h e  ai  ms,   m et h o ds,  a nti ci p at e d  b e n efits,  p ot e nti al  h a z ar ds  a n d  a n y  ot h er  as p e ct  of 
t h e st u d y t h at is r el e v a nt t o t h e  p ati e nt's  d e cisi o n t o  p arti ci p at e. 
 
I nf or  m e d co ns e nt   m ust  b e  gi v e n  b y t h e  p ati e nt  b ef or e t h e  p ati e nt is  e x p os e d t o  a n y st u d y -r el at e d 
pr o c e d ur e, i n cl u di n g s cr e e ni n g t ests f or  eli gi bilit y.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 0 9  of 1 3 1  
1 4. 5  Q u alit y   C o nt r ol ( St u d y   M o nit o ri n g)  
St u d y   m o nit ori n g   will  b e  p erf or  m e d i n  a c c or d a n c e   wit h I  C  H  E 6   G  C P  g ui d eli n es, t h e s p o ns or’s 
a n d   C  R  O’s  S  O Ps, t h e s p o ns or’s  a n d   C  R  O’s   writt e n i nstr u cti o ns, t h e  pr ot o c ol,  a n d  all  a p pli c a bl e 
l a  ws  a n d r e g ul ati o ns.  
 
T h e s p o ns or’s   m o nit ors   will  c o nt a ct t h e si t e  pri or t o t h e st art  of t h e st u d y t o r e vi e  w   wit h t h e sit e 
st aff t h e  pr ot o c ol, st u d y r e q uir e  m e nts,  a n d t h eir r es p o nsi biliti es t o s atisf y r e g ul at or y,  et hi c al,  a n d 
t h e s p o ns or’s r e q uir e  m e nts.  
 
I n c yt e   C or p or ati o n a n d t h e   C  R  O  will   m o nit or t h e st u d y t o  e ns ur e t h at t h e: 
•  D at a  ar e  a ut h e nti c,  a c c ur at e,  a n d  c o  m pl et e  
•  S af et y  a n d ri g hts  of  p ati e nts  ar e  b ei n g  pr ot e ct e d  
•  S t u d y is  c o n d u ct e d i n  a c c or d a n c e   wit h t h e  c urr e ntl y  a p pr o v e d  pr ot o c ol  a n d  a n y  ot h er 
st u d y  a gr e e  m e nts,   G  C P,  a n d  all  a p pli c a bl e r e g ul at or y r e q uir e  m e nts. 
 
T h e i n v esti g at or  a n d t h e  h e a d  of t h e   m e di c al i nstit uti o n (  w h er e  a p pli c a bl e)  a gr e e t o  all o  w t h e 
m o nit or  dir e ct  a c c ess t o  all s o ur c e  d at a  d o c u  m e nts.  
 
1 4. 6  Q u alit y   Ass u r a n c e  
A c c or di n g t o I  C  H  E 6   G  C P  g ui d eli n es, t h e s p o ns or  or r e g ul at or y  a ut h oriti es   m a y  a u dit t h e 
i n vesti g ati o n al sit es.  T h e s p o ns or’s   Q u alit y   Ass ur a n c e   U nit  a n d/ or t h eir  a ut h oris e d 
r e pr es e nt ati v e(s), i n d e p e n d e nt  of t h e   Cli ni c al   O p er ati o ns  a n d   Cli ni c al   D e v el o p  m e nt 
D e p art  m e nt s,  ar e r es p o nsi bl e f or  a u diti n g t h e st u d y.  T h e i n v esti g at or   m ust  a c c e pt s u c h  a u dits  b y 
t h e s p o ns or’s   Q u alit y   Ass ur a n c e   U nit  a n d/ or t h eir  a ut h oris e d r e pr es e nt ati v e(s)  a n d  e ns ur e  a c c ess 
t o  all s o ur c e  d at a/ d o c u  m e nts. 
 
T h e i n v esti g at or   m ust  a c c e pt t h at r e g ul at or y  a ut h oriti es   m a y  c o n d u ct  a n i ns p e cti o n t o  v erif y 
c o  m pli a n c e  of t h e st u d y wit h   G  C P  g ui d eli n es. If i nf or  m e d t h at  a r e g ul at or y i ns p e cti o n   will t a k e 
pl a c e, t h e i n v esti g at or   m ust i nf or  m t h e s p o ns or   wit h o ut  d el a y.  
 
1 4. 7  I ns u r a n c e 
T his st u d y is  c o v er e d  u n d er t h e s p o ns or’s  Li a bilit y I ns ur a n c e  P oli c y  c o v eri n g d a  m a g e t o  p ati e nts 
a c c or di n g t o a p pli c a bl e l e g al r e q uir e  m e nts .   A  c o p y  of t h e   C ertifi c at e  of I ns ur a n c e  a n d/ or  a n 
i nf or  m ati o n l e afl et  c o nt ai ni n g  ess e nti al i nf or  m ati o n  a b o ut t h e i ns ur a n c e  c o v er a g e   will  b e 
pr o vi d e d t o t h e i n v esti g at or  as r e q uir e d  b y   R e g ul at or y   A ut h oriti es, I  R  Bs  or I E  Cs.  
 
T h e  i n v esti g at or   m ust i nf or  m t h e  p ati e nts  a c c or di n gl y  a n d   m ust  als o  p oi nt  o ut t h at t h e  p ati e nts 
ar e  all o  w e d t o  u n d er g o  ot h er   m e di c al tr e at  m e nt ( e x c e pt i n  a n  e  m er g e n c y)  o nl y   wit h t h e 
i n v esti g at or’s  pri or  a p pr o v al  or t o r e c ei v e  a d diti o n al   m e di c ati o n  o nl y   wit h th e i n v esti g at or’s  pri or 
a p pr o v al. 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 0  of  1 3 1  
1 4. 8  P u bli c ati o n  P oli c y  
A n y  pr es e nt ati o n  or  p u bli c ati o n  of  d at a fr o  m t his st u d y   will  b e i nt e n d e d  as  a j oi nt  p u bli c ati o n  b y 
t h e i n v esti g at or(s)/ a p pr o pri at e st u d y  c e ntr e  p ers o n n el  a n d  a p pr o pri at e s p o ns or  p ers o n n el. 
A ut h ors hi p   wi ll f oll o  w t h e I nt er n ati o n al   C o  m  mitt e e  of   M e di c al J o ur n al  E dit ors 
R e c o  m  m e n d ati o ns f or t h e   C o n d u ct,  R e p orti n g,  E diti n g,  a n d  P u bli c ati o n  of  S c h ol arl y   W or k i n 
M e di c al  J o ur n als  (htt p://  w  w  w.i c  mj e. or g/r e c o  m  m e n d ati o ns/ )  a n d   will  b e  d efi n e d  pri or t o t h e first 
p u bli c ati o n. 
 
F or   m ulti c e ntr e st u di es, it is   m a n d at or y t h at t h e first  p u bli c ati o n  b e  b as e d  o n  d at a fr o  m  all 
c e ntr es,  a n d t h at t h e  d at a  ar e  a n al ys e d  a n d s u b  mitt e d  as sti p ul at e d i n t h e  pr ot o c ol  b y  a st atisti ci a n 
assi g n e d  b y t h e s p o ns or. 
 
T h us,  n o i n v esti g at or  or i nstit uti o n   m a y  p u blis h  a n y r es ults  of t h e st u d y  c o n d u ct e d  at t h eir sit e, 
b ef or e s u c h  a first   m ulti c e ntr e  p u bli c ati o n is   m a d e   w hi c h  c o v ers t h e  d at a fr o  m  all  c e n tr es. T h e 
a ut h ors  h a v e t h e fi n al r es p o nsi bilit y f or t h e  d e cisi o n t o s u b  mit t h eir   m a n us cri pt  a n d s h all  b e 
gi v e n f ull  a c c ess t o t h e  d at a r es ulti n g fr o  m t h e st u d y.  
 
T h e  c o or di n ati n g i n v esti g at or  a n d/ or  a ut h ors s h all  c o or di n at e  a n y i nt e n d e d  p u bli c ati o n  of st u d y 
r es ults   wit h t h e s p o ns or, t o  e n a bl e t h e s p o ns or t o  e ns ur e t h at r es ults  ar e  pr es e nt e d i n  a 
r es p o nsi bl e  a n d  c o h er e nt   m a n n er. 
 
T h e s p o ns or r es er v es t h e ri g ht t o r e vi e  w  all   m a n us cri pts  a n d  a bstr a cts  at l e ast  6 0  d a ys  b ef or e 
t h eir s u b  missi o n f or  p u bli c ati o n  or pr es e nt ati o n.  T his is  n ot i nt e n d e d t o r estri ct  or  hi n d er 
p u bli c ati o n  or  pr es e nt ati o n,  b ut is t o  all o  w t h e s p o ns or t o  pr ot e ct t h e  c o nfi d e nti alit y  of 
i nf or  m ati o n  a n d t o  pr o vi d e  c o  m  m e nts t h at   m a y  n ot  y et  b e  a v ail a bl e t o t h e i n v esti g at or. 
 
At t h e s p o ns or’s r e q u est,  a n y  c o nfi d e nti al i nf or  m ati o n ( ot h er t h a n st u d y r es ults)   will  b e  d el et e d 
a n d  all r e as o n a bl e  c o  m  m e nts   m a d e  b y t h e s p o ns or   will  b e i n c or p or at e d  pri or t o t h e s u b  missi o n 
f or  p u bli c ati o n  or  pr es e nt ati o n. I n t h e r ar e  e v e nt t h at s u c h  p u bli c ati o n   w o ul d  aff e ct t h e 
p at e nt a bilit y  of  a n y i n v e nti o n t o   w hi c h t h e s p o ns or  h as ri g hts, t h e s p o ns or  h as t h e ri g ht t o r e q u est 
a n  a d diti o n al  d el a y t o t h e  pr o p os e d  p u bli c ati o n  of  n o   m or e t h a n  9 0 d a ys s o  as t o  all o  w t h e 
s p o ns or t o  pr ot e ct its i nt ell e ct u al  pr o p ert y ri g hts. 
 
T h e r es ults  of t h e st u d y   m a y  b e  us e d  b y I n c yt e   C or p or ati o n f or t h e  p ur p os es  of  n ati o n al  a n d 
i nt er n ati o n al r e gistr ati o n,  p u bli c ati o n,  a n d i nf or  m ati o n f or   m e di c al  pr of essi o n als. If  n e c ess ar y, 
t h e  a ut h oriti es   will  b e  n otifi e d  of t h e i n v esti g at ors’  n a  m es,  a d dr ess es,  q u alifi c ati o ns,  a n d  e xt e nt 
of i n v ol v e  m e nt. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 1  of 1 3 1  
1 5  R  E F  E  R  E  N  C  E S  
A n d ers o n   K  C,   B at es   M P,  Sl a u g h e n h o u pt   B L,  Pi n k us   G S,  S c hl oss  m a n  S F  a n d   N a dl er  L  M. 
E x pr essi o n  of  h u  m a n   B  c ell -ass o ci at e d  a nti g e ns  o n l e u k e  mi as  a n d l y  m p h o  m as:  a   m o d el  of 
h u  m a n   B  c ell diff er e nti ati o n. Bl o o d  1 9 8 4; 6 3 ( 6):  1 4 2 4-1 4 3 3.  
Ar  mit a g e J  O  a n d   W eis e n b ur g er   D  D.   N e  w  a p pr o a c h t o  cl assif yi n g  n o n -H o d g ki n's l y  m p h o  m as: 
cli ni c al f e at ur es  of t h e   m aj or  hist ol o gi c s u bt y p es.   N o n -H o d g ki n's  L y  m p h o  m a   Cl assifi c ati o n 
Pr oj e ct. J   Cli n   O n c ol 1 9 9 8; 1 6 ( 8): 2 7 8 0 -2 7 9 5.  
B alf o ur J  A  a n d   G o a   K L. B e n d a  m usti n e. Dr u gs  2 0 0 1; 6 1 ( 5):  6 3 1-6 3 8;  dis c ussi o n  6 3 9 -6 4 0.  
B ar g o u   R,  L e o  E,  Z u g  m ai er   G,   Kli n g er   M,   G o e b el er   M,   K n o p  S,  et  al. T u  m or r e gr essi o n i n 
c a n c er  p ati e nts  b y  v er y l o  w  d os es  of  a  T  c ell -e n g a gi n g  a nti b o d y. S ci e n c e  2 0 0 8; 3 2 1 ( 5 8 9 1):  9 7 4-
9 7 7.  
B a z ett   H  C.   A n  a n al ysis  of t h e ti  m e ‐r el ati o ns  of t h e  el e ctr o c ar di o gr a  ms. H e art  1 9 2 0; 7 :  3 5 3-3 7 0.  
C ar b o n e  P P,   K a pl a n   H S,   M uss h off   K,  S  mit h ers   D  W  a n d  T u bi a n a   M.   R e p ort  of t h e   C o  m  mitt e e 
o n   H o d g ki n's   Dis e as e  St a gi n g   Cl assifi c ati o n. C a n c er   R es  1 9 7 1; 3 1 ( 1 1):  1 8 6 0-1 8 6 1.  
C art er   R  H,   W a n g   Y  a n d   Br o o ks  S.   R ol e  of   C  D 1 9 si g n al tr a ns d u cti o n i n   B  c ell  bi ol o g y. I  m  m u n ol 
R es  2 0 0 2; 2 6 ( 1-3):  4 5 -5 4.  
C h es o n   B  D,   Br u g g er   W,   D a  m aj   G,   Dr e yli n g   M,   K a hl   B,   Ki  m b y  E,  et  al. O pti  m al  us e  of 
b e n d a  m usti n e i n  h e  m at ol o gi c  dis or d ers:  Tr e at  m e nt r e c o  m  m e n d ati o ns fr o  m  a n i nt er n ati o n al 
c o ns e ns us  p a n el - a n  u p d at e. L e u k  L y  m p h o  m a  2 0 1 6; 5 7 ( 4):  7 6 6-7 8 2.  
C h es o n   B  D,  Fis h er   RI,   B arri n gt o n  S F,   C a v alli  F,  S c h  w art z  L  H,  Z u c c a  E,  et  al. 
R e c o  m  m e n d ati o ns f or i niti al  e v al u ati o n, st a gi n g,  a n d r es p o ns e  ass ess  m e nt  of   H o d g ki n  a n d  n o n -
H o d g ki n l y  m p h o  m a: t h e  L u g a n o  cl assifi c ati o n. J   Cli n   O n c ol 2 0 1 4; 3 2 ( 2 7):  3 0 5 9-3 0 6 8.  
C h es o n   B  D,  Pfist n er   B, J u  w ei d   M E,   G as c o y n e   R  D,  S p e c ht  L,   H or ni n g  SJ,  et  al.   R e vis e d 
r es p o ns e  crit eri a f or   m ali g n a nt l y  m p h o  m a. J   Cli n   O n c ol 2 0 0 7; 2 5 ( 5):  5 7 9-5 8 6.  
C h es o n B  D,   W e n dt n er   C  M,  Pi e p er   A,   Dr e yli n g   M,  Fri e d b er g J,   H o el z er   D,  et  al.   O pti  m al  us e  of 
b e n d a  m usti n e i n  c hr o ni c l y  m p h o c yti c l e u k e  mi a,  n o n -H o d g ki n l y  m p h o  m as,  a n d   m ulti pl e 
m y el o  m a: tr e at  m e nt r e c o  m  m e n d ati o ns fr o  m  a n i nt er n ati o n al  c o ns e ns us  p a n el. Cli n  L y  m p h o  m a 
M y el o  m a  L e u k  2 0 1 0; 1 0 ( 1):  2 1-2 7.  
C h u  P  G,   C h e n   Y  Y,   M oli n a   A,   Ar b er   D  A  a n d   W eiss  L  M.   R e c urr e nt   B -c ell  n e o pl as  ms  aft er 
Rit u xi  m a b t h er a p y:  a n i  m  m u n o p h e n ot y pi c  a n d  g e n ot y pi c st u d y. L e u k  L y  m p h o  m a  2 0 0 2; 4 3 ( 1 2): 
2 3 3 5 -2 3 4 1.  
Cli ni c al  Tri al  F a cilit ati o n   Gr o u p (  C T F  G).   R e c o  m  m e n d ati o ns r el at e d t o  c o ntr a c e pti o n  a n d 
pr e g n a n c y t esti n g i n  cli ni c al tri als.   1 5  S e pt e  m b er  2 0 1 4.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 2  of 1 3 1  
C o c k cr oft   D  W  a n d   G a ult   M  H.  Pr e di cti o n  of  cr e ati ni n e  cl e ar a n c e fr o  m s er u  m  cr e ati ni n e. N e p hr o n  
1 9 7 6; 1 6 ( 1):  3 1-4 1.  
C oiffi er   B,  L e p a g e  E,   Bri er e J,   H er br e c ht   R ,  Till y   H,   B o u a b d all a h   R,  et  al.   C  H  O P  c h e  m ot h er a p y 
pl us rit u xi  m a b  c o  m p ar e d   wit h   C  H  O P  al o n e i n  el d erl y  p ati e nts   wit h  diff us e l ar g e -B -c ell 
l y  m p h o  m a. N  E n gl J   M e d  2 0 0 2; 3 4 6 ( 4):  2 3 5-2 4 2.  
C ol osi a   A,   Nj u e   A,  Tr as k  P  C,   Oli v ar es   R,   K h a n  S,   A b b e   A,  et  al.   Cli ni c al  e ffi c a c y  a n d s af et y i n 
r el a ps e d/r efr a ct or y  diff us e l ar g e   B-c ell l y  m p h o  m a:  a s yst e  m ati c lit er at ur e r e vi e  w. Cli n 
L y  m p h o  m a   M y el o  m a  L e u k  2 0 1 4; 1 4 ( 5):  3 4 3-3 5 5. e 3 4 6.  
F e u gi er  P,   V a n   H o of   A,  S e b b a n   C,  S ol al -C eli g n y  P,   B o u a b d all a h   R,  F er  m e   C,  et  al.  L o n g -t er  m 
r es ults of t h e   R -C  H  O P st u d y i n t h e tr e at  m e nt  of  el d erl y  p ati e nts   wit h  diff us e l ar g e   B -c ell 
l y  m p h o  m a:  a st u d y  b y t h e   Gr o u p e  d' Et u d e  d es  L y  m p h o  m es  d e l'  A d ult e. J   Cli n   O n c ol 
2 0 0 5; 2 3 ( 1 8):  4 1 1 7-4 1 2 6.  
Fri d eri ci a  L S. Di e s yst ol e n d a u er i  m  el e ktr o k ar di o gr a  m  m  b ei  n or  m al e n   m e ns c h e n  u n d  b ei 
h er z kr a n k e n. A ct a   M e d  S c a n d  1 9 2 0; 5 3 :  4 6 9-4 8 6.  
Gi n al di  L,   D e   M arti nis   M,   M at ut es  E,  F ar a h at   N,   M orill a   R  a n d   C at o vs k y   D.  L e v els  of 
e x pr essi o n  of   C  D 1 9  a n d   C  D 2 0 i n  c hr o ni c   B  c ell l e u k a e  mi as . J   Cli n  P at h ol 1 9 9 8; 5 1 ( 5):  3 6 4-3 6 9.  
Giss el br e c ht   C,   Gl ass   B,   M o u ni er   N,  Si n g h   Gill   D,  Li n c h   D  C,  Tr n e n y   M,  et  al.  S al v a g e r e gi  m e ns 
wit h  a ut ol o g o us tr a ns pl a nt ati o n f or r el a ps e d l ar g e   B -c ell l y  m p h o  m a i n t h e rit u xi  m a b  er a. J   Cli n 
O n c ol  2 0 1 0; 2 8 ( 2 7):  4 1 8 4-4 1 9 0.  
H a b er  m a n n  T  M,   W ell er  E  A,   M orris o n   V  A,   G as c o y n e   R  D,   C assil et h  P  A,   C o h n J  B,  et  al. 
Rit u xi  m a b -C  H  O P  v ers us   C  H  O P  al o n e  or   wit h   m ai nt e n a n c e rit u xi  m a b i n  ol d er  p ati e nts   wit h 
diff us e l ar g e   B -c ell l y  m p h o  m a. J   Cli n   O n c ol 2 0 0 6; 2 4 ( 1 9):  3 1 2 1-3 1 2 7.  
H all e k   M,   C h es o n   B  D,  C at o vs k y   D,   C ali g aris -C a p pi o  F,   Di g hi er o   G,   D o h n er   H,  et  al.   G ui d eli n es 
f or t h e  di a g n osis  a n d tr e at  m e nt  of  c hr o ni c l y  m p h o c yti c l e u k e  mi a:  a r e p ort fr o  m t h e I nt er n ati o n al 
W or ks h o p  o n   C hr o ni c  L y  m p h o c yti c  L e u k e  mi a  u p d ati n g t h e   N ati o n al   C a n c er I nstit ut e -W or ki n g 
Gr o u p  1 9 9 6  g ui d eli n es. Bl o o d  2 0 0 8; 1 1 1 ( 1 2):  5 4 4 6-5 4 5 6.  
H e  L,  Z h u   H  Y,   Qi n  S  C,  Li   Y,   Mi a o   Y,  Li a n g J  H,  et  al. L o  w  n at ur al  kill er (  N  K)  c ell  c o u nts i n 
p eri p h er al  bl o o d  a d v ers el y  aff e ct  cli ni c al  o ut c o  m e  of  p ati e nts   wit h f olli c ul ar l y  m p h o  m a. Bl o o d 
C a n c er J  2 0 1 6 ;6 ( 8):  e 4 5 7. 
H or n J,   Kl e b er   M,   Hi e k e  S,  S c h  mitt -Gr aff   A,   W as c h   R  a n d  E n g el h ar dt   M.  Tr e at  m e nt  o pti o n  of 
b e n d a  m usti n e i n  c o  m bi n ati o n   wit h rit u xi  m a b i n  el d erl y  a n d fr ail  p ati e nts   wit h  a g gr essi v e   B -n o n -
H o d g ki n l y  m p h o  m a: r ati o n al,  effi c a c y,  a n d t ol er a n c e. A n n   H e  m at ol 2 0 1 2; 9 1 ( 1 0):  1 5 7 9-1 5 8 6.  
I nt er n ati o n al   N o n-H o d g ki n's  L y  m p h o  m a  Pr o g n osti c  F a ct ors  Pr oj e ct.   A  pr e di cti v e   m o d el f or 
a g gr essi v e  n o n -H o d g ki n's l y  m p h o  m a. N  E n gl J   M e d  1 9 9 3; 3 2 9 ( 1 4):  9 8 7-9 9 4.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 3  of 1 3 1  
J ur c z a k   W,  Zi n z a ni  P L  a n d   G ai d a n o   G.  S u b gr o u p  a n al ys es  of  diff us e l ar g e   B-c ell l y  m p h o  m a 
(  D L  B  C L)  a n d i n d ol e nt l y  m p h o  m a  c o h orts fr o  m  a  p h as e II a st u d y  of si n gl e-a g e nt   M  O  R 2 0 8 i n 
p ati e nts   wit h r el a ps e d  or r efr a ct or y  n o n -H o d g ki n’s l y  m p h o  m a (  R -R   N  H L. J   Cli n   O n c ol 
2 0 1 6; 3 4 (s u p pl;  a bstr  7 5 4 5). 
J ur c z a k   W,  Zi n z a ni  P L,   G ai d a n o   G,   G oy   A,  Pr o v e n ci o   M,   N a g y  Z,  et  al.  P h as e II a st u d y  of t h e 
C  D 1 9  a nti b o d y   M  O  R 2 0 8 i n  p ati e nts   wit h r el a ps e d  or r efr a ct or y   B -c ell  n o n-H o d g ki n's 
l y  m p h o  m a. A n n   O n c ol  2 0 1 8; 2 9 ( 5):  1 2 6 6-1 2 7 2.  
J ur c z a k   W,  Zi n z a ni  P L  a n d   G o y   A.  P h as e II a st u d y  of si n gl e -a g e nt   M  O  R 2 0 8 i n p ati e nts   wit h 
r el a ps e d  or r efr a ct or y   B-c ell  n o n-H o d g ki n’s l y  m p h o  m a (  N  H L). J   Cli n   O n c ol 2 0 1 5; 3 3 (s u p pl; 
a bstr  8 5 0 0).  
J u  w ei d   M E,  Str o o b a nts  S,   H o e kstr a   O S,   M ott a g h y  F  M,   Di etl ei n   M,   G u er  m a zi   A,  et  al.   Us e  of 
p ositr o n  e  missi o n t o  m o gr a p h y f or r es p o ns e  ass ess  m e nt  of l y  m p h o  m a:  c o ns e ns us  of t h e I  m a gi n g 
S u b c o  m  mitt e e  of I nt er n ati o n al   H ar  m o ni z ati o n  Pr oj e ct i n  L y  m p h o  m a. J   Cli n   O n c ol 2 0 0 7; 2 5 ( 5): 
5 7 1 -5 7 8.  
K ar n ofs k y   D  A  a n d   B ur c h e n a J  H.  T h e   Cli ni c al  E v al u ati o n  of   C h e  m ot h er a p e uti c   A g e nts i n 
C a n c er. E v al u ati o n  of   C h e  m ot h er a p e uti c   A g e nts .   M a c L e o d   C  M.   N e  w   Y or k,   C ol u  m bi a 
U ni v ersit y  Pr ess.  1 9 4 9 : 1 9 6.  
Ki  m J  K,   C h u n g J S,  S hi n   HJ,  S o n g   M  K,   Yi J  W,  S hi n   D  H,  et  al. I nfl u e n c e  of   N  K  c ell  c o u nt  o n t h e 
s ur vi v al  of  p ati e nts   wit h  diff us e l ar g e   B-c ell l y  m p h o  m a tr e at e d   wit h   R -C  H  O P. Bl o o d   R es  
2 0 1 4; 4 9 ( 3):  1 6 2-1 6 9.  
Kl a n o v a   M,   O est er g a ar d   M Z,  Tr n ě n ý   M,   Hi d d e  m a n n   W,   M ar c us   R,  S e h n  L  H,  et  al.  L o  w 
P eri p h er al   Bl o o d   N  K   C ell   C o u nt Is   Ass o ci at e d   wit h   W ors e   Cli ni c al   O ut c o  m e i n  P ati e nts   wit h 
F olli c ul ar  L y  m p h o  m a ( F L)  a n d   Diff us e  L ar g e   B -C ell  L y  m p h o  m a (  D L  B  C L)  T r e at e d   wit h 
I  m  m u n o c h e  m ot h er a p y:   R es ults fr o  m t h e  Fr o ntli n e  P h as e  3   G  A L LI  U  M  a n d   G  O  Y  A  Tri als. Bl o o d  
2 0 1 7; 1 3 0 ( S u p pl  1):  7 2 7. 
L e n z   G,   Wri g ht   G  W,  E  mr e   N  C,   K o hl h a  m  m er   H,   D a v e  S S,   D a vis   R E,  et  al.   M ol e c ul ar s u bt y p es 
of  diff us e l ar g e   B -c ell l y  m p h o  m a  aris e  b y  disti n ct  g e n eti c  p at h  w a ys. Pr o c   N atl   A c a d  S ci   U  S   A  
2 0 0 8; 1 0 5 ( 3 6):  1 3 5 2 0-1 3 5 2 5.  
L e o ni  L  M.  T h e  e v ol vi n g r ol e  of  b e n d a  m usti n e i n l y  m p h oi d   m ali g n a n c y:  u n d erst a n di n g t h e  dr u g 
a n d its   m e c h a nis  m  of  a cti o n --i ntr o d u cti o n. S e  mi n   H e  m at ol  2 0 1 1; 4 8  S u p pl  1 :  S 1-3.  
L e o ni  L  M,   B ail e y   B,   R eif ert J,   B e n d all   H  H,  Z ell er   R  W,   C or b eil J,  et  al.   B e n d a  m usti n e ( Tr e a n d a) 
dis pl a ys  a  disti n ct  p att er n  of  c yt ot o xi cit y  a n d  u ni q u e   m e c h a nisti c f e at ur es  c o  m p ar e d   wit h  ot h er 
al k yl ati n g  a g e nts. Cli n   C a n c er   R es  2 0 0 8; 1 4 ( 1):  3 0 9-3 1 7.  
L esli e  L  a n d   Y o u n es   A.   A nti -C  D 1 9 str at e gi es i n  h e  m at ol o gi c al   m ali g n a n ci es. Dr u gs  of t h e 
F ut ur e  2 0 1 3; 3 8 ( 1 2):  8 3 5. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 4  of 1 3 1  
List er  T  A,   Cr o  wt h er   D,  S ut cliff e  S  B,   Gl atst ei n  E,   C a n ell os   G P,   Y o u n g   R  C,  et  al.   R e p ort  of  a 
c o  m  mitt e e  c o n v e n e d t o  dis c uss t h e  e v al u ati o n  a n d st a gi n g  of  p ati e nts   wit h   H o d g ki n's  dis e as e: 
C ots  w ol ds   m e eti n g. J   Cli n   O n c ol 1 9 8 9; 7 ( 1 1):  1 6 3 0-1 6 3 6 . 
M arti n   A,   C o n d e  E,   Ar n a n   M,   C a n al es   M  A,   D e b e n   G,  S a n c h o J  M,  et  al. R -E S  H  A P  as s al v a g e 
t h er a p y f or  p ati e nts   wit h r el a ps e d  or r efr a ct or y  diff us e l ar g e   B-c ell l y  m p h o  m a: t h e i nfl u e n c e  of 
pri or  e x p os ur e t o rit u xi  m a b  o n  o ut c o  m e.   A   G E L/ T  A  M  O st u d y. H a e  m at ol o gi c a  2 0 0 8; 9 3 ( 1 2): 
1 8 2 9 -1 8 3 6.  
M atl a  ws k a -W as o  ws k a   K,   W ar d  E,  St e v e ns  S,   W a n g   Y,   H er bst   R,   Wi nt er  S S,  et  al.   M a cr o p h a g e 
a n d   N  K-m e di at e d  killi n g  of  pr e c urs or -B  a c ut e l y  m p h o bl asti c l e u k e  mi a  c ells t ar g et e d   wit h  a -
f u c os yl at e d  a nti-C  D 1 9  h u  m a ni z e d  a nti b o di es. L e u k e  mi a  2 0 1 3; 2 7 ( 6):  1 2 6 3-1 2 7 4.  
M orris o n   V  A,   H a  mli n  P,  S o u b e yr a n  P,  St a u d er   R,   W a d h  w a  P,   A a pr o   M,  et  al. Diff us e l ar g e   B -
c ell l y  m p h o  m a i n t h e  el d erl y: I  m p a ct  of  pr o g n osis,  c o  m or bi diti es,  g eri atri c  ass ess  m e nt,  a n d 
s u p p orti v e  c ar e  o n  cli ni c al  pr a cti c e.   A n I nt er n ati o nal  S o ci et y  of   G eri atri c   O n c ol o g y ( SI  O  G) 
E x p ert  P ositi o n  P a p er. J   G eri atr   O n c ol 2 0 1 4.  
M ort o n  L  M,   W a n g  S S,   D e v es a  S S,   H art g e  P,   W eis e n b ur g er   D  D  a n d  Li n et   M S.  L y  m p h o  m a 
i n ci d e n c e  p att er ns  b y   W  H  O s u bt y p e i n t h e   U nit e d  St at es,  1 9 9 2-2 0 0 1. Bl o o d  2 0 0 6; 1 0 7 ( 1):  2 6 5-
2 7 6.  
M ost ell er   R  D.  Si  m plifi e d  c al c ul ati o n  of  b o d y -s urf a c e  ar e a. N  E n gl J   M e d  1 9 8 7; 3 1 7 ( 1 7):  1 0 9 8. 
O'  Bri e n  P  C  a n d  Fl e  mi n g  T  R.   A   m ulti pl e t esti n g  pr o c e d ur e f or  cli ni c al tri als. Bi o  m etri cs  
1 9 7 9; 3 5 ( 3):  5 4 9-5 5 6.  
O g ur a   M,   A n d o   K,  T a ni  w a ki   M,   W at a n a b e  T,   U c hi d a  T, O h  m a c hi   K,  et  al. F e asi bilit y  a n d 
p h ar  m a c o ki n eti c st u d y  of  b e n d a  m usti n e  h y dr o c hl ori d e i n  c o  m bi n ati o n   wit h rit u xi  m a b i n r el a ps e d 
or r efr a ct or y  a g gr essi v e   B  c ell  n o n -H o d g ki n's l y  m p h o  m a. C a n c er  S ci  2 0 1 1; 1 0 2 ( 9):  1 6 8 7-1 6 9 2.  
O h  m a c hi   K,   Niits u   N,   U c hi d a  T,   Ki  m  SJ ,   A n d o   K,  T a k a h as hi   N,  et  al.   M ulti c e nt er  p h as e II st u d y 
of  b e n d a  m usti n e  pl us rit u xi  m a b i n  p ati e nts   wit h r el a ps e d  or r efr a ct or y  diff us e l ar g e   B -c ell 
l y  m p h o  m a. J   Cli n   O n c ol 2 0 1 3; 3 1 ( 1 7):  2 1 0 3-2 1 0 9.  
O k e n   M  M,   Cr e e c h   R  H,  T or  m e y   D  C,   H ort o n J,   D a vis  T E,   M c F a d d e n E T,  et  al.  T o xi cit y  a n d 
r es p o ns e  crit eri a  of t h e  E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p. A  m J   Cli n   O n c ol  1 9 8 2; 5 ( 6):  6 4 9-
6 5 5.  
Ol ej ni c z a k  S  H,  St e  w art   C  C,   D o n o h u e   K  a n d   C z u c z  m a n   M S.   A  q u a ntit ati v e  e x pl or ati o n  of 
s urf a c e  a nti g e n  e x pr essi o n i n  c o  m  m o n   B-c ell   m ali g n a n ci es  usi n g fl o  w  c yt o  m etr y. I  m  m u n ol 
I n v est 2 0 0 6; 3 5 ( 1):  9 3-1 1 4.  
Pfr e u n ds c h u h   M.   H o  w I tr e at  el d erl y  p ati e nts   wit h  diff us e l ar g e   B -c ell l y  m p h o  m a. Bl o o d  
2 0 1 0; 1 1 6 ( 2 4):  5 1 0 3-5 1 1 0.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 5  of 1 3 1  
Pfr e u n ds c h u h   M,   K u h nt  E,  Tr u  m p er  L,   Ost er b or g   A,  Tr n e n y   M,  S h e p h er d  L,  et  al. C  H  O P -li k e 
c h e  m ot h er a p y   wit h  or   wit h o ut rit u xi  m a b i n  y o u n g  p ati e nts   wit h  g o o d -pr o g n osis  diff us e l ar g e -B -
c ell l y  m p h o  m a:  6 -y e ar r es ults  of  a n  o p e n -l a b el r a n d o  mis e d st u d y  of t h e   M a b Th er a I nt er n ati o n al 
Tri al (  MI n T)   Gr o u p. L a n c et   O n c ol  2 0 1 1; 1 2 ( 1 1):  1 0 1 3-1 0 2 2.  
Pfr e u n ds c h u h   M,  S c h u b ert J,  Zi e p ert   M,  S c h  mits   R,   M o hr e n   M,  L e n gf el d er  E,  et  al. Si x  v ers us 
ei g ht  c y cl es  of  bi -w e e kl y   C  H  O P -1 4   wit h  or   wit h o ut rit u xi  m a b i n  el d erl y  p ati e nts   wit h  a g g r essi v e 
C  D 2 0 +   B -c ell l y  m p h o  m as:  a r a n d o  mis e d  c o ntr oll e d tri al (  RI  C  O  V E  R -6 0). L a n c et   O n c ol  
2 0 0 8; 9 ( 2):  1 0 5-1 1 6.  
Pfr e u n ds c h u h   M,  Tr u  m p er  L,   Ost er b or g   A,  P ett e n g ell   R,  Tr n e n y   M, I  mri e   K,  et  al. C  H  O P -li k e 
c h e  m ot h er a p y  pl us rit u xi  m a b  v ers us   C  H  O P -li k e  c h e  m ot h er a p y al o n e i n  y o u n g  p ati e nts   wit h 
g o o d -pr o g n osis  diff us e l ar g e -B -c ell l y  m p h o  m a:  a r a n d o  mis e d  c o ntr oll e d tri al  b y t h e   M a b T h er a 
I nt er n ati o n al  Tri al (  MI n T)   Gr o u p. L a n c et   O n c ol  2 0 0 6; 7 ( 5):  3 7 9-3 9 1.  
P hili p  T,   G u gli el  mi   C,   H a g e n b e e k   A,  S o  m ers   R,   V a n  d er  L eli e   H,   Br o n  D,  et  al.   A ut ol o g o us 
b o n e   m arr o  w tr a ns pl a nt ati o n  as  c o  m p ar e d   wit h s al v a g e  c h e  m ot h er a p y i n r el a ps es  of 
c h e  m ot h er a p y -s e nsiti v e  n o n-H o d g ki n's l y  m p h o  m a. N  E n gl J   M e d  1 9 9 5; 3 3 3 ( 2 3):  1 5 4 0-1 5 4 5.  
Pl o n q u et   A,   H ai o u n   C, J ais J P,   D e b ar d   A L,  S all es   G,   B e n e   M  C,  et  al. P eri p h er al  bl o o d  n at ur al 
kill er  c ell  c o u nt is  ass o ci at e d   wit h  cli ni c al  o ut c o  m e i n  p ati e nts   wit h  a aI PI  2 -3  diff us e l ar g e   B -c ell 
l y  m p h o  m a. A n n   O n c ol  2 0 0 7; 1 8 ( 7):  1 2 0 9-1 2 1 5.  
P o e J  C,   Mi n ar d -C oli n   V,   K o u nti k o v  EI,   H a as   K  M  a n d  T e d d er  T F.   A  c -M y c  a n d s urf a c e   C  D 1 9 
si g n ali n g  a  m plifi c ati o n l o o p  pr o  m ot es   B  c ell l y  m p h o  m a  d e v el o p  m e nt  a n d  pr o gr essi o n i n   mi c e. J 
I  m  m u n ol 2 0 1 2; 1 8 9 ( 5):  2 3 1 8-2 3 2 5.  
Ri br a g   V,   D u p uis J,  Till y   H,   M ors c h h a us er  F,  L ai n e  F,   H o u ot   R,  et  al.   A  d os e -es c al ati o n st u d y  of 
S  A  R 3 4 1 9,  a n  a nti -C  D 1 9  a nti b o d y   m a y t a nsi n oi d  c o nj u g at e,  a d  mi nist er e d  b y i ntr a v e n o us i nf usi o n 
o n c e   w e e kl y i n  p ati e nts   wit h r el a ps e d/r efr a ct or y   B -c ell  n o n-H o d g ki n l y  m p h o  m a. Cli n   C a n c er 
R es  2 0 1 4; 2 0 ( 1):  2 1 3-2 2 0.  
Ri g a c ci  L,  P u c ci ni   B,   C ort el a z z o  S,   G ai d a n o   G,  Pi c ci n   A,   D'  Ar c o   A,  et  al.   B e n d a  m ust i n e   wit h  or 
wit h o ut rit u xi  m a b f or t h e tr e at  m e nt  of  h e a vil y  pr etr e at e d  n o n -H o d g ki n's l y  m p h o  m a  p ati e nts :   A 
m ulti c e nt er r etr os p e cti v e st u d y  o n  b e h alf  of t h e It ali a n  L y  m p h o  m a  F o u n d ati o n ( FI L). A n n 
H e  m at ol  2 0 1 2; 9 1 ( 7):  1 0 1 3-1 0 2 2.  
R os e n  w al d   A,   Wri g ht   G,   C h a n   W  C,  C o n n ors J  M,   C a  m p o  E,  Fis h er   RI,  et  al.  T h e  us e  of 
m ol e c ul ar  pr ofili n g t o  pr e di ct s ur vi v al  aft er  c h e  m ot h er a p y f or  diff us e l ar g e -B -c ell l y  m p h o  m a. N 
E n gl J   M e d  2 0 0 2; 3 4 6 ( 2 5):  1 9 3 7-1 9 4 7.  
S e h n  L  H,   D o n al ds o n J,   C h h a n a b h ai   M,  Fit z g er al d   C,   Gill   K,   Kl as a   R,  et  al. I ntr o d u cti o n  of 
c o  m bi n e d   C  H  O P  pl us rit u xi  m a b t h er a p y  dr a  m ati c all y i  m pr o v e d  o ut c o  m e  of  diff us e l ar g e   B -c ell 
l y  m p h o  m a i n   Britis h   C ol u  m bi a. J   Cli n   O n c ol 2 0 0 5; 2 3 ( 2 2):  5 0 2 7-5 0 3 3.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 6  of 1 3 1  
S h af er   D ,  S  mit h   M  R,   B or g h a ei   H,   Mill e ns o n   M  M,  Li  T,  Lit  wi n  S,  et  al.  L o  w   N  K  c ell  c o u nts i n 
p eri p h er al  bl o o d  ar e  ass o ci at e d   wit h i nf eri or  o v er all s ur vi v al i n  p ati e nts   wit h f olli c ul ar 
l y  m p h o  m a. L e u k   R es  2 0 1 3; 3 7 ( 1 0):  1 2 1 3-1 2 1 5.  
S h e n o y  PJ,   M ali k   N,   N o o k a   A,  Si n h a   R,   W ar d   K  C,   Br a  wl e y   O  W,  et  al.   R a ci al  diff er e n c es i n t h e 
pr es e nt ati o n  a n d  o ut c o  m es  of  diff us e l ar g e   B -c ell l y  m p h o  m a i n t h e   U nit e d  St at es. C a n c er  
2 0 1 1; 1 1 7 ( 1 1):  2 5 3 0-2 5 4 0.  
S pi ess e ns   B  a n d   D e b ois   M.   A dj ust e d si g nifi c a n c e l e v els f or s u b gr o u p  a n al ys es i n  cli ni c al t ri als. 
C o nt e  m p   Cli n  Tri als  2 0 1 0; 3 1 ( 6):  6 4 7-6 5 6.  
S u git a ni  T,   Br et z  F  a n d   M a ur er   W.   A si  m pl e  a n d fl e xi bl e  gr a p hi c al  a p pr o a c h f or  a d a pti v e  gr o u p -
s e q u e nti al  cli ni c al tri als. J   Bi o p h ar  m  St at 2 0 1 6; 2 6 ( 2):  2 0 2-2 1 6.  
S  w er dl o  w  S  H,   C a  m p o  E,   H arris   N L  et  al.,  E ds. W  H  O Cl assifi c ati o n  of  T u  m o urs  of 
H a e  m at o p oi eti c  a n d  L y  m p h oi d  Tiss u es .  2 0 0 8;  L y o n,  Fr a n c e, I  A  R  C  Pr ess. 
T hi e bl e  m o nt   C  a n d   C oiffi er   B.  L y  m p h o  m a i n  ol d er  p ati e nts. J   Cli n   O n c ol 2 0 0 7; 2 5 ( 1 4):  1 9 1 6-
1 9 2 3.  
Tr u el o v e  E,  F o x   C,   R o bi ns o n  S,  P e ar c e   R,  P err y J,   Kir kl a n d   K,  et  al.   C ar  m usti n e,  Et o p osi d e, 
C yt ar a bi n e,  a n d   M el p h al a n (  B E  A  M) -C a  m p at h   All o g e n ei c  St e  m   C ell  Tr a ns pl a nt ati o n f or 
A g gr essi v e   N o n -H o d g ki n  L y  m p h o  m a:   A n   A n al ysis  of   O ut c o  m es fr o  m t h e   Britis h  S o ci et y of 
Bl o o d  a n d   M arr o  w  Tr a ns pl a nt ati o n. Bi ol   Bl o o d   M arr o  w  Tr a ns pl a nt  2 0 1 4.  
V a cir c a J L,   A cs  PI,  T a b b ar a I  A,   R os e n  PJ,  L e e  P  a n d  L y n a  m  E.   B e n d a  m usti n e  c o  m bi n e d   wit h 
rit u xi  m a b f or  p ati e nts   wit h r el a ps e d  or r efr a ct or y  diff us e l ar g e   B  c ell l y  m p h o  m a. A n n   H e  m at ol  
2 0 1 4; 9 3 ( 3):  4 0 3-4 0 9.  
v a n  Z el  m   M  C,   R eisli I,  v a n  d er   B ur g   M,   C ast a n o   D,  v a n   N o es el   CJ,  v a n  T ol   MJ,  et  al.   A n 
a nti b o d y-d efi ci e n c y s y n dr o  m e  d u e t o   m ut ati o ns i n t h e   C  D 1 9  g e n e. N  E n gl J   M e d  2 0 0 6; 3 5 4 ( 1 8): 
1 9 0 1 -1 9 1 2.  
Vi ar d ot   A,   G o e b el er   M,   N o p p e n e y   R,   Kr a us e  S  W,   K a ll ert  S,  F erstl   B,  et  al.   Bli n at u  m o  m a b 
M o n ot h er a p y  S h o  ws  Effi c a c y i n  P ati e nts   wit h   R el a ps e d   Diff us e  L ar g e   B   C ell  L y  m p h o  m a. Bl o o d  
2 0 1 1; 1 1 8 ( 2 1):  1 6 3 7. 
W alt er  E,  S c h  mitt  T,   Di etri c h  S,   H o   A  a n d   Wit z e ns -H ari g   M.   Rit u xi  m a b  a n d  b e n d a  m usti n e i n 
p ati e nts   wit h   C  D 2 0 +  diff us e l ar g e   B -c ell l y  m p h o  m a  n ot  eli gi bl e f or  c y cl o p h os p h a  mi d e, 
d o x or u bi ci n,  vi n cristi n e  a n d  pr e d nis o n e -li k e  c h e  m ot h er a p y. L e u k  L y  m p h o  m a  2 0 1 2; 5 3 ( 1 1): 
2 2 9 0 -2 2 9 2.  
W ass  m er   G.  Pl a n ni n g  a n d  a n al y zi n g  a d a pti v e  gr o u p s e q u e nti al s ur vi v al tri als. Bi o  m J  
2 0 0 6; 4 8 (4):  7 1 4 -7 2 9.  
W ass  m er   G.   O n s a  m pl e si z e  d et er  mi n ati o n i n   m ulti -ar  m e d  c o nfir  m at or y  a d a pti v e  d esi g ns. J 
Bi o p h ar  m  St at  2 0 1 1; 2 1 ( 4):  8 0 2-8 1 7.  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 7  of 1 3 1  
W ei d  m a n n  E,   Ki  m  S Z,   R ost   A,  S c h u p p ert   H,  S ei p elt   G,   H o el z er   D,  et  al. B e n d a  m usti n e is 
eff e cti v e i n r el a ps e d  or r efr a ct or y  a g gr essi v e  n o n -H o d g ki n's l y  m p h o  m a. A n n   O n c ol  2 0 0 2; 1 3 ( 8): 
1 2 8 5 -1 2 8 9.  
Wils o n   W  H, J u n g  S  H,  P or c u  P,   H ur d   D, J o h ns o n J,   M arti n  S E,  et  al.   A   C a n c er  a n d  L e u k e  mi a 
Gr o u p   B   m ulti -c e nt er st u d y  of   D  A -E P  O  C  H -rit u xi  m a b i n  u ntr e at e d  diff us e l ar g e   B-c ell 
l y  m p h o  m a   wit h  an al ysis  of  o ut c o  m e  b y   m ol e c ul ar s u bt y p e. H a e  m at ol o gi c a  2 0 1 2; 9 7 ( 5):  7 5 8-7 6 5.  
W o y a c h J  A,   A  w a n  F,  Fli n n I  W,   B er d ej a J  G,   Wil e y  E,   M a ns o or  S,  et  al.   A  p h as e  1 tri al  of t h e  F c -
e n gi n e er e d   C  D 1 9  a nti b o d y   X  m  A b 5 5 7 4 (  M  O  R 0 0 2 0 8)  d e  m o nstr at es s af et y  a n d  pr eli  mi n ar y 
effi c a c y i n r el a ps e d   C L L. Bl o o d  2 0 1 4; 1 2 4 ( 2 4):  3 5 5 3-3 5 6 0.  
Y o u n es   A,   Ki  m  S,   R o  m a g u e r a J,   C o p el a n d   A,  F ari al  S d e   C,   K  w a k  L  W,  et  al.  P h as e I   m ulti d os e-
es c al ati o n st u d y  of t h e  a nti -C  D 1 9   m a yt a nsi n oi d i  m  m u n o c o nj u g at e  S  A  R 3 4 1 9  a d  mi nist er e d  b y 
i ntr a v e n o us i nf usi o n  e v er y  3   w e e ks t o  p ati e nts   wit h r el a ps e d/r efr a ct or y   B-c ell l y  m p h o  m a. J   Cli n 
O n c ol  2 0 1 2; 3 0 ( 2 2):  2 7 7 6-2 7 8 2.  
 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 1 8  of  1 3 1  
1 6  A P P  E  N  DI  C  E S  
1 6. 1  A p p e n di x   A:   C o c k c r oft -G a ult  F o r  m ul a  
C o c k c r oft -G a ult   E q u ati o n:  
T his f or m ula pres u mes wei g ht t o be meas ure d i n  kil o gra ms an d c reati ni ne t o  be meas u re d in 
m g/ d L. 
W he n  seru m  creati ni ne is  meas ure d  in  µm ol/ L:  
W h er e C o nst a nt  is 1. 2 3  f or   m e n  a n d 1. 0 4  f or   w o  m e n. 
S o ur c e:  C o c k cr oft  a n d   G a ult ( 1 9 7 6) . Pr e di cti o n  of  cr e ati ni n e  cl e ar a n c e fr o  m s er u  m  cr e ati ni n e. 
N e p hr o n.  1 9 7 6; 1 6( 1)  3 1- 4 1. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 1 9  of  1 3 1  
1 6. 2  A p p e n di x   B:   Hi g hl y   Eff e cti v e   C o nt r a c e pti o n  
 
