Clinical trial NCT04002401
Conditions: Refractory Large B-cell Lymphoma
Sponsor: Kite, A Gilead Company
Start date: 2019-11-05; Completion date: 2023-01-30
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to estimate the efficacy of axicabtagene ciloleucel in combination with rituximab, as measured by assessment of response rates in adult participants with relapsed/refractory large B-cell lymphoma.

Detailed description:
Following at least 24 months of assessments after axicabtagene ciloleucel infusion, participants will be asked to rollover to a separate long-term follow-up study (Study KT-US-982-5968). Participants will complete the remainder of the 15-year follow-up assessments in the KT-US-982-5968 study.

Arms: arm 1: Participants will receive rituximab 375 mg/m\^2, once on Day -5 along with conditioning chemotherapy (fludarabine 30 mg/m\^2 over 30 minutes and cyclophosphamide 500 mg/m\^2 over 60 minutes) once on Days -5 to -3, followed by axicabtagene ciloleucel 2 x 10\^6 anti-cluster of differentiate 19 (CD19) chimeric antigen receptor (CAR) T cells/kg once on Day 0 and additional rituximab 375 mg/m\^2 of 5 doses, once every 28 days starting from Day 21 up to Day 133.
Interventions: intervention 1: Axicabtagene Ciloleucel intervention 2: Rituximab intervention 3: Fludarabine intervention 4: Cyclophosphamide
Intervention descriptions: intervention 1: A single infusion of CAR-transduced autologous T cells administered intravenously intervention 2: Administered intravenously intervention 3: Administered according to package insert intervention 4: Administered according to package insert

Protocol documents:
SAP_002.pdf: 
 
 
 
 
T R A N S L A TI O N A L  S T A TI S TI C A L  A N A L Y SI S  P L A N  K T -U S - 4 7 1- 0 1 1 4 ( Z U M A- 1 4) 
 
S p o ns o r:  
Kit e  P h ar m a, I n c.  
2 4 0 0  Br o a d w a y 
S a nt a  M o ni c a,  C A  9 0 4 0 4 
U nit e d  St at es  of  A m eri c a  
P r o d u ct  N a m e:  
K T E -C 1 9  
P r ot o c ol : 
K T -U S -4 7 1 -0 1 1 4  
A  P h as e  2  O p e n -L a b el,  M ulti c e nt er  St u d y  E v al u ati n g t h e  
S af et y  a n d  Effi c a c y  of  A xi c a bt a g e n e  Cil ol e u c el i n 
c o m bi n ati o n  wit h  Rit u xi m a b i n  S u bj e cts  wit h  R efr a ct or y  L ar g e 
B -C ell  L y m p h o m a ( Z U M A -1 4)  
P r ot o c ol  V e rsi o n  N u m b e r 
a n d  D at e:  
A m e n d m e nt  4,  8  J U L2 0 2 0 
T S A P  R el e as e  D at e:   
2 5  JU N 2 0 2 1  
R e pl a c es  P r e vi o us 
V e rsi o n(s):  
V ersi o n  1 
 
 
 
 
C O N FI D E N TI A LI T Y  N O TI C E  
T his  d o c u m e nt  c o nt ai ns  c o nfi d e nti al i nf or m ati o n  of  Kit e  P h ar m a I n c.,  a  w h oll y  o w n e d 
s u bsi di ar y  of  Gil e a d  S ci e n c es I n c.   T his  d o c u m e nt  m ust  n ot  b e  dis cl os e d t o  a n y o n e  ot h er t h a n 
t h e sit e r es e ar c h st aff  a n d  m e m b ers  of t h e I nstit uti o n al  R e vi e w  B o ar d/I n d e p e n d e nt  Et hi cs 
C o m mitt e e,  a s ci e ntifi c r e vi e w  b o ar d  or  a n  e q ui v al e nt.   T h e i nf or m ati o n i n t his  d o c u m e nt 
c a n n ot  b e  us e d f or  a n y  p ur p os e  ot h er t h a n t h e  c o n d u ct  of t h e  cli ni c al i n v esti g ati o n  wit h o ut t h e 
pri or  writt e n  c o ns e nt  of  Kit e  P h ar m a I n c.   Q u esti o ns r e g ar di n g  h o w t his  d o c u m e nt s h o ul d  b e 
us e d  or t h e  c o n d u ct  of t h e  cli ni c al tri al s h o ul d  b e  dir e ct e d t o t h e  k e y s p o ns or  c o nt a cts.  
 
 
 
  
 
 




A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  3 
 
2 5 J u n e  2 0 2 1  
LI S T  O F  T A B L E S  
T a bl e   3-1.  
D at a  o v er vi e w  o n  ass a y  m et h o ds  a n d  bi o m ar k er lists  .............................................................. 7 
T a bl e   6-1.  
N o n -p ar a m etri c  C o m p aris o ns  ................................................................................................. 1 6  
T a bl e   8-1.  
A n al yti c  Visit  Wi n d o ws f or  C A R  T  C ells (i n  c o m bi n ati o n  wit h  Rit u xi m a b) i n  Bl o o d  .......... 1 9  
T a bl e   8-2.  
A n al yti c  Visit  Wi n d o ws f or  Rit u xi m a b i n  Bl o o d  ................................................................... 2 0  
T a bl e   8-3.  
A n al yti c  Visit  Wi n d o ws f or  C yt o ki n es i n  S er u m  ................................................................... 2 0  
 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  4 
 
2 5 J u n e  2 0 2 1  
LI S T  O F  A B B R E VI A TI O N S  
A E  
A d v ers e  e v e nt  
A S C T  
A ut ol o g o us st e m  c ell tr a ns pl a nt  
A U C  
Ar e a  u n d er t h e  c ur v e  
C A R  
C hi m eri c  a nti g e n r e c e pt or  
CI  
C o nfi d e n c e  I nt er v al 
C R  
C o m pl et e r es p o ns e /  C o m pl et e  R e missi o n  
C R S  
C yt o ki n e r el e as e s y n dr o m e  
C S F  
C er e br os pi n al fl ui d  
D L B C L  
Diff us e l ar g e  B  c ell l y m p h o m a  
 
 
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  
I H C 
I m m u n o hist o c h e mistr y 
I Q R 
Int er q u artil e r a n g e  
mI T T 
M o difi e d i nt e nt -t o-tr e at 
N E  
N e ur ol o gi c  e v e nt  
N H L  
N o n -H o d g ki n  L y m p h o m a  
P A  
Pri m ar y  A n al ysis  
P B M C  
P eri p h er al  bl o o d  m o n o n u cl e ar  c ells  
P D  
Pr o gr essi v e  dis e as e  
P K  
P h ar m a c o ki n eti c  
P R  
P arti al r es p o ns e  
q P C R  
q u a ntit ati v e  p ol y m er as e  c h ai n r e a cti o n  
R C R  
R e pli c ati o n  c o m p et e nt r etr o vir us  
S A E  
S eri o us  a d v ers e  e v e nt  
S D  
St a bl e  dis e as e  
S O A  
S c h e d ul e  of  ass ess m e nts  
T S A P 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
W B C  
W hit e  Bl o o d  C ell  a n d  als o  c all e d  L e u k o c yt es ( u nit:  1 0 ^ 9/ L)  
 
C CI






A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  7 
 
2 5 J u n e  2 0 2 1  
3.   
E N D P OI N T S,  S U B G R O U P S  A N D  C O V A RI A T E S  
3. 1.   
Bi o m a r k e r  d at as ets  
T a bl e   3- 1.    
D at a  o v e r vi e w  o n  ass a y  m et h o ds  a n d  bi o m a r k e r lists 
D at a t y p e  
Ass a y 
m et h o d/  
S a m pl e t y p e   
Ass ess m e nt ti m e  p oi nts  
Bi o m a r k e r s et  
 C A R  T  P K (i n 
c o m bi n ati o n  wit h 
Rit u xi m a b)   
q P C R/ P B M C   
L e u k a p h er esis , D a y  7, 
1 4,  2 1,  2 8,  4 9,  1 0 5,  a n d 
1 8 0  
N u m b er  of  C A R  T  c ells (/ µ L)  
Rit u xi m a b  P K  
G yr ol a b 
i m m u n o ass a y 
/s er u m 
D a y  - 5, 2 1,  4 9,  7 7,  1 0 5, 
1 3 3  
S er u m rit u xi m a b l e v el  ( n g/ m L) 
P h ar m a c o d y n a mi c  
d at a ( c yt o ki n es)  
C yt o ki n e 
ass a y/s er u m  
( M S D,  E L L A, 
L u mi n e x)  
-  L e u k a p h er esis,  D a y  -
5  0,  1,  3,  5,  7,  1 4,  2 1, 
2 8,  4 9   
-  Bl o o d  dr a w f or 
c h e mistr y  p a n el  
-  Bl o o d  dr a w f or  C R P, 
f erriti n 
•   
R ef er t o  a p p e n di x  8. 5  
M R D  
N G S -b as e d 
Mi ni m u m 
R esi d u al 
Dis e as e  ass a y 
S cr e e ni n g,  D a y  2 8,  1 0 5, 
1 8 0  
•   M R D  +  or  – 
•   Fr e q u e n c y  of s e q u e n c e  wit hi n I g H  of I g L 
p o p ul ati o n  
Pr o d u ct 
c h ar a ct eristi cs   
Fl o w 
C yt o m etr y  
 
•   T ot al  N u m b er  of  T  C ells,   
•   T ot al  N u m b er  of  C A R  T  C ells,   
•   T ot al  n u m b er  of  T n ai v e  c ells  
•   Tr a ns d u cti o n  R at e ( %),   
•   C D 4/ C D 8  R ati o,   
•   %  a n d  n u m b er  of  T n ai v e / Tc m / Te m / Teff  
i n  vi a bl e  C D 3  c ells 
•   ( %  T n ai v e  +  %  T  c e ntr al  m e m or y) / ( % 
T  eff e ct or  m e m or y  +  %  T  eff e ct or  c ells)  
R ati o , 
•   I F N-g a m m a l e v el ( p g/ ml),   
•   V e ct or  C o p y  N u m b er ,  
•   %  vi a bilit y ,  
•   C D 4  C ells ( %  a n d  n u m b er ),  
•   C D 8  C ells ( %  a n d  n u m b er ),   
•   C C R 7 + ( T n ai v e  +  T c m)   % a n d  n u m b er ,  
•   C C R 7 - ( Te m  +  T eff )  %,  
•   T ot al  n u m b er  of  C C R 7 +  T  c ells i nf us e d  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  8 
 