M et h o ds t h at  c a n  a c hi e v e  a f ail ur e r at e  of l ess t h a n  1  %  p er  y e ar   w h e n  us e d  c o nsist e ntl y  a n d 
c orr e ctl y  ar e  c o nsi d er e d  as  hi g hl y  eff e cti v e  birt h  c o ntr ol   m et h o ds.  S u c h   m et h o ds i n cl u d e: 
•  C o  m bi n e d ( o estr o g e n  a n d  pr o g est o g e n  c o nt ai ni n g)  h or  m o n al  c o nt r a c e pti o n  ass o ci at e d 
wit h i n hi biti o n  of  o v ul ati o n: 
o  or al 
o  i ntr a v a gi n al 
o  tr a ns d er  m al 
•  Pr o g est o g e n- o nl y  h or  m o n al  c o ntr a c e pti o n  ass o ci at e d   wit h i n hi biti o n  of  o v ul ati o n: 
o  or al 
o  i nj e ct a bl e 
o  i  m pl a nt a bl e 
•  Intr a ut eri n e  d e vi c e  
•  Intr a ut eri n e h or  m o n e- r el e asi n g s yst e  m 
•  B il at er al t u b al  o c cl usi o n 
•  V as e ct o  mis e d p art n er 
•  S e x u al  a bsti n e n c e 
 
S o ur c e:  Cli ni c al  Tri al  F a cilit ati o n   Gr o u p (  C T F  G) ( 1 5  S e pt e  m b er  2 0 1 4) .   Re c o  m  m e n d ati o ns 
r el at e d t o  c o ntr a c e pti o n  a n d  pr e g n a n c y t esti n g i n  cli ni c al tri als. 
 
N  O T E: P eri o di c  a bsti n e n c e ( e . g.,  c al e n d ar,  o v ul ati o n, s y  m pt ot h er  m al,  p ost-o v ul ati o n   m et h o ds) 
a n d   wit h dr a  w al  ar e  n ot  hi g hl y  eff e cti v e   m et h o ds  of  c o ntr a c e pti o n. 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 0  of  1 3 1  
1 6. 3  A p p e n di x   C:   O v e r vi e  w  of  p u blis h e d  d at a  o n   N  K  C  C  as  a  p r o g n osti c 
f a ct o r i n D  L  B  C  L  a n d  F  L  
 
P u bli c ati o n  
(st u d y  n a  m e) 
St u d y t y p e  
N u  m b e r  of 
p ati e nts  
P ati e nt 
p o p ul ati o n  
T r e at  m e nt  
N  K  C  C 
c ut - off 
( c ells/ µ  L) 
T r e at  m e nt  eff e ct  b as e d 
o n   N  K  C  C  
(  N  K  C  C-l o  w  vs.   N  K  C  C-
hi g h  c o  m p a ris o n *)  
Kl a n o v a  et  al. 
( 2 0 1 7) 
(  G  O  Y  A) 
Pr os p e cti v e, 
r a n d o  mi z e d 
p h as e III  
n = 1 2 8 7  
N e  wl y 
di a g n os e d 
D L  B  C L 
R- C  H  O P  
vs  
o bi n ut u z u  m a b -
C  H  O P  
1 0 0  
U ni v ari at e   A n al ysis - P F S 
H  R ( 9 5  %   CI):  
1. 3 6 ( 1. 0 7 -1. 7 2)  
I n v ers e:  0. 7 4 ( 0. 5 8-0. 9 3)  
p = 0. 0 1  
Kl a n o v a  et  al. 
( 2 0 1 7) 
(  G  A L LI  U  M) 
Pr os p e cti v e, 
r a n d o  mi z e d 
p h as e III  
n = 1 0 6 4  
Pr e vi o usl y 
u ntr e at e d  
F L  
R- c h e  m o  
vs  
o bi n ut u z u  m a b - 
c h e  m o  
1 0 0  
U ni v ari at e   A n al ysis:  P F S 
H  R ( 9 5  %  CI):  
1. 5 7 ( 1. 1 0 -2. 2 5)  
I n v ers e: 0. 6 4 ( 0. 4 4-0. 9)  
p = 0. 0 1  
Ki  m  et  al. ( 2 0 1 4)  R etr os p e cti v e  
n = 7 2  
N e  wl y 
di a g n os e d 
D L  B  C L 
R- C  H  O P  
1 0 0  
U ni v ari at e  a n al ysis:  P F S 
H  R ( 9 5  %   CI):  
6. 0 3 ( 1. 7 9 -1 3. 5 5)  
I n v ers e:  0. 1 7 ( 0. 0 7-0. 5 6)  
p < 0. 0 0 1  
Pl o n q u et  et  al. 
( 2 0 0 7)  
( L  N  H 9 8  B 3) 
Pr os p e cti v e 
r a n d o  mi z e d 
p h as e II 
( aft er   A S  C T) 
n = 1 3 6  
N e  wl y 
di a g n os e d 
D L  B  C L 
A S  C T f oll o  w e d 
b y 
r a n d o  mi z ati o n 
t o   R T  X  or  n o 
R T  X 
8 0  
U ni v ari at e  a n al ysis  E F S 
H  R ( 9 5  %   CI):  
1. 8 5 ( 1. 1 4 -3)  
I n v ers e: 0. 54 ( 0. 3 3 -0. 8 8)  
 p  =  0. 0 1  
H e  et  al. ( 2 0 1 6)  
R etr os p e cti v e  
n = 1 1 4  
Pr e vi o usl y 
u ntr e at e d  
F L  
R T  X- c o nt ai ni n g 
t h er a p y 
1 0 0  
U ni v ari at e  a n al ysis:  P F S 
H  R ( 9 5  %  CI)  
U ni v ari at e  a n al ysis:  P F S 
H  R ( 9 5  %   CI)  
3. 4 9 ( 1. 6 -7. 6 3)  
I n v ers e:  0. 2 9 ( 0. 1 3-0. 6 2)  
p = 0. 0 0 2  


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 1  of  1 3 1  
P u bli c ati o n  
(st u d y  n a  m e) 
St u d y t y p e  
N u  m b e r  of 
p ati e nts  
P ati e nt 
p o p ul ati o n  
T r e at  m e nt  
N  K  C  C 
c ut - off 
( c ells/ µ  L) 
T r e at  m e nt  eff e ct  b as e d 
o n   N  K  C  C  
(  N  K  C  C-l o  w  vs.   N  K  C  C-
hi g h  c o  m p a ris o n *)  
S h af er  et  al. 
( 2 0 1 3) 
R etr os p e cti v e  
n = 7 5  
N e  wl y 
di a g n os e d 
F L  
R a di ot h er a p y 
( 1 1  p ati e nts) 
a n d/ or si n gl e 
a g e nt  or   R T  X -
c o nt ai ni n g 
r e gi  m e ns,  or 
o bs er v ati o n 
( n = 3 5) 
1 5 0  
M ulti v ari at e  a n al ysis:   O S 
H  R ( 9 5  %   CI)  
6. 7 3 ( 0. 7 6 – 5 9)  
I n v ers e:  0. 1 5 ( 0. 0 1 7-1. 3 ) 
p  = 0. 0 8  
J ur c z a k  et  al. 
( 2 0 1 8) a n d 
M or p h o S ys /I n c yt e 
d at a  o n fil e  
(  M  O  R 2 0 8  C 2 0 1) 
Pr os p e cti v e 
p h as e II 
( n = 3 1) 
R-  R 
D L  B  C L 
M  O  R 0 0 2 0 8 
m o n ot h er a p y  
1 0 0  
U ni v ari at e  a n al ysis  P F S 
H  R ( 9 5  %   CI) 
0. 2 4 ( 0. 0 9,  0. 7 0)  
Pr os p e cti v e 
p h as e II 
( n = 3 1) 
R- R i  N  H L, 
( p o ol e d  F L 
&  ot h er 
i  N  H L 
p ati e nts)  
U ni v ari at e  a n al ysis  P F S 
H  R ( 9 5  %   CI)  
 0. 3 9 ( 0. 1 2,  1. 2 5)  
*   N ot e t h at i n r a n d o  mi z e d st u di es,  h a z ar d r ati os s h o  w n i n t his  c ol u  m n  ar e f or t h e   N  K  C  C -l o  w  v ers us t h e   N  K  C  C-hi g h 
s u b gr o u p  usi n g  p o ol e d  d at a fr o  m  b ot h tr e at  m e nt  ar  ms  
A S  C T:  a ut ol o g o us st e  m  c ell tr a ns pl a nt;   CI:  c o nfi d e n c e i nt er v als;   D L  B  C L:  diff us e l ar g e   B  c ell l y  m p h o  m a;  E F S: 
e v e nt-fr e e s ur vi v al;  F L: f olli c ul ar l y  m p h o  m a;  F LI PI: f olli c ul ar l y  m p h o  m a I nt er n ati o n al  Pr o g n osti c I n d e x;   H  R: 
h a z ar d r ati o;   N  K  C  C:  n at ur al  kill er  c ell  c o u nt;   O S:  o v er all s ur vi v al;  P F S:  pr o gr essi o n -fr e e s ur vi v al;   R-C  H  O P; 
rit u xi  m a b,  c y cl o p h os p h a  mi d e,  d o x or u bi ci n,  vi n cristi n e,  a n d  pr e d nis o n e/ pr e d nis ol o n e;   R-R: r el a ps e d/r efr a ct or y; 
R T  X: rit u xi  m a b  
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 2  of  1 3 1  
1 6. 4  A p p e n di x   D: K a r n o fs k y  P e rf o r  m a n c e  St at us  S c al e 
 
D efi niti o n  of   R ati n g (  %)   C rit e ri a  
 
A bl e t o  c arr y  o n  n or  m al  a cti vit y  a n d t o   w or k;  n o 
s p e ci al  c ar e  n e e d ed.  
1 0 0   N or  m al  n o  c o  m pl ai nts;  n o  e vi d e n c e  of 
dis e as e.  
9 0  
A bl e t o  c arr y  o n  n or  m al  a cti vit y;   mi n or 
si g ns  or s y  m pt o  ms  of  dis e as e. 
8 0  
N or  m al  a cti vit y   wit h  eff ort; s o  m e si g ns  or 
s y  m pt o  ms  of  dis e as e.  
U n a bl e t o   w or k;  a bl e t o li v e  at  h o  m e  a n d  c ar e f or   m ost 
p ers o n al  n e e ds;  v ar yi n g  a  m o u nt  of  assist a n c e  n e e d e d.  
7 0  
C ar es f or s elf;  u n a bl e t o  c arr y  o n  n or  m al 
a cti vit y  or t o  d o  a cti v e   w or k.  
6 0  
R e q uir es  o c c asi o n al  assist a n c e,  b ut is  a bl e 
t o  c ar e f or   m ost  of  his  p ers o n al  n e e ds. 
5 0  
R e q uir es  c o nsi d er a bl e  assist a n c e  a n d 
fr e q u e nt   m e di c al  c ar e.  
U n a bl e t o  c ar e f or s elf; r e q uir es  e q ui v al e nt  of 
i nstit uti o n al  or  h os pit al  c ar e;  dis e as e   m a y  b e 
pr o gr essi n g r a pi dl y.  
4 0  
Dis a bl e d; r e q uir es s p e ci al  c ar e  a n d 
assist a n c e.  
3 0  
S e v er el y  dis a bl e d;  h os pit al  a d  missi o n is 
i n di c at e d  alt h o u g h  d e at h  n ot i  m  mi n e nt. 
2 0  
V er y si c k;  h os pit al  a d  missi o n  n e c ess ar y; 
a cti v e s u p p orti v e tr e at  m e nt  n e c ess ar y.  
1 0  
M ori b u n d; f at al  pr o c ess es  pr o gr essi n g 
r a pi dl y. 
0  
D e a d  
S o ur c e:  K ar n ofs k y  a n d   B ur c h e n a ( 1 9 4 9) . T h e   Cli ni c al  E v al u ati o n  of   C h e  m ot h er a p e uti c   A g e nts i n   C a n c er. I n: 
M a c L e o d   C  M ( e d).  E v al u ati o n  of   C h e  m ot h er a p e uti c   A g e nts.   N e  w   Y or k:   C ol u  m bi a   U ni v ersit y  Pr ess;  1 9 4 9:  1 9 6.  
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 3  of 1 3 1  
1 6. 5  A p p e n di x E : N e  w   Y o r k   H e a rt   Ass o ci ati o n  F u n cti o n al   Cl assifi c ati o n  
 
C rit e ri a f o r N  Y  H  A  F u n cti o n al   Cl assifi c ati o n  
N  Y  H  A 
Cl ass  
C rit e ri a  
I 
N o s y  m pt o  ms  a n d  n o li  mit ati o n i n  or di n ar y  p h ysi c al  a cti vit y; s h ort n ess  of  br e at h   w h e n 
w al ki n g, st air  cli  m bi n g,  et c.  
II 
Mil d s y  m pt o  ms (  mil d s h ort n ess  of  br e at h  a n d/ or  a n gi n a  p ai n)  a n d sli g ht li  mit ati o n  d uri n g 
or di n ar y  a cti vit y  
III 
M ar k e d li  mit ati o n i n  a cti vit y  d u e t o s y  m pt o  ms,  e v e n  d uri n g l ess -t h a n-or di n ar y  a cti vit y ( e. g. 
w al ki n g s h ort  dist a n c es,  a p pr o xi  m at el y  > 2 0 – 1 0 0  m et ers); c o  mf ort a bl e  o nl y  at r est  
I  V 
S e v er e li  mit ati o ns;  p ati e nt  e x p eri e n c es s y  m pt o  ms  e v e n   w hil e  at r est,   m ostl y  b e d b o u n d  
A b br e vi ati o n:   N  Y  H  A,   N e  w   Y or k   H e art   Ass o ci ati o n  
 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 4  of 1 3 1  
1 6. 6  A p p e n di x F : I nf o r  m ati o n  o n I n v esti g ati o n al  a n d   R e gist e r e d  P r o d u cts 
 
T h e I n v esti g at or’s   Br o c h ur e f or   M  O  R 0 0 2 0 8, a n d S u  m  m ar y  of  Pr o d u ct   C h ar a ct eristi cs ( E  M  A)  or 
Pr es cri bi n g I nf or  m ati o n (  U S  F  D  A) f or R T  X  a n d   B E  N, will  b e s u p pli e d t o t h e st u d y sit es.  
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 5  of 1 3 1  
1 6. 7  A p p e n di x G : E q ui v al e nt   D os es f o r   C o rti c ost e r oi ds  
 
E q ui v al e nt  d os es f o r  c o rti c ost e r oi ds  
 
N a  m e (I  N  N)  
E x a  m pl e  
E q ui v al e nt  d os es f o r 
8 0 –  1 0 0 –  1 2 0   m g 
m et h yl p r e d nis ol o n e  
P ot e n c y  
H y dr o c ortis o n e  
H y dr o c ort o n e  ®  
4 0 0 –  5 0 0 –  6 0 0   m g  
1  
Pr e d nis o n e  
D e c orti n  ®  
1 0 0 –  1 2 5 –  1 5 0   m g  
4  
Pr e d nis ol o n e  
D e c orti n  ®   H  
1 0 0 –  1 2 5 –  1 5 0   m g  
4  
M et h yl pr e d nis ol o n e  
Ur b as o n  ®  
8 0 –  1 0 0 –  1 2 0   m g  
5  
D e x a  m et h as o n e  
F ort e c orti n  ®  
1 4 –  1 6 –  2 0   m g  
3 0  
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 6  of 1 3 1  
1 6. 8  A p p e n di x H :   B o d y  S u rf a c e   A r e a (  B S  A)   C al c ul ati o n 
 
T h e  al g orit h  m t o  b e  us e d i n t his st u d y is:  
 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 7  of  1 3 1  
1 6. 9  A p p e n di x I:   A n n   A r b o r  St a gi n g - C ots  w ol ds   R e c o  m  m e n d ati o ns  
 
St a g e I: i n v ol v e  m e nt  of  a si n gl e l y  m p h ati c r e gi o n (I),  or l o c alis e d i n v ol v e  m e nt  of  a si n gl e e xtr a 
l y  m p h ati c or g a n  or sit e (I E).  
 
St a g e II: i n v ol v e  m e nt  of t  w o  or   m or e l y  m p h ati c r e gi o ns  o n t h e s a  m e si d e  of  di a p hr a g  m (II)  or 
l o c alis e d i n v ol v e  m e nt  of  a n e xtr a l y  m p h ati c  or g a n  or sit e  a n d  o n e  or   m or e l y  m p h  n o d e r e gi o ns 
t h e s a  m e si d e  of  di a p hr a g  m (II E). 
 
St a g e III: i n v ol v e  m e nt  of t  w o  or   m or e l y  m p h ati c r e gi o ns  o n  b ot h si d es  of  di a p hr a g  m (III)   w hi c h 
m a y  als o  b e  a c c o  m p a ni e d  eit h er  b y l o c alis e d i n v ol v e  m e nt  of  a n  e xtr a l y  m p h ati c or g a n  or sit e 
(III E),  or  b y i n v ol v e  m e nt  of t h e s pl e e n (III S). 
 
St a g e I  V: Diff us e  or  diss e  mi n at e d i n v ol v e  m e nt  of  o n e  or   m or e  e xtr a l y  m p h ati c  or g a ns  or tiss u e, 
wit h  or   wit h o ut  ass o ci at e d l y  m p h  n o d e i n v ol v e  m e nt.  
B o n e   m arr o  w  or li v er i n v ol v e  m e nt   will  al  w a ys  b e  c o nsi d er e d  as st a g e I  V.  
 
 
C rit e ri a f o r   B -s y  m pt o  ms 
T h e  pr es e n c e  of: ( a)  u ni nt e nti o n al   w ei g ht l oss  of   m or e t h a n  1 0  %   wit hi n t h e  pr e vi o us  6   m o nt hs 
a n d/ or ( b) f e v ers  of  gr e at er t h a n  1 0 0. 5°  F  or  3 8. 0°   C f or  at l e ast  3  c o ns e c uti v e  d a ys   wit h o ut  ot h er 
e vi d e n c e of i nf e cti o n  a n d/ or ( c)  dr e n c hi n g  ni g ht s  w e ats   wit h o ut e vi d e n c e  of i nf e cti o n, is  d e n ot e d 
b y t h e s uffi x l ett er ‘  B’. ‘  A’ i n di c at es t h e  a bs e n c e  of t h es e s y  m pt o  ms.  
 
 
 
S o ur c es:  
 
A n n   Ar b or  St a gi n g 
C ar b o n e  et  al. ( 1 9 7 1) . R e p ort  of t h e  c o  m  mitt e e  o n   H o d g ki n's  dis e as e st a g i n g  cl assifi c ati o n. 
C a n c er   R es; 3 1: 1 8 6 0- 6 1. 
 
C ots  w ol ds   R e c o  m  m e n d ati o ns 
List er  et  al. ( 1 9 8 9) .  St a gi n g f or   H o d g ki n's  dis e as e.   R e p ort  of  a  c o  m  mitt e e  c o n v e n e d t o  dis c uss 
t h e  e v al u ati o n  a n d st a gi n g  of  p ati e nts   wit h   H o d g ki n's  dis e as e:   C ots  w ol ds   m e eti n g. J   Cli n 
O n c ol; 7: 1 6 3 0- 3 6 [ Err at u  m; J   Cli n   O n c ol.  1 9 9 0; 8: 1 6 0 2]. 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
V  V -C LI  N -0 1 9 4 2 9
C o nfi d e nti al  
P a g e 1 2 8  of  1 3 1  
1 6. 1 0  A p p e n di x J : I nt e r n ati o n al  P r o g n osti c I n d e x (I PI) 
O n e  p oi nt is  assi g n e d f or  e a c h  of t h e f oll o  wi n g c h ar a ct eristi cs : 
•
A ge ol der t ha n 6 0
•
Lactate de h y dr o ge nase le vel hi g her t ha n n or mal
•
E C O G  p erf or ma nce  stat us sc ore  of 2 or greate r (see A p pe n di x K )
•
St a ge III  or I V disease
•
M o re t ha n one i n v o l ve d e xtra n o dal  disease site
T h e t ot al s c or e r a n ges fr o  m  z er o t o fi v e,  c orr es p o n di n g t o t h e f oll o  wi n g ris k  gr o u ps: 
•
L o w ris k:  0 – 1  p oi nts
•
L o  w- i nt er  m e diat e ris k:  2  p oi nts
•
Hi g h-i nt er  m e di at e ris k:  3  p oi nts
•
H i g h ris k:  4– 5  p oi nts.
S o ur c e:  I nt er n ati o n al   N o n-  H o d g ki n's  L y  m p h o  m a  Pr o g n osti c  F a ct ors  Pr oj e ct ( 1 9 9 3). A  pr e di cti v e 
m o d el f or  a g gr essi v e  n o n-  H o d g ki n's l y  m p h o  m a.   N  E n gl J   M e d.  1 9 9 3; 3 2 9( 1 4): 9 8 7- 9 4. 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 2 9  of  1 3 1  
1 6. 1 1  A p p e n di x K: E  C  O  G  P e rf o r  m a n c e  St at us  
 
E  C  O  G  P e rf o r  m a n c e  St at us   G r a d es  
G r a d e  
E  C  O  G  
0 
F ull y  a cti v e,  a bl e t o  c arr y  o n  all  pr e -dis e as e  p erf or  m a n c e   wit h o ut r estri cti o n  
1 
R estri ct e d i n  p h ysi c all y str e n u o us a cti vit y  b ut  a  m b ul at or y  a n d  a bl e t o  c arr y  o ut   w or k  of 
a li g ht  or s e d e nt ar y  n at ur e,  e. g., li g ht  h o us e   w or k,  offi c e   w or k  
2 
A  m b ul at or y  a n d  c a p a bl e  of  all s elf c ar e  b ut  u n a bl e t o  c arr y  o ut  a n y   w or k  a cti viti es. 
U p  a n d  a b o ut   m or e t h a n  5 0  %  of   w a ki n g  h o urs  
3 
C a p a bl e  of  o nl y li  mit e d s elf c ar e,  c o nfi n e d t o  b e d  or  c h air   m or e t h a n  5 0  %  of   w a ki n g 
h o urs  
4 
C o  m pl et el y  dis a bl e d.   C a n n ot  c arr y  o n  a n y s elf c ar e.  T ot all y  c o nfi n e d t o  b e d  or  c h air  
5 
D e a d  
 
S o ur c e : O k e n  et  al. ( 1 9 8 2) .  To xi cit y  a n d   R es p o ns e   Crit eri a  of t h e  E ast er n   C o o p er ati v e   O n c ol o g y 
Gr o u p.   A  m J   Cli n   O n c ol.  1 9 8 2; 5( 6): 6 4 9- 5 5. 
Cr e dit: T h e   E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p,   R o b ert   C o  mis   M.  D.,   Gr o u p   C h air. 
 
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0- A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 3 0  of  1 3 1  
1 6. 1 2  A p p e n di x L: R es p o ns e   C rit e ri a  
T h e r es p o ns e  crit eri a i n t his st u d y  ar e t h os e  d efi n e d i n t h e t a bl e  b el o  w.   All  of t h e  m  ar e  b as e d  o n 
t h e I nt er n ati o n al   W or ki n g   Gr o u p r es p o ns e  crit eri a (C h es o n  et  al.  2 0 0 7 ). 
 
D efi niti o n  of R es p o ns e   C rit e ri a  
R es p o ns e  D efi niti o n  
N o d al   m ass es  
S pl e e n, li v e r  
B o n e   m a r r o  w  
C  R 
Dis a p p e ar a n c e  of  all 
e vi d e n c e  of  dis e as e  
a) F  D  G -a vi d  or  P E T 
p ositi v e  pri or t o 
t h er a p y;   m ass  of 
a n y si z e  p er  mitt e d 
if  P E T  n e g ati v e 
b) V ari a bl e  F  D  G -a vi d 
or  P E T  n e g ati v e; 
r e gr essi o n t o 
n or  m al si z e  o n   C T  
N ot  p al p a bl e, 
n o d ul es 
dis a p p e ar e d  
I nfiltr at e 
cl e ar e d  o n 
r e p e at  bi o ps y; 
if 
i n d et er  mi n at e 
b y 
m or p h ol o g y, 
i  m  m u n o hist o-
c h e  mistr y 
s h o ul d  b e 
n e g ati v e  
P  R  
R e gr essi o n  of   m e as ur a bl e 
dis e as e  a n d  n o  n e  w sit es  
≥ 5 0  %  d e cr e as e i n 
S P  D  of  u p t o  6 
l ar g est  d o  mi n a nt 
m ass es;  n o i n cr e as e 
i n si z e o n   C T  
a) F  D  G -a vi d  or  P E T 
p ositi v e  pri or t o 
t h er a p y;  o n e  or 
m or e  P E T  p ositi v e 
at  pr e vi o usl y 
i n v ol v e d sit e 
b) V ari a bl e  F  D  G -a vi d 
or  P E T  n e g ati v e; 
r e gr essi o n  o n   C T 
≥ 5 0  %  d e cr e as e 
i n  S P  D  of 
n o d ul es (f or 
si n gl e  n o d ul e i n 
gr e at est 
tr a ns v ers e 
di a  m et er);  n o 
i n cr e as e i n si z e 
of li v er  or 
s pl e e n 
Irr el e v a nt if 
p ositi v e  pri or 
t o t h er a p y;  c ell 
t y p e s h o ul d  b e 
s p e cifi e d 
S  D  
F ail ur e t o  att ai n   C  R/ P  R  or 
P  D  
a) F  D  G -a vi d  or  P E T 
p ositi v e  pri or t o 
t h er a p y;  P E T 
p ositi v e  at  pri or 
sit es  of  dis e as e  a n d 
n o  n e  w sit es  o n   C T 
or  P E T  
b) V ari a bl e  F  D  G -a vi d 
or  P E T  n e g ati v e; 
n o  c h a n g e i n si z e 
of  pr e vi o us l esi o ns 
o n   C T  
 
 


I n c yt e   C or p or ati o n 
Pr ot o c ol   N u  m b er:   M  O  R 2 0 8  C 2 0 4 (  B -MI  N  D)  
D at e: 1 0 -A pr -2 0 2 4  
I  N  D   N u  m b er:  1 1 4, 8 5 6 
C T P   A  m e n d  m e nt N o. 8 ,   V ersi o n 1 1 . 0 
E u dr a  C T   N u  m b er: 2 0 1 4 -0 0 4 6 8 9 -1 1  
 
V  V -C LI  N -0 1 9 4 2 9  
C o nfi d e nti al  
P a g e 1 3 1  of 1 3 1  
D efi niti o n  of R es p o ns e   C rit e ri a  
R es p o ns e  D efi niti o n  
N o d al   m ass es  
S pl e e n, li v e r  
B o n e   m a r r o  w  
R el a ps e d 
dis e as e  or 
P  D  
A n y  n e  w l esi o n  or i n cr e as e 
b y ≥5 0  %  of  pr e vi o usl y 
i n v ol v e d sit es fr o  m  n a dir 
A p p e ar a n c e  of  a  n e  w 
l esi o n(s)  > 1. 5  c  m i n 
a n y  a xis, ≥ 5 0  % 
i n cr e as e i n  S P  D  of 
m or e t h a n  o n e  n o d e, 
or  ≥ 5 0  % i n cr e as e i n 
l o n g est  di a  m et er  of  a 
pr e vi o usl y i d e ntifi e d 
n o d e  > 1  c  m i n s h ort 
a xis 
L esi o ns  P E T  p ositi v e 
if  F  D  G-a vi d 
l y  m p h o  m a  or  P E T 
p ositi v e  pri or t o 
t h er a p y 
> 5 0  % i n cr e as e 
fr o  m  n a dir i n 
t h e  S P  D  of  a n y 
pr e vi o us l esi o ns  
N e  w  or 
r e c urr e nt 
i n v ol v e  m e nt 
A b br e vi ati o ns:   C  R  =  c o  m pl et e r es p o ns e;  F  D  G  =  [1 8F]fl u or o d e o x y gl u c os e;  P E T  =  p ositr o n  e  missi o n t o  m o gr a p h y; 
C T  =  c o  m p ut e d t o  m o gr a p h y;  P  R  =  p arti al r es p o ns e;  S P  D  =  s u  m  of t h e  pr o d u ct  of t h e  di a  m et ers;  S  D =  st a bl e 
dis e as e;  P  D  =  pr o gr essi v e  dis e as e . 
 