2 5 J u n e  2 0 2 1  
D at a t y p e  
Ass a y 
m et h o d/  
S a m pl e t y p e   
Ass ess m e nt ti m e  p oi nts  
Bi o m a r k e r s et  
C A R -T  c ell 
p h e n ot y p e 
( P B M C) if  d at a is 
a v ail a bl e  
Fl o w 
c yt o m etr y  
 
•   C A R +  T  c ells ( %  a n d  n u m b er ): 
-  
C D 4  T  n aï v e/ T c m /T e m /T eff  c ells ( %); 
P D -1 +;  TI M 3 +;  L A G 3 +;  C D 2 8 +; 
C D 2 7 +,  4 1 B B +.  
-  
C D 8  T  n aï v e /T c m /T e m /T eff  c ells  ( %); 
P D -1 +;  TI M 3 +;  L A G 3 +;  C D 2 8 +; 
C D 2 7 +,  4 1 B B +  
•   C A R -  T c ells ( n e g ati v e) ( %  a n d n u m b er ):  
-  
C D 4  T  n aï v e /T c m /T e m /T eff  c ells  ( %); 
P D -1 +;  TI M 3 +;  L A G 3 +;  C D 2 8 +; 
C D 2 7 +,  4 1 B B +.  
-  
C D 8  T  n aï v e /T c m /T e m /T eff  c ells  ( %); 
P D -1 +;  TI M 3 +;  L A G 3 +;  C D 2 8 +; 
C D 2 7 +,  4 1 B B +  
C C R 7 : C h e m o ki n e  R e c e pt or  7 ; I F N: I nt erf er o n; T c m : C e ntr al  M e m or y  T -c ell  p h e n ot y p e ; T eff : Eff e ct or  T -c ell  p h e n ot y p e ; T e m : 
Eff e ct or  M e m or y  T -c ell  p h e n ot y p e;  T n aï v e : N aï v e  T -c ell  p h e n ot y p e   
3. 2.   
E n d p oi nt s 
T h e f oll o wi n g  p h ar m a c o ki n eti c  e n d p oi nts f or  a nti -C D 1 9  C A R  T  a n d rit u xi m a b   a n d 
p h ar m a c o d y n a mi c  e n d p oi nts  f or  3 3  a n al yt es ( A p p e n di x  X) will  b e i n cl u d e d f or t h e  a n al ysis 
list e d i n s e cti o n  2. 1  a n d  2. 2.  D et ail e d  d efi niti o ns  c a n  b e f o u n d i n  S e cti o n 4 . 
•   F ol d  c h a n g e fr o m  b as eli n e  at  D a y  X ( c yt o ki n e  a n al yt es) 
•   F ol d  c h a n g e fr o m  D a y  0  ( pr e-d os e)  at  D a y  X  ( c yt o ki n e  a n al yt es) 
•   P e a k ( C m a x)   ( a nti-C D 1 9  C A R  T  a n d rit u xi m a b  P K)  
•   Ti m e t o  p e a k  ( a nti-C D 1 9  C A R  T  a n d rit u xi m a b  P K)  
Ar e a - U n d er- C ur v e (D a y  0  t o  2 8 f or a nti -C D 1 9  C A R  T  P K;  D a y - 5 t o  1 3 3 f or  rit u xi m a b  P K) 
All  m e as ur a bl e  v al u es  at  e a c h  visit  will  b e  us e d  as  m ai n  e n d p oi nts f or  all  bi o m ar k ers list e d i n 
T a bl e   3- 1 as f oll o wi n g  
•   L e v els  of  a nti -C D 1 9  C A R  T  c ells i n  bl o o d s a m pl es  m e as ur e d  as  a nti -C D 1 9  C A R +  c ells/ µ L 
b y  visit,  p e a k,  D a y  0- 2 8  A U C,  a n d ti m e t o  p e a k ( d et ails f or t h e  d eri v ati o ns  ar e i n cl u d e d i n 
t h e  d efi niti o n s e cti o n) 
•   L e v els  of rit u xi m a b i n  bl o o d s a m pl es  m e as ur e d  as  n g/ m L  b y  visit ( pr e  a n d  p ost),  p e a k  
( m a xi m u m  v al u e  b et w e e n  D a y - 5 t o  1 3 3), A U C ( D a y  - 5 t o  1 3 3) 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  9 
 
2 5 J u n e  2 0 2 1  
•   L e v els  of  c yt o ki n es i n s er u m  b y  visit, f ol d  c h a n g e fr o m  b as eli n e,  D a y  0,  p e a k,  D a y  0- 2 8 
A U C,  a n d ti m e t o  p e a k 
•   Pr o d u ct  attri b ut es  m e as ur e m e nts  aft er  pr o d u ct  m a n uf a ct uri n g  a n d  pri or t o  d osi n g. 
3. 3.   
O ut c o m e s,  S u b g r o u ps,  a n d  C o v a ri at es 
1)   O bj e cti v e r es p o ns e:  r es p o n d er ( C R/ P R)  vs.  n o n-r es p o n d er *;  C R  vs.  P R  vs.  C R + P R  vs.  n o n-
r es p o n d er * 
2)   O n g oi n g r es p o n s e:  o n g oi n g r es p o ns e  vs. r el a ps e d  vs  n o n-r es p o nd er * 
3)   B est r es p o ns e:  c o m pl et e  res p o ns e ( C R)  vs.  p arti al  r es p o ns e ( P R)  vs. st a bl e  dis e as e ( S D)  vs. 
pr o gr essi v e  dis e as e ( P D) ;  C R  vs.  P R  vs.  n o n-r es p o n d er * 
4)   W orst  N e ur ol o gi c  e v e nt  ( N E)  gr a d e: gr a d e  3  or  hi g h er  vs.  gr a d e  2  or l o w er 
5)   W orst  N E  gr a d e:  gr a d e  2  or  hi g h er  vs.  gr a d e  1  or l o w er 
6)   W orst  c yt o ki n e r el e as e  s y n dr o m e ( C R S)  gr a d e:  gr a d e  3  or  hi g h er  vs.  gr a d e  2  or l o w er 
7)   W orst  C R S  gr a d e:  gr a d e  2  or  hi g h er  vs.  gr a d e  1  or l o w er 
8)   B as eli n e  c o v ari at es  will  b e  utili z e d  w h e n  a p pr o pri at e:  
a)   R efr a ct or y  s u b gr o u p ( pri m ar y r efr a ct or y, r efr a ct or y t o  2 n d  or  gr e at er li n e t h er a p y, 
refr a ct or y  aft er  a ut ol o g o us st e m  c ell tr a ns pl a nt [ A S C T ]) 
b)   B as eli n e  c o v ari at es  
i)  a g e ( < 6 5  vs.  > = 6 5  y e ars)  
ii)  ra c e  ( Asi a n,  W hit e,  Ot h er) 
iii) e t h ni cit y ( His p a ni c  or  L ati n o  vs.  N ot  His p a ni c  or  L ati n o) 
i v) g e n d er  ( F e m al e  vs.  M al e) 
c)   C orti c o st er oi d ( Y es  vs.  N o) 
d)   T o cili z u m a b  us e ( Y es  vs.  N o)  
e)   B as eli n e t u m or  b ur d e n ( S P D  i n  m m ^ 2)  q u artil e/ m e di a n s u b gr o u ps 
f)  Ot h er  b as eli n e  c o v ari at es if  a p pli c a bl e  
* N o n -r es p o n d er is  d efi n e d  as s u bj e cts  w h o  h a d  n eit h er  C R  n or  P R  b y t h e  a n al ysis  d at a 
c ut off.  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 0  
 