 
 


Si g nat ure Pa ge f or V V- C LI N- 0 1 9 4 2 9 v 3. 0
Si g nat ure Pa ge f or V V- C LI N- 0 1 9 4 2 9 v 3. 0
A p pr o val Tas k
o ver
 O nc ol o g y Tar gete d T hera pe utics
1 0- A pr- 2 0 2 4 1 5: 2 2: 4 7 G M T + 0 0 0 0
A p pr o val Tas k
 Cli nical Researc h Scie ntist
1 0- A pr- 2 0 2 4 1 5: 4 5: 3 0 G M T + 0 0 0 0
A p pr o val Tas k
A p pr o ver
 Se ni or Cli nical Trial Hea d
1 0- A pr- 2 0 2 4 1 7: 0 4: 5 3 G M T + 0 0 0 0
A p pr o val Tas k
A p pr o ver
 Bi ostatistics
1 1- A pr- 2 0 2 4 0 9: 4 7: 1 7 G M T + 0 0 0 0

SAP_001.pdf: 
Official Title: 
A Phase II/III, Randomised, Multicentre Study of MOR00208 With 
Bendamustine Versus Rituximab With Bendamustine in Patients 
With Relapsed or Refractory Diffuse Large B-Cell Lymphoma 
(R-R DLBCL) Who Are Not Eligible for High-Dose Chemotherapy 
(HDC) and Autologous Stem-Cell Transplantation (ASCT) – 
B-MIND 
NCT Number: 
NCT02763319 
Document Date: 
MOR208C204 Statistical Analysis Plan Am 7 05 SEP 2024 
 
 
 




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1. 
DOCUMENT HISTORY 
Summary of Changes From Version 6.2 to Version 7 
SAP Section 
Changes 
Rationale 
Section 4 
Added Incyte as the study sponsor. 
Change in study sponsorship. 
Sections 5, 6, 9, 10, and 14 
Changed "co-primary endpoints" to "dual 
primary endpoints." 
Co-primary endpoints do not require 
adjustment of the study-wise Type 1 error. 
As adjustment of Type I error was required, 
the correct terminology is dual primary 
endpoint. This is a discrepancy with the 
protocol. 
Sections 6, 8, and 10 
Changed "anti-DLBCL" to "anti-lymphoma." 
Anti-lymphoma is a more accurate term. 
Sections 8.2, 8.5, and 8.7.2 
Disposition information has been simplified. 
Update on baseline characteristic and disease 
characteristics. 
Disposition information has been simplified 
to increase clarity. Moved information from 
baseline characteristic section to the disease 
characteristic section as it was more accurate 
for population description. 
Section 8.9.4 
Added that the dose reduction for BEN only 
might be displayed.  
BEN is the only drug with dose reduction.  
Section 8.9.6 
Added the relative dose intensity and overall 
compliance definition. 
To measure a surrogate measurement of the 
compliance and to clarify how the overall 
compliance will be calculated. 
Section 9 
Updated the hierarchical testing text and the 
associated Figure 9-1. Added clarification of 
the overall alpha and the local significance. 
Allow testing the NKCC-low population 
when both of the key secondary endpoints 
are met. 
Section 9, Table 9-1 
Clarified that one-sided p-value will be used 
to implement the Inverse Normal Method and 
will be back-transformed to two-sided 
p-value. 
To follow the original publication. 
Section 10.2.3, Table 10-5 
Sensitivity analysis Supp 4.2.a-b will not be 
performed. Information will be listed only 
It was assessed the current data are not as 
useful and information will be in listing only. 
Section 11 
Clarified that there are only 2 keys secondary 
endpoints, ORR and OS 
DoR removed as a key secondary endpoint 
and from hierarchical testing as requested by 
FDA and according to current EU anticancer 
guideline. DoR remains secondary endpoint. 
(Protocol Amendment 6) 
Section 11.8.2.1  
Removed the descriptive analysis for 
individual items for the EORTC QLQ-C30. 
The key information is contained in the 
sub-scale scores and scores of the scale. 
Section 11.8.2.2 
Clarified that the Mixed model with repeated 
measures will be only run on the VAS score. 
Only the VAS is a continuous score. 
Section 12.2 
Added information regarding censoring rules 
and response. 
To provide additional details on the analysis 
method for the time to response exploratory 
endpoint. 
Section 13 
Updated safety section with required outputs 
per Incyte standard. 
Updated to align with Incyte standard. 
Section 13.1.12 
Clarified that the kit number information can 
be retrieved either from IRT or the kit history 
report. 
To explain how the information will be 
retrieved. 
Section 15 
Clarified the header labels for the treatment 
groups and the overall columns. 
There were deviations to the original plan to 
increase the readability of the outputs. 
Section 16 
Deleted references that are not cited in the 
SAP. 
To align the reference section with the SAP 
body and appendices 
Appendix C 
Appendix C, titled "Calculation of 
Significance Levels Based on 'Adjusted 
Significance Levels for Subgroup Analyses 
in Clinical Trials' Background" was removed. 
The calculation presented is not used for the 
analysis. 
Signature page 
Removed MorphoSys signature page. 
Change in study sponsorship. 


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Summary of Changes From Version 6.1 to Version 6.2 
A new SAP is created for the B-MIND study for the following reasons: 
• The analyses for the efficacy endpoints were streamlined 
• Made clarifications and corrections on analyses specifications  to align the SAP with 
the protocol and to add analysis details needed Final Analysis statistical programming 
SAP Section 
Changes 
Rationale 
Signature page 
Update in signatories. 
Staff changes and company SOP update. 
5 
Updated endpoints to reference the target 
population instead of the analysis set. 
Align with protocol. 
7.11, 11.8.1.3 
Deleted reference to time-slotting of 
scheduled and unscheduled visits and 
definition of visit windows for Quality of 
Life (QoL). 
Analyses by visits will use the nominal visit 
recorded in the eCRF. 
7.12 
Added clarifications on treatment arms for 
SAF to better handle patients who receive 
Tafa/RTX only and no BEN. 
Added the definition of "Enrolled patients". 
Deleted specification about including in OS 
analyses, death which occur after withdrawal 
of consent if death is reported in public 
record. 
Analyses on SAF will be based on actual 
treatment received and very few patients 
deviated from planned treatment and 
received Tafasitamab or RTX only with no 
BEN. 
Missing definition of "Enrolled patients". 
No data after withdrawal of consent will be 
used in any of the analyses, including OS 
analyses. 
7.13 
Updated the list of subgroups for the efficacy 
analyses forest plot of Hazard Ratio(HR) or 
(Odds Ratio) OR for treatment effect. 
Dropped subgroups which were not relevant 
and added subgroups which are relevant to 
the efficacy endpoints. 
7.16 
Dropped the subsection on Multiple 
Imputation (MI) for missing values. 
None of the analyses used MI for missing 
values. 
8.1, 8.3 
Reorganized the disposition summary tables 
for screened and enrolled patients. 
Disposition table on screened patients will 
include patient flow from screening to 
randomization. Disposition table on enrolled 
patients will summarize patient flow from 
randomization to treatment and follow-up 
phases of the study. 
Added the generation of the disposition table 
of randomized patients for NKCC-Low 
(FAS) 
Aligned the disposition summary table with 
phases of the study consort diagram. 
Flow of patients in the FAS and NKCC-Low 
(FAS) are of interest. 
8.2 
Updated the disposition summary table 
(treatment phase) to delete summaries 
applicable to Interim Analyses but not 
applicable to the Final Analysis (FA) and 
added summaries relevant to FA. 
For patients who are on treatment with 
Tafasitamab or RTX after disease 
progression, added details on summarizing 
lag between earliest post-baseline PD 
assessment and end of treatment of 
Tafasitamab or RTX. 
Previous specifications were for Interim, 
Primary and Final Analysis (FA) which were 
simplified to focus on FA. 
Details needed for CSR. 
8.4 
Dropped reporting of center-related protocol 
deviations (PDs).  
Only patient-related PDs will be summarized 
in FA. 
8.5 
Dropped generation of demographic and 
baseline summary table for SAF. 
Updated list of baseline characteristics. 
Streamlined analyses for FA.  
Updated list of baseline characteristics 
include characteristics used in study endpoint 
analyses. 


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SAP Section 
Changes 
Rationale 
8.7 
Moved specifications on summary tables and 
listings to top of the section since applicable 
to all sub-sections.  
Updated the list of characteristics for DLBL-
specific medical history and diagnosis. 
To facilitate consistency of planned analyses 
for medical history and current medical 
conditions. 
Included relevant characteristics for 
DLBL-specific medical history and 
diagnosis. 
8.8 
Updated the whole section to specify that 
analyses will be on FAS only, i.e. dropped 
analyses on SAF and NKCC-Low (FAS). 
Clarified that concomitant medications will 
be coded using WHO Drug Dictionary 
Enhanced (WHO-DDE) and concomitant 
medical procedures and non-drug therapies 
will be coded using MedDRA.  
Streamlined analyses for FA. 
Clarifications were needed for the summary 
of concomitant medications, procedures and 
non-drug therapies. 
8.9 
Updated specifications to reflect that 
analyses will be on SAF only, i.e. dropped 
the analyses for FAS. 
Streamlined analyses for FA.  
9 
While retaining the significance levels to be 
used for the hierarchical testing strategy for 
the efficacy endpoints, the calculation of 
confidence intervals 9CI) for PFS, ORR and 
OS for the overall population and the NKCC-
Low subgroup is simplified to calculating 
95% CIs. 
Simplified CI estimates. 
10.1.3.2, 10.1.3.3, 11.2.1.1 
Clarified censoring rule for PFS/DoR if event 
occurs after two or more consecutive 
missing/non-adequate tumour assessments 
for scheduled visits and added censoring rule 
for unscheduled visits. 
Dropped censoring rule not applicable to 
retained analyses after streamlining analyses 
for efficacy endpoints. 
Consistency across different sections of the 
SAP. There were unscheduled disease 
assessments so censoring rule for PFS/DoR 
had to be added. 
Streamlined efficacy analysis. 
10.2.3, 11.1.1.3, 11.2.1.2, 
11.3.1.4, 11.4.1.1, 11.5.1.2 
Simplified and reorganized the tables which 
list the planned analyses. 
Specified the subgroups for the forest plots of 
95% CI for Hazard Ratio (HR) or for Odds 
Ratio (OR) for treatment effect. 
Improved readability of summary of the 
planned efficacy main, sensitivity and 
supportive analyses. 
Completed the specifications on subgroups 
for the forest plots of HRs and ORs. 
10.2.3, 11.1.1.3, 
11.2.1.2,11.4.1.1, 11.5.1.2 
Dropped some of the sensitivity and 
supportive analyses for endpoints PFS, Best 
ORR, DoR, DCR, TTP. 
Added missing tabulation of events/censored 
and KM estimation for sensitivity analysis 
where COVID-19 deaths are considered 
censored rather than as event for endpoints 
PFS and DoR. 
Added summary of patients with CR under 
the analysis for endpoint Best Objective 
Response. 
Streamlined efficacy analyses. 
Missing analyses were added. 
For endpoint Best Objective Response of 
interest is the proportion who reached CR or 
PR as well of proportion who reached CR. 
11.3.1.4. 
Dropped some sensitivity analyses for 
endpoint OS. 
Streamlined efficacy analyses. 
11.6.1.2 
Dropped all sensitivity and supportive 
analyses for endpoint TTNT. 
Streamlined efficacy analyses. 
11.9.1. 
Reorganization of the section on 
immunogenicity. 
To provide more clarity on the required 
analyses. 
12.1.2 
Dropped CD16 expression on NK cells, 
ADCC capacity 
Reporting in CSR not required due to 
exploratory nature. 


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SAP Section 
Changes 
Rationale 
12.3, 12.4 
Corrected analysis groups from SAF and 
NKCC-Low (SAF) to FAS and NKCC-Low 
(FAS).  
Efficacy analyses are on FAS and NKCC-
Low (FAS). 
13.1. 
Reorganized the section and added analysis 
details. Added in Section 13.1.1 that select 
PTs in the Investigational SOC will count 
towards the blood and lymphatic disorder 
SOC. Added summary of post-treatment 
TEAEs in SAF and NKCC-Low(SAF). 
Switched the categories for cause of death 
from related or unrelated to disease 
progression to related or unrelated to AE. 
Added analysis for NKCC-Low (SAF) and 
Enrolled patients. Dropped the summary of 
AEs for Screened patients. 
To provide more clarity on how to 
summarize the adverse events and deaths. 
Updated the categories for cause of death to 
match how details on death is collected in the 
study. 
The analysis sets are SAF and NKCC-
Low(SAF) to match the study objective on 
AEs. Summary of AEs in Enrolled patients 
was added to summarize the safety data on 
all patients who participated in the study. 
13.1.12. 
Specified that possible effect of Tafasitamab 
production batch on safety analyses will be 
checked, but not for efficacy analyses. Added 
analysis specifications.  
Streamlined analyses for FA. 
14 
Added that baseline summary table will be 
on FAS and NKCC-Low (FAS) and not on 
FAS and SAF; and QoL data will be 
summarized for the overall population only. 
Updated to list of changes from the protocol 
with current SAP version. 
All sections, as applicable 
Added generation of listings which supports 
the summary tables and figures. 
Correction of typos and clerical errors, as 
well as harmonization of wordings and 
formatting. 
Listings were inadvertently left out. 
Summary of Changes From Version 6 to Version 6.1 
SAP Section 
Changes 
Rationale 
Signature page 
Update in signatories. 
Staff change. 
5 
Table 5-1 was corrected. For Co-Primary 1, 
the objective was changed to PFS in the 
overall (FAS) population, while the objective 
for Co-Primary 2 was changed to NKCC-low 
subgroup to be in line with respective 
endpoints. 
Alignment of endpoints and objectives.  
6.2 
Table 6-2 was corrected. The overall 
significance level for the NKCC-low 
subgroup at Primary Analysis is 1.4%. 
Typo correction. 
6.2.1 
Tables 6-3 and 6-4 were harmonized. 
The PFS-IRC event projections for the Final 
Analysis were slightly different between the 
tables (338 vs. 340 for the FAS and 135 vs. 
136 for the NKCC-low subgroup). Numbers 
have been aligned to avoid confusion. 
6.2.1 
Table 6-4: the information fraction (IF) was 
re-defined. In SAP version 6, the number of 
events corresponding to 80% power had been 
defined as IF=1. In SAP version 6,1, the 
number of events expected at Final Analysis 
have been defined as having an IF of 1.  
As per FDA request. 


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Summary of Changes From Version 5 to Version 6 
A new SAP is created for the B-MIND study for the following reasons: 
− The new SAP is based on protocol version 10 (dated 02-December-2022) 
− A section was added on doing sensitivity analyses on effects of different production 
batches on safety and efficacy endpoints. 
SAP Section 
Changes 
Rationale 
Section 5 Study Objectives 
Order of FAS and NKCC-Low subgroup 
changed. 
Order was changed to align with the 
protocol. 
6.1 Study Design 
Figure 6.1 updated 
Footnotes were updated to better explain 
study flow 
6.2.1 Sample Size 
Assumptions 
References to "primary analysis" were 
changed to "primary efficacy analysis" 
Planned primary analysis was removed from 
the protocol. 
6.3.3 Primary Analysis (PA) 
Section was amended to note that the 
planned Primary Analysis will not be 
performed. Instead, the primary efficacy 
analysis will be done at the Final Analysis. 
Based on anticipated PFS rate, the pre-
specified N=369 IRC-PFS events for primary 
analysis will not be reached. 
Section 7.14.3 No baseline 
tumour assessments 
1. "no contrast CTs read by IRC" added as 
an example of acceptable PET/CT 
examination 
2. Reference to "primary analysis" changed 
to "primary efficacy analysis in FA". 
1. IRC reads no-contrast CTs. 
2. Planned primary analysis will not be 
done; instead, the primary efficacy 
analysis will be done at FA 
Section 7.14.4 Lugano 
Classification 
Whole section was removed. 
This supplemental measure is deemed not 
necessary. B-MIND was designed for 
Cheson 2007 and response assessment by 
Cheson 2014 will not be used in the study. 
Section 7.17.4 Specifications 
and Analysis Database 
Reference to database lock for primary 
analysis was deleted. 
Planned primary analysis will not be done; 
instead, the primary efficacy analysis will be 
done at FA. 
Section 9 Efficacy Analysis 
of Primary and Key 
Secondary Endpoint 
1. References to primary analysis were 
changed to "primary efficacy analysis in 
FA" or "Final Analysis" 
2. Text was added to emphasize that local 
significance level will be adjusted based 
on the actually observed IRC-PFS events 
to ensure the FWER is controlled at 2-
side level of 0.05. 
3. A section on impact of COVID-19 on the 
analysis of the primary and key secondary 
endpoints. 
1. Planned primary analysis will not be 
done; instead, the primary efficacy 
analysis will be done at FA 
2. Text was added to ensure that FWER is 
controlled at 2-side level of 0.05. 
3. Section was added to consider the 
impact of COVID-19 on analysis of the 
primary and key secondary endpoints 
Section 8.1 Screened 
Patients 
Added category of "Successfully screened 
but not randomized" 
There were patients who were successfully 
screened but not randomized. 
Section 8.4 Protocol 
Deviations 
1. Listing of protocol deviations changed. 
2. Listing of PDs limited to major/key PDs, 
not all PDs. 
1. New listing was made to align with the 
Protocol Deviation SOP. 
2. Only major/key PDs are needed fo the 
Final Analysis. 
Section 10.1.3.2 Censoring 
Rules (PFS) 
In Table 10-2, the case of "death or 
progression after two or more missed visits" 
was corrected to "death or progression after 
two or more missed consecutive tumour 
assessments" 
What is relevant to analysis is to consider 
missed consecutive tumour assessments, not 
missed visits, as censored. 
Section 10.1.3.3 Missed 
Tumour Assessment 
Reference to "primary analysis" changed to 
"primary efficacy analysis" 
Planned primary analysis will not be done, 
and the primary efficacy analysis will be 
done at FA. 


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SAP Section 
Changes 
Rationale 
Section 10.2.2 
Implementation of the 
Inverse Normal Method 
Reference to "primary analysis" changed to 
"primary efficacy analysis in the FA". 
Planned primary analysis will not be done, 
and the primary efficacy analysis will be 
done at FA. 
Section 10.2.3 Main 
Analysis, Sensitivity 
Analysis and Supportive 
Analysis - PFS, Table 10-4: 
1. Sens.1.5 a-b TA as per Lugano (2014) 
deleted 
2. Sens.1.5 a-b (Considering patients who 
started new anti-DLBCL treatment as 
having IRC-PFS event) added 
3. Sens.1.8 a-b (Considering patients with 
clinical progression not confirmed by 
Cheson criteria) deleted 
4. Sens.1.8 a-b (Considering COVID-19 
deaths as censored rather than as event) 
added 
5. Sens1.10 a-b on production batch was 
added. 
6. Sens.3.3 a-b Lugano was deleted 
7. Sens 3.3 a-b (Considering patients who 
initiated new anti-DLBCL treatment as 
having IRC-PFS event) was added. 
8. Sens3.6a-b (Considering patients with 
clinical progression not confirmed by 
Cheson criteria) was deleted. 
9. Sens 3.6 a-b (Considering COVID-19 
deaths as censored and not an event) was 
added. 
10. Sens 3.8 a-b on production batch was 
added. 
1. Lugano Classification deleted from 
protocol. 
2. Added to address potential informative 
censoring due to the study's open label 
status at site level.  
3. Sensitivity analysis for patients starting 
NALT was instead added. 
4. To consider the impact of COVID-19 on 
the PFS analysis. 
5. To consider the effect of production 
batch on efficacy endpoint added. 
6. Lugano Classification was removed 
from protocol. 
7. Added to address potential informative 
censoring due to the study's open label 
status at site level. 
8. Sensitivity analysis for patients starting 
NALT was instead added. 
9. To consider the impact of COVID-19 on 
the PFS analysis. 
10. To consider the effect of production 
batch on efficacy endpoint added. 
Section 11.1.1.2 
Implementation of the 
Inverse Normal Method 
Reference to "primary analysis" changed to 
"primary efficacy analysis in the FA" 
Planned primary analysis will not be done, 
and the primary efficacy analysis will be 
done at FA 
Section 11.1.1.3 Main 
Analysis, Sensitivity 
Analysis and Supportive 
Analysis – ORR, Table 11-1 
Sens 1.6 a-b Lugano was deleted, changed to 
analysis on production batch. 
The Lugano Classification deleted from the 
protocol. 
Change was made to consider the effect of 
production batch on efficacy endpoint added. 
Section 11.2.1.2 Main 
Analysis, Sensitivity 
Analysis and Supportive 
Analysis – DOR, Table 11-3 
Sens 1.7 a-b on production batch was added. 
To consider the effect of production batch on 
efficacy endpoint added 
Section 11.3.1.2 
Implementation of the 
Inverse Normal Method  
Reference to "primary analysis" changed to 
"primary efficacy analysis in the FA" 
Planned primary analysis will not be done; 
instead, the primary efficacy analysis will be 
done at FA 
Section 11.3.1.4 Main 
Analysis, Sensitivity 
Analysis and Supportive 
Analysis – OS, Table 11-5 
1. Sens 2.4 a-b (Considering COVID-19 
deaths as censored rather than as OS 
event) was added. 
2. Sens 2.5 a-b on production batch was 
added. 
1. To consider the impact of COVID-19 on 
OS analysis. 
2. To consider the effect of production batch 
on efficacy endpoint added. 
Section 11.5.1.1 Censoring 
Rules – TTP, Table 11-7 
The case of "death or progression after two 
or more missed visits" was corrected to 
"death or progression after two or more 
missed consecutive tumour assessments" 
What is relevant to analysis is to consider 
missed consecutive tumour assessments, not 
missed visits, as censored. 
Section 13.1.9.4 Deaths 
The following text was added "Deaths due to 
COVID-19 will be summarized by treatment 
arm and overall. 
To consider the impact of COVID-19 deaths 
by treatment arm and overall. 
Section 13.1.12 Production 
Batch 
Section on Production Batch was added. 
To see if production line supplies affect 
safety profile and efficacy endpoints 


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SAP Section 
Changes 
Rationale 
Section 15.1 Document 
headers 
Reference to Primary Analysis was deleted. 
Planned primary analysis will not be done, 
and the primary efficacy analysis will be 
done at FA. 
Section 17.2 Appendix B: 
Lugano Classification 
Criteria for SLL (adapted 
from Cheson, et al. 2014) 
Section deleted. 
Lugano Classification was deleted from the 
protocol. 
Summary of Changes From Version 4 to Version 5 
SAP Section 
Changes 
Rationale 
10.2 Statistical Analysis of 
Co-Primary Endpoints 
1. A stratified Cox model will be used for 
treatment effect estimation 
2. Sensitivity/supportive analyses based on 
imputed data were removed 
3. Sensitivity/supportive analyses based on 
propensity score matching were removed 
4. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
5. Change in censoring rules for PFS 
sensitivity analyses based on the 
investigator assessment. 
1. Stratification used to account for 
potential non-proportional hazard. 
Modification also requested by FDA 
2. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
3. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
4. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
5. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
11.1.1 Statistical Analysis 
(for the endpoint Best 
Objective Response Rate) 
1. Sensitivity/supportive analyses based on 
imputed data were removed 
2. Sensitivity/supportive analyses based on 
propensity score matching were removed 
3. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
1. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
2. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
3. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
11.2.1 Statistical Analysis 
(for the endpoint Duration of 
Response) 
1. Kaplan-Meier analyses are conducted 
based on responders only 
2. Change in censoring rules for DoR 
sensitivity analyses based on the 
investigator assessment. 
1. Modification requested by FDA 
2. Sensitivity / supportive analyses 
obsolete. Modification also requested by 
FDA. 
11.3.1 Statistical Analysis 
(for the endpoint Overall 
Survival) 
1. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
2. A statistical test for OS will only be 
performed at Final Analysis 
1. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
2. The power at Primary Analysis will be 
low due to a limited number of observed 
OS events. 
11.4.1 Statistical Analysis 
(for the endpoint Disease 
Control Rate) 
1. Sensitivity/supportive analyses based on 
imputed data were removed 
2. Sensitivity/supportive analyses based on 
propensity score matching were removed 
3. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
1. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
2. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
3. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 


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SAP Section 
Changes 
Rationale 
11.5.1 Statistical Analysis 
(for the endpoint Time to 
Progression) 
1. A stratified Cox model will be used for 
treatment effect estimation 
2. Sensitivity/supportive analyses based on 
imputed data were removed 
3. Sensitivity/supportive analyses based on 
propensity score matching were removed 
4. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
5. Change in censoring rules for TTP 
sensitivity analyses based on the 
investigator assessment. 
1. Stratification used to account for 
potential non-proportional hazard. 
Modification also requested by FDA 
2. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
3. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
4. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
5. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
11.5.1 Statistical Analysis 
(for the endpoint Time to 
Next Treatment) 
1. A stratified Cox model will be used for 
treatment effect estimation 
2. Sensitivity/supportive analyses based on 
imputed data were removed 
3. Sensitivity/supportive analyses based on 
propensity score matching were removed 
4. Multivariable models including 
covariates or interaction terms beyond 
the randomization stratification factors 
were removed 
5. Change in censoring rules for PFS 
sensitivity analyses based on the 
investigator assessment. 
1. Stratification used to account for 
potential non-proportional hazard. 
Modification also requested by FDA 
2. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
3. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
4. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
5. Sensitivity / supportive analyses 
considered redundant. Modification also 
requested by FDA. 
Summary of Changes From Version 3 to Version 4 
SAP Section 
Changes 
Rationale 
Signature page 
Update in signatories. 
Staff change. 
6.2 
Table 6-2 was corrected. The overall 
significance level for the NKCC-low 
subgroup at Primary Analysis is 1.4%. 
Typo correction. 
8.4 Protocol Deviations 
Including analysis of protocol deviations and 
serious breaches pertaining to study centers 
Revised according to FDA's 
recommendation received on 18th November 
2019 
8.9.1 Treatment Cycle and 
Study Drug Regimen 
Revised wording to clarify the treatment 
schedule for BEN 
Revised according to FDA's 
recommendation received on 18th November 
2019 
9 Efficacy Analysis of 
primary and key-secondary 
endpoints 
1. Addition of Figure and Table labeling 
2. Further details on the indices of 
Z-statistics and p-values 
3. Correction of "Final" analysis to 
"Primary" analysis in the section 
1. Previous figure and table without label 
have now correctly been labeled. 
2. Further details add clarification of the 
indices. 
3. Revised wording of "Final" analysis 
according to FDA's comment on 18th 
November 2019. 


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Summary of Changes From Version 2 to Version 3 
SAP Section 
Changes 
Rationale 
High Level Summary of 
changes 
The SAP has been re-written with  
1. Additional sections (Eg: 7.12.1 Screened 
patients),  
2. Additional definitions. (Eg: 7.2.1 Date of 
first administration of study drug) 
3. Additional details (Eg: 7.6 Baseline), 
 
1. Additional Sections are added for the 
sake of completeness and providing 
added clarification on Statistical 
programming to be performed. 
2. Additional definitions are provided 
because they were not provided in the 
previous SAP and they are needed for the 
sake of completeness and clear guidance 
on Statistical programming. 
3. Additional Details are added for the sake 
of completeness and providing added 
clarification on Statistical programming 
to be performed. 
3 List of abbreviations 
NKCC, OR, TA added 
New abbreviations added 
4 Introduction 
1. Overview from last SAP version deleted 
2. Shortened introduction 
1. Restructure of the SAP due to protocol 
amendment and reference to the clinical 
protocol 
2. Reference to study protocol version 8 
(finalized on 14-Feb-2019), which 
includes deleted part of introduction 
5 Study Objectives and 
Endpoints 
1. Section "3. Study objectives" and "4. Study 
endpoints" from previous SAP version 
combined to one section. 
2. Including 2 co-primary endpoint (In 
addition to overall: NKCC-low subgroup) 
3. Secondary endpoints will be analysed in 
overall population NKCC-low subgroup 
4. Secondary endpoint definition for QoL 
expanded to "Change from baseline in 
global health status/QoL and pain scale 
scores of the EORTC QLQ-C30 and 
EQ-5D-5L" 
5. Secondary endpoint definition for anti-
MOR00208 antibody formation expanded 
to "Anti-MOR00208 antibody formation 
(ADA): number and percentage of patients 
who develop anti-MOR00208 antibodies; 
Titer determination; Characterization of 
ADA-positive samples (neutralizing vs 
non-neutralizing)" 
6. Secondary endpoint definition for the 
pharmacokinetic profile of MOR00208 
expanded to "Summary statistics for PK: 
plasma concentration-time profiles of 
MOR00208 and appropriate individual PK 
parameters" 
7. Deletion of "to be investigated during the 
course of the study" in the definition of 
exploratory endpoints and minor wording 
changes 
1. The new table with combined information 
on study objectives and endpoints 
provides direct link between objectives 
and endpoints 
2. Introduction of co-primary endpoints 
amendment 
3. Addition of new co-primary endpoints 
due to amendment 
4. Definition extended. With the protocol 
amendment the subgroups will be 
included in the definition of endpoints. 
5. Definition extended. With the protocol 
amendment the subgroups will be 
included in the definition of endpoints. 
6. Definition extended. With the protocol 
amendment the subgroups will be 
included in the definition of endpoints. 
7. This information is redundant, minor 
changes clarify and specify exploratory 
endpoints in more detail. 


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SAP Section 
Changes 
Rationale 
6.1 Study Design  
1. Introduction of study design from last SAP 
version deleted and replaced by reference 
to Section 8.2 of the study protocol 
2. Section "8.1.3 Stratified Randomisation" 
renamed to "6.1.1 Randomization and 
Stratification Factors" 
3. Expansion of Disease relapse/recurrence to 
"≤12 months versus >12 months from 
completion of last treatment" 
4. Details on discrepancies between 
stratification factor values in IWRS and 
eCRF moved to section 8 
5. Section "6. Schedule of Assessments" from 
previous SAP version moved to this 
section as subsection 
1. Since this information is not needed for 
the conduct of the analysis, a reference to 
the study protocol is sufficient 
2. Details on Randomization and 
Stratification belong to Study Design 
section. 
3. To bring more clarity of the definition of 
Disease relapse/recurrence 
4. Due to restructuring of the SAP, the 
display of concordance is now in section 
8 where patient characteristics are 
described. 
5. Details on schedule of assessments 
belong to Study Design section 
6.2 Sample size, Power 
Considerations and 
Randomization 
1. Section "8.1.6 Determination of Sample 
Size" from previous SAP version renamed 
to "6.2 Sample Size, Power considerations 
and Randomization" 
2. Section "8.1.6.1 Parameters and Results of 
Sample Size Determination" from previous 
SAP version is renamed to "6.2.1 Sample 
Size Assumptions" and includes more 
details on O'Brien-Fleming approach for 
the local significance levels at interim and 
primary analysis and the rational for an 
increase in sample size to 450 patients 
based NKCC-low subgroup assumptions 
3. Removal of "8.1.6.2 Overall Survival 
Assumption" from previous SAP version 
1. Since sample size and power 
considerations belong to the study design, 
it is moved to its section. 
2. Details on sample size estimations with 
interim analysis added. NKCC subgroup 
is now implemented with corresponding 
sample size adjustments. 
3. Information on overall survival 
assumption is not relevant for sample size 
calculation and thus deleted. 
6.3 Timing of Statistical 
Analysis 
1. Section "8.8 Independent Data Monitoring 
Committee" from previous SAP version 
renamed to "6.3.1 Safety IDMC Meetings" 
and shortened with reference for more 
details to the IDMC charter and Section 
13.12 of the study protocol. Addition of 
IDMC Safety Evaluation time-points of the 
study 
2. Section "8.7 Interim Analysis" from 
previous SAP version renamed to "6.3.2 
Interim Analysis (IA)" with changes in the 
details of the IA, addition of details on 
IDMC recommendations, information on 
sponsor's decision after IDMC 
recommendations from section "8.8 
Independent Data Monitoring Committee" 
from previous SAP version moved to this 
section 
3. Section "6.3.3 Primary analysis (PA)", 
"6.3.4 Final Analysis (FA)" and "6.3.5 
Statistical analyses Deliverables" added 
4. Section "8.4.1 Follow-up Analyses" from 
previous SAP version renamed to "6.3.6 
Additional Analysis" with deletion of 
"After the final analysis" and "to satisfy 
regulatory requirements" 
1. With the addition of the section "6.3 
Timing of Statistical Analysis", also 
safety IDMC meetings are covered and 
thus moved to this section. Information 
on IDMC meetings not related to 
statistical analysis are delete and a 
reference to IDMC charter is given. 
Details on analysis time-points added 
2. Details, including reviewing of IDMC 
recommendation added. Details on 
interim analysis in previous SAP under 
different subsections and now covered in 
one section. 
3. Details on these subsections added. This 
provides a clear overview of the different 
statistical analyses 
4. Additional analyses cover also follow-up 
analyses but include possibility to 
perform analyses before final analysis. 
Regulatory requirements will be 
addressed in any case and need not to be 
mentioned in particular 


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SAP Section 
Changes 
Rationale 
7 Definition and general 
Methodology 
Addition of new sections with details: 
7.1.1 Study drug and study treatment 
7.1.2 Treatment Arms 
7.2.1 Date of first administration of study drug 
7.2.2 Date of last administration of study drug 
7.2.3 Date of first administration of study 
treatment 
7.2.4 Date of last administration of study 
treatment 
7.3 Reference start date and Study day 
7.4 Screening failure 
7.5 Time unit 
7.6 NKCC at baseline and NKCC-low subgroup 
7.7 On treatment assessment/event 
7.8 Start and end date for time to event variables 
7.9 Last contact date  
All sections with information and details 
added. This provides a general understanding 
and definition of variables, which is needed 
for most of the calculations regarding the 
endpoints.  
7.6 Baseline 
Definition of "Baseline" in section "8.1.4.1 
Analysis Window" from previous SAP version 
changed and expanded with more details to 
section "7.6 Baseline" 
Additional details provided. This provides an 
extensive definition of Baseline, which is the 
basis for the calculation of most endpoints 
7.11 Analysis Window 
Section "8.1.4.2 Selection of Data in the Event 
of Multiple Records in a Window" renamed to 
"7.11.1 Selection of Data in the event of 
Multiple Records in a Window" with minor 
wording changes and addition of time-slot 
definition 
Time-slot definition provides possibility of 
summarizing parameters over time. Definition 
and details on multiple records gives a 
guidance on the procedure in order to analyze 
the endpoints 
7.12 Analysis 
Populations 
1. Addition of Section "7.12.1 Screened 
patients" with description of analysis set 
2. Section "7.12.2 Full Analysis Set (FAS)" 
includes definition "According to the intent-
to-treat principle, patients will be analyzed 
according to the treatment and stratification 
factors they have been assigned to during 
the randomization procedure. The FAS will 
be the primary population for the analysis of 
efficacy and baseline characteristics." 
3. Section "7.12.3 Per Protocol Set (PPS)" 
includes definition of PPS with regards to 
protocol deviations and purpose of PPS as 
sensitivity analysis for the primary efficacy 
endpoint 
4. Section "7.12.4 Safety Set (SAF)" includes a 
more detailed description of SAF 
5. Section "7.12.5 PK Analysis Set (PKAS)" 
includes a more detailed description of 
PKAS 
6. Section "7.12.6 Immunogenicity Analysis 
Set (IAS)" includes a changed definition of 
IAS as "IAS includes all patients who were 
randomized and have at least one anti-
MOR00208 antibody assessment." 
7. Addition of details on data handling with 
regards to "Withdrawal of Informed 
Consent" 
1. Definition with details provided. This 
information is needed for listings and 
tables where patients without 
randomization are included as well. 
2. Definition of FAS includes more details. 
Clarification that FAS will be the primary 
population. This provides a guidance on 
how to define the study population for the 
main analyzes. 
3. Definition of PPS includes more details, 
addition of descriptions on protocol 
deviations. The extension of the definition 
provides a detailed guidance on how to 
define this study population. 
4. More details are added to SAF definition. 
This provides a detailed guidance on how 
to define this study population. 
5. More details are added to PKAS definition. 
This provides a detailed guidance on how 
to define this study population. 
6. Additional details provided. This provides 
a detailed guidance on how to define this 
study population. 
7. Information on patients, who withdrew 
Informed consent added. This provides a 
guidance on reporting and handling these 
cases. 


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SAP Section 
Changes 
Rationale 
7.13 Subgroups 
1. Addition of subgroups considered for 
efficacy analysis  
Addition of further subgroups to be analyzed. 
Results from analyses on these subgroups can 
provide more details and conclusions on the 
treatment. 
7.14 Implementation of 
CHESON Criteria 
1. Section "7.14 Implementation of CHESON 
criteria" added with description and 
inclusion of table "Definition of Response 
Criteria" from Section 11.1 from previous 
SAP version 
2. Section "7.14.1 Disease Progression", 
"7.14.2 Change in imaging modality", 
"7.14.3 No baseline tumour assessments", 
"7.14.4 Lugano Classification" added 
1. Section with details added. This provides 
consistency in defining the response. 
2. Sections with details added. This provides 
consistency in defining the response. 
7.15 General convention 
for Missing Data 
Section added with details on convention for 
missing data 
Sections with details provided. This provides 
a general rule on handling missing data 
7.16 Multiple Imputation 
Section added with details on convention for 
multiple imputation 
Sections with details provided. This provides 
a general rule on handling missing data and 
how to impute these. 
7.17 General points 
1. Section "7.17.1 General Principles of 
Statistical programming" with change to 
SAS version 9.4 or higher and deletion of 
ADDPLAN version 6.1  
2. Section "8.1.1 Statistical Methods" from 
previous SAP version renamed to "7.17.2 
Variable Types and Descriptive Statistics" 
with addition of definition of reference 
number of subjects and more detailed 
description of continuous and categorical 
variables. Addition of definition of "Time 
variables" and "Time to Event Variables" 
3. Section "7.17.3 Data included in the 
analysis and Cut-off date", "7.17.4 
Specifications and Analysis Database" 
added 
4. Section "8.1.5 Pooling of Investigative 
Sites" from previous SAP version renamed 
to "7.17.5 Pooling of Investigative Sites" 
1. Statistical programming is now performed 
only in SAS. 
2. Information on variable types and analysis 
methods added. Also time to event 
variables and time variables with details 
are provided. 
3. Sections with details added. This is to 
specify which data will be included in the 
analysis. 
4. Section moved to General points. 
8.1 Patient disposition 
1. Section "8.1 Screened patients" and "8.2 
Enrolled patients" added 
2. Section "8.3.1 Summary Statistics" for the 
follow-up period added 
3. Section "8.2.7.1 Duration of Follow-up" 
from previous SAP version renamed to 
"8.3.2 Duration of Follow-up" with addition 
of definitions for cut-off calculations/ 
follow-up times  
1. Section with details added. This is to 
provide information on patient disposition 
on screened and randomized patients. 
2. Section with details added. This provides 
guidance on how to analyses in the follow-
up period 
3. Section with details added. This provides 
guidance on how to analyses in the follow-
up period. 
8.4 Protocol deviations 
Section "8.2.2 Protocol Deviations" from 
previous SAP version renamed to "8.4 Protocol 
Deviations" with new categories for protocol 
deviation  
New categories for protocol deviations allow 
an easier summary of protocol deviations. 
8.5 Background and 
demographic 
characteristics 
Section "8.2.3 Background and demographic 
characteristics" from previous SAP version 
renamed to "8.5 Demographic and Baseline 
characteristics" with additional variables to be 
analyzed 
More variables for demographic 
characteristics added. 
8.6 Randomization 
stratification 
Section "8.6 Randomization stratification" 
added 
Section with details added. This provides 
essential details. 


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SAP Section 
Changes 
Rationale 
8.7 Medical History and 
current medical 
conditions 
1. Details are extracted from section "8.2.3 
Background and demographic 
characteristics" from previous SAP version.  
2. Additional variables to be summarized for 
the DLBCL-specific medical history  
3. Specific medical history will be summarized 
for DLBCL (not only low grade lymphoma 
transformed into DLBCL) 
1. Diagnosis and extent of cancer added as a 
separate section, thus details moved to 
this section. 
2. Inclusion of more variables to be 
analyzed. This provides a broader 
overview of the medical history. 
3. Subgroup extended to all DLBCL, since 
other DLBCL subtypes are seen in the 
patient population. 
8.7.1 Coding and 
definitions 
1. Section "8.2.6 Medical History and Current 
Medical Conditions" from previous SAP 
version renamed to "8.7.1 Coding and 
definitions" 
2. Study population is changed to FAS 
3. Medical history and current medical 
conditions summarized by changed 
variables: body system, preferred term and 
toxicity grade 
1. Details in this section covers only the 
definition used for medical history and 
conditions and thus moved to the coding 
and definitions section. 
2. Study population defined 
3. Instead of counts and percentages, new 
variables are introduced, which allow a 
more detailed summary on medical 
history. 
8.7.2 DLBCL-specific 
medical history and 
diagnosis 
1. Details are extracted from section "8.2.3 
Background and demographic 
characteristics" from previous SAP version. 
2. Addition of more variables to be 
summarized 
3. Addition of description of summaries for 
Diagnostic Lymph Node Biopsy and Bone 
marrow Aspiration and Biopsy 
4. Addition of analysis description for 
Concordance between cell-of-origin 
determination by gene expression profiling 
and immune-histochemistry 
5. Section "8.7.2.1 Handling of incomplete 
dates regarding DLBCL-specific medical 
history" and "8.7.2.2 Calculation of the 
International Prognostic Index (IPI)" added 
1. Information on DLBCL-specific history 
are more relevant in this section. 
2. Addition of more variables for an 
extension of analysis 
3. Analysis added. This provides a broader 
overview of the medical history. 
4. Analysis added. This provides a broader 
overview of the medical history. 
5. Analysis added. This provides guidance 
for the analysis. 
8.7.3 Reason for ASCT 
ineligibility 
Section added 
Section with details added. This is important 
information since ASCT belongs to the 
inclusion criteria. 


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SAP Section 
Changes 
Rationale 
8.8 Prior and 
Concomitant 
Medications and 
Therapies/Pre-
medication for 
MOR00208 Infusion 
1. Section "8.8.1 Coding" is extracted from 
section "8.2.5 Prior and Concomitant 
medications and Therapies/Pre-medication 
for MOR00208 Infusion" from previous 
SAP version, addition of coding for surgical 
and medical procedures 
2. Section "8.8.2 Definitions" added with 
definitions from section "8.2.5 Prior 
Concomitant Medications and 
Therapies/Pre-medication for MOR00208 
Infusion" plus additional definitions on 
times 
3. Section "8.8.3 Data presentation" added 
with description from section "8.2.5 Prior 
and Concomitant medications and 
Therapies/Pre-medication for MOR00208 
Infusion" plus list of variables to be 
summarized 
4. Section "8.8.4.1 Prior therapy procedures", 
"8.8.4.2 handling of incomplete dates 
regarding prior therapies", "8.8.4.3 
Refractoriness to prior therapies", "8.8.6 
Pre-Medication for MOR00208/RTX/BEN 
infusion", "8.6.7 Concomitant medication" 
added 
1. In order to provide more details, section 
for prior and concomitant medication is 
separated into several subsections. In this 
section, more comprehensive details and 
definitions are included, which were 
missing in previous SAP version. 
2. Details on the calculation of times added. 
3. Variables for summary tables added. This 
allows a broader overview of prior 
medications. 
4. Sections with details added. These details 
provide guidance and information 
regarding prior medication. 
8.9 Study treatment 
1. Section "8.9.1 Treatment Cycle and Study 
Drug Regimen" – "8.9.7 Treatment Kits" 
added 
2. Section "8.9.6 Compliance" includes 
definition of study drug compliance per 
infusion from section "8.2.4 Treatment 
Exposure and Compliance" from previous 
SAP version, with addition of definition of 
study drug compliance per circle and further 
details for presenting data 
1. Sections with details added. This 
provides guidance and definitions 
regarding the study treatment. 
2. Some definitions and descriptions for 
drug compliance added. 
9 Efficacy analysis of 
primary and key-
secondary endpoint 
Strategy for hierarchical analysis of co-primary 
and key-secondary endpoints 
Following the protocol amendment, a 
hierarchical approach for testing the co-
primary endpoints and key-secondary 
endpoints was introduced. 
10.1 Endpoints 
1. Definition of PFS based on definition in 
section "8.3.1 Primary Efficacy Analysis" 
from previous SAP with addition of tumour 
assessments definition 
2. Section "10.1.1 Co-Primary Endpoint 1" – 
"10.1.2 Co-Primary Endpoint 2" added 
3. Section "10.1.3.1 Disease Assessments" 
added 
4. Section "10.1.3.2 Censoring Rules" based 
on Table in section "8.3.1 Primary Efficacy 
analysis" from previous SAP version, 
expanded with more situations to consider 
and censoring reasons 
5. Section "10.1.3.3 Missing tumour 
assessment" added 
1. Tumour assessments definition added. 
This information is essential since it 
belongs to the primary endpoint analysis. 
2. Sections with details added. This 
information is essential since it describes 
the co-primary endpoints 
3. Sections with details added. This is to 
provide guidance on the disease 
assessment since it belongs to the primary 
endpoint. 
4. More situations for censoring or 
progression outcomes added. This is to 
cover all scenarios with regard to 
censoring. 
5. Section with details added. This is 
essential since the information belongs to 
the primary endpoint. 


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SAP Section 
Changes 
Rationale 
10.2 Statistical Analysis 
of Co-Primary Endpoints 
1. Section "10.2.1 Null and Alternative 
Hypothesis" added 
2. Section "10.2.2 Implementation of Inverse 
Normal method" with more details added 
3. Table with all main, sensitivity and 
supportive analyses added 
1. Section with details added. Statement of 
hypothesis is essential for the statistical 
testing. 
2. Information on the use of inverse normal 
method is added following the new 
protocol amendment. 
3. New structure of analyses for a complete 
overview  
11 Secondary Efficacy 
Objectives 
Section "8.3.2 Secondary Efficacy Variable(s)" 
from previous SAP version renamed to 
"11 Secondary Efficacy Objectives" with 
modification regarding co-primary endpoints 
and extension of description with more details 
on statistical analysis 
Minor wording changes are for consistency. 
Information regarding procedure after 
hypothesis is rejected or not rejected added. 
11.1 Secondary 
Objective 1a 
1. Section "8.3.2.1 Best Objective Response 
Rate (ORR)" from previous SAP version 
renamed to "11.1 Secondary Objective 1a" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details and analyses 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Section from previous SAP remains 
primarily unchanged with minor wording 
corrections, but essential additional 
details added, such as statistical 
methodology for the analysis of ORR. 
Details on sensitivity analysis added. 
11.2 Secondary 
Objective 1b 
1. Section "8.3.2.2 Duration of Response 
(DoR)" from previous SAP version renamed 
to "11.2 Secondary Objective 1b" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details and analyses 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP remains 
primarily unchanged with minor wording 
corrections, but essential additional 
details added, such as statistical 
methodology for the analysis of ORR. 
Details on sensitivity analysis added. 
11.3 Secondary 
objective 1c 
1. Section "8.3.2.5 Overall Survival (OS)" 
from previous SAP version renamed to 
"11.3 Secondary objective 1c" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details and analyses 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP remains 
primarily unchanged, but essential details 
added, such as statistical methodology for 
the analysis of OS. In addition, rules for 
censoring in previous SAP expanded. 
Details on sensitivity analysis added. 
10.4 Secondary 
Objective 1d 
1. Section "8.3.2.3 Disease Control Rate 
(DCR)" from previous SAP version 
renamed to "11.4 Secondary Objective 1d" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details and analyses 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP remains 
primarily unchanged with minor wording 
corrections. Essential details are added, 
such as the statistical methodology for the 
analysis of DCR. Details on sensitivity 
analysis added. 


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SAP Section 
Changes 
Rationale 
11.5 Secondary 
Objective 1e 
1. Section "8.3.2.4 Time to Progression (TTP)" 
from previous SAP version renamed to 
"11.5 Secondary Objective 1e" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details and analyses 
3. Addition of censoring rule table 
1. 
New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Only first paragraph from previous SAP 
version included. Rest of the section in 
previous SAP replaced by more detailed 
information, such as statistical 
methodology. 
3. Censoring rules added. 
11.6 Secondary 
Objective 1f 
1. Section "8.3.2.6 Time to next treatment 
(TTNT)" from previous SAP version 
renamed to "11.6 Secondary Objective 1f" 
2. Addition of subsections with information 
from previous SAP and addition of more 
details  
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP remains 
unchanged. Additional details are 
included. 
11.7 Secondary 
Objective 1g 
Section added and refers to safety section 
Section with details added. 
11.8 Secondary 
Objective 1h 
1. Section "8.3.2.7 Quality of Life 
Questionnaire EORTC QLQ-C30 and EQ-
5D-5L" from previous SAP renamed to 
"11.8 Secondary Objective 1h" 
2. Addition of subsections with information 
from previous SAP 
3. Addition of Assessments and visit windows 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP remains 
unchanged with essential details added. 
Last paragraph from this section in 
previous SAP version deleted, 
information from this part is presented in 
other sections, where it is more suitable. 
3. Information added. This is to allow 
guidance on the analysis of this objective. 
11.9 Secondary 
Objective 2 
1. Section "8.4.3 Immunogenicity Analysis" 
from previous SAP renamed to "11.9 
Secondary Objective 2" 
2. Addition of information regarding missing 
values 
3. Addition of details for analysis of 
immunogenicity 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information from previous SAP version 
remains unchanged with minor wording 
corrections. Information regarding 
missing values added. 
3. Details added. 
11.11 Secondary 
Objective 3 
1. Section "8.4.2 Pharmacokinetic (PK) 
Analysis" from previous SAP version 
renamed to "11.11 Secondary Objective 3" 
2. Addition of more details regarding serum 
concentration 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Information expanded. 
12 Exploratory Efficacy 
Objectives 
1. Section "8.4.4 Exploratory Endpoints" from 
previous SAP version renamed to "11 
Exploratory Efficacy Objectives" 
2. Deletion of "DoR of CR" description from 
previous SAP version 
3. Addition of "12.1 Exploratory Objective 1" 
with information on biomarkers based on 
section "8.4.6 Exploratory Biomarkers" 
from previous SAP version including 
additional details on biomarkers and 
corresponding statistical analysis 
4. Section 12.2-12.4 added with additional 
analyses 
1. New structure and numbering of 
secondary endpoints present a better 
overview of secondary endpoints. 
2. Moved to secondary endpoints, 
sensitivity analysis of DoR, because it is 
not an exploratory endpoints described in 
the protocol. 
3. Information from previous SAP version 
remains unchanged with minor wording 
corrections. Additional details provided. 
4. Section with details added for further 
exploratory analyses. 


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SAP Section 
Changes 
Rationale 
13 Safety Evaluation 
13.1 Adverse events 
1. 
Section "8.5 Safety Analysis" from 
previous SAP version renamed to "13 
Safety Evaluation" with general 
information added, including description of 
detailed safety assessment 
2. 
Section "8.5.1 Adverse Events (AEs)" 
from previous SAP version renamed to 
"13.1.1 Adverse Event (AE) and Treatment 
emergent Adverse Events (TEAE)" and 
information until "AEs of special interest 
(AESI)" from previous SAP version is 
included, item "Toxicity grade" removed 
3. 
Section "13.1.2 Treatment Emergent 
Adverse Event (TEAE)" added with a 
more detailed description of TEAE and 
description of approach for missing date 
and time of AEs from section "8.5 Safety 
Analysis" from previous SAP version 
4. 
Section "13.1.3 Non-treatment emergent 
Adverse Events" added 
5. 
Section "13.1.4 Adverse Events of Special 
Interest (AESI)" added with information 
from section "8.5 Safety Analysis" from 
previous SAP version 
6. 
Section "13.1.5 Relationship to Study 
Drug" added with information from section 
"8.5 Safety Analysis" from previous SAP 
version and minor wording changes 
7. 
Section "13.1.6 Dictionary coding of 
Adverse Events" added with more details 
on Adverse events coding 
8. 
Section "13.1.7 Grading of Adverse 
Events" added with information on 
"Toxicity Grade" from section "8.5 Safety 
Analysis" from previous SAP and addition 
of details on "Common Terminology 
Criteria for Adverse Events (CTCAE)" 
9. 
Section "13.1.8 General rules for AE 
reporting" added with information from 
section "8.5 Safety Analysis" from 
previous SAP version and additional 
details on patients with more than one AE 
reported 
10. Section "13.1.9 Adverse Event 
Summaries" added with changes in 
summaries, addition of subsections for 
summaries for serious AEs, non-serious 
AEs and deaths 
11. Section "13.1.11 Adverse Event Listings" 
added with information from section "8.5 
Safety Analysis" from previous SAP 
version with additional listings 
1. New structure and numbering of safety 
section for a better overview. Information 
from previous SAP version remain 
unchanged with addition of a description 
on safety assessments. 
2. Information remains primarily unchanged 
from previous SAP version. Information 
on "Toxicity grade" is presented in a 
different section, where it is more 
suitable. 
3. Section added. Additional details 
provided. 
4. Section added. This is to provide a better 
overview on different types of AEs. 
5. Separate section added. Information from 
previous SAP remains unchanged. 
6. Separate section added. Information from 
previous SAP remains unchanged. 
7. Separate section added. Information from 
previous SAP remains unchanged with 
minor corrections. 
8. Separate section added. Information from 
previous SAP remains unchanged. 
Additional details provided. 
9. Separate section added. Information from 
previous SAP remains unchanged. 
Additional details provided. 
10. Separate section added. Description for 
variables for AE summary tables changed 
in accordance to L-MIND. 
11. Information from previous SAP version 
remains unchanged with minor 
corrections. Additional listings included. 


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SAP Section 
Changes 
Rationale 
13.2 Vital signs 
1. 
Section "8.5.3 Vital Signs" from previous 
SAP version renamed to "13.2 Vital signs" 
2. 
Section "13.2.1 Vital Sign variables" added 
3. 
Section "13.2.2 Vital Sign Analysis" added 
with information from section "8.5.3 Vital 
Signs" from previous SAP version and 
additional details 
1. New structure and numbering of section 
provides a better overview. 
2. Section with details added. This is to 
provide guidance on the analysis of vital 
signs. 
3. Section with details added. Details on 
vital sign analysis added. This is to 
provide guidance on the analysis of vital 
signs. 
13.3 Physical 
Examination 
Section "8.5.2 Physical Examination" from 
previous SAP renamed to "13.3 Physical 
Examination" with additional information 
Information from previous SAP version 
remains unchanged with additional details 
provided. 
13.4 Electrocardiogram 
(ECG) 
1. Section "8.5.4 Electrocardiograms (13-lead 
ECG)" from previous SAP renamed to "13.4 
Electrocardiogram (ECG)" 
2. Section "13.4.1 ECG Variables" added 
3. Section "13.4.2 ECG Analysis" added with 
information on normal ranges for ECG 
variables from section "8.5.4 
Electrocardiograms (12-lead ECG)" from 
previous SAP version and additional details 
on analyses with detailed table on clinically 
notable ECG values 
1. New structure and numbering of section 
provides a better overview. 
2. Section with details added. This is to 
provide guidance on the analysis of ECG. 
3. Information from previous SAP remains 
unchanged. Additional details provided, 
including table on clinically notable ECG 
values. 
13.5 Laboratory data 
1. Section "8.5.5 Clinical Laboratory 
Evaluations" from previous SAP version 
renamed to "13.5 Laboratory data" 
2. Section "13.5.1 Laboratory Variables" 
added with additional laboratory parameters 
3. Section "13.5.2 Grading of Laboratory data" 
added 
4. Section "13.5.3 Laboratory Analysis" added 
with information from section "8.5.5 
Clinical Laboratory Evaluations" from 
previous SAP version with minor changes in 
wording and additional analysis items 
1. New structure and numbering of section 
provides a better overview. 
2. Information from previous SAP version 
remains unchanged. Additional 
laboratory parameters provided. 
3. Section with details added. This is to 
provide guidance on the analysis of 
laboratory data. 
4. Information from previous SAP version 
remains unchanged with minor wording 
corrections. Additional details provided. 
13.6 Performance Status 
(ECOG) 
1. Section "8.5.6 ECOG Performance Status" 
from previous SAP version renamed to 
"13.6 Performance Status (ECOG)" 
2. Section "13.6.1 ECOG Scores" added 
3. Section "13.6.2 ECOG Scores Analyses" 
added with information from section "8.5.6 
ECOG Performance Status" from previous 
SAP version and additional analyses items 
1. New structure and numbering of section 
provides a better overview 
2. Section with details added. This is to 
provide guidance on the analysis of 
ECOG scores. 
3. Information from previous SAP remains 
unchanged with minor wording 
corrections. Additional details on ECOG 
score analyses provided. 
13.7 B-symptoms 
Section "8.5.7 B-Symptoms" from previous 
SAP version renamed to "13.7 B-symptoms" 
with addition of B-symptoms definition and 
additional details 
Information from previous SAP version 
remains unchanged. Additional details are 
provided. 
14 Changes from 
protocol 
Section added 
Section added to provide information and 
details of changes with regards to the 
protocol. 
15 General Guidance on 
reporting 
Section with subsections added with 
information from section "10 Tables, Listings, 
and Figures Layout" from previous SAP version 
included in section "13.7 Tables/Listings with 
no data" 
Information added with new convention for 
presenting dates. 


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2. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
DOCUMENT HISTORY .............................................................................................2 
2. 
TABLE OF CONTENTS ...........................................................................................20 
3. 
LIST OF ABBREVIATIONS.....................................................................................29 
4. 
INTRODUCTION ......................................................................................................32 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................32 
6. 
STUDY DESIGN AND SAMPLE SIZE ...................................................................34 
6.1. 
Study Design ...............................................................................................................34 
6.1.1. 
Randomization and Stratification Factors ..................................................................35 
6.1.2. 
Schedule of Assessments ............................................................................................36 
6.2. 
Sample Size, Power Considerations and Randomization ...........................................36 
6.2.1. 
Sample Size Assumptions...........................................................................................36 
6.3. 
Timing of Statistical Analysis ....................................................................................39 
6.3.1. 
Safety IDMC Meetings ...............................................................................................39 
6.3.2. 
Interim Analysis (IA) ..................................................................................................39 
6.3.3. 
Primary Analysis (PA) ................................................................................................40 
6.3.4. 
Final Analysis (FA) ....................................................................................................40 
6.3.5. 
Statistical Analyses Deliverables ................................................................................40 
6.3.6. 
Additional Analysis ....................................................................................................41 
7. 
DEFINITIONS AND GENERAL METHODOLOGY ..............................................41 
7.1. 
Study Treatment Nomenclature ..................................................................................41 
7.1.1. 
Study Drug and Study Treatment ...............................................................................41 
7.1.2. 
Treatment Arms ..........................................................................................................41 
7.2. 
Study Drug Administration Dates ..............................................................................41 
7.2.1. 
Date of First Administration of Study Drug ...............................................................41 
7.2.2. 
Date of Last Administration of Study Drug ...............................................................42 
7.2.3. 
Date of First Administration of Study Treatment .......................................................42 
7.2.4. 
Date of Last Administration of Study Treatment .......................................................42 
7.3. 
Reference Start Date and Study Day ..........................................................................42 
7.4. 
Screening Failure ........................................................................................................43 
7.5. 
Time Unit ....................................................................................................................43 


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7.6. 
Baseline .......................................................................................................................43 
7.7. 
NKCC at Baseline and NKCC-Low Subgroup ..........................................................43 
7.8. 
On-Treatment and Post-Treatment Assessment/Event ...............................................44 
7.8.1. 
On-Treatment ..............................................................................................................44 
7.8.2. 
Post-treatment .............................................................................................................44 
7.9. 
Start and End Date for Time to Event Variables ........................................................44 
7.10. 
Last Contact Date .......................................................................................................45 
7.11. 
Analysis Windows ......................................................................................................45 
7.11.1. 
Selection of Data in the Event of Multiple Records in a Window .............................46 
7.12. 
Analysis Populations ..................................................................................................46 
7.12.1. 
Screened Patients ........................................................................................................46 
7.12.2. 
Enrolled Patients .........................................................................................................46 
7.12.3. 
Full Analysis Set (FAS) ..............................................................................................46 
7.12.4. 
Per Protocol Set (PPS) ................................................................................................46 
7.12.5. 
Safety Set (SAF) .........................................................................................................47 
7.12.6. 
PK Analysis Set (PKAS) ............................................................................................47 
7.12.7. 
Immunogenicity Analysis Set (IAS) ...........................................................................47 
7.12.8. 
Withdrawal of Informed Consent ...............................................................................47 
7.13. 
Subgroups ...................................................................................................................48 
7.14. 
Implementation of CHESON Criteria ........................................................................48 
7.14.1. 
Disease Progression ....................................................................................................48 
7.14.2. 
Change in Imaging Modality ......................................................................................48 
7.14.3. 
No Baseline Tumour Assessments .............................................................................49 
7.15. 
General Convention for Missing Data ........................................................................49 
7.16. 
General Points .............................................................................................................49 
7.16.1. 
General Principles of Statistical Programming...........................................................49 
7.16.2. 
Variable Types and Descriptive Statistics ..................................................................49 
7.16.3. 
Data Included in the Analysis and Cut-off Date .........................................................50 
7.16.4. 
Specifications and Analysis Database ........................................................................51 
7.16.5. 
Pooling of Investigative Sites .....................................................................................51 
8. 
SUBJECT DISPOSITION, BACKGROUND AND DEMOGRAPHIC 
CHARACTERISTICS ................................................................................................51 
8.1. 
Screened Patients ........................................................................................................51 


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8.2. 
Enrolled Patients (Treatment Phase) ..........................................................................51 
8.3. 
Patients Randomized, and Entered the Treatment, PFS Follow-Up and OS 
Follow-Up Phases .......................................................................................................52 
8.3.1. 
Summary Statistics .....................................................................................................52 
8.3.2. 
Duration of Follow-Up ...............................................................................................53 
8.4. 
Protocol Deviations ....................................................................................................54 
8.5. 
Demographic and Baseline Disease Characteristics ...................................................54 
8.6. 
Randomization Stratification ......................................................................................55 
8.7. 
Medical History and Current Medical Conditions ......................................................55 
8.7.1. 
Coding and Definitions ...............................................................................................55 
8.7.2. 
DLBCL-Specific Medical History and Diagnosis ......................................................56 
8.7.2.1. 
Handling of Incomplete Dates Regarding DLBCL-Specific Medical History ...........58 
8.7.2.2. 
Calculation of the International Prognostic Index (IPI): ............................................58 
8.7.3. 
Reason for ASCT Ineligibility ....................................................................................59 
8.8. 
Prior and Concomitant Medications and Therapies/Pre-medication for 
Tafasitamab/RTX/BEN Infusion ................................................................................59 
8.8.1. 
Coding.........................................................................................................................59 
8.8.2. 
Definitions ..................................................................................................................60 
8.8.3. 
Data Presentation ........................................................................................................60 
8.8.4. 
DLBCL-Specific Prior Therapies ...............................................................................61 
8.8.4.1. 
Prior Therapy Procedures ...........................................................................................61 
8.8.4.2. 
Time to Progression in the Most Recent Prior Therapy .............................................62 
8.8.4.3. 
Handling of Incomplete Dates Regarding Prior Therapies .........................................63 
8.8.4.4. 
Refractoriness to Prior Therapies ...............................................................................64 
8.8.5. 
Early Vs. Late Relapse After First Line Therapy .......................................................66 
8.8.6. 
Pre-Medication for Tafasitamab/RTX/BEN Infusion ................................................67 
8.8.7. 
Concomitant Medication, Concomitant Medical Procedures, and Significant 
Non-Drug Therapies ...................................................................................................67 
8.8.8. 
Non-Study Anti-lymphoma Treatment .......................................................................67 
8.9. 
Study Treatment ..........................................................................................................68 
8.9.1. 
Treatment Cycle and Study Drug Regimen ................................................................68 
8.9.1.1. 
For Tafasitamab ..........................................................................................................68 
8.9.1.2. 
For Rituximab (RTX) .................................................................................................69 


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8.9.1.3. 
For Bendamustine (BEN) ...........................................................................................69 
8.9.2. 
Duration of Exposure to Study Drug ..........................................................................69 
8.9.3. 
Duration of Exposure to Study Treatment ..................................................................70 
8.9.4. 
Dose Skipping/Postponement .....................................................................................70 
8.9.5. 
Infusion Interruption ...................................................................................................70 
8.9.6. 
Compliance .................................................................................................................71 
8.9.7. 
Treatment Kits ............................................................................................................72 
9. 
EFFICACY ANALYSIS OF PRIMARY AND KEYSECONDARY 
ENDPOINT ................................................................................................................72 
9.1. 
Impact of COVID-19 on Analysis of Primary and Key Secondary Endpoints ..........74 
10. 
PRIMARY OBJECTIVE ............................................................................................75 
10.1. 
Endpoints ....................................................................................................................75 
10.1.1. 
Dual Primary Endpoint 1 ............................................................................................75 
10.1.2. 
Dual Primary Endpoint 2 ............................................................................................75 
10.1.3. 
Disease Assessment and Censoring Rules ..................................................................75 
10.1.3.1. 
Disease Assessments ..................................................................................................75 
10.1.3.2. 
Censoring Rules ..........................................................................................................76 
10.1.3.3. 
Missed Tumour Assessment .......................................................................................77 
10.2. 
Statistical Analysis of Dual Primary Endpoints .........................................................78 
10.2.1. 
Null and Alternative Hypothesis for Main Analysis ..................................................78 
10.2.2. 
Implementation of the Inverse Normal Method .........................................................78 
10.2.3. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................79 
11. 
SECONDARY EFFICACY OBJECTIVES ...............................................................81 
11.1. 
Secondary Objective 1a and Endpoint: Best Objective Response Rate (ORR) .........81 
11.1.1. 
Statistical Analysis ......................................................................................................81 
11.1.1.1. 
Null and Alternative Hypothesis for Main Analysis ..................................................81 
11.1.1.2. 
Implementation of the Inverse Normal Method .........................................................82 
11.1.1.3. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................82 
11.2. 
Secondary Objective 1b and Endpoint: Duration of Response (DoR) .......................84 
11.2.1. 
Statistical Analysis ......................................................................................................84 
11.2.1.1. 
Censoring Rules ..........................................................................................................84 
11.2.1.2. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................85 
11.3. 
Secondary Objective 1c and Endpoint: Overall Survival (OS) ..................................86 


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11.3.1. 
Statistical Analysis ......................................................................................................86 
11.3.1.1. 
Null and Alternative Hypothesis for Main Analysis ..................................................86 
11.3.1.2. 
Implementation of the Inverse Normal Method .........................................................86 
11.3.1.3. 
Censoring Rules ..........................................................................................................87 
11.3.1.4. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................87 
11.4. 
Secondary Objective 1d and Endpoint: Disease Control Rate (DCR) .......................88 
11.4.1. 
Statistical Analysis ......................................................................................................89 
11.4.1.1. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................89 
11.5. 
Secondary Objective 1e and Endpoint: Time to Progression (TTP) ..........................89 
11.5.1. 
Statistical Analysis ......................................................................................................89 
11.5.1.1. 
Censoring Rules ..........................................................................................................89 
11.5.1.2. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................91 
11.6. 
Secondary Objective 1f and Endpoint: Time to Next Treatment (TTNT) .................91 
11.6.1. 
Statistical Analysis ......................................................................................................91 
11.6.1.1. 
Censoring Rules ..........................................................................................................91 
11.6.1.2. 
Main Analysis, Sensitivity Analysis and Supportive Analysis ..................................91 
11.7. 
Secondary Objective 1g ..............................................................................................91 
11.8. 
Secondary Objective 1h ..............................................................................................92 
11.8.1. 
Endpoint: Health Related Quality of Life (HRQoL) ..................................................92 
11.8.1.1. 
EORTC QLQ-C30 ......................................................................................................92 
11.8.1.2. 
EQ-5D-5L ...................................................................................................................92 
11.8.1.3. 
HRQOL Visit Assessments ........................................................................................93 
11.8.2. 
Method of Analysis of HR-QOL Endpoints ...............................................................93 
11.8.2.1. 
EORTC QLQ-C30 ......................................................................................................94 
11.8.2.2. 
EQ-5D-5L ...................................................................................................................94 
11.9. 
Secondary Objective 2 ................................................................................................94 
11.9.1. 
Analysis of Immunogenicity .......................................................................................95 
11.10. 
Secondary Objective 3 ................................................................................................96 
11.10.1. 
PK Analysis ................................................................................................................96 
12. 
EXPLORATORY EFFICACY OBJECTIVES ..........................................................97 
12.1. 
Exploratory Objective 1 ..............................................................................................97 
12.1.1. 
Biomarkers of interest .................................................................................................97 
12.1.2. 
Analysis of Biomarkers ..............................................................................................97 


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12.2. 
Time to Response and Time to Complete Response ..................................................97 
12.3. 
Tumour Shrinkage Over Time: Assessment of Indicator Lesions..............................98 
13. 
SAFETY EVALUATION ..........................................................................................98 
13.1. 
Adverse Events ...........................................................................................................98 
13.1.1. 
Adverse Event (AE) ....................................................................................................98 
13.1.2. 
Adverse Events of Special Interest (AESI) ................................................................99 
13.1.3. 
General Rules for AE Reporting ...............................................................................100 
13.1.4. 
Adverse Event Summaries ........................................................................................100 
13.2. 
Vital Signs ................................................................................................................103 
13.2.1. 
Vital Sign Variables ..................................................................................................103 
13.2.2. 
Vital Sign Analysis ...................................................................................................104 
13.3. 
Physical Examination ...............................................................................................104 
13.4. 
Electrocardiogram (ECG) .........................................................................................105 
13.4.1. 
ECG Variables ..........................................................................................................105 
13.4.2. 
ECG Analysis ...........................................................................................................105 
13.5. 
Laboratory Data ........................................................................................................106 
13.5.1. 
Laboratory Variables ................................................................................................106 
13.5.2. 
Grading of Laboratory Data......................................................................................106 
13.5.3. 
Laboratory Analysis ..................................................................................................107 
13.6. 
Performance Status (ECOG) .....................................................................................108 
13.6.1. 
ECOG Scores ............................................................................................................108 
13.6.2. 
ECOG Scores Analyses ............................................................................................109 
13.7. 
B-Symptoms .............................................................................................................109 
13.8. 
Exposure ...................................................................................................................109 
14. 
CHANGES FROM THE PROTOCOL ....................................................................109 
15. 
GENERAL GUIDANCE ON REPORTING............................................................109 
15.1. 
Document Headers ....................................................................................................109 
15.2. 
Presentation of Output Numbering and Titles Within This Document ....................110 
15.3. 
Treatment Arm Labels and Ordering ........................................................................110 
15.4. 
Presentation of Analysis Sets....................................................................................111 
15.5. 
General Rules for Presenting Frequencies and Percentages .....................................111 
15.6. 
General Rule for Tables/Listings ..............................................................................111 
15.7. 
Tables/Listings With No Data ..................................................................................111 


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15.8. 
Precision Rules .........................................................................................................112 
15.9. 
General Rules for Presenting Listings ......................................................................112 
15.10. 
Presentation of Dates ................................................................................................113 
16. 
REFERENCES .........................................................................................................114 
17. 
APPENDICES ..........................................................................................................115 
17.1. 
Appendix A: Response Criteria for Malignant Lymphoma (Cheson et al 
2007) .........................................................................................................................115 
17.2. 
Appendix B: ECOG Performance Status (Oken et al 1982) .....................................116 
17.3. 
Appendix C: Statistical Method for Expected Duration of Response 
Following Ellis et al 2008 .........................................................................................116 
 


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LIST OF TABLES 
Table 3-1: Table of Abbreviations ...............................................................................................29 
Table 5-1: Study Objectives and Endpoints .................................................................................32 
Table 6-1: Assumptions for Sample Size Estimation (Original Study Design and 
Assumptions) ..............................................................................................................36 
Table 6-2: Assumptions for Sample Size Increase to 450 Patients (Revised Study 
Design and Assumptions); NKCC-Low Subgroup (≤ 100 cells/µL) .........................37 
Table 6-3: Operating Characteristics of the Endpoint OS at Final Analysis ...............................38 
Table 6-4: Power Analyses for OS ...............................................................................................38 
Table 6-5: Deliverables by Statistical Analyses ...........................................................................40 
Table 8-1: Imputation Rules for the 'Date of Initial Diagnosis of DLBCL' .................................58 
Table 8-2: Imputation Rules for the 'Date of Progression/Relapse' .............................................58 
Table 8-3: Imputation Rules for the 'Date of Initial Response', 'Start Date of Therapy' 
and 'Date of Progression/Relapse'...............................................................................63 
Table 8-4: Imputation Rules for 'End Date' of Last Prior Anti-lymphoma Medication, 
the 'Date of Procedure' (for Surgery, Radiation, ASCT) ............................................63 
Table 8-5: Overview of Imputation Rules for 'End Date' and 'Date of 
Progression/Relapse' for the Therapy Line of Interest ...............................................66 
Table 8-6: Overview of Imputation Rules for a Partially Completed 'Start Date' or 'End 
Date' for the Therapy Line Subsequent to the Therapy Line of Interest (if the 
'Date of Progression/Relapse' for the Therapy Line of Interest Has to Be 
Imputed) ......................................................................................................................66 
Table 9-1: Z-Statistic and Corresponding P-Values for FAS and NKCC-Low Subgroup ..........73 
Table 9-2: Rejection Rules for the Dual Primary and Key-Secondary Endpoints .......................74 
Table 10-1: Tumour Assessments ..................................................................................................75 
Table 10-2: Censoring Rules for PFS Analysis .............................................................................76 
Table 10-3: Censoring Rule if Event Happens After Two Consecutive Missed/Inadequate 
Disease Response Assessment ....................................................................................77 
Table 10-4: Censoring Rule if Event Happens After Two or More Consecutive 
Missed/Inadequate Tumour Assessment Relative to an Unscheduled But 
Adequate Response Assessment .................................................................................78 
Table 10-5: Main, Sensitivity and Supportive Analysis for the Primary Endpoint PFS ................79 
Table 11-1: Main, Sensitivity and Supportive Analysis for the Endpoint ORR ............................82 
Table 11-2: Censoring Rules for the Dor Analysis (IRC and Local Tumour Assessment) ...........85 
Table 11-3: Main, Sensitivity and Supportive Analysis for the Endpoint DoR .............................85 


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Table 11-4: Censoring Rules for OS Analysis ...............................................................................87 
Table 11-5: Main, Sensitivity and Supportive Analysis for the Endpoint OS ...............................87 
Table 11-6: Main, Sensitivity and Supportive Analysis for the Endpoint DCR ............................89 
Table 11-7: Censoring Rules for the TTP Analysis (IRC evaluation) ...........................................90 
Table 11-8: Main, Sensitivity and Supportive Analysis for the Endpoint TTP .............................91 
Table 11-9: Main, Sensitivity and Supportive Analysis for the Endpoint TTNT ..........................91 
Table 13-1: Clinically Notable ECG Values ................................................................................105 
Table 13-2: ECOG Performance Status .......................................................................................108 
 
LIST OF FIGURES 
Figure 6-1: Recruitment and Study Flow ......................................................................................34 
Figure 6-2: Study Design ...............................................................................................................35 
Figure 9-1: Overview of the Hierarchical Testing Strategy ..........................................................72 
 




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Abbreviation 
Term 
HDC 
High-dose chemotherapy 
HR 
Hazard ratio (statistics) 
IAS 
Immunogenicity analysis set 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
IDMC 
Independent Data Monitoring Committee 
IND 
Investigational New Drug Application 
IPI 
International Prognostic Index 
IRC 
Independent Radiology/Clinical Review Committee 
IRR 
Infusion-related reaction 
IWG 
International Working Group 
IWRS 
Interactive web response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
NK 
Natural killer (cell) 
NKCC 
Natural Killer Cell Count 
OR 
Odds Ratio 
ORR 
Objective response rate (complete response + partial response) 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PKAS 
PK analysis set 
PPS 
Per-protocol set 
PR 
Partial response 
PR (ECG) 
PR interval 
PT 
Preferred Term 
Q1 
1st quartile = 25% quantile 
Q3 
3rd quartile = 75% quantile 
QC/QA 
Quality control/quality assurance 
QoL 
Quality of life 
QRS 
QRS interval 
QT 
QT interval 
QTc 
QT interval corrected 
QTcB 
QT interval, Bazett's correction 


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Abbreviation 
Term 
QTcF 
QT interval, Fridericia's correction 
RR (ECG) 
RR interval 
R-R DLBCL 
Relapsed or refractory diffuse large B-cell lymphoma 
RTX 
Rituximab 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SLL 
Small lymphocytic lymphoma 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SPM 
Second primary malignancy 
StD 
Standard deviation 
TA 
Tumour Assessment 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings and figures 
TTNT 
Time to next treatment 
TTP 
Time to progression 
WHO-DDE 
World Health Organization–Drug Dictionary Enhanced 
 


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4. 
INTRODUCTION 
This document describes the detailed statistical methodology of the Statistical Analysis Plan 
(SAP) of study MOR208C204 (B-MIND): A Phase II/III, Randomised, Multicentre Study of 
MOR00208 with Bendamustine versus Rituximab with Bendamustine in Patients with Relapsed 
or Refractory Diffuse Large B-Cell Lymphoma (R-R DLBCL) Who Are Not Eligible for 
High-Dose Chemotherapy (HDC) and Autologous Stem-Cell Transplantation (ASCT). This SAP 
is written as per the study Protocol Amendment 8 (Version 11.0) dated 10 APR 2024. 
MOR00208 is referred to as tafasitamab throughout the document. 
The data will be analyzed by Incyte and/or a designated CRO. It is planned that the data from all 
centers that participate in this study will be used. 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
The Study Objectives and related endpoints are described in Table 5-1 below: 
Table 5-1: 
Study Objectives and Endpoints 
 
Objectives 
Endpoint 
Dual Primary 1 
To determine the efficacy of a combination of 
tafasitamab with BEN versus a combination of RTX 
with BEN in terms of progression-free survival (PFS) 
in adult patients with R-R DLBCL in overall 
population  
PFS in the overall population  
Dual Primary 2 
To determine the efficacy of a combination of 
tafasitamab with BEN versus a combination of RTX 
with BEN in terms of progression-free survival (PFS) 
in adult patients with R-R DLBCL and low baseline 
peripheral blood natural killer cell count (NKCC), i.e 
NKCC-low subgroup 
PFS in NKCC-low subgroup, defined as 
≤ 100 cells/µL 
Secondary 1a 
To determine and compare both study arms, 
tafasitamab with BEN versus RTX with BEN, for the 
overall population and NKCC-low subgroup in terms 
of: 
best objective response rate (ORR = complete 
response [CR] + partial response [PR]) based on the 
best response achieved at any time during the study 
Best objective response rate (ORR = 
complete response [CR] + partial response 
[PR]) based on the best response achieved 
at any time during the study in 
− Overall population  
− NKCC-low subgroup 
Secondary 1b 
To determine and compare both study arms, 
tafasitamab with BEN versus RTX with BEN, for the 
overall population and NKCC-low subgroup in terms 
of: 
duration of response (DoR) 
Duration of response (DoR) in 
− Overall population 
− NKCC-low subgroup 
Secondary 1c 
To determine and compare both study arms, 
tafasitamab with BEN versus RTX with BEN, for the 
overall population and NKCC-low subgroup in terms 
of: 
overall survival (OS) 
Overall Survival in 
− Overall population 
− NKCC-low subgroup 




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6. 
STUDY DESIGN AND SAMPLE SIZE 
6.1. 
Study Design 
The Study design is described in Section 8.2 of the study protocol. 
Figure 6-1: 
Recruitment and Study Flow 
 
After screening, eligible patients will be randomized into one of two study arms. Patients will either receive 
tafasitamab + Bendamustine or Rituximab + Bendamustine from cycle 1 to cycle 6. From cycle 7 onwards, they 
may receive tafasitamab or Rituximab only. 
During the initial safety evaluation phase of the trial the first 3 patients in both arms will be dosed sequentially with 
a 48-hour lag period between the enrolments of 2 consecutive patients (counted from C1D4). Following a positive 
recommendation of the IDMC, seven additional patients in each arm may be dosed in parallel. An additional 
IDMC review will take place after the last of 10 patients in each arm have completed C3D1 visit in their respective 
treatment allocation arm. Should the IDMC maintain their initial recommendation that the combination treatments 
are safe, the trial may proceed further with recruitment (Phase III part of the trial). 
An interim analysis was performed after 128 PFS events have been observed. The final sample size was adjusted 
after the interim analysis to N=450 per IDMC recommendation. 
 The final analysis including but not limited to primary and secondary endpoint analyses will be conducted at the 
end of the trial. 
Abbreviations: BEN = bendamustine; C = Cycle ; IDMC = Independent Data Monitoring Committee; 
MOR = MOR00208; R = randomisation (1:1); RTX = rituximab. 