2 5 J u n e  2 0 2 1  
4.   
D E FI NI TI O N S  
4. 1.   
G e n e r al  
St u d y  D a y  0  is d efi n e d  as t h e  d a y t h e s u bj e ct r e c ei v e d t h e first  K T E -C 1 9  i nf usi o n.   T h e  d a y 
pri or t o st u d y  d a y  0  will  b e st u d y  d a y  − 1.   A n y  d a ys  aft er  e nr oll m e nt  a n d  pri or t o st u d y  d a y  − 1 
will  b e s e q u e nti al  a n d  n e g ati v e i nt e g er - v al u e d. 
4. 2.   
K e y  M e as u r e m e nts  of   Ph a r m a c o ki n eti cs  
4. 2. 1.   
A nti -C D 1 9  C A R +  T -C ell  
T h e  e x p a nsi o n  a n d  p ersist e n c e  of  a nti - C D 1 9  C A R  T  c ells i n  p eri p h er al  bl o o d  will  b e  m e as ur e d 
b y  q u a ntit ati v e  p ol y m er as e  c h ai n r e a cti o n ( q P C R ) a n al ysis.  
B as eli n e   v al u e f or t h e n u m b er  of  a nti - C D 1 9  C A R  T i n  bl o o d ( c ells/ µ L) is d efi n e d  as  0 si n c e 
K T E - C 1 9 is i nf us e d  o n  D a y  0. 
S c h e d ul e d  bl o o d  d r a w f o r  a nti -C D 1 9  C A R  T  c ell  
T his  T S A P  will f o c us  o n t h e  a nti -C D 1 9  C A R  T  c ell  d at a  c oll e ct e d  as  p er  pl a n n e d  ass ess m e nt. 
T h e s c h e d ul e  of  ass ess m e nts  a n d t h e  a n al yti c  visit  wi n d o ws  ar e  d ef i n e d i n  A p p e n di x  S e cti o n 8. 1 . 
N u m b e r  of  a nti -C D 1 9  C A R  T  ( c ells/ u L  bl o o d)  is  d efi n e d  as: 
( A bs ol ut e  M o n o c yt es  +  A bs ol ut e L y m p h o c yt es)  * % C A R + P B M C  
N ot e:  u nit   c o n v e rsi o ns f o r  a bs ol ut e  m o n o c yt es  a n d l y m p h o c yt es will  n e e d t o  b e  c o nsi d e r e d  
w h e n  c al c ul ati n g t h e  n u m b e r  of  a nti -C D 1 9  C A R  T  c ell s ( c ells/ u L  bl o o d)  usi n g t h e f o r m ul a 
a b o v e. 
P e a k  of  a nti -C D 1 9  C A R  T  c ell ( c ells/  u L  bl o o d)  is  d efi n e d  as t h e  m a xi m u m  a bs ol ut e  n u m b er 
of  a nti- C D 1 9  C A R  T  c ells i n s er u m  att ai n e d  aft er  D a y  0.  
Ti m e -t o-P e a k  of  a nti - C D 1 9  C A R  T  c ell ( d a ys) is  d efi n e d  as  “ P e a k  D at e –  K T E -C 1 9  D osi n g 
D at e  +  1 ”.  
D a y  0 - 2 8  A U C  of l e v el  of  a nti -C D 1 9  C A R  T  c ell ( c ells/  u L  ▪  d a ys) is  d efi n e d  as t h e  ar e a 
u n d er t h e  c ur v e i n  a  pl ot  of l e v els  of  a nti- C D 1 9  C A R  T  c ells  a g ai nst s c h e d ul e d  visits fr o m  D a y  0 
t o  Da y  2 8.  T his  A U C  m e as ur es t h e t ot al l e v els  of  a nti - C D 1 9  C A R  T  c ells  o v erti m e.  Gi v e n t h e 
a nti- C D 1 9  C A R  T  c ell is  m e as ur e d  at  c ert ai n  dis cr et e ti m e  p oi nts, t h e tr a p e z oi d al r ul e  will  b e 
us e d t o  esti m at e t h e  A U Cs.  
4. 2. 2.   
Rit u xi m a b  P h a r m a c o ki n eti cs  
T h e  e x p a nsi o n  a n d  p ersist e n c e  of  rit u xi m a b i n  p eri p h er al  bl o o d  will  b e  m e as ur e d  b y  G yr ol a b 
i m m u n o ass a y a n al ysis.  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 1  
 
2 5 J u n e  2 0 2 1  
S c h e d ul e d  bl o o d  d r a w f o r  rit u xi m a b  
T his  T S A P  will f o c us  o n t h e rit u xi m a b  d at a  c oll e ct e d  as  p er  pl a n n e d  ass ess m e nt   b ef or e  a n d  aft er 
e a c h i nf usi o n  of  Rit u xi m a b .  T h e s c h e d ul e  of  ass ess m e nts  a n d t h e  a n al yti c  visit  wi n d o ws  ar e 
d efi n e d i n  A p p e n di x  S e cti o n  8. 2 . 
P e a k  of  r it u xi m a b i n bl o o d  ( n g/ m L) is  d efi n e d  as t h e  m a xi m u m l e v el  of rit u xi m a b ( n g/ m L) i n 
Bl o o d fr o m  B as eli n e ( D a y  - 5  pr e  d os e) t o  D a y  1 3 3 ( p ost  d os e). 
Ti m e t o  p e a k  is  d efi n e d  as t h e  n u m b er  of  d a ys fr o m  D a y  0 (K T E - C 1 9 i nf usi o n d at e)  t o t h e  d at e 
w h e n t h e rit u xi m a b i n  Bl o o d firstl y r e a c h e d  t h e  p e a k. 
A U C  of  rit u xi m a b i n  bl o o d ( n g/ m L ▪  d a ys) is  d efi n e d  as t h e  ar e a  u n d er t h e  c ur v e i n  a  pl ot  of 
l e v els  of rit u xi m a b i n  Bl o o d ( n g/ m L)  a g ai nst s c h e d ul e d  visits fr o m  B as eli n e ( D a y - 5 t o 
D a y   1 3 3). 
4. 3.   
K e y  M e as u r e m e nts  of  P h a r m a c o d y n a mi cs:  S e r u m  C yt o ki n es,  C h e m o ki n es 
a n d  ot h e r  Bl o o d  Bi o m a r k e rs  
S c h e d ul e d  bl o o d  d r a w f o r  c yt o ki n es:  
T his  T S A P   will f o c us  o n t h e  c yt o ki n e  d at a  c oll e ct e d fr o m  b as eli n e t o  D a y  2 8.  T h e  S c h e d ul e  of 
Ass ess m e nt  a n d  a n al y ti c  visit  wi n d o w is  d efi n e d i n A p p e n di x  S e cti o n  8. 3 . 
B as eli n e  of  c yt o ki n es  is  d efi n e d  as t h e l ast  v al u e  m e as ur e d  pri or t o  c o n diti o ni n g  c h e m ot h er a p y. 
F ol d  c h a n g e f r o m  b as eli n e  at  D a y  X  is  defi n e d  as  
C yt o ki n e l e v el  at  D a y  X
C yt o ki n e l e v el  at  B as eli n e  
P e a k  of  c yt o ki n e  p ost  b as eli n e  is  d efi n e d  as t h e  m a xi m u m l e v el  of  c yt o ki n e i n s er u m  att ai n e d 
aft er  b as eli n e  u p t o  D a y  2 8. 
Ti m e t o  p e a k  of  c yt o ki n e  p ost  K T E -C 1 9  i nf usi o n is  d efi n e d  as  “ P e a k  D at e –  K T E -C 1 9  D osi n g 
D at e  +  1 ”.  
A U C  of  c yt o ki n e l e v els f r o m  b as eli n e t o  D a y  2 8 : is  d efi n e d  as t h e  ar e a  u n d er t h e  c ur v e i n  a  pl ot 
of l e v els  of  c yt o ki n e  a g ai nst s c h e d ul e d  visits fr o m  b as eli n e t o  D a y  2 8.  T his  A U C  m e as ur es t h e 
t ot al l e v els  of  c yt o ki n e b et w e e n  b as eli n e   a n d  d a y  2 8.  Gi v e n t h e  c yt o ki n e is m e as ur e d  at  c ert ai n 
dis cr et e ti m e  p oi nts, t h e tr a p e z oi d al r ul e  will  b e  us e d t o  esti m at e t h e  A U Cs.  
4. 4.   
K e y  M e as u r e m e nts  of  P r o d u ct  C h a r a ct e risti cs  
•   All  pr o d u ct  c h ar a ct eristi cs  as  d efi n e d i n  T a bl e   3- 1 will  b e s u m m ari z e d i n di vi d u all y  a n d  als o 
f or t h e  c orr el ati v e  a n al ysis  wit h  a nti- C D 1 9  C A R  T l e v els i n  bl o o d, s er u m  a n al yt e l e v els,  a n d 
cli ni c al   o ut c o m e  e n d p oi nts. 
•   T w o  a d diti o n al  c o- v ari at es  will  b e  d eri v e d f or  e x pl or ati o n:  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 2  
 