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Figure 6-2: 
Study Design 
 
*Subsequent to the completion of combination treatment, patients with an ongoing response of at least PR after 
Cycle 6, as assessed locally, will continue antibody monotherapy treatment until disease progression in accordance 
with the initial treatment allocation (RTX or tafasitamab). 
#BEN is to be administered on Days 2+3 of the first cycle. Subsequently, BEN can be administered on Days 1+2 or 
Days 2+3 according to institutional/ patients /physician choice. 
Note: Stratification will not be applied to patients randomized during the Initial Safety Evaluation Phase. 
Abbreviations: BEN = bendamustine; ECOG = Eastern Cooperative Oncology Group; OS = overall survival; 
PFS = progression-free survival; R-R DLBCL = relapsed or refractory diffuse large B-cell lymphoma; 
R = randomization (1:1); RTX = rituximab. 
6.1.1. 
Randomization and Stratification Factors 
A 1:1 allocation to experimental vs comparator arm will be implemented through an interactive 
web response system (IWRS). Centralized block randomization with allocation of patients within 
the 16 strata is defined by the intersection of 4 binary stratification factors: 
• Early vs. late disease relapse/recurrence: ≤12 months versus >12 months from 
completion of last treatment 
• Age: ≤65 versus >65 years 
• ECOG performance status: 0-1 versus 2 
• Number of previous systemic therapy lines ≤2 versus >2 
The block size and block permutation algorithm is specified in a separate Randomization Plan. 
Stratification will not be applied to patients randomized during the Initial Safety Evaluation 
Phase. Nevertheless, the information about stratification factors will be collected for these 
patients as well to be used in the analysis of the study data. 


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6.1.2. 
Schedule of Assessments 
For the detailed schedule of assessments, please refer to the Protocol Section 10.1. 
6.2. 
Sample Size, Power Considerations and Randomization 
Approximately 330 patients with R-R DLBCL who meet the inclusion criteria and have not met 
any of the exclusion criteria were to be randomized into one of the two parallel treatment arms in 
a ratio of 1:1. The study will be performed according to a two-stage, group-sequential, adaptive 
design with a possible sample size adjustment after a planned interim analysis with a check for 
futility. The possible sample size adjustment might increase the number of patients to 450. 
6.2.1. 
Sample Size Assumptions 
The primary objective of the study is to detect a statistically significant difference in PFS for the 
experimental treatment arm relative to the comparator arm. It was assumed that the median PFS 
in the tafasitamab with BEN group would equal 7.0 months versus 4.9 months in the comparator 
standard treatment RTX with BEN group (HR of 0.70), based on literature data (Ohmachi et al 
2013, Vacirca et al 2014). 
A two-stage, group-sequential, adaptive design with one interim analysis was planned applying 
O'Brien-Fleming boundary (Hwang et al 1990). 
The assumed overall type I error rate/significance level for the primary efficacy parameter is 5%. 
Due to the interim analysis and possibility of sample size adaptation based on the effect size, the 
significance level for the primary efficacy analysis of the Final Analysis is adjusted using the 
O'Brien-Fleming approach, applying a local significance level at the interim analysis of 0.0052 
(two-sided) and a local significance level of 0.048 (two-sided) at the primary efficacy analysis of 
the Final Analysis. Early stopping for efficacy is not allowed even if a p-value of < 0.0052 can 
be seen at interim analysis. 
As shown in Table 6-1, a total number of 256 PFS events are required based on a hazard ratio 
(HR) of 0.70 with 80% power at final analysis, using a two-sided log-rank test at an alpha level 
of 4.8% and a 1:1 randomization ratio between the two treatment groups. Based on 18 months of 
enrolment and a 12-month Follow-Up, 286 evaluable patients need to be enrolled. Applying a 
13% drop-out rate would result in a total number of patients of approximately 330. 
Table 6-1: 
Assumptions for Sample Size Estimation (Original Study Design and 
Assumptions) 
Parameter for Sample Size Estimation 
 
Tafasitamab with BEN treatment arm: median PFS 
7.0 months 
RTX with BEN treatment arm: median PFS 
4.9 months 
Hazard ratio (experimental/comparator)  
0.70 
Overall significance level (overall type I error rate of α) 
5.0% 
Adjusted significance level at interim analysis (O'Brien-Fleming) 
0.52% 
Adjusted significance level at final analysis (O'Brien-Fleming) 
4.8% 
Power 
80% 


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Table 6-1: 
Assumptions for Sample Size Estimation (Original Study Design and 
Assumptions) (Continued) 
Parameter for Sample Size Estimation 
 
Enrolment duration (months) 
18 
Follow-up duration (months) 
12 
Accrual rate 
About 17 patients/month 
Events required 
256 
Evaluable patients to be enrolled 
286 
Overall patient number (including 13% drop-out) 
330 
At the time of the interim analysis, the Independent Data Monitoring Committee (IDMC) had the 
option of recommending an increase in sample size to 450 patients. The rationale for a sample 
size of 450 patients, based on the revised study design (i.e., with two dual primary endpoints and 
alpha spending) are summarized in Table 6-2. 
Table 6-2: 
Assumptions for Sample Size Increase to 450 Patients (Revised Study Design 
and Assumptions); NKCC-Low Subgroup (≤ 100 cells/µL) 
Parameter for sample size estimation for NKCC-low subgroup 
 
Tafasitamab with BEN treatment arm: median PFS in NKCC-low 
subgroup 
5 months  
RTX with BEN treatment arm: median PFS in NKCC-low subgroup 
3 months  
Hazard ratio (experimental/comparator) in NKCC-low subgroup 
0.60 
Significance level (overall type I error rate of α) for subgroup 
0.9% 
Power 
80% 
Enrolment duration in Phase III part (months)* 
36 
Follow-up duration (months) 
12 
Events required in NKCC-low subgroup 
183 
Evaluable patients needed to be enrolled in NKCC-low subgroup 
190 
NKCC-low patient number (including 13% drop-out) 
215 
Assuming NKCC-low subgroup is approximately 50% of the overall 
population, overall patient number 
450 
*Assuming linear recruitment after safety run in 
In addition to PFS, OS is considered an important endpoint to inform both efficacy and safety. 
Table 6-3 below provides details on the operating characteristics for OS at the time of Final 
Analysis. 


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Table 6-3: 
Operating Characteristics of the Endpoint OS at Final Analysis 
Sample Size Considerations 
Details  
Sample Size 
450 
Median OS in control arm (RTX with BEN) 
Full population: 10 months 
NKCC-low subgroup: 7 months 
Median OS in experimental arm (tafasitamab with BEN) 
Full population: 14.3 months 
NKCC-low subgroup: 11.7 months 
Assumed OS HR  
Full population: 0.7 
NKCC-low subgroup: 0.6 
Test 
2-sided stratified log-rank test 
Global significance level 
two-sided 5% 
Expected OS events1  
Full population: ~3401 
NKCC-low subgroup: 1352 
Local two-sided significance level 
Full population: 3.4% 
NKCC-low subgroup: 1.4% 
Power at the time of Final Analysis 
Full population: 88% 
NKCC-low subgroup: 70% 
1 These numbers are based on the assumption that Final Analysis will occur when approximately 75% of patients have died but 
using local significance levels as stated in Figure 9-1 of the SAP. 
2 Assuming 40% of all patients belong to the NKCC-low subgroup. 
In connection with the above, Table 6-4 below provides the power calculations for OS given the 
different number of possible OS events in the FAS and the NKCC-low subgroup. 
Table 6-4: 
Power Analyses for OS 
Full Population 
NKCC-Low Subgroup 
Number of OS 
Events 
Information 
Fraction 
Power 
Number of OS 
Events 
Information 
Fraction 
Power 
260 
~76% 
~76% 
95 
~70% 
~51% 
280 
~82% 
~81% 
105 
~78% 
~56% 
300 
~88% 
~83% 
115 
~85% 
~61% 
320 
~94% 
~86% 
125 
~93% 
~66% 
340 
(projected for 
Final Analysis) 
100% 
~88% 
135 
(projected for 
Final Analysis) 
100% 
~70% 
*at two-sided alpha of 3.4% for the FAS, and 1.4% for the NKCC-low subgroup. The calculations are based on following 
assumptions: median OS for BR in FAS: 10 months, true hazard ratio of 0.7; median OS for BR in NKCC-low: 7 months, true 
hazard ratio of 0.6. 


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6.3. 
Timing of Statistical Analysis 
6.3.1. 
Safety IDMC Meetings 
The IDMC will perform a Safety Evaluation at the following time-points of the study: 
Initial Safety Evaluation (Phase II part of the trial) 
i. 
1st IDMC Meeting: After first 3 patients in both the treatment arms 
(Tafasitamab+BEN and RTX+BEN) have finished their first week of treatment 
(C1D8). 
ii. 
2nd IDMC Meeting: After 10 patients in both the treatment arms (Tafasitamab+BEN 
and RTX+BEN) have finished their first two cycles of treatment (C3D1). 
Study Progress Evaluation (Phase III of the trial) 
iii. 
3rd IDMC Meeting: After 20% of the planned 330 patients are enrolled into the trial, 
that is after approximately 66 patients have been enrolled in the trial. 
iv. 
4th IDMC Meeting: After 50% of the planned 330 patients are enrolled into the trial, 
that is after approximately 165 patients have been enrolled in the trial. 
v. 
5th IDMC Meeting: After 80% of the planned 330 patients are enrolled into the trial, 
that is after approximately 264 patients have been enrolled in the trial. 
If one of the IDMC Data Review Meetings (e.g. after 80% of patients enrolled) coincides with 
the Interim Analysis, then the Interim Analysis meeting will serve both purposes. 
In addition to these planned IDMC Data Review Meetings, the IDMC will have the ability to 
hold ad hoc meetings, should they be deemed necessary as identified by the IDMC, the Sponsor 
or ICON.  
6.3.2. 
Interim Analysis (IA) 
The Interim Analysis will be performed when approximately 128 PFS events (50% of the 
planned 256 events) based on Independent Radiology/Clinical Review Committee (IRC) have 
been observed. 
The results of the Interim Analysis will be provided to IDMC to interpret and provide their 
recommendation. Additional details are provided in the IDMC charter. 
During the time of the Interim Analysis, the IDMC will make a recommendation on  
• Continue the study as planned (enrolling a total of 330 patients), 
• Continue the study with an increased sample size (450 patients), 
• Stop for futility. 
If the recommendation is not to stop the study for futility, they will also make a recommendation 
on development of a companion diagnostic for assessing NKCC (Yes/No recommendation). 
Early stopping for efficacy is not allowed. 


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The sponsor will be responsible for reviewing the IDMC recommendations, to decide whether to 
continue or terminate the trial due to futility, and to determine whether amendments to the 
protocol or changes in study conduct are required. 
If the sponsor decides to stop the trial due to futility, disclosure of the results will be performed 
as usual following the defined principles at a final analysis. If the sponsor decides to continue the 
trial or to continue the trial with modifications, the interim results will be kept confidential. 
Investigators will only be informed about the decision to continue/to continue with 
modifications/or to discontinue the trial. 
6.3.3. 
Primary Analysis (PA) 
The timing of Primary Analysis depended on the IDMC recommendation during the time of 
Interim Analysis. If IDMC decision is to continue the study as originally designed, the Primary 
Analysis would have been performed when approximately 256 PFS events based on Independent 
Radiology/Clinical Review Committee (IRC) have been observed. The IDMC decision was to 
increase sample size to 450, with the Primary Analysis to be performed when approximately 
369 PFS events based on Independent Radiology/Clinical Review Committee (IRC) have been 
observed. 
When amending the protocol to Version 10, it was noted that based on anticipated PFS rate, the 
pre-specified N=369 IRC-PFS events for primary analysis will not be reached. Hence, the 
planned PA will not be performed. Instead, the primary efficacy analysis will be done at the 
Final Analysis. 
6.3.4. 
Final Analysis (FA) 
The Final Analysis will be performed when study end is reached, defined as 3 years after the last 
patient was randomized or after approximately 75% of patients have died, whichever occurs first 
(protocol Section 8.4). 
6.3.5. 
Statistical Analyses Deliverables 
The table below outlines which analyses will be performed at each of the aforementioned 
Analyses: 
Table 6-5: 
Deliverables by Statistical Analyses 
 
Safety IDMC 
IA 
FA 
Disposition 
Yes 
Yes 
Yes 
Baseline 
Yes 
Yes 
Yes 
Medical History 
Yes 
Yes 
Yes 
Prior and Con-meds 
Yes 
Yes 
Yes 
Anti-lymphoma treatment after start of 
study drug 
No 
Yes 
Yes 
Study treatment/Exposure to Treatment 
Yes 
Yes 
Yes 
Tumour Assessments 
Yes 
Yes 
Yes 
B-Symptoms 
No 
Yes 
Yes 


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Table 6-5: 
Deliverables by Statistical Analyses (Continued) 
6.3.6. 
Additional Analysis 
Additional supplemental analyses of efficacy and safety may be performed according to the 
requests from the Authorities and to perform long-term efficacy, safety, and overall survival 
(OS) follow-up. 
7. 
DEFINITIONS AND GENERAL METHODOLOGY 
7.1. 
Study Treatment Nomenclature 
7.1.1. 
Study Drug and Study Treatment 
Study Drug refers to the individual drugs: tafasitamab or BEN or RTX. 
Study treatment refers to tafasitamab in combination with Bendamustine (BEN), or Rituximab 
(RTX) in combination with Bendamustine (BEN). 
7.1.2. 
Treatment Arms 
The study consists of two arms: 
Treatment Arm A: tafasitamab in combination with BEN, 
Treatment Arm B: RTX in combination with BEN. 
7.2. 
Study Drug Administration Dates 
7.2.1. 
Date of First Administration of Study Drug 
The date of first administration of study drug is the first date when a non-zero dose of study drug 
is administered and is referred as "start date of study drug". 
Start date of study drug is defined for each drug which is part of study treatment. 
 
Safety IDMC 
IA 
FA 
Overall Survival 
Yes 
Yes 
Yes 
EORTC QLQ-C30 
No 
No 
Yes 
EQ-5D-5L 
No 
No 
Yes 
PK 
No 
No 
Yes 
Immunogenicity 
No 
No 
Yes 
Biomarkers 
No 
NKCC 
Yes 
AE/SAE 
Yes 
Yes 
Yes 
Vital Signs 
Yes 
Yes 
Yes 
ECG 
Yes 
Yes 
Yes 
ECOG 
No 
Yes 
Yes 
Lab Parameters 
Yes 
Yes 
Yes 
Physical Examination 
Yes 
Yes 
Yes 


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7.2.2. 
Date of Last Administration of Study Drug 
The date of last administration of study drug ("last date of study drug") is the last date when a 
non-zero dose of study drug is administered. 
Last date of study drug is defined for each drug, which is part of study treatment. 
7.2.3. 
Date of First Administration of Study Treatment 
The date of first administration of study treatment ("start date of study treatment") is the first 
date when a non-zero dose of any component of study treatment is administered. 
For example: if the 1st dose of tafasitamab is taken on 03JAN2017, and 1st dose of 
Bendamustine, is taken on 05JAN2017, then the "Start date of study treatment" is 03JAN2017. 
7.2.4. 
Date of Last Administration of Study Treatment 
The date of last administration of study treatment ("last date of study treatment") is the last date 
when a non-zero dose of any component of study treatment is administered. 
For example: if the last dose of tafasitamab is administered on 13APR2017, and last dose of 
Bendamustine, is administered on 20APR2018, then the "last date of study treatment" is 
20APR2018. 
7.3. 
Reference Start Date and Study Day 
The reference start date for all safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption etc.) will be the start date of 
study treatment. 
The reference start date for all efficacy assessments (e.g. tumour assessment, death, PROs, 
ECOG performance status) will be the randomization date. 
For any non-safety screening assessments or events such as baseline disease characteristics or 
medical history (e.g., time since diagnosis of disease) that occurred prior to randomization the 
reference start date will be the randomization date. 
The study day describes the day of the event or assessment date, relative to the reference start 
date (randomization date or start date of study treatment). 
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined. 
The study day will be calculated as: 
• [The date of the event (visit date, onset date of an event, assessment date etc.) - 
reference start date + 1], if event is on or after the reference start date 
• [The date of the event (visit date, onset date of an event, assessment date etc.) - 
reference start date], if event precedes the reference start date 
The study day will be displayed in the data listings. It is not to be used for numerical 
computations for example calculating exposure. 


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7.4. 
Screening Failure 
Screening failures are patients who have signed informed consent and failed screening criteria in 
a study. 
Patients who are randomized but never received study treatment in a randomized study are not 
screening failures. 
7.5. 
Time Unit 
A month-length is 30.4375 days (365.25 / 12). If duration is to be reported in months, duration in 
days is divided by 30.4375. 
If duration is to be reported in years, duration in days will be divided by 365.25. 
7.6. 
Baseline 
Baseline is the result of an investigation describing the "true" uninfluenced state of the patient, 
defined as the period prior to the start date of study treatment or the date of randomization. 
Assessments, specified to be collected post-dose on the first date of treatment are not considered 
as baseline values. 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments on 
or before the date of randomization is taken as "baseline" value or "baseline" assessment. In the 
context of baseline definition, the efficacy evaluations also include PROs (EORTC QLQ-30, 
EQ-5D-5L), ECOG and Karnofsky performance status. 
For safety evaluations, unless otherwise stated, the last available assessment, including 
unscheduled assessments on or before the date of start of study treatment is taken as "baseline" 
value or "baseline" assessment. In case the patient does not receive study treatment, then the last 
available assessment will be used. 
If patients have no value as defined above, the baseline result will be missing. 
7.7. 
NKCC at Baseline and NKCC-Low Subgroup 
For the NK cell count, the baseline value will be the NK cell count measured on Cycle 1 Day 1 
(C1D1) prior to the first study drug administration. For patients with a missing value on C1D1, 
the baseline value is defined as the NK cell count measured at screening. 
A patient with baseline value ≤ 100 cells/µL is included in the NKCC-low subgroup. A patient 
with baseline value >100 cells/µL is included in the NKCC-high subgroup. 
NKCC-low subgroup in different analysis populations will be denoted by "NKCC-low (analysis 
population)". For example analyses in the NKCC-low subgroup based on FAS will be denoted 
by "NKCC-low (FAS)", which includes all patients in FAS who are classified in the NKCC-low 
subgroup. 


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7.8. 
On-Treatment and Post-Treatment Assessment/Event 
7.8.1. 
On-Treatment 
An on-treatment assessment/event is defined as any assessment/event performed after the date of 
first administration of study treatment i.e. assessments/events performed in the following time 
interval (including the lower and upper limits): 
[date of first administration of study treatment + 1; date of last administration of study 
treatment + 30 days] 
Assessments collected post-dose on the date of first administration of study treatment are 
on-treatment assessments. 
If the last date of study drug administration is missing, on-treatment assessments/events include 
any assessment/event recorded in the database and which occur after the start date of study 
treatment. Safety summary tables including summaries of on-treatment deaths will be based only 
on on-treatment assessments/events. 
7.8.2. 
Post-treatment 
A post-treatment assessment/event is defined as any assessment/event happening after the 
completion of on-treatment phase, that is assessments/event happening in the following time 
interval (including the lower and upper limits): 
[date of last administration of study treatment + 30 days + 1; date of study discontinuation] 
Data listings will include all assessments/events, flagging those which are not on-treatment 
assessments/events. 
7.9. 
Start and End Date for Time to Event Variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of all 
measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK/NE. 
Otherwise - if overall lesion response is progression – the assessment date is calculated as the 
earliest date of all measurement dates at that evaluation number. 
Start dates 
For all "time to event" variables, other than duration of response, the randomization date will be 
used as the start date. 
For the calculation of duration of response the following start date should be used: 
Date of first documented response is the assessment date of the first overall lesion response 
of CR or PR. 


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End dates 
The end dates which are used to calculate 'time to event' variables are defined as follows: 
• Date of death (during treatment as recorded on the treatment completion page or 
during follow-up as recorded on the study evaluation completion page or the survival 
follow-up page). 
• Date of progression is the first assessment date at which the overall lesion response 
was recorded as progressive disease. 
• If no post-baseline assessments are available (before an event or a censoring reason 
occurred) the date of randomization is used as the end date. 
Calculation of 'time to event' variables 
Time to event = End Date - Start date + 1 (in days). 
7.10. 
Last Contact Date 
The last contact date is derived for patients not known to have died at the analysis cut-off date 
based on the latest complete date among the following: 
• Actual assessment dates – Scheduled or unscheduled visits (Labs, vital signs, 
performance status, tumour imaging, EOT completion, PK sample collection dates, 
etc.). 
• Antineoplastic therapies administered after study drug discontinuation. 
• Adverse events dates. 
• Study treatment start/end date. 
• "Date of contact" or "Last known date patient alive" collected on the "Survival 
Follow-up" eCRF page (if applicable). 
• Date of study completion or discontinuation from the "End of Survival Follow-up" 
eCRF page. 
The last contact date is defined as the latest date from the above list or the cut-off date whichever 
comes first. 
In case that a date is only partially complete the following rules will be applied: 
• If month and year are present and only the day is missing, the first day of the month 
will be used to impute the missing date 
• If day and month or year is missing, the date will not be imputed 
The last contact date is used for censoring of patients in the analysis of overall survival and time 
to next treatment. 
7.11. 
Analysis Windows 
For parameters that will be summarized by visit, the nominal visit as recorded in the eCRF will 
be used. 


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7.11.1. 
Selection of Data in the Event of Multiple Records in a Window 
Depending on the statistical analysis method, single values may be required for each analysis 
window. For example, change from baseline by visit usually requires a single value per visit, 
whereas a time-to-event analysis would not require one value per analysis window but rather one 
value for the study. 
Unless otherwise noted throughout the rest of this document, when a single value is needed, the 
following rule(s) will be used: 
• If more than one assessment occurs during the time window of the planned visit, 
select the record closest to the particular visit day, 
• If there are two assessments that are equidistant from the planned visit day, the data 
of the assessment after the scheduled study day will be used, 
• The last measurement will be used if multiple measurements are all taken on the same 
day. 
7.12. 
Analysis Populations 
7.12.1. 
Screened Patients 
The Screened patients population consists of all patients who signed informed consent. 
7.12.2. 
Enrolled Patients 
Enrolled patients include all patients who signed informed consent and met all the study 
eligibility criteria. 
7.12.3. 
Full Analysis Set (FAS) 
FAS includes all patients who were randomized to either treatment arm. 
According to the intent-to-treat principle, patients will be analyzed according to the treatment 
and stratification factors they have been assigned to during the randomization procedure. 
The FAS will be the primary population for the analysis of efficacy and baseline characteristics. 
7.12.4. 
Per Protocol Set (PPS) 
PPS includes all patients in the FAS who have received at least one dose of tafasitamab or RTX, 
and BEN. 
The PPS includes all patients in the FAS who do not have any protocol deviations that could 
confound the interpretation of the primary analyses conducted on the FAS. 
All protocol deviations will be specified in the "Protocol deviation specification form" and 
protocol deviations leading to exclusion from the PPS will be tabulated. 
The PPS will be used to perform sensitivity analysis for the primary efficacy endpoint (i.e. PFS). 


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7.12.5. 
Safety Set (SAF) 
The SAF includes all patients who received at least one dose of Tafa or RTX or BEN. 
Analyses using the SAF will be based on the study drug actually received. For summary tables 
and figures on SAF, a patient who received at least one dose of tafasitamab will be included in 
the tafasitamab + BEN treatment arm; and a patient who receives at least one dose of RTX will 
be in the included in the RTX + BEN treatment arm. Listings on SAF will reflect drug actually 
received. 
Treatment actually received is defined as the study drug the patient receives on Cycle 1. 
7.12.6. 
PK Analysis Set (PKAS) 
The PKAS includes all patients who receive at least one dose of tafasitamab and have at least 
one quantifiable serum tafasitamab concentration (PK parameters will be calculated as data 
permit). 
7.12.7. 
Immunogenicity Analysis Set (IAS) 
IAS includes all patients who were randomized and have at least one anti-tafasitamab antibody 
assessment. 
7.12.8. 
Withdrawal of Informed Consent 
A patient can withdraw his consent from participating in the study at any point in time. 
The patient will be asked if his/her stored sample has to be destroyed or can be used in the 
analysis. 
In case, the patient asks for samples to be destroyed, any data collected in the clinical database 
after a patient withdraws informed consent from all further participation in the trial, will not be 
included in the analysis data sets. 
However, if the patient agrees to the use of stored samples for analysis, the data can be used even 
after his withdrawal of consent. 
The date on which a patient withdraws full consent is recorded in the eCRF. Note: Patients who 
withdraw consent from treatment but consent to PFS follow up and/or OS follow up are not 
considered as having withdrawn full consent and no such withdrawal of consent date is recorded 
in the eCRF. Such post-treatment assessments will be included in the analysis data sets. 
Patients can also exclusively withdraw consent from Pharmacogenomics Analysis. In case, the 
patient asks for samples to be destroyed, Pharmacogenomics data collected in the clinical 
database after a patient withdraws informed consent, will not be included in the analysis data 
sets. 
However, if the patient agrees to the use of stored samples for analysis, the data can be used even 
after his withdrawal of consent. 


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7.13. 
Subgroups 
Primary and key secondary efficacy endpoints will be examined in the following biomarker 
subgroups: 
• Cell-of-origin (determined by immuno-histochemistry (IHC)/central pathology): 
germinal center B cell (GCB) vs. non-GCB 
In addition, the following non-biomarker subgroups may also be considered for Efficacy 
Analysis: 
• Primary refractoriness (yes vs. no) 
• Number of prior treatment lines (1 vs. >= 2) 
• Prior ASCT (yes vs. no) 
• Gender (Male or Female) 
• Elderly (No (<80 years) vs. Yes (i.e. >=80 years)) 
• Unfit, elderly, defined as: Elderly (see definition above) and reason for ASCT 
ineligibility is "Inadequate performance status", "Inadequate major organ function" 
and/or "Comorbidities" (Yes vs No) 
For NKCC-low subgroup please see Section 7.7. 
Listings of subgroups for each patient will be included in the analysis of the efficacy endpoints. 
7.14. 
Implementation of CHESON Criteria 
The primary efficacy analysis will be evaluated through central review by an Independent 
Radiology/Clinical Review Committee (IRC) that will apply Cheson 2007 criteria (see 
Appendix A). The review process will be defined in the Independent Radiology/Clinical Review 
Committee (IRC). 
The response criteria in this study are those defined in the table in Appendix A. All of them are 
based on the International Working Group response criteria for malignant Lymphoma 
(Cheson et al 2007). 
7.14.1. 
Disease Progression 
Only objective progressive disease (PD) Cheson criteria as mentioned in Appendix A is 
considered in all Efficacy Analyses. 
In particular, discontinuation due to PD (from the "End of Treatment Completion" eCRF page), 
without supporting objective evidence (as defined above and in Section 7.14), will not be 
considered as PD in the determination of best overall response (BOR) and in the analysis for 
progression-free survival (PFS) when based on Local Assessments. 
7.14.2. 
Change in Imaging Modality 
Magnetic resonance imaging (MRI) may be used in lieu of CT, and PET/MRI in lieu of PET/CT 
for patients with contraindications to the administration of contrast agents, or due to other 
medical reasons, at the same time points as CT, or in addition to CT, at the discretion of the 


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investigator (in this case, MRI may be performed as/when appropriate). The method used at 
baseline should be used throughout the study unless otherwise medically indicated. 
7.14.3. 
No Baseline Tumour Assessments 
If available and of acceptable quality (e.g., no contrast CTs read by IRC, CT portion of PET/CT 
scan was performed with contrast), previously performed PET/CT examinations, in accordance 
with the standard of care, that were done up to 4 weeks prior to Screening may be used for a 
patient's baseline central radiology assessment. 
Since the timing of disease progression cannot be determined for patients with a missing baseline 
tumour assessment, these patients are censored in the PFS analysis at the randomization date. 
This rule, however, only applies to the "progressive disease" component of the PFS assessment. 
Patients without any baseline tumour assessment who die before missing the first two scheduled 
assessments, will be counted as having an event in the primary efficacy analysis in the FA of 
PFS at the date of death. 
All deaths will be counted in the overall survival analysis regardless of presence or absence of 
the baseline tumour assessment. 
7.15. 
General Convention for Missing Data 
For the statistical analysis, some particular data handling conventions (handling of missing data, 
pooling of centers) are planned. The details are present in the respective sections. 
7.16. 
General Points 
7.16.1. 
General Principles of Statistical Programming 
The statistical analysis will be performed on the analysis study database with appropriate 
software, SAS Software version 9.4 or above (SAS Institute, Cary, N.C.). 
7.16.2. 
Variable Types and Descriptive Statistics 
Descriptive statistics will be calculated using as reference the number of subjects in the relevant 
analysis population (any exception will be specified) according to the nature of the data as 
follows: 
Continuous variables: (e.g. age, body weight, etc.) number of non-missing observations, 
arithmetic mean, standard deviation, minimum and maximum values, median and quartiles 
(Q1, Q3). 
If there are fewer than 5 observations only the number of non-missing observations, arithmetic 
mean, median, minimum and maximum will be presented. 
Descriptive statistics of plasma concentrations and PK parameters will include n, arithmetic 
mean, geometric mean, SD, median, coefficient of variation CV (%), geometric CV (%), 
minimum and maximum. Geometric mean and the geometric CV (%) will be derived from 
non-zero values. For plasma concentrations, the number of non-zero values (m) will also be 
reported. 


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Categorical variables: (e.g. ECOG, Ethnicity, etc.) number of non-missing observations, the 
number of missing and the relevant percentage on the analysis population, number and relative 
frequencies. If not defined otherwise, the percentage denominator will be the number of all 
subjects included in the analysis set. 
In case of subcategories, the relative frequencies will be calculated on the basis of the subjects in 
the respective category, in this case a footnote will be added explaining the different 
denominators. 
Time variables: (e.g. time to progression in the most recent prior therapy) will be summarized 
using arithmetic mean, standard deviation, minimum and maximum values, median and quartiles 
(Q1, Q3) and will be presented in weeks (unless otherwise stated). 
Time to Event Variables: (e.g. PFS, OS, etc.) unless otherwise stated, Kaplan Meier estimates 
of Q1, Median, Q3 along with their 95% Confidence Intervals will be presented. 
7.16.3. 
Data Included in the Analysis and Cut-off Date 
All the analyses mentioned in Section 6.3 will be performed using data collected in the database 
up to the data cut-off date based on the deliverables mentioned in Table 6-5 Deliverables by 
Statistical Analyses. 
A cut-off date will be defined for each of these analyses and will be specified in the outputs. 
Of all the termination dates of the subjects included in the final analysis, the last termination visit 
date will be defined as the cut-off date and will be specified in the outputs. 
Analyses will be based on the data collected for patients who did not fail screening, and for all 
patients randomized prior to or on the cut-off date. 
Any data collected beyond the cut-off date will not be included in the analysis. Only data with an 
assessment date or event start date (e.g. vital sign assessment date or start date of an adverse 
event) prior to or on the cut-off date will be included in the analysis. For example, if the cut-off 
date is 15 June 2017 then an AE starting on 13 June 2017 will be reported, whereas an AE with 
start date on 17 June 2017 will not be reported. 
All events with an event start date either before or on the cut-off date and an event end date after 
the cut-off date will be reported as "continuing at the cut-off date". The same rule will be applied 
to events starting either before or on the cut-off date and not having a documented end date. This 
approach applies, in particular, to adverse events and concomitant medication reports. For these 
events, the end date will not be imputed and therefore will appear as missing in listings. 
If it is required to impute an end date to be able to perform a specific analysis (e.g. end date after 
the cut-off date) the cut-off date needs to be imputed as an end date. The imputed date will be 
displayed and flagged in the listings. 
Any data collected without the consent of the patient will not be included in the analysis; except 
for SAEs and the date of death provided confirmed by a public registry and patient status entered 
after the date of withdrawal of consent e.g. End of Treatment, End of Post treatment follow-up 
(PFS or OS). 


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7.16.4. 
Specifications and Analysis Database 
Based on dataset in SDTM format provided by ICON's Clinical Data Services group analysis 
datasets adhering to CDISC ADaM standard will be generated with SAS software, version 9.4 or 
above, based on the soft lock of data for the interim analysis or hard lock study database for the 
full final statistical analysis and according to agreed Analysis Dataset Specifications (ADS). 
7.16.5. 
Pooling of Investigative Sites 
Data will be pooled from all investigative sites for the analyses. The justification for this is based 
on the following factors:  
• the sites implement one common protocol  
• the sponsor provides close monitoring of study procedures and compliance  
• several sites are expected to recruit a few patients only 
• the study sites use common data collection procedures  
• for primary endpoint analysis the disease response assessments will be made centrally 
8. 
SUBJECT DISPOSITION, BACKGROUND AND 
DEMOGRAPHIC CHARACTERISTICS 
8.1. 
Screened Patients 
The number (%) of patients who were  
• Screened 
• Screen failure  
− Reason for screen failure (percent calculated using number of screen failures) 
• Successfully screened but not randomized 
−  Reasons not randomized (percent calculated using number of patients who were 
successfully screened but not randomized) 
• Randomized 
will be summarized by country, centre, treatment arm and overall. Unless otherwise indicated, 
percentages will be calculated based on the number of patients screened.  
8.2. 
Enrolled Patients (Treatment Phase) 
The number (%) of randomized patients included in the FAS and NKCC-Low (FAS) will be 
presented overall and by treatment arm. 
The following summaries will be provided: 
• Number (%) of patients who were randomized (based on data from IWRS system) 
• Number (%) of patients who were randomized and treated with any study drug 


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• Number (%) of patients treated with BEN + tafasitamab/RTX, with BEN only, with 
RTX or tafasitamab only 
• Number (%) of patients who discontinued only BEN in Cycle 1-6 
− Primary reason for discontinuation of only BEN in Cycle 1-6 
• Number (%) of patients who discontinued tafasitamab/RTX in Cycle 1-6 
− Primary reason for discontinuation of tafasitamab/RTX in Cycle 1-6 
• Number (%) of patients who completed Cycle 1-6 on BEN only 
• Number (%) of patients who completed Cycle 1-6 on tafasitamab/RTX 
• Number (%) of patients who completed Cycle 1-6 on tafasitamab/RTX but did not 
continue with mAb monotherapy (Cycle 7 onwards) 
• Number (%) of patients who remained on RTX or tafasitamab during monotherapy 
treatment phase (Cycle 7 onwards) 
• Number (%) of patients who discontinued RTX or tafasitamab during monotherapy 
treatment phase (Cycle 7 onwards) 
− Primary reason for discontinuation of RTX or tafasitamab during monotherapy 
treatment (Cycle 7 onwards) 
• Number (%) of patients who are on treatment with tafasitamab or RTX after disease 
progression. 
Listings will also be provided. 
8.3. 
Patients Randomized, and Entered the Treatment, PFS Follow-Up 
and OS Follow-Up Phases 
8.3.1. 
Summary Statistics 
• The number (%) of randomized patients included in the FAS and NKCC-Low (FAS) 
who entered the treatment, PFS follow-up phase (directly post randomization or post 
treatment phase) and OS follow-up phase (post randomization, post treatment phase 
or post PFS follow-up phase) will be presented overall and by treatment arm. The 
reasons for treatment, PFS follow-up, OS follow-up and study discontinuation will be 
summarized overall and by treatment arm. 
• Randomized but did not receive study treatment 
− Reasons patient did not receive study treatment (percent calculated using total 
number of patients who were randomized but did not receive study treatment) 
• Randomized and treated 
− Discontinued treatment 
▪ Reasons for treatment discontinuation (percent calculated using total number 
of patients who discontinued treatment) 


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− Discontinued study after treatment phase 
▪ Reasons for study discontinuation - Consider the reason for treatment 
discontinuation (percent calculated using total number of patients who 
discontinued study after treatment phase) 
• Entered PFS follow-up directly after randomization 
• Entered PFS follow-up after treatment phase 
• Entered PFS follow-up phase 
− Discontinued PFS follow-up 
▪ Reasons for PFS follow-up discontinuation (percent calculated using total 
number of patients who discontinued PFS FU) 
− Discontinued study after PFS follow-up phase 
▪ Reasons for study discontinuation - Consider the reason for PFS follow-up 
discontinuation (percent calculated using total number of patients who 
discontinued study after PFS follow-up phase) 
• Entered OS follow-up directly after randomization 
• Entered OS follow-up after treatment phase 
• Entered OS follow-up after PFS follow-up phase 
• Entered OS follow-up phase 
− Discontinued OS follow-up. 
▪ Reasons for study discontinuation – Consider reason for OS follow-up 
discontinuation (percent calculated using total number of patients who 
discontinued OS follow-up) 
• Discontinued the study 
− Reasons for study discontinuation – Consider the reason for discontinuation for 
the latest among the study phases: treatment, PFS follow-up, OS follow-up or 
soon after randomization if patient will not participate in treatment and the 
PFS/OS follow-up phases. 
Participation in the PFS/OS follow-up phases and reasons for discontinuation of treatment, PFS 
follow-up, OS follow-up will be as indicated in 'End of Treatment Status', 'End of Treatment', 
'End of Follow-up for PFS Measurement' and 'End of Follow-up for OS' eCRFs. 
Listings will also be provided. 
8.3.2. 
Duration of Follow-Up 
Summary information regarding the follow-up of patients will be displayed to describe the 
maturity of data and quality of follow-up. The duration of follow-up will be calculated using the 
reverse Kaplan-Meier method and will be displayed in the respective tables of the time-to-event 
endpoint, such as in the summary table for PFS. 


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8.4. 
Protocol Deviations 
Key protocol deviations will be identified based on reviews of the data prior to database lock. 
Protocol deviations affecting the patient or data integrity will be summarized overall and by 
center, and tabulated according to the following categories: 
• Subject enrolled and did not satisfy the entry criteria  
• Subject developed clinical trial/treatment withdrawal criteria during the trial, but was 
not withdrawn 
• Subject received the wrong treatment or incorrect dose 
• Subject received a prohibited concomitant treatment 
• Assessment and procedure deviation 
The protocol deviations leading to exclusion from PPS will be tabulated overall and by treatment 
arm. 
All major/key protocol deviations will be listed. 
8.5. 
Demographic and Baseline Disease Characteristics 
Descriptive statistics will be presented for continuous variables at baseline. Continuous variables 
include: 
• Height (in cm) 
• Weight (in kg) 
• BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline, 
• Body Surface Area (BSA) will be calculated using Mosteller formula, i.e., 
BSA (m2) = [(weight(kg) × height(cm)/3600)]1/2 
• Age (in years) 
• Systolic Blood Pressure 
• Diastolic Blood Pressure 
• Heart Rate 
• Respiratory rate 
The number and percentage of patients in each category will be presented for categorical 
variables at Baseline. For categorical variables, the number and percentage of patients with 
missing data will be provided. Categorical variables include: 
• Sex 
• Child Bearing Potential (for Female subjects only) 
• Race (Black or African American, American Indian or Alaskan native, Asian, Native 
Hawaiian or other Pacific Islander, White, Other). 
Note: A patient may identify to more than one race or may opt not to report their race. 
• ECOG status as per eCRF 


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• ECOG status as per eCRF dichotomized (0-1 vs. 2) 
• Age (< 65 years, ≥ 65 years; and < 75 years, ≥ 75 years) as per eCRF 
• Overall interpretation of Vital Signs (normal, abnormal not clinically significant, 
abnormal clinically significant) 
• LDH levels at baseline (within reference range vs. beyond reference range) 
• Cell of origin (GCB vs. non-GCB based on immuno-histochemistry/central 
pathology) 
• Cell of origin (GCB vs. ABC based on gene expression profiling, Unclassified, 
Not evaluable, Missing) 
Randomization is expected to balance treatment arms among baseline characteristics. No 
statistical test will be performed to check comparability of treatment arms regarding baseline 
characteristics. 
All summaries will be presented overall and by treatment arm in the FAS and NKCC-Low 
(FAS). Listings will also be provided. 
8.6. 
Randomization Stratification 
The number (%) of patients in each stratum: 
• Disease relapse/recurrence: ≤12 months versus >12 months from completion of last 
treatment 
• Age: ≤65 versus >65 years 
• ECOG performance status: 0-1 versus 2 
• Number of previous systemic therapy lines ≤2 versus >2 
based on data obtained from the IWRS system as well as calculated based on eCRF data will be 
summarized overall and by treatment arm for the FAS and NKCC-low (FAS) subgroup. 
Concordance/discordances between the stratum recorded in IWRS at the time of randomization 
and the actual stratum recorded in the clinical database (eCRF) will be summarized based on 
FAS. 
Listings will also be provided. 
8.7. 
Medical History and Current Medical Conditions 
The following analysis will be performed on FAS and will be presented by treatment arm. 
Listings will also be provided. 
8.7.1. 
Coding and Definitions 
Medical history and current medical conditions will be summarized by body system, preferred 
term and by toxicity grade. Coding will be performed using the current version of the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 26 or higher). 


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Notes:  
• Toxicity grade will be coded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) V4.03 or higher 
• Medical history is defined as records in the "Medical History and Current Medical 
Conditions"- eCRF form which are not ongoing at Day 1 Cycle 1 
• Current medical conditions are defined as records in the "Medical History and 
Current Medical Conditions"- eCRF form which are ongoing at Day 1 Cycle 1 
8.7.2. 
DLBCL-Specific Medical History and Diagnosis 
Data on the diagnosis of DLBCL will be presented in a summary table which will include the 
following: 
• Ann Arbor Stage at screening and initial diagnosis 
• Ann Arbor stage dichotomized (I or II vs. III or IV) 
• Summary statistics of Disease risk (IPI) at screening 
• Disease risk (IPI) at screening by category (0, 1, 2, 3, 4, 5) 
• Disease risk (IPI) at screening (dichotomized: low risk and low-intermediate risk vs. 
intermediate-high risk and high risk) 
• Number of previous systemic therapy lines (DLBCL medications) 
• Number of previous systemic therapy lines (DLBCL medications) dichotomized: 
2 vs. >2 
• Time since first DLBCL diagnosis (months) 
• Time since first progression/relapse (months) 
• Time since last progression/relapse (months) 
• Time since completion of last treatment (months) 
• Bulky disease (present vs. absent) at screening (defined as having a longest lesion 
diameter of ≥ 7.5 cm as assessed by central radiological assessment). 
• Indolent NHL type (for participants with indolent NHL transformed to DLBCL) 
− Time since first indolent NHL diagnosis (months) 
− Prior therapy type to indolent NHL (Chemotherapy, Immunotherapy, Targeted 
therapy, Chemoimmunotherapy, Other) 
− Medication for indolent NHL (Rituximab, RCHOP, CHOP, etc.) 
− Best Overall response to Therapy type to indolent NHL (CR, PR, SD, etc.) 
• Reason for discontinuation of Therapy type to indolent NHL (Completed course of 
treatment, Toxicity/AE, Disease progression, etc.) 
• Primary refractory to first line anti-lymphoma therapy (yes vs. no) 
• Refractoriness to last prior line of anti-lymphoma therapy (yes vs. no) 


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• Rituximab refractoriness (yes vs. no) 
• Relapse after of prior treatment therapy line (Early relapse vs. Late relapse) 
• Time since discontinuation of last prior anti-lymphoma therapy (months). Refers to 
last therapy prior to study entry among all prior anti-lymphoma therapy including 
systemic treatment, surgery, radiation, or ASCT. 
• Duration of Response to last prior anti-lymphoma therapy (months). Refers to last 
therapy prior to study entry among all prior anti-lymphoma therapy including 
systemic treatment, surgery, radiation, or ASCT. 
The event times (in months) are defined as (for example): 
[(reference start date) – (date of initial diagnosis)]/30.4375 
Diagnostic Lymph Node Biopsy 
A listing of the recorded diagnostic lymph node biopsy will also be presented depicting the 
information on the Diagnostic Lymph Node Biopsy eCRF page. Another listing will show 
information on NHL subtype as determined by central pathology (the pathological description of 
the sample as well as the NHL entity used for tabulation). 
Bone Marrow Aspiration and Biopsy 
Data on bone marrow aspiration and biopsies as recorded throughout the study (by visit) will be 
summarized in a table and also listed. The data table will summarize the following information 
on: 
• Potential complete response 
• Type of examination 
• Percentage of lymphocytes 
• Type of infiltration 
• Degree of lymphoma involvement 
Disease involvement assessment of the spleen/liver may occur as part of the full or limited 
physical examinations throughout the study and recorded data will be presented in a listing. 
Concordance between cell-of-origin determination by gene expression profiling and 
immuno-histochemistry 
The concordance rate represents the agreement regarding the cell-of-origin as determined by 
gene expression profiling (GEP) and immuno-histochemistry (IHC). The concordance rate is the 
number of patients that are concordant over the total number of patients assessed and will be 
calculated across all cell-of-origin categories. The concordance rate will be calculated using the 
following categories: 
• Analysis 1: ABC (GEP) and GCB (GEP) vs. Non-GCB (IHC) and GCB (IHC) 
• Analysis 2: (ABC (GEP) + Unclassified (GEP)) and GCB (GEP) vs. Non-GCB (IHC) 
and GCB (IHC) 


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A confusion matrix (i.e., a contingency table with GEP cell-of origin as rows and IHC cell-of-
origin as columns) will be generated. The concordance rate will be calculated by adding the 
diagonal counts and dividing by the total number of patients assessed. 
As only a fraction of patients have undergone GEP and IHC analysis, only those patients will be 
considered for the concordance analysis who have been evaluated by both assessments (i.e., GEP 
and IHC). Listings will be provided. 
8.7.2.1. 
Handling of Incomplete Dates Regarding DLBCL-Specific Medical History 
If the 'Date of initial diagnosis of DLBCL' is only partially completed, the 'Time since first 
DLBCL diagnosis' will be calculated based on the following imputation rules: 
Table 8-1: 
Imputation Rules for the 'Date of Initial Diagnosis of DLBCL' 
Component of the Date 
Variable  
DD 
MMM 
YYYY 
Date of initial diagnosis of DLBCL 
 
 
 
No imputation 
X 
 
 
Day 15 of the month 
X 
X 
 
No imputation 
X
X
x 
If the 'Date of initial diagnosis of DLBCL' cannot be imputed, the 'Time since first DLBCL 
diagnosis' will be considered as 'Unknown'. 
If the 'Date of progression/relapse' is missing, the 'Time since first/last progression/relapse' will 
be calculated based on the following imputation rules: 
Table 8-2: 
Imputation Rules for the 'Date of Progression/Relapse' 
Component of the Date 
Variable  
DD 
MMM 
YYYY 
Date of progression/relapse 
 
 
 
No imputation 
X 
 
 
First day of the month 
X 
X 
 
No imputation 
X
X
x 
If the 'Date of progression/relapse' cannot be imputed, the 'Time since first/last 
progression/relapse' will be considered as 'Unknown'. 
8.7.2.2. 
Calculation of the International Prognostic Index (IPI): 
The IPI is being calculated from the following items: 
• Age older than 60 years 
• Lactate dehydrogenase level (based on Central laboratory) higher than upper limit of 
normal  
• ECOG performance status score of 2 or greater 


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• Stage III or IV disease  
• More than one involved extranodal disease site  
The IPI gives one point for each of the above characteristics, for a total score ranging from zero 
to five correlating with the following risk groups: 
• Low risk: 0–1 point 
• Low-intermediate risk: 2 points 
• High-intermediate risk: 3 points 
• High risk: 4–5 points 
Number and % of patients in each of the IPI categories will be presented.  
The categories above will also be collapsed into low risk (0-2 points) and high risk (3-5 points). 
8.7.3. 
Reason for ASCT Ineligibility 
Number and % of patients who are eligible for high-dose chemotherapy with autologous stem 
cell transplantation will be presented. 
The reason for ineligibility will be summarized for the following reason: 
• Inadequate performance status (Karnofsky Performance Status ≤ 80%) 
• Disease not responsive to salvage chemotherapy. Responsiveness is defined as a 
tumour demonstrating either CR or PR to salvage chemotherapy 
• Inadequate major organ function (mention organ) 
• History or evidence of significant co-morbid medical or psychiatric illness which 
would significantly compromise the patient's clinical care and chances of survival 
• Inability to collect adequate stem cell graft (e.g. < 1-2 × 10^6 CD34+ cells free of 
tumour contamination/kg recipient body weight) 
8.8. 
Prior and Concomitant Medications and Therapies/Pre-medication 
for Tafasitamab/RTX/BEN Infusion 
8.8.1. 
Coding 
Prior, concomitant and pre-medications will be recorded and coded using the current WHO Drug 
Dictionary Enhanced (WHO-DDE) and grouped by Anatomical Therapeutic Chemical (ATC) 
Levels 2 and preferred name. Surgical and medical procedures will be coded using MedDRA and 
summarized by SOC and preferred term. 


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8.8.2. 
Definitions 
• Pre-medication: Medication given prior to tafasitamab infusion to mitigate potential 
infusion-related reactions. Pre-medication encompasses antipyretics, histamine 
receptor blockers, glucocorticosteroids, meperidine 
• Prior medication: If the medication start and stop dates are both before the start date 
of study treatment, the medication will be classified as prior medication. Patients will 
only be counted once for multiple drug use (by preferred drug name). 
• Concomitant medication/non-drug treatment (Con-medication): If the medication 
start date is after start of study treatment the medication will be considered as 
concomitant medication. Patients will only be counted once for multiple drug use (by 
preferred drug name). If the medication stop date is incomplete, the following 
algorithm will apply to exclude the medication from the category con-medication: 
− If stop day is missing but month is complete, medication will only be excluded 
from concomitant medication if stop month is before month of treatment start 
− If stop day and month are missing but year is complete, medication will only be 
excluded from concomitant medication if stop year is before year of treatment 
start 
− If stop date is completely missing, medication will not be excluded 
• Prior and concomitant medication/non-drug treatment: Medications with start 
date before start date of study treatment but ongoing or with stop date after the start of 
study treatment will be considered both as prior and as concomitant medications. 
Patients will only be counted once for multiple drug use (by preferred drug name) 
• Duration of response (DoR) to prior anti-lymphoma medication or ASCT (in 
months): 
(date of assessment of tumour progression – date of assessment of first documented 
response + 1) / 30.4375 
• Time since last anti-lymphoma medication/radiation therapy/surgery (in 
months): 
(date of randomization – end of treatment date for last prior anti-lymphoma 
medication/radiation therapy/surgery) / 30.4375 
• Time since last ASCT (in months): 
(date of randomization – date of procedure) / 30.4375 
8.8.3. 
Data Presentation 
Patients will only be counted once for multiple drug use (by preferred drug name) per patient. 
The incomplete dates handling method used for AE summaries will be used for concomitant 
medication summaries (see adverse events Section 13.1). 
Tabulations with counts/percentages will show number of medications/percentage used in each 
class. 


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Summary tables will be presented for: 
• Prior medications 
• Concomitant medications which started before start of study treatment 
• Concomitant medications which started after start of study treatment 
• Prior non-drug treatments and procedures 
• Concomitant non-drug treatments and procedures which started before start of study 
treatment  
• Concomitant non-drug treatments and procedures which started after start of study 
treatment 
All summaries will be conducted on FAS. Listings will be shown for pre-medication, prior 
medication, and concomitant medication; and for prior and concomitant non-drug 
treatments/procedures. 
8.8.4. 
DLBCL-Specific Prior Therapies 
8.8.4.1. 
Prior Therapy Procedures 
Prior anti-lymphoma therapies will be summarized for patients in FAS by treatment arm in four 
separate tables: medications, radiotherapy, surgery, Autologous Stem Cell Transplant based on 
the following variables: 
1. Prior anti-lymphoma medication 
− Patients with at least one prior anti-lymphoma Medication 
− Number of prior anti-lymphoma medication therapy lines (as categorical variable) 
− Therapy Type 
− Name of prior anti-lymphoma medication 
− Time since last prior anti-lymphoma medication (summary statistics in months) 
− Duration of response to prior anti-lymphoma Medication 
2. Prior anti-lymphoma radiotherapy 
− Patients with at least one prior anti-lymphoma radiotherapy 
− Number of prior anti-lymphoma radiotherapy lines (as categorical variable) 
− Irradiated locations (Bone, Brain, Breast, etc.) 
− Method of irradiation  
− Total cumulative dose (present in CRF by units – centi-grays, rads, grays, 
unknown, others, and centi-grays and grays will be summarized together in grays) 
− Time since last prior anti-lymphoma radiotherapy (summary statistics in months) 


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3. Prior anti-lymphoma surgery  
− Patients with at least one prior anti-lymphoma surgery 
− Number of prior anti-lymphoma surgery lines 
− Anatomical location (Bone, Brain, Breast, etc.) 
− Time since last prior anti-lymphoma surgery (summary statistics in months) 
4. Prior anti-lymphoma autologous stem cell transplantation 
− Patients with autologous stem cell transplantation performed 
− Time since last prior ASCT (summary statistics in months) 
− Duration of response to ASCT 
Separate Listings will be presented on prior anti-lymphoma medications, radiation therapies, 
surgeries, and ASCT.  
Listings on individual DLBCL-specific procedures will include information on: 
• the type and date of the initial response 
• the type and date of the best overall response 
• date of progression 
• reason for therapy discontinuation 
• therapy start date 
• therapy end date 
• the number of cycles 
• therapy type 
• medication name 
• number of the particular therapy line 
• Duration of response (only for anti-lymphoma medication, and prior ASCT) 
8.8.4.2. 
Time to Progression in the Most Recent Prior Therapy 
Last therapy for a patient is the therapy as entered on the "Prior Cancer Therapies for 
DLBCL-Medications" eCRF page. 
Time to progression to last prior therapy (months) is defined as follows:  
[Date of progression to the most recent prior therapy – Start date of the most recent prior 
therapy + 1]/30.3475 
Descriptive statistics will be provided for Time to progression to the most recent prior therapy. 


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8.8.4.3. 
Handling of Incomplete Dates Regarding Prior Therapies 
Handling of missing values for 'Duration of Response (DoR)', 'Time to progression in the 
most recent therapy' to prior therapies: 
In case the date of initial response or progression is only partially completed the DoR as entered 
on the eCRF pages for 'Prior Cancer Therapies for DLBCL-Autologous Stem Cell Transplants' 
and 'Prior Cancer Therapies for DLBCL Medications' will be used. If the entry for DoR to 
previous therapy line is missing and the date of initial response or progression is only partially 
completed the following imputation rules will apply: 
Table 8-3: 
Imputation Rules for the 'Date of Initial Response', 'Start Date of Therapy' 
and 'Date of Progression/Relapse' 
Component of the Date 
Variable  
DD 
MMM 
YYYY 
Date of initial response/ 
Start Date of therapy 
Date of progression/relapse 
 
 
 
No imputation 
No imputation 
x 
 
 
First day of the month 
Last day of the month 
x 
X 
 
No imputation 
No imputation 
x
X
x 
The 'Duration of Response' to a particular prior therapy will be considered as 'Unknown' if the 
dates required for derivation cannot be imputed. 
Handling of missing values for the derived variables 'Time since the last prior anti-
lymphoma medication/radiation/surgery/ASCT': 
A partial completion date for the completion of the last prior therapy will be imputed using the 
following algorithm for the last regimen: 
Table 8-4: 
Imputation Rules for 'End Date' of Last Prior Anti-lymphoma Medication, 
the 'Date of Procedure' (for Surgery, Radiation, ASCT) 
Component of the Date 
Variable 
DD 
MMM 
YYYY 
'End Date' of last prior 
anti-lymphoma medication 
Date of procedure 
(surgery, radiation, ASCT) 
 
 
 
No imputation 
No imputation 
x 
 
 
Day 15 of the month 
Day 15 of the month 
x 
X 
 
No imputation 
No imputation 
x
X
x 
The 'Time since last prior anti-lymphoma medication/radiation/surgery/ASCT' will be 
considered as 'Unknown' if the dates required for derivation cannot be imputed. 


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8.8.4.4. 
Refractoriness to Prior Therapies 
Three subgroups for treatment refractoriness in prior therapy lines will be defined using 
information on prior anti-lymphoma medications collected in the eCRF. 
• Primary refractoriness 
• Refractoriness to the last prior treatment line 
• Rituximab refractoriness 
The number (%) of patients in each of these subgroups will be presented. The information will 
also be provided in listings. 
8.8.4.4.1. Primary Refractoriness 
Primary refractoriness is defined as disease progression in the course of the first line treatment, 
or showing a response of less than PR (i.e., PD or SD) as best response to the first line treatment, 
or disease progression within ≤ 6 months from the completion of first-line therapy (i.e. the "End 
Date" for the first therapy line as entered on the eCRF page "Prior Cancer Therapies for 
DLBCL-Medications"). The following treatments will be considered as first line treatment: 
• Only systemic anti-lymphoma medication as entered on the "Prior Cancer Therapies 
for DLBCL-Medications" eCRF page will be considered as first line treatment 
• If the status for "Primary refractoriness" cannot be determined the patient will be 
considered as having an "Unknown" status 
8.8.4.4.2. Refractoriness to the Last Prior Treatment Line 
Refractoriness to the last prior treatment is defined as having less than a PR (i.e., SD or PD) as 
best overall response to the most recent therapy, progression during the course of treatment, or 
progression within ≤ 6 months from the completion of the most recent therapy (i.e. the "End 
Date" for the most recent therapy line as entered on the eCRF page "Prior Cancer Therapies for 
DLBCL-Medications"). 
The following treatments will be considered as last prior treatment: 
• Only systemic anti-lymphoma medication as entered on the "Prior Cancer Therapies 
for DLBCL-Medications" eCRF page will be considered as last prior treatment 
• If the status for "Refractoriness to the last prior treatment line" cannot be determined 
the patient will be considered as having an "Unknown" status 
8.8.4.4.3. Rituximab Refractoriness 
Rituximab refractoriness is defined as having reached less than a partial response to any 
rituximab-containing treatment regimen, progression during the course of treatment, or 
progression within ≤ 6 months from the completion of any rituximab-containing therapy line 
(i.e. the "End Date" for any rituximab-containing therapy line as entered on the eCRF page 
"Prior Cancer Therapies for DLBCL-Medications"). If the status for "Rituximab refractoriness" 
cannot be determined the patient will be considered as having an "Unknown" status. 


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8.8.4.4.4. Imputation of Missing Values Required for Defining Refractoriness Subgroups 
The 'End Date' for the first treatment line, or the last prior treatment line or any Rituximab-
containing treatment line, will be imputed as follows: 
• In case day is missing but month and year are complete, the first day of the month or 
the starting date of the next treatment, whichever is later will be used 
• In case day and month are missing but year is complete, the date will be considered as 
missing 
• In case day, month and year are missing, the date will be considered as missing 
The 'Date of progression/relapse' for a particular therapy line will be imputed as follows: 
• In case day is missing but month and year are complete, the last day of the month will 
be used 
• In case day and month are missing but year is complete, the date will be considered as 
missing 
• In case day, month and year are missing, the date will be considered as missing 
• If the 'Date of progression/relapse' is completely missing or cannot be replaced by 
imputation, the following strategy will be used: 
− If the 'Start Date' of the subsequent therapy line is present, the 'Start Date' will be 
used as a surrogate for the 'Date of progression/relapse' for the previous line of 
treatment. If the day for the Start Date missing, the day will be imputed using the 
last day of the month.  
− If the 'Start Date' of the subsequent therapy line is missing, but the 'End Date' of 
the subsequent therapy line is present the 'End Date' will be used as a surrogate 
for the 'Date of progression/relapse' for the treatment line of interest (the patient 
will be considered as 'refractory'). If the day for the 'End Date' missing, the day 
will be imputed using the last day of the month. 
NOTE: The 'End Date' of the subsequent therapy will only be used as a surrogate 
if the time interval between the 'End Date' of the subsequent line and the 'End 
Date' of the previous line is ≤ 6 months (the patient will be considered 
'refractory'). Otherwise the refractory status will be considered as 'Unknown'. 
− If B-MIND constitutes the immediate treatment line after the line of interest the 
'Informed Consent' date as entered on the 'Informed Consent' eCRF page will be 
used  


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Table 8-5: 
Overview of Imputation Rules for 'End Date' and 'Date of 
Progression/Relapse' for the Therapy Line of Interest 
Component of the Date 
Variable 
DD 
MMM 
YYYY 
'End Date' for the treatment 
line of interest 
'Date of progression/relapse' for the 
treatment line of interest 
 
 
 
No imputation 
No imputation 
x 
 
 
1st day of the month 
Last day of the month 
x 
X 
 
No imputation 
'Start Date' of the subsequent treatment 
(a partially completed date can be 
imputed as outlined in Table 8-6) 
'Stop Date' of the subsequent treatment 
if the 'Stop Date' is ≤ 6 months after the 
'End Date' of the therapy line of interest 
(a partially completed date can be 
imputed as outlined in Table 8-6) 
'Informed Consent' date for B-MIND 
study participation if the subsequent 
treatment is B-MIND 
x
X
x 
Table 8-6: 
Overview of Imputation Rules for a Partially Completed 'Start Date' or 'End 
Date' for the Therapy Line Subsequent to the Therapy Line of Interest (if the 
'Date of Progression/Relapse' for the Therapy Line of Interest Has to Be 
Imputed) 
Component of the Date 
Variable  
DD 
MMM 
YYYY 
'Start Date' 
'End Date' 
 
 
 
No imputation 
No imputation 
x 
 
 
Last day of the month 
Last day of the month 
x 
X 
 
No imputation 
No imputation 
x
X
x 
8.8.5. 
Early Vs. Late Relapse After First Line Therapy 
Patients having an 'early relapse' or 'late relapse' after their initial DLBCL diagnosis will be 
summarized. The following definitions will apply: 
• Early relapse after first line therapy: relapse ≤12 months after initial DLBCL 
diagnosis 
• Late relapse after first line therapy: relapse >12 months after initial DLBCL diagnosis 
In the situation of missing data, the same imputation rules as in Table 8-3 will be used (Date of 
initial response will be used for date of initial diagnosis of DLBCL). If the relapse category 
cannot be determined, the patient will be considered as "Unknown". The following additional 
rule apply: 
If day and month are missing, but only the year is present for one or both variables, the patient 
will be assigned to the category "Late relapse after initial DLBCL diagnosis" if the difference 
between the year for the "Date of initial diagnosis of DLBCL" and the year for the "Date of first 


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progression/relapse" is two years or higher. In case the difference for the years is only one year 
the, the relapse category after initial DLBCL diagnosis will be considered as "Unknown". In case 
the year is the same for both variables, the patient will be assigned to the category "Early relapse 
after initial DLBCL diagnosis". 
A listing will be provided indicating patients with an early or late relapse after first line therapy. 
8.8.6. 
Pre-Medication for Tafasitamab/RTX/BEN Infusion 
Due to the occurrence of infusion related reactions (IRRs), patients may receive pre-medications 
administered prior to tafasitamab, RTX and/or BEN infusions. 
These will be also coded using the WHODD and summarized by ATC Levels 2 and preferred 
name. 
The number and percentage of patients receiving Pre-Medication will be presented by Cycle and 
Treatment Arm based on the WHODD coding along with the Route of Administration. 
Pre-medications and their doses will be listed for all patients who received either RTX, BEN or 
tafasitamab. 
8.8.7. 
Concomitant Medication, Concomitant Medical Procedures, and Significant 
Non-Drug Therapies 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures, 
excluding contrast agents) other than the study treatment administered to a patient coinciding 
with the study treatment period. 
Concomitant therapy includes medications (other than study drugs) starting on or after the start 
date of study treatment or medications starting prior to the start date of study treatment and 
continuing after the start date of study treatment.  
Concomitant medications will be coded using the WHODD and summarized by ATC Levels 2 
and preferred name using frequency counts and percentages. 
Concomitant medical procedures will be coded using MedDRA and summarized by SOC and 
preferred term using frequency counts and percentages. 
Significant non-drug therapies taken concurrently with study treatment will be coded using 
MedDRA summarized by SOC and preferred term using frequency counts and percentages. 
8.8.8. 
Non-Study Anti-lymphoma Treatment 
Non-study anti-lymphoma treatment might consist of medication, radiation or surgery. 
For patients who are on-treatment, or discontinued treatment or in Overall Survival follow-up, 
the following will be presented by treatment arm and overall in the FAS population: 
• The number (%) of patients who received non-study anti-lymphoma treatment prior 
to study treatment discontinuation 
• The number (%) of patients who received non-study anti-lymphoma treatment after 
study treatment discontinuation 


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• The number (%) of patients who received non-study anti-lymphoma treatment 
without a documented radiological progression as per CHESON Criteria 
• The number (%) of patients with at least one non-study anti-lymphoma treatment  
• The type of anti-lymphoma treatment received by ATC level 2 class and preferred 
name (for medication) 
• Irradiated locations, method of irradiation and total cumulative dose per therapy lines 
(for radiation) 
• Anatomical locations, anti-lymphoma surgeries by SOC and PT (for surgery) 
• Time to start of non-study anti-lymphoma treatment (days) 
• The therapy line of non-study anti-lymphoma treatment 
• Reason for stopping non-study anti-lymphoma treatment 
The above analysis will be presented by type of treatment (medication, radiation or surgery). 
Time to start of anti-cancer therapy (days) is defined as 
[start date of anti-cancer treatment – date of last dose of study treatment + 1] 
If the start date of anti-cancer treatment is missing, then the time to start of anti-cancer treatment 
for that patient will be missing. In case, a non-study anti-cancer therapy starts before the last 
dose of study treatment, will be set to 0. 
Palliative antineoplastic radiotherapy administered during the on- treatment phase and during the 
Survival follow-up phase may also be summarized by treatment arm. 
Listings of the above information will be presented. 
8.9. 
Study Treatment 
The following parameters will be listed and summarized overall and by treatment arms for the 
SAF. 
Duration of exposure to each study drug will be summarized. 
8.9.1. 
Treatment Cycle and Study Drug Regimen 
The patients will be administered study treatment according to cycles. Each treatment cycle will 
consist of 28 days.  
The duration of exposure for each study treatment drug is defined according to regimen as 
outlined below. 
8.9.1.1. 
For Tafasitamab 
The planned administration of tafasitamab is as follows: 
• Cycle 1: Day 1, Day 4 (loading dose), Day 8, Day 15, Day 22 
• Cycle 2: Day 1, Day 8, Day 15, Day 22 
• Cycle 3: Day 1, Day 8, Day 15, Day 22 
• Cycle 4 onwards: Day 1 and Day 15 


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Tafasitamab will be administered at a dose of 12.0 mg/kg IV. Dose reductions of tafasitamab are 
not allowed during the course of the study. 
Unless contraindicated the tafasitamab treatment should continue, even if the patient 
discontinues BEN treatment.  
8.9.1.2. 
For Rituximab (RTX) 
The administration of Rituximab is on Day 1 of every treatment cycle. 
RTX will be administered at a dose of 375 mg/m2 IV. Dose reductions of RTX are not allowed 
during the course of the study. 
Unless contraindicated the RTX treatment should continue, even if the patient discontinues BEN 
treatment. 
8.9.1.3. 
For Bendamustine (BEN) 
As per protocol, the planned administration of BEN is as follows: 
• Cycle 1: Day 2 Day 3 
• Cycles 2 to 6: (Day 1 + Day 2) or (Day 2 + Day 3) 
BEN is administered at a dose of 90mg/m². 
BEN dose may be modified in a de-escalating fashion or discontinued based upon clinical and 
laboratory findings. In the case of early BEN discontinuation, the antibody treatment should 
continue unless contraindicated. 
8.9.2. 
Duration of Exposure to Study Drug 
For patients in either treatment arm, duration of exposure to study treatment and each study drug 
will be calculated as follows: 
Duration of exposure (days) = (last date of exposure to study drug) – (date of first 
administration of study drug) + 1,  
where the "last date of exposure to study drug" is identified taking into account period of rest for 
the last cycle.  
• For RTX and BEN: When the study drug is administered over one or several days in 
the beginning of the cycle (RTX or Bendamustine), the last date of exposure is 
identified based on the planned cycle duration. For example, in a 28-day cycle with 
one or several infusions at the beginning of the cycle, the last date of exposure is the 
date of first infusion in the last cycle + 27 days.  
• For tafasitamab: When the study drug is administered over several regular doses with 
regular time intervals, the last date of exposure is identified according to the planned 
dose schedule of the cycle. That is, the last date of exposure is: 
(last date of administration of the study drug) + (length of time interval-1) 
Length of time interval is 7 days in Cycle 1-3 and 14 days from Cycle 4 onwards. 


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In case a patient dies before the end of the time interval the date of death will be used to truncate 
the time interval, i.e., in this case the last date of exposure will be set as the date of death. 
The Duration of exposure to study drug will be calculated in weeks, and in months, respectively, 
duration of exposure (days)/7, duration of exposure (days)/30.4375. 
8.9.3. 
Duration of Exposure to Study Treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to each study drug: 
Duration of exposure (days) = (last date of exposure of all the study drugs) – (date of first 
administration of study treatment) + 1. 
Analysis of Duration of Study Drug and Study Treatment: 
• The number of patients completing each cycle will be summarized and listed. A 
patient is considered to have completed a cycle for tafasitamab/RTX if he/she was 
compliant for all tafasitamab/RTX infusions during the cycle. A patient is considered 
to have completed a cycle for BEN if he/she was compliant for BEN administration 
during the cycle. 
• Duration of exposure is categorized as: (0-4], (4-8], (8-12], etc. in weeks, as well as 
Month 1-2, 3-4, 5-6, 7-8, etc. Number and % of each category will be presented. 
• Summaries (i.e. mean, standard deviation etc.) based on continuous variable will be 
displayed in weeks and in months. 
• Number of infusions with study drugs will be summarized as follows: 
− The total number of study drug infusions will be summarized 
− The number (%) of patients belonging to the following categories will be derived: 
0-2 infusions, 3-4 infusions, 5-6 infusions, 7-8 infusions, etc. 
The duration of exposure to study treatment will be calculated in weeks, and in months, 
respectively, duration of exposure (days)/7, duration of exposure (days)/30.4375. 
8.9.4. 
Dose Skipping/Postponement 
The number (%) of patients with dose skipping/postponements, and associated reasons, will be 
summarized separately for each study drug. 
The number and percentage of patients with a skipped or postponed study drug (tafasitamab, 
RTX, BEN) dose will be presented, along with reasons for skipping/postponing the dose. This 
will be presented by Cycle based on SAF. 
The number of dose reductions for BEN only might be displayed. 
8.9.5. 
Infusion Interruption 
The number and percentage of patients with an interruption in study drug (tafasitamab, RTX, 
BEN) infusion will be presented, along with reasons for interruption of infusion. This will be 
presented by Cycle based on FAS. 


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8.9.6. 
Compliance 
Compliance for each study drug (tafasitamab/RTX/BEN) will be calculated by taking the actual 
infusion dose divided with the planned infusion dose (multiplied by 100, to report in percentage). 
Compliance will be calculated per single infusion and per cycle: 
• Study drug compliance per single infusion: if the study drug dose administered is 
≥80% and ≤120% of the planned dosage  
• Study drug compliance per cycle: if this quantity is ≥80% and ≤120% of the planned 
dosage for the cycle, then the patient will be considered compliant for that cycle  
A patient who has missed a dose or have received doses outside the above range will be 
considered as non-compliant. 
The number and percentage of patients considered compliant and non-compliant will be 
presented by study drug, for each treatment arm by cycle and also for overall. 
The percentage will be calculated based on the number of patients ongoing at the beginning of 
the respective cycle. 
Compliance for the study drug will be derived as follows: 
• For each single infusion (%): 
(𝐴
𝑃)
× 100 
Where, A = actual infusion volume and is as collected on the CRF. 
− For tafasitamab, a uses patient weight to calculate the required dose for 
administration and is measured in mg/kg.  
− For RTX/BEN, BSA is used and measured in mg/m². 
P = Planned infusion dose and is as collected on the CRF. 
− 12 mg/kg per infusion for tafasitamab. 
− 375 mg/m² for RTX 
− 90 mg/m² for BEN 
• For each cycle (%): 
∑(
𝐴𝑖
𝑃𝑖× 𝐶)
𝑛
𝑘=0
× 100 
C is the number of planned infusions per cycle:  
− For tafasitamab, 5 at Cycle 1, 4 at Cycles 2 and 3, and 2 per Cycle at Cycle 4 
onwards. 
− For RTX this is 1 per cycle 
− For BEN, this is 2 per cycle. 


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All percentages will be rounded to 1 decimal place for reporting. 
• For overall (%): the same principle will be applied. It  is the percentage of the amount 
of drug administered during the study divided by the planned amount of drug during 
the study. 
8.9.7. 
Treatment Kits 
The date of administration and the kit number will be presented for each treatment drug based on 
SAF as a listing. 
9. 
EFFICACY ANALYSIS OF PRIMARY AND KEYSECONDARY 
ENDPOINT 
The following scheme will be followed to test the dual primary endpoints and the key secondary 
endpoints: 
The total Type I error in this study consisting of 5% will be distributed over the two dual primary 
endpoints and the key secondary endpoints according to the following scheme with a local 
significance level of 0.048 (two-sided): 
Figure 9-1: 
Overview of the Hierarchical Testing Strategy 
 


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If the primary endpoint is met for the overall (FAS) population, the secondary endpoints will be 
hierarchically tested for the FAS population with the alpha that was provided for the overall 
population (i.e. 3.4%). If any of the key-secondary endpoint is not met in FAS, the dual primary 
endpoint of PFS and the key-secondary endpoints will be tested following the same hierarchical 
plan in the NKCC-low subgroup at the allocated alpha of 𝜶𝟐
∗ = 1.4%. 
If both of the key secondary endpoints are met in FAS, the dual primary endpoint of PFS and the 
key secondary endpoints will be tested following the same hierarchical plan in the NKCC-low 
subgroup at the allocated alpha of 𝜶𝟐
∗ = 1.4%. 
For the Final Analysis efficacy endpoints main analysis, the 95% confidence intervals for PFS, 
ORR, and OS for the overall population and for the NKCC-low subgroup will be reported. 
If the primary endpoint is not met for the FAS, but is met in the NKCC-low subgroup, the 
secondary endpoints will be hierarchically tested for the NKCC-low subgroup. 
For confirmatory hypothesis testing at the primary efficacy analysis in the Final Analysis, the 
p-values of the statistical tests for the primary and key secondary endpoints will be combined 
from stage I (information up to Interim Analysis) and stage II (information between Interim 
Analysis and Final Analysis) of the study using the inverse normal method for the overall 
population and the NKCC-low subgroup. This procedure preserves the overall (experiment-wise) 
type I error rate at the desired alpha (Wassmer 2006). 
The pre-specified weights to be used for combining the p-values from the two stages should 
satisfy the condition that the sum of the square of the weights add up to 1. The square of the 
weight at stage 1 will be equal to 0.4 and at stage 2 will be equal to 0.6. 
The table below shows the Z-statistic and the corresponding one-sided p-values for FAS and 
NKCC-Low subgroup (FAS) calculated at Interim and the primary efficacy analysis in FA for 
the primary and key-secondary endpoints. The indices for the Z-statistic and p-values are as 
follows: 
• i indicates the stage: stage I (1) vs. stage II (2), 
• j indicates the full population (F) vs. the NKCC-low subgroup (S), 
• k indicates the endpoint (k=PFS, ORR, DoR, OS). 
That is, p1,F,PFS will indicate the p-value of stage 1 for the full population for the endpoint PFS. 
Table 9-1: 
Z-Statistic and Corresponding P-Values for FAS and NKCC-Low Subgroup 
 
 
Test 
 
FAS 
NKCC-Low (FAS) 
Primary 
PFS 
Stratified 
Log-rank test 
Interim 
Z1,F,PFS = Φ-1(1- p1,F,PFS)  
Z1,S,PFS = Φ-1(1- p1,S, PFS)  
Primary 
Z2,F,PFS = Φ-1(1- p2,F,PFS) 
Z2,S,PFS = Φ-1(1- p2,S, PFS) 
Key-
Secondary 
ORR 
Stratified 
CMH test 
Interim 
Z1,F,ORR = Φ-1(1- p1,F,ORR)  
Z1,S,ORR = Φ-1(1- p1,S, ORR)  
Primary 
Z2,F,ORR = Φ-1(1- p2,F,ORR) 
Z2,S,ORR = Φ-1(1- p2,S, ORR) 
Key-
Secondary 
OS 
Stratified 
Log-rank test 
Interim 
Z1,F,OS = Φ-1(1- p1,F, OS)  
Z1,S,OS = Φ-1(1- p1,S, OS)  
Primary 
Z2,F,OS = Φ-1(1- p2,F, OS) 
Z2,S,OS = Φ-1(1- p2,S, OS) 


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For primary and key-secondary endpoints, weights are pre-specified such that, 𝑤1
2 = 0.4 and 
𝑤2
2 = 0.6, so that 𝑤1
2 + 𝑤2
2 = 1. 
The following table presents the Rejection rules for the dual primary and key-secondary 
endpoints to be applied at the time of Final Analysis. 
Table 9-2: 
Rejection Rules for the Dual Primary and Key-Secondary Endpoints 
 
Endpoint 
FAS 
Reject Null if: 
NKCC-Low (FAS) 
Reject Null if: 
Primary 
PFS 
ZF,PFS =  
w1,F,PFSZ1,F,PFS  + 
w2,F,PFSZ2,F,PFS   
ZF,PFS >  
Φ-1(1-0.034/2) 
ZS,PFS =  
w1,S,PFSZ1,S,PFS  + 
w2,S,PFSZ2,S,PFS   
ZS,PFS >  
Φ-1(1-0.014/2) 
Key-
Secondary 
ORR 
ZF,ORR =  
w1,F,ORRZ1,F,ORR  +  
w2,S,ORRZ2,F,ORR   
ZF,ORR >  
Φ-1(1-0.034/2) 
ZS,ORR =  
w1,S,ORR Z1,S,ORR  +  
w2,S,ORR Z2,S,ORR   
ZS,ORR >  
Φ-1(1-0.014/2) 
Key-
Secondary 
OS 
ZF,OS =  
w1,F,OSZ1,F,OS  +  
w2,S,OSZ2,F,OS   
ZF,OS >  
Φ-1(1-0.034/2) 
ZS,PFS =  
w1,S,OSZ1,S,OS  +  
w2,S,OSZ2,S,OS   
ZS,OS >  
Φ-1(1-0.014/2) 
The Inverse Normal Method will require to use the one-sided p-values, and the weighted one will 
be back-transformed to two-sided p-value for result presentation. 
The local significance levels of 0.52% for the Interim Analysis and 4.8% for the Final Analysis 
specified in the protocol are derived from an O´ Brien Fleming alpha-spending function with an 
Interim Analysis at 50% information fraction (i.e., once 128 out of 256 PFS-IRC events have 
been observed). 
The local significance level at the Final Analysis will be determined based on the actually 
observed number of PFS-IRC events, taking into account that the Interim Analysis was based on 
135 PFS-IRC events with 0.52% alpha (two-sided) spent. Of note, the sponsor does not expect to 
observe substantially more than 300 PFS-IRC events at the time of the Final Analysis and 
therefore the local significance level is expected to remain at two-sided 4.8%. 
The family-wise type I error at the Final Analysis will be split according to Bonferroni: 70% of 
the alpha will be used for inference based on the FAS (e.g., 3.4% alpha), while 30% will be used 
for inference based on the NKCC-low subgroup (e.g., 1.4% alpha). 
9.1. 
Impact of COVID-19 on Analysis of Primary and Key Secondary 
Endpoints 
Sensitivity analyses will be done to assess the impact of COVID-19 on the efficacy analysis of 
the primary and key secondary endpoints by considering COVID-19 deaths as censored. 