2 5 J u n e  2 0 2 1  
   C D 4/ C D 8  R ati o  is  d efi n e d  as: 
C D 4 +  C ell s   ( % )
C D 8 +  C ell s   ( % ) 
   C C R 7 + i n ( %)  o r ( #)  is d efi n e d  as:  N ai v e ( %)  or ( #)  +  C e ntr al  M e m or y ( %)  or ( #), 
r es p e cti v el y 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 3  
 
2 5 J u n e  2 0 2 1  
5.   
A N A L Y SI S  S E T S  
•   M o difi e d i nt e nt- t o-tr e at ( mI T T)  a n al ysis s et  c o nsists  of  all s u bj e cts  e nr oll e d  a n d tr e at e d  wit h 
t h e t ar g et  d os e  of  a xi c a bt a g e n e  cil ol e u c el  at  2  x  1 06  C A R  T  c ells/ k g ( 1. 0  x  1 06 t o  2. 4  x  1 06 
a nti  C D 1 9  C A R  T  c ells/ k g)  a n d  at l e ast  o n e  d os e  of  Rit u xi m a b  aft er  a xi c a bt a g e n e  cil ol e u c el 
i nf usi o n. S u bj e cts  ar e  c o nsi d er e d t o  h a v e r e c ei v e d t h e t ar g et  d os e if t h e y r e c ei v e  at l e ast  1  x  1 0 6  
a nti - C D 1 9  C A R  T  c ells/ k g. T his  a n al ysis s et  will  b e  us e d f or  all  effi c a c y  a n al ys es  a n d 
Rit u xi m a b  P K  a n al ys es. 
•   S af et y  a n al ysis s et  c o nsists  of  all s u bj e cts tr e at e d  wit h  a n y  d os e  of  a xi c a bt a g e n e  cil ol e u c el.  
T his  a n al ysis s et  will  us e d t o  e x pl or e t h e  ass o ci ati o n  b et w e e n  bi o m ar k er  d at a  wit h s af et y 
o ut c o m es. 
G e n er all y, t his  T S A P  will  utili z e t h e s a m e  effi c a c y  a n al ysis str at e g y  d es cri b e d  i n t h e S A P , s u c h 
as  a n al ysis s ets  a n d r el at e d  o ut c o m e  d efi niti o ns.  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 4  
 