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10. 
PRIMARY OBJECTIVE 
The primary objective is to determine the efficacy of a combination of tafasitamab with BEN 
versus a combination of RTX with BEN in terms of progression-free survival (PFS) in: 
• Adult patients with R-R DLBCL (overall population/full analysis set (FAS)) 
• Adult patients with R-R DLBCL and low baseline peripheral blood NKCC 
(NKCC-low subgroup, defined as ≤ 100 cells/µL) 
For NKCC-low subgroup, please see Section 7.7. 
The tumour assessments will be derived according to the IWG treatment response criteria for 
malignant lymphoma (Cheson et al 2007; see Appendix A) by an Independent 
Radiology/Clinical Review Committee (IRC) and also locally by the investigator. The review 
process will be defined in the IRC Charter. 
10.1. 
Endpoints 
The dual primary efficacy endpoints will be based on PFS, defined as the time (in months) from 
date of randomization to date of tumour progression or death from any cause (see Independent 
Review Charter version 4.0 of 18 July 2018). The date of progression will be the first date for 
which progressive disease was assessed as the objective response (see Appendix A). 
For censoring reasons, please see Section 10.1.3.2. 
10.1.1. 
Dual Primary Endpoint 1 
PFS in the overall (FAS) population. 
10.1.2. 
Dual Primary Endpoint 2 
PFS in NKCC-low (FAS) subgroup. 
10.1.3. 
Disease Assessment and Censoring Rules 
10.1.3.1. Disease Assessments 
Disease assessments will be performed with either UNS scans, PET/CT scans or CT/MRI scans 
as per the schedule below: 
Table 10-1: 
Tumour Assessments 
Evaluation 
Screening 
Visit 
C3D1 
C5D1 
C6D28 
C7D1 
C10D1 
C13D1 
Every 3 
months 
EOT 
Visit 
Disease response 
assessment (PET/CT 
or PET/MRI) 
X 
 
 
X 
 
 
 
 
X 
CT or MRI scan for 
tumour measurement 
and disease response 
assessment 
 
X 
X 
 
X* 
X 
X 
X 
 
* CT or MRI scan for tumour measurement and disease response assessment will be performed on C7D1 only if 
Disease response assessment (PET/CT or PET/MRI) is not performed in C6D28. 


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A window of ± 2 weeks is allowed by the protocol for these assessments. 
The tumour assessments will continue until disease progression, death or study discontinuation 
(whichever occurs first). 
10.1.3.2. Censoring Rules 
If a patient is alive and progression free at the date of the analysis (i.e., cut-off date), the patient 
will be censored, and the reason for censoring will be provided as per Table 10-2 provided 
below. 
Table 10-2: 
Censoring Rules for PFS Analysis 
Situation 
Date of Progression 
or Censoring 
Outcome 
Censoring Reason 
Ongoing and no event until 
data cut-off 
Date of last tumour assessment 
Censored 
Ongoing 
Discontinued PFS follow-up 
with no event 
Date of last tumour assessment 
Censored 
Discontinued without 
event 
No baseline tumour 
assessment 
Date of Randomization 
Censored 
No baseline tumour 
assessment 
Lost to follow-up 
Date of last tumour assessment  
Censored 
Lost to follow-up 
Patient received non-study 
cancer treatment before 
disease progression 
Date of last tumour assessment 
before start of non-study cancer 
treatment 
Censored 
New anti-cancer 
therapy started 
Death before any date of PD 
assessment 
Date of death 
Progressed 
 
Death between adequate 
assessments 
Date of death 
Progressed 
 
Progression or Death after 
exactly one missed 
assessment 
Date of Progression or Death 
Progressed 
 
Death or progression after two 
or more missed/non-adequate 
consecutive tumour 
assessments 
Date of last adequate tumour 
assessment 
Censored 
Event documented after 
two or more 
missing/non-adequate 
consecutive tumour 
assessments 
Patient discontinued study 
after two or more missed/non-
adequate consecutive 
assessments without disease 
progression 
Date of last adequate tumour 
assessment 
Censored 
Adequate assessment 
no longer available 
 
• Continuation of control drug monotherapy (RTX or BEN) as 1st new anti-neoplastic 
therapy after end of treatment without prior PD and collected in the 'antineoplastic 
Medication therapies after end of study drug treatment' -eCRF page, will be 
considered as an anti-lymphoma therapy and the patient will be censored at the last 
tumour assessment date. This is because study treatment is considered discontinued 
when the patient discontinues any of the study drugs in the combination. 


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10.1.3.3. Missed Tumour Assessment 
If a Death or progression after two or more consecutive missed/non-adequate Tumour 
Assessments (TA), then the event is censored. 
• In the analysis for PFS, an event occurring after two or more consecutive missing 
assessments or non-adequate tumour assessments will be censored on the date of last 
adequate tumour assessment. 
Table 10-3 shows censoring rule in case of death or disease progression after two consecutive 
missed/inadequate disease assessment. 
Table 10-3: 
Censoring Rule if Event Happens After Two Consecutive Missed/Inadequate 
Disease Response Assessment 
Study Phase in Which 
Last Valid Response 
Assessment Happens 
Missed/Inadequate 
Disease Response 
Assessments 
No Disease Response 
Assessment Within 
Censored At 
Treatment phase 
C3D1, C5D1 
115 (4x28+3) days from 
randomization date 
Randomization date 
C5D1, C6D28 
115 (3x28+27+4) days from 
date of C3D1 response 
assessment  
C3D1 response 
assessment date  
C6D28, C10D1 
143 (5x28+3) days from date 
of C5D1 response assessment  
C5D1 response 
assessment date 
C10D1, C13D1 
172 (6*28 + 1 + 3) days from 
date of C6D28 response 
assessment  
C6D28 response 
assessment date 
C13D1, C16D1 
171 (6x28 + 3) days from date 
of C10D1 response assessment 
C10D1 response 
assessment 
Every sequence of 
response assessments 
after Cycle 10 
 171 (6x28 + 3) days from 
date of last prior response 
assessment  
Censored at the date of 
the last valid tumour 
response assessment date 
Post-treatment PFS 
follow-up phase 
PFS follow-up visit 1 
and 2 
194 (6x30 + 14) days from 
date of last response 
assessment in the treatment 
phase (including response 
assessments at the EOT visit) 
Date of last response 
assessment date in the 
treatment phase 
(including EOT response 
assessments) 
PFS follow-up visit 2 
and 3 
194 (6x30 + 14) days from 
date of last response 
assessment in the PFS 
follow-up phase  
Date of last response 
assessment  
Every sequence of 
response assessments 
after PFS follow-up 
visit 3 
194 (6x30 + 14) days from 
date of last response 
assessment in the PFS 
follow-up phase  
Date of last response 
assessment 
In case of an unscheduled visit with an adequate disease response assessment between any two 
planned disease response assessments, for example between C3D1 and C5D1, the reference time 
point is the date of the unscheduled assessment. The strategy to identify patients with two or 


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more missed tumour response assessments after an unscheduled tumour response assessment is 
as follows: 
Table 10-4: 
Censoring Rule if Event Happens After Two or More Consecutive 
Missed/Inadequate Tumour Assessment Relative to an Unscheduled But 
Adequate Response Assessment 
Study Phase in Which 
Unscheduled Response 
Assessment Happens 
Time Point of 
Unscheduled Tumour 
Response Assessment 
No Disease Response 
Assessment Between 
Censoring Date 
Treatment phase 
Before C5D1 response 
assessment 
115 days from date of 
unscheduled tumour response 
assessment 
Date of unscheduled 
response assessment 
Between C5D1 and 
C6D28 response 
assessment 
143 days from date of 
unscheduled tumour response 
assessment 
Date of unscheduled 
response assessment 
After C6D28 response 
assessment 
171 days from date of 
unscheduled tumour response 
assessment 
Date of unscheduled 
response assessment 
Post-treatment PFS 
follow-up phase 
Between two tumour 
response assessments 
194 days from date of 
unscheduled tumour response 
assessment 
Date of unscheduled 
response assessment 
However, if after any unscheduled adequate response assessment there is a scheduled study 
response assessment then rules specified under Table 10-3 apply. 
10.2. 
Statistical Analysis of Dual Primary Endpoints 
10.2.1. 
Null and Alternative Hypothesis for Main Analysis 
The Null and Alternative Hypotheses for each dual primary endpoint are: 
Null Hypothesis: H0: SM+B(t) = SR+B(t) for all t vs. 
Alternative Hypothesis: H1: SM+B(t) ≠ SR+B(t),  
where  
SM+B(t) : PFS distribution function in MOR208 + BEN treatment arm, 
SR+B (t) : PFS distribution function in RTX + BEN treatment arm. 
10.2.2. 
Implementation of the Inverse Normal Method 
Inverse Normal method will be used to combine information (p-value) from stage I of the study 
(information obtained up to the data cut-off for interim analysis) and stage II of the study 
(information obtained from data-cut-off of interim analysis up to data cut-off for final analysis) 
for FAS and NKCC-low subgroup. 
The pre-specified weights to combine the information are: 𝑤1
2 = 0.4 and 𝑤2
2 = 0.6, so that 𝑤1
2 +
𝑤2
2 = 1. 
The inverse normal test-statistic is given by equation 3.3 of Wassmer (2006) and will be applied 
only for the main analysis. 


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10.2.3. 
Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 10-5: 
Main, Sensitivity and Supportive Analysis for the Primary Endpoint PFS 
Progression Free Survival 
Analysis: 
1. Stratified Log-rank test 
2. Tabulation of PFS event types and reason for censoring 
Events[ Death, PD] 
Censored [Censoring Reason]  
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
1. Main 1 a-b 
IWRS 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
 
Sens. 1.1 a-b 
IWRS 
Local TA 
a. FAS  
b. NKCC-Low (FAS) 
 
Sens 1.2 a-b 
IWRS 
IRC 
a. PPS 
b. NKCC-Low (PPS) 
 
Sens. 1.3 a-b 
IWRS 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
Considering patients who started new 
anti-lymphoma treatment as having 
IRC-PFS event 
Sens. 1.4 a-b 
IWRS 
IRC 
FAS 
NKCC—Low (FAS) 
Considering COVID-19 deaths as 
censored rather than as event 
Analysis: 
Unstratified Log-rank test 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 1.5 a-b 
 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
 
Analysis: 
Stratified Cox Model 
[1. HR point estimate and 95% CI for Treatment] 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Main 2 a-b 
IWRS  
IRC 
a. FAS 
b. NKCC-Low (FAS) 
Cofactors:  
1. Treatment  
Sens. 2.1 a-b 
IWRS 
Local TA 
a. FAS 
b. NKCC-Low (FAS) 
Cofactors:  
1. Treatment  
Sens. 2.2 a-b 
IWRS  
IRC 
a. PPS 
b. NKCC-Low (PPS) 
Cofactors:  
1. Treatment  
Sens. 2.3 a-b 
IWRS  
IRC 
a. FAS 
b. NKCC-Low (FAS,) 
Cofactors:  
1. Treatment  
Considering patients who started new 
anti-lymphoma treatment as having 
IRC-PFS events. 
Sens. 2.4. a-b 
IWRS 
IRC 
FAS 
NKCC-Low (FAS) 
Considering COVID-19 deaths as 
censored rather than as event 


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Table 10-5: 
Main, Sensitivity and Supportive Analysis for the Primary Endpoint PFS 
(Continued) 
Progression Free Survival 
Analysis: 
1. KM Estimates for PFS 
[Q1,Median,Q3 point and 95%CI estimates (Brookmeyer and Crowley 1982), 
PFS point and 95% CIs (Greenwood formula)] estimates at: 3,6,9,12,18,24,30 months 
 and every 6 months thereafter] 
2. KM Plots for PFS 
3. Median follow-up time including 95% CI based on reverse Kaplan-Meier method 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Main 3 a-b 
 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
 
Sens. 3.1 a-b 
 
Local TA 
a. FAS 
b. NKCC-Low (FAS) 
 
Sens. 3.2 a-b 
 
IRC 
a. PPS 
b. NKCC-Low (PPS) 
 
Sens. 3.3 a-b 
 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
Considering patients who initiated new 
anti-lymphoma therapy as having 
IRC-PFS event 
Sens. 3.4 a-b 
 
IRC 
FAS 
NKCC-Low (FAS) 
Considering COVID-19 deaths as 
censored instead of event 
Analysis: 
PFS events by Local vs. IRC 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 4.1 a-b 
 
IRC vs 
Local 
a. FAS 
b. NKCC-Low (FAS) 
Concordance-Discordance Table of PFS 
events 
Supp. 4.2 a-b 
 
IRC vs 
Local 
a. FAS  
b. NKCC-Low (FAS) 
Summary of missing/unknown tumour 
assessments will not be investigated and 
information will only be in listing 
Analysis:  
Forest plots of PFS hazard ratio (HR) for treatment in subgroups  
Stratified Cox Model to calculate 95% CI HR for Treatment 
Forest Plot of 95% CI HR for treatment across subgroups listed in Section 7.13: 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 5.1a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-low (FAS) 
a. Add 95% CI HR for treatment from 
FAS main analysis as reference 
b. Add 95% CI HR for treatment from 
NKCC-Low (FAS) main analysis as 
reference 


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11. 
SECONDARY EFFICACY OBJECTIVES 
The Secondary Objective is to compare both study arms, tafasitamab with BEN versus RTX with 
BEN, for the overall population and NKCC-low subgroup in terms of different endpoints as 
mentioned below. 
The two Key Secondary Endpoints are: 
• Key secondary 1: Best Objective Response Rate (ORR) in FAS 
• Key secondary 2: Overall Survival (OS) in FAS 
Hierarchical testing will be employed for key secondary endpoints, with the primary endpoint 
PFS serving as a gatekeeper. The alpha at which the primary endpoint is rejected, will be carried 
forward to test the secondary endpoints accordingly to support labelling claims for key 
secondary endpoints. The details are discussed in Section 9. 
11.1. 
Secondary Objective 1a and Endpoint: Best Objective Response Rate 
(ORR) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-low subgroup in terms of: 
Best Objective Response Rate (ORR = complete response (CR) + partial response (PR)) based 
on the best response achieved at any time during the study. 
The best ORR is defined as the proportion of patients with CR or PR based on the best response 
achieved at any time during the study. The denominator will be the total number of patients 
included in the analysis population. 
The proportion of patients who achieved CR at any time during the study will be reported. The 
denominator will be the total number of patients included in the analysis population. 
The patients having a CR or PR at any time during the study will be classified as a "Best 
Responder". If any alternative cancer therapy is taken while on study any subsequent 
assessments would be excluded from the best overall response determination. 
11.1.1. 
Statistical Analysis 
11.1.1.1. Null and Alternative Hypothesis for Main Analysis 
The Null and Alternative Hypotheses are: 
Null Hypothesis: H0: ORRM+B = ORRR+B vs. 
Alternative Hypothesis: H1: ORRM+B ≠ ORRR+B, 
where  
ORRM+B: Best ORR in the tafasitamab + BEN treatment arm, 
ORRR+B: Best ORR observed in the RTX + BEN treatment arm. 


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11.1.1.2. Implementation of the Inverse Normal Method 
Inverse Normal method will be used to combine information from stage I of the study 
(information obtained up to the data cut-off for interim analysis) and stage II of the study 
(information obtained from data-cut-off of interim analysis up to data cut-off for primary 
efficacy analysis in the FA) for FAS and NKCC-low subgroup. 
To calculate the p-value for ORR in stage 1, all patients randomized in stage 1 with a CR, PR, 
SD, PD, Death, or discontinued study for any reason prior to interim analysis cutoff-date will be 
considered in the denominator. The number of patients having a best response of PR or CR out 
of these patients will be considered in the numerator. 
To calculate the p-value ORR in stage 2, all patients randomized and not considered in stage 1 
will be considered in the denominator. The number of patients having a best response of PR or 
CR out of these patients will be considered in the numerator. 
The pre-specified weights to combine the information are: 𝑤1
2 = 0.4 and 𝑤2
2 = 0.6, so that 𝑤1
2 +
𝑤2
2 = 1. 
The inverse normal test-statistic is given by equation 3.1 of Wassmer (2006), where the pk's are 
calculated using stratified CMH test and described in the following section. 
The analysis described above will be repeated for CR. 
11.1.1.3. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-1: 
Main, Sensitivity and Supportive Analysis for the Endpoint ORR 
Overall Best Objective Response Rate 
Analysis: 
1. Tabulation of Best Objective Response (CR, PR, SD, PD, Not Evaluable (NE)) and 
Tabulation of reasons for NE (No post-baseline assessment, 
All post-baseline assessments have overall response UNK, 
New anti-cancer therapy started before first post-baseline assessment) 
 
2. Proportion with best objective response (CR + PR): Point estimate and 95% CI using  
Clopper-Pearson exact method by treatment arm (Clopper and Pearson 1934) 
[Patients with no post-baseline assessment of response will be considered as non-responders] 
 
3. Proportion with CR: Point estimate and 95% CI using Clopper-Pearson exact 
method by treatment arm 
[Patients with no post-baseline assessment of response will be considered as non-responders] 
 
4. Testing for treatment effect for best objective response (CR + PR ) using Stratified CMH test 
[1. PROC FREQ with the CMH option.  
2. Coding: 1 for <response> and 0 for <non-response>.  
3. The p-value corresponding to the CMH test for "general association" will be presented] 
 
5. Testing for treatment effect for CR using Stratified CMH test 
[1. PROC FREQ with the CMH option.  
2. Coding: 1 for <response> and 0 for <non-response>.  
3. The p-value corresponding to the CMH test for "general association" will be presented] 


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Table 11-1: 
Main, Sensitivity and Supportive Analysis for the Endpoint ORR 
(Continued) 
Overall Best Objective Response Rate 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Main 1 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
 
Sens. 1.1 a-b 
IWRS  
Local 
a. FAS 
b. NKCC-Low (FAS) 
 
Analysis: Odds Ratio (OR) for treatment effect  for best objective response (CR + PR) 
[1. Logistic regression: PROC GENMOD by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT 
to calculate 95% CI OR for treatment 
2. OR point and 95% CI estimates for Treatment effect ] 
 
Analysis: Odds Ratio (OR) for treatment effect  for CR  
[1. Logistic regression: PROC GENMOD by adding the model options: TYPE3, DIST=BIN, and LINK=LOGIT 
to calculate 95% CI OR for treatment 
2. OR point and 95% CI estimates for Treatment effect ] 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 2.1 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
Covariates:  
1. Treatment 
2. Stratification factors 
Supp. 2.2 a-b 
IWRS 
Local TA 
a. FAS 
b. NKCC-Low (FAS) 
Covariates:  
1. Treatment 
2. Stratification factors 
Analysis: 
ORR by Local vs. IRC 
[1. Patients without any baseline or post-baseline response assessment will be considered as not evaluable (NE) 
in both the IRC and INV assessment 
2. Patients who have been evaluated by investigator assessment but not by IRC will be presented as "Not 
performed" and will be excluded from the analysis] 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 3 
 
IRC vs 
Local 
FAS 
Concordance-Discordance Table of 
ORR by response type 
Analysis for best objective response (CR+PR): 
Forest plot of odds ratios for treatment in subgroups 
Logistic Regression using PROC GENMOD by adding the model options: TYPE3, DIST=BIN, and 
LINK=LOGIT to calculate OR 95% CI 
Forrest plot of OR 95% CIs for treatment across subgroups listed in Section 7.13: 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 4 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
a. Add OR 95% CI estimate for 
treatment from FAS main analysis as 
reference 
b. Add OR 95% CI estimate for 
treatment from NKCC-Low (FAS) 
main analysis as reference 


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Table 11-1: 
Main, Sensitivity and Supportive Analysis for the Endpoint ORR 
(Continued) 
Overall Best Objective Response Rate 
Analysis for CR: 
Forest plot of odds ratios for treatment in subgroups 
Logistic Regression using PROC GENMOD by adding the model options: TYPE3, DIST=BIN, and 
LINK=LOGIT to calculate OR 95% CI 
Forrest plot of OR 95% Cis for treatment across subgroups in Section 7.13: 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Supp. 4 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
a. Add OR 95% CI estimate for 
treatment from FAS main analysis as 
reference 
b. Add OR 95% CI estimate for 
treatment from NKCC-Low (FAS) 
main analysis as reference 
11.2. 
Secondary Objective 1b and Endpoint: Duration of Response (DoR) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-Low subgroup in terms of: Duration of Response. 
Duration of overall response (DoR) is defined as the elapsed time (in months) between the date 
of first documented response (CR or PR) and the following date of event defined as the first 
documented progression or death. 
That is, 
DoR (months) = (date of assessment of tumour progression or death – date of assessment of 
first documented response of (CR or PR) + 1)/30.4375. 
If any alternative cancer therapy is taken while on study any subsequent assessments would be 
excluded from the best overall response determination. 
The study arms will also be compared based on duration of response for patients whose best 
response is CR. 
11.2.1. 
Statistical Analysis 
Descriptive analysis will be done for DoR among patients who responded in each arm, 
tafasitamab with BEN versus RTX with BEN, for the overall population and for the NKCC-Low 
subgroup. 
11.2.1.1. Censoring Rules 
If a patient is still on response at the date of the analysis (i.e., cut-off date), the patient will be 
censored. The following censoring rules will be applied for DoR endpoint. 


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Table 11-2: 
Censoring Rules for the Dor Analysis (IRC and Local Tumour Assessment) 
Situation 
Date of Progression or 
Censoring 
Outcome 
Lost to follow-up 
Date of last tumour assessment 
Censored 
Patient received non-study cancer 
treatment before disease progression 
Date of last tumour assessment 
before start of non-study cancer 
treatment 
Censored 
Death before any date of PD 
assessment 
Date of death 
Progressed 
Death between adequate assessments 
Date of death 
Progressed 
Death or progression after 2 or more 
missed/non-adequate consecutive 
tumour assessment 
Date of last adequate tumour 
assessment 
Censored 
Abbreviations: DoR = duration of response; IRC = Independent Review Committee; PD = progressive disease 
*Progression as per Investigator's decision and without meeting PD criteria as listed in Appendix A. 
11.2.1.2. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-3: 
Main, Sensitivity and Supportive Analysis for the Endpoint DoR 
Duration of Response (DoR) 
Analysis: DoR for patients who reached CR or PR 
1. Tabulation of event types and reason for censoring 
Events[ Death, PD] 
Censored [Censoring Reason] 
 
2. KM Estimates 
[Q1,Median,Q3 point and 95%CI (Brookmeyer and Crowley 1982), 
PFS point and 95% CIs (Greenwood formula)]estimates at: 3,6,9,12,18,24 months and every 6 months thereafter ] 
 
3. KM Plots 
 
4. Median follow-up time including 95% CI based on reverse Kaplan-Meier method 
Main Sens. / 
Supp. 
Strat. factor 
TA as per 
Population 
Main 1 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
Sens 1.2 a-b 
IWRS 
Local TA 
a. FAS 
b. NKCC-Low (FAS) 


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Table 11-3: 
Main, Sensitivity and Supportive Analysis for the Endpoint DoR (Continued) 
Duration of Response (DoR) 
Analysis: DoR for patients who reached CR 
1. Tabulation of event types and reason for censoring 
Events[ Death, PD] 
Censored [Censoring Reason] 
 
2. KM Estimates 
[Q1,Median,Q3 point and 95%CI (Brookmeyer and Crowley 1982), 
PFS point and 95% CIs (Greenwood formula) estimates at: 3,6,9,12,18,24 months and every 6 months thereafter] 
 
3. KM Plots 
 
4. Median follow-up time including 95% CI based on reverse Kaplan-Meier method 
Main Sens. / 
Supp. 
Strat. factor 
TA as per 
Population 
Supp. 1.3 a-b 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
Supp. 1.4 a-b 
IWRS 
Local TA 
a. FAS 
b. NKCC-Low (FAS) 
11.3. 
Secondary Objective 1c and Endpoint: Overall Survival (OS) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-Low subgroup in terms of: Overall Survival.  
Overall survival (OS) is defined as the time (in months) from randomization until death from any 
cause and documented by the date of death. 
11.3.1. 
Statistical Analysis 
11.3.1.1. Null and Alternative Hypothesis for Main Analysis 
The Null and Alternative Hypotheses are: 
Null Hypothesis: H0: SM+B(t) = SR+B(t) vs. 
Alternative Hypothesis: H1: SM+B(t) ≠ SR+B(t), 
where 
SM+B(t): OS distribution function in tafasitamab + BEN treatment arm, 
SR+B (t): OS distribution function in RTX + BEN treatment arm. 
To have sufficient power, a statistical test for OS (here a stratified log-rank test; see Table 10-4) 
will only be performed at the Final Analysis (see Section 6.3.4). 
11.3.1.2. Implementation of the Inverse Normal Method 
Inverse Normal method will be used to combine information (p-value) from stage I of the study 
(information obtained up to the data cut-off for interim analysis) and stage II of the study 


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(information obtained from data-cut-off of interim analysis up to data cut-off for primary 
efficacy analysis in the FA) for FAS and NKCC-low subgroup. 
The pre-specified weights to combine the information are: 𝑤1
2 = 0.4 and 𝑤2
2 = 0.6, so that 𝑤1
2 +
𝑤2
2 = 1. 
The inverse normal test-statistic is given by equation 3.3 of Wassmer (2006). 
11.3.1.3. Censoring Rules 
The following rules will be applied to ascertain censoring rules for OS: 
Table 11-4: 
Censoring Rules for OS Analysis 
Situation 
Date of Death or 
Censoring 
Outcome 
Censoring reason 
Ongoing and No event until 
data cut-off 
Cut-off date 
Censored 
Ongoing 
Discontinued with no event 
Date of Last Contact 
Censored 
Discontinued without 
EOT 
Lost to follow-up 
Date of Last Contact 
Censored 
Lost to follow-up 
Death 
Date of Death 
OS Event 
 
Missing Date for Deaths 
If a patient's death month and year are provided but the day is missing, the day will set to the first 
day of the month, unless other qualifying study data support survival until a later date during the 
same month. If day and month or year is missing, no imputation will be done and the completion 
date will be censored at date of last contact. 
11.3.1.4. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-5: 
Main, Sensitivity and Supportive Analysis for the Endpoint OS 
Overall Survival 
Analysis: 
1. Stratified Log-rank test (at the Final Analysis) 
2. Tabulation of OS event types and reason for censoring 
Events[ Death] 
Censored [Censoring Reason] 
Main Sens. / 
Supp. 
Strat. 
factor 
TA as per 
Population 
Comment 
Main 1 a-b 
IWRS 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
 
Sens. 1.1 a-b 
IWRS 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
Considering COVID-19 death as 
censored rather than as OS event 


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Table 11-5: 
Main, Sensitivity and Supportive Analysis for the Endpoint OS (Continued) 
Overall Survival 
Analysis: 
1. Stratified Cox PH Model 
[HR point estimate and 95% CI for Treatment] 
 
2. KM Estimates for OS 
[Q1,Median,Q3 95%CI (Brookmeyer and Crowley 1982), 
OS point and 95% CIs (Greenwood formula) estimates at: 3,6,9,12,18,24, 30 months and every 6 months 
thereafter] 
 
3. KM Plots for OS 
 
4. Median follow-up time including 95% CI based on reverse Kaplan-Meier method 
Main Sens. / 
Supp. 
Strat. 
Factor 
TA as per 
Population 
Comment 
Main 2 a-b 
IWRS 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
 
Analysis: 
Unstratified Log-rank test (at the Final Analysis) 
Main Sens. / 
Supp. 
Strat. 
Factor 
TA as per 
Population 
Comment 
Supp. 3 a-b 
 
IRC 
a. FAS  
b. NKCC-Low (FAS) 
 
Analysis: 
Stratified Cox Model 
Stratified Cox Model to calculate 95% CI HR for Treatment 
Forest Plot of 95% CI HR for treatment across subgroups in listed in Section 7.13: 
Main Sens. / 
Supp. 
Strat. 
Factor 
TA as per 
Population 
Comment 
Supp. 5 
IWRS 
IRC 
a. FAS 
b. NKCC-Low (FAS) 
a. Add 95% CI HR for treatment from 
FAS main analysis as reference 
b. Add 95% CI HR for treatment from 
NKCC-Low (FAS) main analysis as 
reference 
11.4. 
Secondary Objective 1d and Endpoint: Disease Control Rate (DCR) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-low subgroup in terms of: 
Disease Control Rate (DCR = complete response (CR) + partial response (PR) + Stable Disease 
(SD)) based on the best response achieved at any time during the study. 
Disease control rate (DCR) is defined as the proportion of patients having CR, PR or SD based 
on the best response achieved at any time during the study. The denominator will be the total 
number of patients included in the analysis population. 


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If any alternative cancer therapy is taken while on study any subsequent assessments would be 
excluded from the best overall response determination. 
11.4.1. 
Statistical Analysis 
The Null and Alternative Hypotheses are: 
Null Hypothesis: H0: DCRM+B = DCRR+B vs. 
Alternative Hypothesis: H1: DCRM+B ≠ DCRR+B, 
where  
DCRM+B: DCR observed in the tafasitamab + BEN treatment arm, 
DCRR+B: DCR observed in the RTX + BEN treatment arm. 
11.4.1.1. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-6: 
Main, Sensitivity and Supportive Analysis for the Endpoint DCR 
Disease Control Rate (DCR) 
Main Sens. / Supp. 
Analysis Reference 
Main 
All Main from ORR 
Sens. 
All Sens. From ORR 
Supp. 
All Supp. From ORR 
11.5. 
Secondary Objective 1e and Endpoint: Time to Progression (TTP) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-low subgroup in terms of: 
Time to progression. 
Time to progression (TTP) is defined as the time (in months) from randomization until 
documented DLBCL progression or death as a result of lymphoma. Death from other causes than 
lymphoma will not be considered in relation to the TTP evaluation. 
11.5.1. 
Statistical Analysis 
11.5.1.1. Censoring Rules 
If a patient does not have an event, TTP will be censored on the date of the last tumour 
assessment before the data analysis cut-off date or the anti-neoplastic therapy start date or the 
date of death for Death from other causes than lymphoma. 
Censoring Rules for TTP 
If a patient has not experienced an event at the date of the analysis (i.e., cut-off date), the patient 
will be censored, and the reason for censoring will be provided as per Table 11-7 provided 
below. 
Censoring rules for the TTP analysis will be based on the IRC evaluation. 


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Table 11-7: 
Censoring Rules for the TTP Analysis (IRC evaluation) 
Situation 
Date of Progression or 
Censoring 
Outcome 
Censoring Reason 
Ongoing and No event until 
data cut-off 
Date of last tumour 
assessment 
Censored 
Ongoing 
Discontinued with no event 
Date of last tumour 
assessment 
Censored 
Discontinued without 
EOT 
No baseline tumour 
assessment 
Date of Randomization 
Censored 
No baseline tumour 
assessment 
Lost to follow-up 
Date of last tumour 
assessment (or C1D1 in 
case of study 
discontinuation without 
progression before any 
post-baseline assessment) 
Censored 
Lost to follow-up 
Patient received non-study 
cancer treatment before 
disease progression 
Date of last tumour 
assessment before start of 
non-study cancer treatment 
Censored 
New anti-cancer 
therapy started 
Death due to Lymphoma 
before any date of PD 
assessment 
Date of death 
Progressed 
 
Death due to Lymphoma 
between adequate assessments 
Date of death 
Progressed 
 
Death due to any cause other 
than Lymphoma before any 
date of PD assessment 
Date of death 
Censored 
Death Due to Other 
causes 
Death due to any cause other 
than Lymphoma between 
adequate assessments 
Date of death 
Censored 
Death Due to Other 
causes 
Progression or Death due to 
Lymphoma after exactly one 
missed assessment 
Date of Progression or 
Death 
Progressed 
 
Death due to any cause or 
progression after two or more 
missed consecutive tumour 
assessments 
Date of last tumour 
assessment 
Censored 
Event documented 
after two or more 
missing tumour 
assessments 
Patient discontinued after two 
or more missed/non-adequate 
consecutive assessment 
without disease progression 
Date of last adequate 
tumour assessment 
Censored 
Adequate assessment 
no longer available 
Abbreviations: IRC = Independent Review Committee; PD = progressive disease: PFS = progression-free survival 
For number of missed tumour assessments, the same rule as mentioned for PFS in 
Section 10.1.3.3 will be followed. 


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11.5.1.2. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-8: 
Main, Sensitivity and Supportive Analysis for the Endpoint TTP 
Time to Progression (TTP) 
Main Sens. / Supp. 
Analysis Reference 
Main 
All Main from PFS 
Sens. 
Sens. 1.1. a-b from PFS 
Supp. 
HR point and 95%CI for treatment and KM estimation for main and sensitivity 
analysis for TTP similar to that in PFS 
In addition, the following supportive analyses will be performed with regards to TTP on the 
patient's most recent prior therapy: 
11.6. 
Secondary Objective 1f and Endpoint: Time to Next Treatment 
(TTNT) 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-low subgroup in terms of: Time to Next Treatment. 
Time to next treatment (TTNT) is defined as the time (in months) from randomization to the 
institution of next anti-neoplastic therapy (for any reason including disease progression, 
treatment toxicity and patient preference) or death due to any cause, whatever comes first. 
11.6.1. 
Statistical Analysis 
11.6.1.1. Censoring Rules 
Patients without documented institution of a new anti-neoplastic therapy or death will be 
censored at the date of last contact. 
If the start date of non-study anti-cancer treatment is missing, then the time to start of next 
anti-cancer treatment for that patient will be considered missing. 
11.6.1.2. Main Analysis, Sensitivity Analysis and Supportive Analysis 
Table 11-9: 
Main, Sensitivity and Supportive Analysis for the Endpoint TTNT 
Time to Next Treatment (TTNT) 
Main Sens. / Supp. 
Analysis Reference 
Main 
All Main from PFS 
11.7. 
Secondary Objective 1g 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population and NKCC-low subgroup in terms of: safety, based on the frequency, incidence and 
severity of adverse events (AEs). 
The analysis of Safety Events is discussed in Section 13. 


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11.8. 
Secondary Objective 1h 
To compare both study arms, tafasitamab with BEN versus RTX with BEN, for the overall 
population (FAS) and NKCC-low subgroup in terms of Heal Related Quality of life (HRQoL) 
using  
• EORTC QLQ-C30 
• EQ-5D-5L questionnaires 
11.8.1. 
Endpoint: Health Related Quality of Life (HRQoL) 
11.8.1.1. EORTC QLQ-C30 
The EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality 
of Life Questionnaire), version 3.0 QLQ-C30 is composed of both multi-item scales and 
single-item measures. These includes 
• five functional scales (physical functioning, role functioning, emotional functioning, 
cognitive functioning, social functioning) 
• three symptom scales (fatigue, nausea and vomiting, pain)  
• a global health status/QoL scale and six single items (dyspnoea, insomnia, loss of 
appetite, constipation, diarrhoea, financial difficulties) 
Each of the multi-item scales includes a different set of items – no item occurs in more than one 
scale. A high scale score represents a higher response level. Thus, a high score for a functional 
scale represents a high or healthy level of functioning, a high score for the global health status 
represents a high quality of life but a high score for a symptom scale or symptom item represents 
a high level of symptomatology and problems. 
Raw scores and normalised scores of each scale will be calculated following procedures in the 
EORTC manual. 
11.8.1.2. EQ-5D-5L 
The EQ-5D-5L questionnaire comprises a descriptive system and a visual analogue scale (VAS). 
The EQ-5D-5L contains five questions 
• mobility 
• self-care 
• usual activities 
• pain/discomfort 
• anxiety/depression 
Respondents could choose one of five levels to describe their health state on the day of survey. 
These five levels include "no problem", "slight problems", "moderate problems" and "severe 
problems" in all five dimensions, and "unable" in mobility, self-care and usual activities or 
"extreme problems" in pain/discomfort and anxiety/depression. 


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The health of the respondent is indicated by a tick or a cross in the box against the most 
appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number 
expressing the level selected for that dimension. The digits for 5 dimensions can be combined in 
a 5-digit number describing the respondent's health state. EQ-5D-5L health states, defined by the 
EQ-5D-5L descriptive system, may be converted into a single index value. 
A vertical, hash-marked visual analogue scale (EQ-VAS) is anchored by 0 (the worst imaginable 
health state) at the bottom and 100 (the best imaginable health state) on the top for respondents 
to rate their overall health. A cross in the EQ-5D-5L VAS scale indicates how the respondent's 
health is today and then the number is transcribed in a box. 
11.8.1.3. HRQOL Visit Assessments 
The HRQOL instruments (EORTC QLQ-C30 and EQ-5D-5L) are planned to be administered on: 
• Screening Visit 
• Cycle 1 Day 1 
• Cycle 3 Day 1 
• Cycle 5 Day 1  
• And subsequently on D1 of the odd-numbered Antibody Monotherapy Treatment 
cycles (e.g., C7D1, C9D1, C11D1 etc.) until end of treatment (except for patients 
treated despite progression, for these patients no HRQOL will be performed after 
progression) 
• EOT 
• During FUP for PFS measurements 
• 1st OS FUP visit 
11.8.2. 
Method of Analysis of HR-QOL Endpoints 
For the analysis of EORTC QLQ-C30 and EQ-5D-5L: 
• The baseline assessment is the last available assessment before the first 
administration of any study drug 
• The stratification factors considered will be as per Randomization (IWRS) 
• Patients with no post-baseline assessment of response will be excluded 
• It will be performed on NKCC-low (FAS) and FAS 


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11.8.2.1. EORTC QLQ-C30 
The following analysis will be performed on EORTC QLQ-C30: 
1. The number (%) of patients completing EORTC QLQ-C30 assessments and the number 
(%) of patients completely missing and partially missing EORTC QLQ-C30 assessments 
will be summarized by treatment group for each scheduled assessment time point. 
2. Descriptive statistics (N, mean, median, SD, Q1, Q3, minimum-maximum) will be used 
to summarize the sub-scale scores of EORTC QLQ-C30 data at each scheduled 
assessment time point. Descriptive statistics for each of the scores will be tabulated by 
treatment arm. 
3. A longitudinal plot over time will be produced presenting the mean and the 95% CI of the 
mean by treatment arm for each subscales and overall. 
4. Change from baseline for each score, and numbers of patients with improvement, no 
change, and deterioration will be summarized by visit. For the functional and global 
health status/QoL scale, an improvement is defined as a higher score than baseline. A 
lower score than baseline indicates a deterioration. For the symptom scales and the six 
single items, an improvement is defined as a lower score than baseline. A higher score 
than baseline indicates a deterioration. 
5. Change from baseline in the sub-scale scores at the time of each assessment will be 
summarized. Patients with an evaluable baseline score and at least one evaluable post 
baseline score during the treatment period will be included in the change from baseline 
analyses. 
6. A mixed model with repeated measures (implemented via SAS PROC MIXED) that 
includes terms for treatment, randomization stratification factors, baseline value, visit, 
visit by baseline interaction, visit by treatment arm interaction will be used to compare 
the two treatment arms with respect to changes from baseline in the subscales and overall 
longitudinally over time. Visits will be used as repeated measurement. If the visit by 
treatment arm interaction term is not significant, it will be deleted from the model and the 
treatment difference will be used to make inference on the treatment effect. Otherwise, an 
estimate of the mean difference across time will be used to make the inference on the 
treatment effect. Compound Symmetry covariance structure will be used for this analysis. 
95% CI for the difference between treatment arms will be presented at each visit. 
7. All scores will be listed, and those assessments performed later than 30 days after the last 
date of study treatment will be flagged in the listings. 
11.8.2.2. EQ-5D-5L 
The analyses mentioned for EORTC QLQ-C30 will be performed for EQ-5D-5L. 
The Mixed model with repeated measures will be used on the VAS score only. 
11.9. 
Secondary Objective 2 
To assess the potential immunogenicity of tafasitamab (anti-tafasitamab antibody formation) for 
the patients in the immunogenicity analysis set (IAS). 