2 5 J u n e  2 0 2 1  
6.   
S T A TI S TI C A L  A N A L Y SI S  
6. 1.   
G e n e r al  M et h o ds  
T h e f oll o wi n g  m et h o ds  will  b e  a p pli e d t o t h e  d at a  a n al ysis  w h e n  a p pli c a bl e.  All  p -v al u es 
g e n er at e d  will  b e  d es cri pti v e.  
•   S u m m a r y st atisti cs  will s u m m ari z e  d at a i n fr e q u e n c y ( N,  %)  a n d  q u artil e  r a n g e ( Mi ni m u m, 
1 st  q u artil e ( Q 1),  M e di a n,  3r d q u artil e ( Q 3) ,  M a xi m u m) i n  o v er all  a n d  b y  a p pr o pri at e 
s u b gr o u ps  a n d  c o v ari at es ( S e cti o n  3. 3 ). 
•   Si m pl e li n e a r  R e g r essi o n ( S L R)   will  b e  c o n d u ct e d t o  e x pl or e r el ati o ns hi ps  b et w e e n 
bi o m ar k ers  wit h  c o nti n u o us  v al u es  { G el m a n  2 0 0 6 }.  T h e  e sti m at e d sl o p e  a n d its  9 5 % 
C o nfi d e n c e I nt er v al ( CI)  wit h t h e  u n a dj ust e d  p- v al u e  will  b e r e p ort e d. 
•   N o n -p a r a m et ri c  Wil c o x o n  r a n k s u m t ests   
N o n -p ar a m etri c  Wil c o x o n r a n k s u m t ests  { Si e g el  1 9 5 6 , Wil c o x o n  1 9 4 5 }  will  b e  utili z e d t o 
e x pl or e t h e  ass o ci ati o ns  b et w e e n  P K/   P h ar m a c o d y n a mi c ,  pr o d u ct  c h ar a ct eristi cs,  a n d 
o ut c o m es.  U n a dj ust e d  p- v al u es  will  b e r e p ort e d.  T h e  m ulti pli cit y  a dj ust m e nt ( H ol m-
B o nf err o ni st e p - d o w n  m et h o d,  {H ol m  1 9 7 9 , H o m m el  1 9 8 8 }  m a y  b e i m pl e m e nt e d  w h e n 
f urt h er  c h ar a ct eri z ati o n  of  p ot e nti al  ass o ci ati o n ar e i d e n tifi e d  a n d  a dj ust e d  p-v al u es  will  b e 
r e p ort e d.  M e di a n f ol d  c h a n g e  will  b e  utili z e d t o  d es cri b e t h e  diff er e n c es i n t h e  o ut c o m e. 
•   N o n -p a r a m et ri c  K r us k al - W allis t est  
N o n -p ar a m etri c  Kr us k al -W allis t est  { Kr us k al  1 9 5 2 }  will  b e  c o n d u ct e d f or t hr e e  or 
m or e -gr o u p  c o m p aris o n f oll o w e d  b y  p air wis e  c o m p aris o ns  usi n g  D u n n’s t est  wit h  H ol m’s 
a dj ust m e nt  m et h o d  { D u n n  1 9 6 4 }  i m pl e m e nt e d i n t h e ‘ d u n n.t est’  p a c k a g e f or  R. 
•   Cl o p p e r  P e a rs o n  M et h o d  will  b e  us e d t o  c al c ul at e  e x a ct  9 5 %  c o nfi d e n c e i nt er v als f or 
O bj e cti v e  R es p o ns e  R at e ( O R R)  a n d  c o m pl et e r es p o ns e r at e  { Br o w n  2 0 0 2 }. 
6. 2.   
P ri m a r y  A n al ysis 
6. 2. 1.   
S u m m a ri z e  a nti -C D 1 9  C A R  T  c ell  p h a r m a c o ki n eti c  e x p a nsi o n , rit u xi m a b 
P K , a n d s e r u m  c yt o ki n e  ( P h a r m a c o d y n a mi c)  p r ofil e 
•   mI T T  will  b e  us e d f or  Rit u xi m a b  P K  pr ofil e  a n d  S af et y  A n al ysis s et  will  b e  us e d  f or  a nti-
C D 1 9  C A R  T  c ell  pr ofil e.  
•   T h e  M e di a n  Li n e  pl ot  o v er ti m e  wit h i nt er q u artil e r a n g e  (I Q R)  will  b e  pr o d u c e d f or  a nti-
C D 1 9  C A R  T  a n d rit u xi m a b. 
•   A nti -C D 1 9  C A R  T  C ell  pr ofil e  i n  bl o o d ( P K) a n d  A U C  o v er  ti m e  will  b e s u m m ari z e d  usi n g 
s u m m ar y st atisti cs  d es cri b e d i n  S e cti o n  6. 1  i n  o v er all  a n d  b y  b as eli n e  c o v ari at es s p e cifi e d i n 
S e ct i o n 3. 3 . 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 5  
 