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11.9.1. 
Analysis of Immunogenicity 
The below described analysis will be performed in the IAS. 
In order to determine the patient's anti-tafasitamab antibody status, as a first step, a screening 
assay will be performed. Then all screened positive samples will be tested again in a 
confirmatory assay. For all confirmed positive samples the following additional assays will be 
done: a semi-quantitative ADA titer will be determined, the specificity towards 
MOR00208-hIgG1 or MOR00208-hIgG1/2a will be determined, a neutralizing antibody assay 
(nAb) will be performed. 
Anti-tafasitamab antibody samples are defined as "negative" if they are screened or confirmed 
negative. Anti-tafasitamab antibody samples are defined as "positive" if they are reported 
positive in both the screening and the confirmatory assay. For all positive samples, 
anti-tafasitamab antibody titer, specificity of the ADA response and neutralizing potential will be 
determined. 
1. The result of the anti-tafasitamab antibody assessment (including specificity and nAb 
results) will be listed by patient for each anti-tafasitamab sample collected, including 
immunogenicity time points and date and time of collection.  
2. The number and percentage of patients in the following categories will be tabulated by 
visit:  
Patient has positive anti-tafasitamab antibodies (yes/no/missing): 
− yes, if a titre is available 
− no, if result is reported as "Negative" 
− missing, if anti-tafasitamab measurement is not available 
3. In addition, the number and percentage of patients who develop anti-tafasitamab 
antibodies will be tabulated using the following categories: 
− Patients with pre-existing anti-tafasitamab antibodies (i.e. patients who are 
positive for anti-tafasitamab antibodies on cycle 1 day 1). 
− Patients without anti-tafasitamab antibodies after treatment initiation (i.e. patients 
who are negative for anti-tafasitamab antibodies on all occasions after cycle 1 
day 1, irrespective of the baseline result). 
− Patients with anti-tafasitamab antibodies after treatment initiation (i.e. patients 
who are positive for anti-tafasitamab antibodies on any occasion after cycle 1 
day 1). 
− Patients with treatment-induced anti-tafasitamab antibodies (i.e. patients who are 
negative for anti-tafasitamab antibodies on cycle 1 day 1 and positive on any 
other occasion). 
− Patients with treatment-boosted anti-tafasitamab antibodies (i.e. patients who are 
positive for anti-tafasitamab antibodies on cycle 1 day 1 and who developed an 
increased titer on any other occasion). 


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4. Summary Statistics (n, mean, StD, median, minimum, maximum) of semi-quantitative 
anti-tafasitamab antibody titer determinations of confirmed positive samples assessments 
will be tabulated by visit. 
11.10. 
Secondary Objective 3 
To assess the pharmacokinetic (PK) profile of tafasitamab for the patients in the PK Analysis 
Set. 
11.10.1. 
PK Analysis 
Individual plasma samples for the analysis of tafasitamab PK will be collected on various study 
days from patients in the tafasitamab treatment group. For evaluation of PK metrics, a patient 
subsample will be taken who have at least one quantifiable tafasitamab serum concentration (the 
PK analysis set, PKAS). 
Tafasitamab concentration values for each serum sample are to be determined using a validated 
Ligand Binding Assay. A separate bioanalytical phase plan and report will be generated that 
provide details on samples handling and processing, methods used for sample analysis, 
statements on quality control/quality assurance (QC/QA) and results of each individual sample 
analysed for each patient by the bioanalytical labs. 
The following elapsed time will be calculated for each record: 
• Elapsed time from the first administration of tafasitamab [days]: Date/time of 
assessment – date/time of the first administration of tafasitamab 
For samples collected 1 hour after the end of the tafasitamab infusion, results will be excluded 
from summary statistics if the deviation of the actual collection time is beyond ± 15 min from the 
scheduled collection time. Such values will be flagged accordingly in the listing of PK data. 
In the summary statistics and concentration-time profile graph the value of BLQ will be set to 
0 for the cycle 1 day 1 pre-dose assessment as well as for the first BLQ value between two 
tafasitamab administrations or after last tafasitamab administration. BLQ values for other time 
points will be treated as missing data. 
The tafasitamab serum concentration data [µg/mL] will be summarized based on nominal 
(scheduled) sample times using the PKAS population set. Detailed analyses are presented as 
below: 
• Descriptive statistics of tafasitamab concentrations will be tabulated by visit and 
timepoint, including n, n-missing, arithmetic mean, geometric mean, StD, coefficient 
of variation CV (%) and geometric CV (%), median, minimum and maximum. 
• Serum concentration-time profile with mean +/- StD will be visualized across visit 
and timepoint. This will be performed on both original serum concentration value and 
log(serum concentration value). 
• Listings of PK data will be generated to display the patient identifier, cohort, visit, 
date/time of assessment, assessment timepoint, result, elapsed time, flag of collection 
time deviation, reason for undone assessment. The concentration data will be 
presented with maximum three decimals. 




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Moreover, the time to complete response (CR) will be calculated and tabulated for patients 
achieving complete response. The time to complete response (months) is defined as follows: 
[date of assessment of first documented response of CR – start date of study treatment) + 
1]/30.4375 
The time to response will be calculated using the FAS and NKCC-low (FAS) for the INV (local 
assessment) and IRC assessment. 
Censoring rules are similar to those described in Section 10.1.3.2. 
For time to response, patients will be considered with an event at the date of tumour assessment 
when they are assessed as having a Response (Complete or Partial). If the patient does not 
respond to treatment, then they will be censored at the date of their last adequate tumour 
assessment/date of death or progression. 
12.3. 
Tumour Shrinkage Over Time: Assessment of Indicator Lesions 
Listings showing individual lesion sizes over time will be produced for FAS and 
NKCC-Low(FAS). 
13. 
SAFETY EVALUATION 
13.1. 
Adverse Events 
13.1.1. 
Adverse Event (AE) 
A treatment-emergent adverse event (TEAE) is defined as any adverse event reported in the 
following time interval (including the lower and upper limits): 
[date of first administration of any study drug; date of last administration of any study drug + 
30 days] 
An adverse event present prior to the study treatment start but increased in severity during the 
treatment-emergent period, will also be included as TEAE. 
All AEs that occur after the completion of on-treatment phase, that is in the following time 
interval (including the lower and upper limits): 
[date of last administration of study treatment + 30 days + 1; date of study discontinuation] 
will be considered as post-treatment emergent AEs. 
If the start date and time of an AE are partially or completely missing, the AE will be assumed to 
be TEAE if it cannot be definitely shown that the AE did not occur or worsen during the 
treatment emergent period (worst case approach). Missing dates and times will not be replaced. 


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Thus, the following approach will be taken: 
• If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded from TEAE if start day is before day of first treatment or start day is after 
end day of treatment emergent period 
• If start time and day are missing but the start month is complete, an AE will only be 
excluded from TEAE if start month is before month of first treatment or start month 
is after end month of treatment emergent period or if stop date/time is before start of 
first treatment 
• If start day and months are missing but the start year is complete, an AE will only be 
excluded from TEAE if start year is before year of first treatment or if start year is 
after end year of treatment emergent period or if stop date/time is before start of first 
treatment 
• If start date is completely missing, an AE will not be excluded from TEAE unless the 
stop date/time is before start of first treatment 
If the last date of study treatment is missing, on-treatment assessments/events include any 
assessment/event recorded in the database and which occur after the start date of study treatment. 
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be reported by primary system organ class (SOC) and preferred term (PT). 
Severity of adverse events will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE). 
The causal relationship of all AEs to the study drug will be judged as either suspected or not 
suspected. A suspected causal relationship means at least a reasonable possibility that the event 
is caused by the study drug. If no relationship has been provided by the Investigator, the event 
will be considered as suspected to the study drug. 
13.1.2. 
Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) for tafasitamab are: 
• Tumour lysis syndrome (TLS) 
• Second primary malignancy (SPM) 
• Infusion-related reactions (IRRs) ≥ Grade 3 
• Allergic reactions to study drug ≥ Grade 3 
• Cytokine release syndrome 
• Overdoses (defined as exceeding the planned dose by >20%) 


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13.1.3. 
General Rules for AE Reporting 
The following rules will be applied to AE tables: 
• All safety analyses will be done using the Safety Analysis Set (SAF) and will be 
presented by treatment arm. 
• AEs will be summarised by SOC and PT using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 26 and will be updated to the most current version at 
the end of the trial. The SOCs and PTs will be used for tabulation. 
• AE frequency tables will display the number of patients experiencing an event and 
the percentage of patients with the event by System Organ Class (SOC) and Preferred 
Term (PT), i.e. will display n (%). 
13.1.4. 
Adverse Event Summaries 
An overall summary of AEs by treatment arms in SAF and SAF NKCC-Low subgroup will 
include the following: 
• Number (%) of patients who had any TEAEs 
• Number (%) of patients who had any serious TEAEs 
• Number (%) of patients who had any Grade 3 or higher TEAEs 
• Number (%) of patients who had any fatal TEAEs 
• Number (%) of patients who had any study treatment-related TEAEs 
• Number (%) of patients who had any study treatment-related serious TEAEs 
• Number (%) of patients who had any study treatment-related Grade 3 or higher 
TEAEs 
• Number (%) of patients who had any study treatment-related fatal TEAEs 
• Number (%) of patients who had any monoclonal antibody–related TEAEs 
• Number (%) of patients who had any monoclonal antibody–related serious TEAEs 
• Number (%) of patients who had any monoclonal antibody–related Grade 3 or higher 
TEAEs 
• Number (%) of patients who had any monoclonal antibody–related fatal TEAEs 
• Number (%) of patients who had any bendamustine-related TEAEs 
• Number (%) of patients who had any bendamustine-related serious TEAEs 
• Number (%) of patients who had any bendamustine-related Grade 3 or higher TEAEs 
• Number (%) of patients who had any bendamustine-related fatal TEAEs 
• Number (%) of patients who has any TEAEs leading to discontinuation of study 
treatment 


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• Number (%) of patients who has any TEAEs leading to discontinuation of 
monoclonal antibody 
• Number (%) of patients who has any TEAEs leading to discontinuation of 
bendamustine 
The following summary tables showing number (%) of patients will be provided by treatment 
arms in SAF and SAF NKCC-Low subgroup. 
• Summary of TEAEs by MedDRA SOC and PT 
• Summary of TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of TEAEs by MedDRA SOC, PT, and maximum severity 
• Summary of Grade 3 or higher TEAEs by MedDRA SOC and PT 
• Summary of Grade 3 or higher TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of serious TEAEs by MedDRA SOC and PT 
• Summary of serious TEAEs by MedDRA PT in decreasing order of frequency 
• Summary of TEAEs related to COVID-19 by MedDRA SOC, PT, and maximum 
severity 
• Summary of study treatment-related TEAEs by MedDRA SOC and PT 
• Summary of monoclonal antibody–related TEAEs by MedDRA SOC and PT 
• Summary of bendamustine-related TEAEs by MedDRA SOC and PT 
• Summary of study treatment-related TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of monoclonal antibody–related TEAEs by MedDRA PT in decreasing 
order of frequency 
• Summary of bendamustine-related TEAEs by MedDRA PT in decreasing order of 
frequency 
• Summary of study treatment-related TEAEs by MedDRA SOC, PT, and maximum 
severity 
• Summary of monoclonal antibody–related TEAEs by MedDRA SOC, PT, and 
maximum severity 
• Summary of bendamustine-related TEAEs by MedDRA SOC, PT, and maximum 
severity 
• Summary of Grade 3 or higher study treatment–related TEAEs by MedDRA SOC and 
PT 
• Summary of Grade 3 or higher monoclonal antibody–related TEAEs by MedDRA 
SOC and PT 


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• Summary of Grade 3 or higher bendamustine-related TEAEs by MedDRA SOC and 
PT 
• Summary of study treatment-related serious TEAEs by MedDRA SOC and PT 
• Summary of monoclonal antibody–related Serious TEAEs by MedDRA SOC and PT 
• Summary of bendamustine-related Serious TEAEs by MedDRA SOC and PT 
• Summary of TEAEs with a fatal outcome by MedDRA SOC and PT 
• Summary of TEAEs leading to study treatment dose reduction by MedDRA SOC and 
PT 
• Summary of TEAEs leading to monoclonal antibody dose reduction by MedDRA 
SOC and PT 
• Summary of TEAEs leading to bendamustine dose reduction by MedDRA SOC and 
PT 
• Summary of TEAEs leading to study treatment dose interruption by MedDRA SOC 
and PT 
• Summary of TEAEs leading to monoclonal antibody dose interruption by MedDRA 
SOC and PT 
• Summary of TEAEs leading to bendamustine dose interruption by MedDRA SOC 
and PT 
• Summary of TEAEs leading to discontinuation of study treatment by MedDRA SOC 
and PT 
• Summary of TEAEs leading to discontinuation of monoclonal antibody by MedDRA 
SOC and PT 
• Summary of TEAEs leading to discontinuation of bendamustine by MedDRA SOC 
and PT 
• Summary of treatment-emergent AESIs by MedDRA SOC and PT 
• Summary of treatment-emergent AESIs by MedDRA PT in decreasing order of 
frequency 
• Summary of study treatment-related AESIs by MedDRA SOC and PT 
• Summary of monoclonal antibody–related AESIs by MedDRA SOC and PT 
• Summary of bendamustine-related AESIs by MedDRA SOC and PT 
• Summary of treatment-emergent AESIs by MedDRA SOC, PT, and maximum 
severity 
• Summary of Grade 3 or higher treatment-emergent AESIs by MedDRA SOC and PT 
• Summary of post-treatment serious AEs by MedDRA SOC, PT, and maximum 
severity 


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• Summary of post-treatment AESIs by MedDRA SOC, PT, and maximum severity 
• Summary of TEAEs by demographic characteristics subgroup (age: < 65 years, 
≥ 65 years, < 75 years, ≥ 75 years; sex: male, female; race: white, Asian, other) 
Deaths in SAF and SAF NKCC-Low subgroup will be summarized by treatment arm as follows: 
• On-treatment deaths (deaths observed between first administration of study treatment 
and 30 days after last administration of study treatment) in total and grouped by: 
− Deaths related to AE: All on-treatment deaths with at least one Grade 5 AE in the 
Adverse Event eCRF. 
− Deaths unrelated to AE: All on-treatment deaths with no Grade 5 AE in the 
Adverse Event eCRF. These deaths can be considered to be related to the 
underlying disease. 
• Post-treatment deaths (deaths observed after 30 days after last administration of study 
treatment) overall and grouped by: 
− Deaths related to AE: All post-treatment deaths with at least one Grade 5 AE in 
the Adverse Event eCRF. These deaths can be considered related to AE suspected 
to be related to the study drug. 
− Deaths unrelated to AE: All post-treatment deaths with no Grade 5 AE in the 
Adverse Event eCRF. These deaths may be due to AEs not suspected to be related 
to study drug, underlying disease, or other reasons. 
• Total number of deaths (All deaths (On-treatment + post treatment) are included) 
overall and grouped by: 
− Deaths related to AE 
− Deaths unrelated to AE 
Pre-treatment deaths on enrolled patients will be summarized. A pre-treatment death is one 
which occur between informed consent and date of first administration of study treatment. 
13.2. 
Vital Signs 
13.2.1. 
Vital Sign Variables 
The Vital Signs captured in the eCRF for each patient are the following: 
• Weight (All Visits) 
• Height (Only Screening Visit) 
• BSA 
• Systolic Blood Pressure (All Visits) 
• Diastolic Blood Pressure (All Visits) 
• Heart Rate (All Visits) 
• Respiratory Rate (All Visits) 


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• Temperature (All Visits) 
• Overall interpretation of Vital Signs (All visits) 
13.2.2. 
Vital Sign Analysis 
The following analysis will be performed on these variables: 
• These variables will be summarized by visit by means of descriptive statistics of 
actual values and change from baseline. 
• Overall interpretation of Vital Signs will be tabulated to present the corresponding 
frequency count and percentage at each visit. 
• The normal ranges for the vital sign variables are: 
− Systolic blood pressure: 90-155 mm Hg, 
− Diastolic blood pressure: 60-100 mm Hg, 
− Heart rate: 
▪ 50-110 beats per minute 
▪ ≤ 50 and decrease from Baseline of ≥ 25% 
▪ ≥ 120 and increase from Baseline of ≥ 25% 
− Respiratory rate: 10-30 breaths per minute 
− Body temperature: 36.0-37.5 C 
Number and frequency count of patients outside the normal range will be presented 
by visit. 
• Vital Signs will be listed by visit and abnormal value will be flagged to show whether 
it is a value below or above the normal limit. 
The analysis will be performed on SAF and will be presented by treatment arm. Listings will be 
provided with information on NKCC at baseline (low vs high). 
13.3. 
Physical Examination 
Baseline and End of Treatment Full Physical Examinations will be summarized by body system. 
New and worsening abnormal physical examination findings during the study will be entered as 
AEs and analysed within the AE tables. 
Limited Physical Examination performed at all visits other than baseline and EOT will be 
summarized by descriptive statistics. 
The analysis will be performed on SAF and will be presented by treatment arm. Listings will be 
provided with information on NKCC at baseline (low vs high). 


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13.4. 
Electrocardiogram (ECG) 
13.4.1. 
ECG Variables 
The Electrocardiogram variables captured in the eCRF for each patient at each visit are the 
following: 
• QRS Interval, 
• RR Interval, 
• PR Interval, 
• QT Interval, 
• QTcB: Bazett's correction for QT given by 𝑄𝑇𝑐𝐵=
𝑄𝑇𝑚𝑎𝑥
√𝑅𝑅, where RR=60/heart rate, 
• QTcF: Fridericia's correction for QT given by 𝑄𝑇𝑐𝐹=
𝑄𝑇𝑚𝑎𝑥
3√𝑅𝑅, where RR=60/heart 
rate, 
• Overall Interpretation of 12 Lead ECG tracing 
13.4.2. 
ECG Analysis 
The following analysis will be performed on these variables: 
• Overall interpretation of 12 Lead ECG tracing will be tabulated to present the 
corresponding frequency count and percentage at each visit. 
• These variables will be summarized by visit by means of descriptive statistics of 
actual values and change from baseline. 
• The normal ranges for the ECG variables are: 
− PR interval: 120-200 ms  
− QRS interval: 80-100 ms 
− RR interval: 600-1200 ms 
− QT interval (also corrected): ≤ 460 ms 
• As recommended in the FDA guidance on clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs (FDA 2005), 
the number and percentage of patients having notable ECG interval values will be 
summarized by treatment arm as follows in Table 13-1: 
Table 13-1: 
Clinically Notable ECG Values 
ECG Parameter (unit) 
Clinically Notable Criteria 
QTcF (ms) 
New > 450 ms  
New > 480 ms  
New > 500 ms 
Increase from Baseline > 30 ms 
Increase from Baseline > 60 ms  
PR duration (ms) 
Increase > 25% from Baseline and to PR duration > 200 ms 
QRS duration (ms) 
Increase > 25% from Baseline and to QRS duration > 110 ms  


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• All assessments will be listed and those collected outside of the treatment window 
will be flagged. 
The summaries will include only assessments on treatment. 
The analysis will be performed on SAF and will be presented by treatment arm. Listings will be 
provided with information on NKCC at baseline (low vs high). 
13.5. 
Laboratory Data 
13.5.1. 
Laboratory Variables 
Laboratory measured in the central laboratory parameters can be separated into 
• Hematology 
• Serum Chemistry 
• Coagulation parameters 
• Serology, Hepatitis B (HbsAg, HbsAbs, anti-Hbc) 
• Serology, Hepatitis C 
• Serum pregnancy test 
• Urinalysis 
• Flow Cytometry Biomarker 
• FcgR Polymorphism (Optional) 
13.5.2. 
Grading of Laboratory Data 
Laboratory data grades of severity will be derived according to the Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03. A severity grade of 0 will be assigned when the 
value is within normal limits. The laboratory values for which CTCAE grades are defined for 
only one direction of deviation (e.g., platelet count) will be assigned grade 0 in case a laboratory 
value is outside the normal limits, but in a direction for which CTCAE grading is not defined. 
In the case when a local laboratory normal range overlaps into the higher (i.e. non-zero) CTCAE 
grade, the CTCAE grade will be taken. Grade 5 will not be used. Lab values having hyper or 
hypo shifts will be classified into the same CTCAE grades irrespective of the shift direction (no 
differentiation between CTCAE grades due to increased, or decreased lab values). 
For laboratory tests for which grades of severity are not defined by CTCAE, results will be 
presented by the low/normal/high classifications based on laboratory normal ranges. 
For duplicate laboratory measurements taken at the last assessment date on or before the start 
date of study treatment, the value of lower CTCAE grade will be considered as the baseline 
value. 
In some cases when several records taken at the last assessment date on or before the start date of 
study treatment have the same absolute grade, but in different directions, 2 baselines should be 


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created, the record with grade below 0 should be the baseline of the 'Hypo' parameter, and the 
other record should be the baseline for the 'Hyper' parameters. 
For non-gradable labs with duplicate laboratory measurements taken at the last assessment date 
on or before the start date of study treatment: 
• If both within normal range: take average value 
• If one within normal range and the other outside: take the one within normal range 
• If both outside normal range: take the one closest to the normal range 
Laboratory values with missing units or normal range may not be able to be graded or included 
in laboratory tables. 
13.5.3. 
Laboratory Analysis 
Laboratory data that are continuous in nature but are less than the lower limit of quantitation or 
above the upper limit of quantitation will be imputed. The limit of quantitation will be used for 
calculation of descriptive statistics if the data is reported in the form of "≤ x" or "< x" or "≥ x" 
(x is considered as the limit of quantitation). 
The following analysis on Laboratory parameters will be performed: 
• Laboratory parameters will be summarised by treatment arm. Descriptive summaries 
of actual (absolute) values and change-from-baseline values will be presented for 
haematology and serum chemistry for the safety population by treatment and visit. SI 
units will be used in the generation of these descriptive summaries. The assessment of 
categorical urinalysis variables will be tabulated by treatment and time point for each 
urine parameter. 
• Abnormal values will be flagged to indicate whether the value is below or above the 
reference range and whether investigator´s assessed the abnormal value as clinically 
significant. A clinically significant result can be commented with "Adverse Event", 
"Due to primary disease", "Pre-existing condition and not worsened due to CTCAE 
4.03" or free text. 
• The assessment of the clinical significance of laboratory variables will be tabulated 
by treatment and time point for each clinical laboratory analyte. 
• For each laboratory parameter, shifts in assessments from baseline to worst-post 
baseline will be presented. 
• If NCI-CTCAE grades are available for a clinical laboratory analyte, they will be 
derived according to NCI-CTCAE, Version 4.03 or higher and used to present 
additional frequency and shift tables based on NCI-CTCAE grades. 
The following summary will be produced for the laboratory data (by laboratory parameter): 
− Number (%) of patients with worst post-baseline CTCAE grade (regardless of the 
baseline status). Each patient will be counted only for the worst grade observed 
on-treatment  


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− Shift tables to compare baseline to the worst post-baseline value will be produced 
for hematology and biochemistry laboratory parameters using: 
▪ CTCAE grades for laboratory parameters where CTCAE grades are defined 
▪ The classifications relative to the laboratory reference ranges 
(low/normal/high) for laboratory parameters where CTCAE grades are not 
defined 
• For each urine parameter shifts in assessments from baseline to worst-post baseline 
value will be presented if possible (shift tables). 
• All data will be listed. Laboratory values that are outside the reference range will also 
be flagged in the data listings, along with the corresponding reference ranges. The 
laboratory assessments collected outside the on-treatment period will be flagged in 
the listings.  
• The following listing will be produced for: 
− Listing of all laboratory data with values flagged to show the corresponding 
CTCAE grades and the classifications relative to the laboratory reference ranges 
The summaries will include only assessments on treatment. 
The analysis will be performed on SAF and will be presented by treatment arm. Listings will be 
provided with information on NKCC at baseline (low vs high). 
13.6. 
Performance Status (ECOG) 
13.6.1. 
ECOG Scores 
Performance status is assessed to attempt to quantify the impact of disease on daily life activities 
of patients. 
ECOG PS scale is used to assess physical health of patients, ranging from 0 (most active) to 
5 (least active): 
Table 13-2: 
ECOG Performance Status 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 


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13.6.2. 
ECOG Scores Analyses 
The analysis will be performed on FAS and will be presented by treatment arm. 
The following analyses will be performed on ECOG scores: 
• The ECOG performance status will be summarized categorically in a frequency table 
by visit and treatment arm. 
• Shift Tables in ECOG status from baseline to worst-post baseline will be presented. 
• The ECOG status will be listed. 
13.7. 
B-Symptoms 
B-symptoms are defined as any one or more of the following disease-related symptoms or signs: 
• Unintentional weight loss of ≥ 10% within the preceding 6 months or less 
• Fever of >100.5 F or 38 C for at least 3 consecutive days without evidence of 
infection 
• Drenching night sweats without signs of infection 
The presence of B-symptoms will be summarized categorically in a frequency table by visit and 
treatment arm.  
The analysis will be performed on FAS and will be presented by treatment arm. 
Data listings with information on NKCC at baseline (low vs high) will be presented. 
13.8. 
Exposure 
See Section 8.9. 
14. 
CHANGES FROM THE PROTOCOL 
Baseline summary table will be on FAS and NKCC-Low (FAS) and instead of on FAS and SAF. 
This will provide baseline summary statistics for patients in efficacy analyses dual primary 
endpoints. 
The incidence rate of AEs in selected AE categories will not be presented with 95% CIs based on 
the number of patients and the number of AEs. 
15. 
GENERAL GUIDANCE ON REPORTING 
15.1. 
Document Headers 
The following header will be used for all tables, listings and figures outlined in this document: 
MOR208C204 – reporting event (Cut-off date ddMONyyyy). 


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The following labels of reporting event will be used for all outputs: 
• IA  
for Interim Analysis 
• FA  
for Final Analysis 
The following display will be used for outputs: 
- footnote 1 
- footnote 2 
- footnote 3 
program source, date and version information. 
For example: 
MOR208C204 - CSR (Cut-off date: 06JUN2014) 
"/report/pgm_saf/program.sas 07MAY14:15:27" 
In the applicable outputs, the MedDRA version and WHO-DDE version used for reporting the 
study will be specified as a footnote. 
- MedDRA Version <xx.x> has been used for the reporting  
- WHO-DDE Version <xx.x> has been used for the reporting 
The latest available version of dictionaries at the time of reporting will be used. 
15.2. 
Presentation of Output Numbering and Titles Within This Document 
In practice, the numbering and title for all tables, figures and listings in Sections 14 and 16 
defined in this document will be formatted as follows, respectively: 
 
Table XX.X-X.X 
Title Title Title Title Title Title 
Population 
 
Listing XX.X-X.X 
Title Title Title Title Title Title 
Population 
15.3. 
Treatment Arm Labels and Ordering 
The following treatment labels will be used for all tables and figures in the order provided here: 
• Treatment A = Tafa + BEN 
• Treatment B = Rituximab + BEN 
An 'Overall' column will only be presented in tables summarizing demographic and other 
baseline characteristics, to give an overview of the patient population used in the study, and in 
additional selected tables as appropriate, such as summaries of gap analysis and follow-up times. 


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15.4. 
Presentation of Analysis Sets 
The outputs to be produced based on this document will use 'Screened Patients', ''Enrolled 
Patients', FAS', "PPS', "SAF', "PKAS', 'IAS" in the table/figure/listing titles. 
15.5. 
General Rules for Presenting Frequencies and Percentages 
If a summary table displays only categorical variables then the convention illustrated in the 
following example will be used: 
However, if a summary table displays both continuous and categorical variables than the 
convention illustrated in the following example will be used: 
15.6. 
General Rule for Tables/Listings 
All other data as documented in the eCRF will be listed and/or tabulated using descriptive 
statistics or counts/percentages depending on the nature of data. 
All the data collected and derived in the trial will be presented in patient data listings. 
15.7. 
Tables/Listings With No Data 
Where a listing or table has been planned, but no data meet the criteria, then a single line stating 
'No data meeting the criteria are present' will be provided in the output. 
Preferred Term 
Treatment A 
N=xx 
  n (%) 
Treatment B 
N=xx 
  n (%) 
Total 
xx (xx.x) 
xx (xx.x) 
 
 
 
Fatigue 
xx (xx.x) 
xx (xx.x) 
Nausea 
xx (xx.x) 
xx (xx.x) 
Anemia 
xx (xx.x) 
xx (xx.x) 
 
Treatment A 
N=xx 
Treatment B 
N=xx 
Overall 
N=xx 
Sex, n (%) 
 
 
 
  Male 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Female 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Age (Years) 
 
 
 
   n 
xx 
xx 
xx 
   Mean 
xx.x 
xx.x 
xx.x 
   SD 
xx.xx 
xx.xx 
xx.xx 
   Median 
xx.x 
xx.x 
xx.x 
   Minimum 
xx.x 
xx.x 
xx.x 
   Maximum 
xx.x 
xx.x 
xx.x 


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The default tables, listings and figures (TLF) layout will be as follows. 
Orientation 
Landscape 
Paper Size 
A4 
Margins 
Top: 2 cm  
Bottom: 2 cm 
Left: 2 cm 
Right: 2 cm 
Header: 1.27 cm 
Footer: 1.27 
Font 
Courier New 8pt 
Headers 
Protocol number – Type of Analysis (cut-off date) (Left); Page X of Y (Right) 
TLF Number and Title 
Footers 
SAS program name 
Source Data 
File name 
Extract date  
Date, Time TLF generated 
The font size may be reduced as necessary to allow additional columns to be presented but not at 
the expense of clarity. Also the orientation may be changed to portrait if appropriate. 
CRF data collected will be presented within data listings. The data listings will be sorted by 
treatment arm, site number, patient number, visit, and time point. 
15.8. 
Precision Rules 
For continuous variables, minimum and maximum will be presented to the same precision as the 
raw data. Mean, median, 25th and 75th percentiles will be presented to one more decimal place 
and standard deviation to two more decimal places than the raw data. Geometric mean will be 
presented to one more decimal place than the raw data. CV of mean and CV of geometric mean 
will be shown to one decimal place. 
For concentrations and PK parameters 3 significant digits applies for mean, geometric mean, 
median, standard deviation, min and max. Elapsed time and Tmax should have 2 decimal places 
in the listings. 
For categorical variables, the number (n) and percentage (%) of patients per category will be 
presented. If the count is zero in a cell, then only '0' count will be presented and not '0.0 (0.0). 
The number of missing values will be presented as a "Missing" category. Percentage values are 
to be rounded and presented to one decimal place. If percentages are equal to 100, then 0 decimal 
places will be presented 'xx (100)'. 
The confidence intervals of a percentage will be presented to the same precision as the 
percentage. The p-values will be presented with three decimals. P-values below 0.001 will be 
denoted as <0.001. Hazard ratios and respective confidence intervals will be presented to two 
decimal places. 
15.9. 
General Rules for Presenting Listings 
The following general rules for presenting listings should be applied by default for all listings. 


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For listings, the default sorting order is by patient number and event/assessment date unless 
otherwise stated. 
The first column of the listing will always be "Patient identifier". 
Where a listing or table has been planned, but no data meet the criteria, then a single line stating 
'No data meeting the criteria are present' will be provided in the output. 
The study day will always be displayed in the listings. It will be printed under the label 'Day' in 
all listings. The definition of study day is: 
The reference start date for all safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, etc.) will be the start date of 
study treatment. The following footnote will be added in all safety listings: "Day is relative to the 
first day of study treatment (Day 1)". 
The reference start date for all efficacy assessments (e.g. tumour assessment, death, disease 
progression, tumour response, performance status, patient-reported outcomes (PROs)) will be the 
randomization date. The following footnote will be added in all efficacy listings: "Day is relative 
to randomization date (Day 1)". 
For data collected at the visit level: 'Visit' column will be displayed in the listings. Unscheduled 
visits will appear as "Unsch" (or similar) in all the listings, if any. 
For all laboratory parameters, SI units are used as default. 
When a variable collected in the eCRF is linked to another variable, one or both variables will be 
presented in the same column of the listing. 
For example: 
• 'Setting'='OTHER' and 'Other, specify'='Lung' 
− "OTHER: Lung" will be displayed in the column as 'Setting'. 
• 'Dose'='120' and Dose unit ='mg' 
− '120 mg' will be displayed in the column as 'dose (unit)' 
• Date = "12MAY2012" and Study day ="5" 
− "12MAY2012 / 5" will be displayed in the column as 'Date /[Study Day]' 
• End date = "22MAY2012" and Study day ="15" or End date = " " and ongoing is 
ticked: 
− "22MAY2012 / 15" will be displayed in the column as 'End date /[Study Day]' 
− "Ongoing" will be displayed in the column as 'End date / /[Study Day]'. 
15.10. 
Presentation of Dates 
Calendar dates and times (optional) in all the listings will be displayed in the format: 
DDMMMYYYY Thh:mm:ss e.g. 15JAN2011 T10:20:23. 
Note: If time is not collected, calendar dates will be displayed as: DDMMMYYYY. 


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16. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. 
J Clin Oncol 2007;25:579-586. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 1934;26:404-413. 
Ellis S, Carroll KJ, Pemberton, K. Analysis of duration of response in oncology trials. Contemp 
Clin Trials 2008;29:456-465. 
FDA. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 2005. 
Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I error 
probability spending functions. Stat Med 1990;9:1439-1445. 
Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab 
in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 
2013;31:2103-2109. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Spiessens B, Debois M. Adjusted significance levels for subgroup analyses in clinical trials. 
Contemp Clin Trials 2010;31:647-656. 
Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with 
rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol 
2014;93:403-409. 
Wassmer G. Planning and analyzing adaptive group sequential survival trials. Biom J 
2006;48:714-729. 


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17. 
APPENDICES 
17.1. 
Appendix A: Response Criteria for Malignant Lymphoma 
(Cheson et al 2007) 
The response criteria in this study are those defined in the table below. All of them are based on 
the International Working Group response criteria (Cheson et al 2007). 
Definition of Response Criteria 
Response 
Definition 
Nodal masses 
Spleen, liver 
Bone marrow 
CR 
Disappearance of all 
evidence of disease 
a) FDG-avid or PET positive 
prior to therapy; mass of 
any size permitted if PET 
negative 
b) Variable FDG-avid or 
PET negative; regression 
to normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared 
on repeat biopsy; if 
indeterminate by 
morphology, 
immunohisto-
chemistry should 
be negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in SPD of up 
to 6 largest dominant masses; 
no increase in size on CT 
a) FDG-avid or PET positive 
prior to therapy; one or 
more PET positive at 
previously involved site 
b) Variable FDG-avid or 
PET negative; regression 
on CT 
≥50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if 
positive prior to 
therapy; cell type 
should be specified 
SD 
Failure to attain 
CR/PR or PD 
a) FDG-avid or PET 
positive prior to therapy; 
PET positive at prior 
sites of disease and no 
new sites on CT or PET 
b) Variable FDG-avid or 
PET negative; no change 
in size of previous 
lesions on CT 
 
 
Relapsed 
disease or 
PD 
Any new lesion or 
increase by ≥50% of 
previously involved 
sites from nadir 
Appearance of a new 
lesion(s) >1.5 cm in any axis, 
≥50% increase in SPD of 
more than one node, or ≥50% 
increase in longest diameter 
of a previously identified 
node >1 cm in short axis 
Lesions PET positive if 
FDG-avid lymphoma or PET 
positive prior to therapy 
>50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
Abbreviations: CR = complete response; FDG = [18F]fluorodeoxyglucose; PET = positron emission tomography; CT = 
computed tomography; PR = partial response; SPD = sum of the product of the diameters; SD = stable disease; PD = 
progressive disease. 


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17.2. 
Appendix B: ECOG Performance Status (Oken et al 1982) 
ECOG Performance Status 
Scale Grades 
Performance status 
0  
Fully active, able to carry on all pre-disease performance without restriction 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2  
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3  
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4  
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5  
Dead 
Source: Oken et al 1982. 
17.3. 
Appendix C: Statistical Method for Expected Duration of Response 
Following Ellis et al 2008 
The comparison of the duration of response in responding patients between treatment groups can 
lead to bias since the groups are defined by the post-treatment outcome. With this regard, 
Ellis et al (2008) proposed an approach of comparing the mean or expected duration of response 
(EDoR) across all patients between the treatment groups and allow a formal comparative 
analysis. 
Define the following quantities: 
𝑥
= duration of response,
𝑝
= probability of response,
𝑔(𝑥)
= probability density function of 𝑥,
𝑓𝑝(𝑥)
= probablity density function of 𝑥 in responding patients,
𝑓1−𝑝(𝑥)
= probability density function of 𝑥 in non −responding patients, and
𝐸𝑠(𝑥)
= expection over s(x).
 
Then 𝑔(𝑥) can be expressed as a mixture distribution 
𝑔(𝑥) = 𝑝𝑓𝑝(𝑥) + (1 −𝑝)𝑓1−𝑝(𝑥) 
and the EDoR is given as 
𝐸𝑔(𝑥) = 𝑝𝐸𝑓𝑝(𝑥) + (1 −𝑝)𝐸𝑓1−𝑝(𝑥). 
Define the duration of response in non-responding patients as zero, then 𝑥= 0 with probability 1 
and 𝑓1−𝑝(𝑥) = 0 for 𝑥> 0. Thus 𝐸𝑓1−𝑝(𝑥) = 0 and EDoR reduces to 𝐸𝑔(𝑥) = 𝑝𝐸𝑓𝑝(𝑥), which is 
the product of the estimated fraction of patients with a response and the mean duration of 
response in responding patients. 
Let 𝑝𝐸=
𝑟𝐸
𝑁𝐸 and 𝑝𝐶=
𝑟𝐶
𝑁𝐶 denote the proportion of patients responding (𝑟𝐸, 𝑟𝐶) in the 
experimental (𝑁𝐸) and the control (𝑁𝐶) group, respectively. Note that 𝑁𝐸 and 𝑁𝐶 are defined as 


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all patients in each group, also including patients who have neither responded nor progressed. 
Furthermore, denote 𝑀𝐸 and 𝑀𝐶 as the true mean duration of response in responding patients in 
the experimental and control arm, respectively. 
For the comparison of the experimental arm (E) tafasitamab+ Bendamustine with the control arm 
(C) Rituximab + Bendamustine, the following hypothesis are tested: 
𝐻0: 𝑅= EDoR𝐸
EDoR𝐶
= 1  vs. 𝐻1: 𝑅= EDoR𝐸
EDoR𝐶
≠1, 
where the ratio 𝑅 is defined as 𝑅=
EDoR𝐸
EDoR𝐶=
𝑝𝐸𝑀𝐸
𝑝𝐶𝑀𝐶. The corresponding test statistic on the 
log-scale is given as 
𝑧=
log(𝑅^)
√Var
ˆ (log(𝑅^))
, 
which can be compared with a standard Normal (0,1) distribution. The estimations in the test 
statistics are obtained as follows: 
log(𝑅^) = log(
𝑝^
𝐸
𝑝^
𝐶
) + log(𝑀^
𝐸
𝑀^
𝐶
) 
and 
Var
ˆ (log(𝑅^)) =
1 −𝑝^
𝐸
𝑁𝐸 𝑝^
𝐸
+
1 −𝑝^
𝐶
𝑁𝐶 𝑝^
𝐶
+ 1
𝑀^
𝐸
2 Var
ˆ (𝑀^
𝐸) + 1
𝑀^
𝐶
2 Var
ˆ (𝑀^
𝐶). 
The last two terms of the equation above represent the variance of the estimated ratio of mean 
response durations in responding patients and applies when each treatment group is examined 
separately. These estimations depend on underlying assumptions for the probability density 
function𝑓𝑝(𝑥). The mean response duration for each treatment arm (i.e., the expected durations 
of response) will be derived from a parametric Weibull survival function.