2 5 J u n e  2 0 2 1  
•   Si mil arl y,  p h ar m a c o d y n a mi cs  pr ofil e  as  m e as ur e d  b y s er u m  a n al yt e  l e v els  o v erti m e  will b e 
s u m m ari z e d  usi n g s u m m ar y st atisti cs  d es cri b e d i n  S e ct i o n 6. 1  i n  o v er all 
   Pr e -s el e ct e d  k e y s er u m  a n al yt es  as list e d i n  T a bl e   3- 1 will  b e  pr es e nt e d i n t h e  Cli ni c al 
P h ar m a c ol o g y r e p ort.  
6. 2. 2.   
E x pl o r e  ass o ci ati o n  b et w e e n  a nti -C D 1 9  C A R  T , rit u xi m a b  p h a r m a c o ki n eti c , 
s e r u m c yt o ki n e  wit h s af et y  a n d  cli ni c al  o ut c o m es  
•   S af et y  a n al ysis s et  will  b e  us e d f or  e x pl or ati o n  b et w e e n  P K,  a n d  P h ar m a c o d y n a mi c  wit h 
s af et y  o ut c o m es  a n d  mI T T  a n al ysis s et  will  b e  us e d t o  e x pl or e t h e  ass o ci ati o n  b et w e e n  P K , 
a n d  P h ar m a c o d y n a mi c  wit h  effi c a c y  o ut c o m es . 
•   Cli ni c al r es p o ns e  o ut c o m es:  
   R es p o n d er  vs  N o n-r es p o n d er 
   C R  vs  P R  vs  N o n -r es p o n d ers 
   O n g oi n g  R es p o ns e  vs  R el a ps e d  vs  N o n -r es p o n d ers 
•   S af et y  o ut c o m es:  
   N e ur ol o gi c  e v e nt   gr a d e  3  or  hi g h er  vs gr a d e  2  or l o w er 
   N e ur ol o gi c  e v e nt   gr a d e 2  or  hi g h er  vs  gr a d e  1  or l o w er 
   C R S  gr a d e  3  or  hi g h er  vs  gr a d e  2  or l o w er 
   C R S  g r a d e 2  or  hi g h er  vs  gr a d e  1  or l o w er 
•   St atisti c al t ests  ar e list e d i n  T a bl e   6- 1. 
   Wil c o x o n r a n k s u m t est  will  b e  us e d t o  c o m p ar e t h e  P K /s er u m  a n al yt e  pr ofil es  a m o n g t h e 
s u b gr o u ps.  S e e  T a bl e   6- 1 f or  d et ails. 
F or  c o m p aris o ns  a m o n g  C R  vs.  P R  vs.  S D + P D, t h e  Kr us k al- W allis t est  will  b e  c o n d u ct e d. 
F urt h er  p air wis e  c o m p aris o ns  a m o n g t h es e  3  gr o u ps, f oll o wi n g  a si g nifi c a nt  Kr us k al- W allis t es t, 
will  b e  usi n g  D u n n’s t est  wit h  H ol m’s  a dj ust m e nt  m et h o d.  






A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 8  
 
2 5 J u n e  2 0 2 1  
7.   
R E F E R E N C E S  
Br o w n  L D,  C ai  T T,  D as G u pt a  A.  C o nfi d e n c e I nt er v als f or  a  Bi n o mi al  Pr o p orti o n  a n d 
As y m pt oti c  E x p a nsi o ns.  T h e  A n n als  of  St atisti cs  2 0 0 2; 3 0 ( 1): 1 6 0- 2 0 1. 
D u n n  OJ.  M ulti pl e  C o m p aris o ns  Usi n g  R a n k  S u ms.  T e c h n o m etri cs  1 9 6 4; 6 ( 3): 2 4 1- 5 2. 
G el m a n  A ,  Hill J.  Li n e ar r e gr essi o n. I n: G el m a n  A , Hill J ,  e ds.   D at a  A n al ysis  Usi n g  R e gr essi o n 
a n d  M ultil e v el/ Hi er ar c hi c al  M o d els.  5t h  e d.  N e w  Y or k:  C a m bri d g e  U ni v ersit y 
Pr ess;  2 0 0 6:  3 1- 7 7.  
H ol m  S.  A  Si m pl e  S e q u e nti all y  R ej e cti v e  M ulti pl e  T est  Pr o c e d ur e.  S c a n di n a vi a n J o ur n al  of 
St atisti cs  1 9 7 9; 6 ( 2): 6 5 - 7 0. 
H o m m el  G.  A  St a g e wis e  R ej e cti v e  M ulti pl e  T est  Pr o c e d ur e  B as e d  o n  a  M o difi e d  B o nf err o ni 
T est.  Bi o m etri k a  1 9 8 8; 7 5 ( 2): 3 8 3- 6. 
Kr us k al  W H,  W allis  W A.  Us e  of  R a n ks i n  O n e -Crit eri o n  V ari a n c e  A n al ysis. J o ur n al  of t h e 
A m eri c a n  St atisti c al  Ass o ci ati o n  1 9 5 2; 4 7 ( 2 6 0): 5 8 3- 6 2 1. 
Si e g el  S.  T h e  O n e -S a m pl e  R u ns  T est. I n:  M or g a n  C T,  e d.   N o n p ar a m etri c  St atisti cs:  F or t h e 
B e h a vi or al  S ci e n c es.  N e w  Y or k:  M c Gr a w - Hill  B o o k  C o m p a n y, I n c.;  1 9 5 6:  7 5-
8 3.  
Wil c o x o n  F. I n di vi d u al  C o m p aris o ns  b y  R a n ki n g  M et h o ds.  Bi o m etri cs  B ull eti n  1 9 4 5; 1 ( 6): 8 0- 3. 
 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  1 9  
 
2 5 J u n e  2 0 2 1  
8.   
A P P E N DI X  
8. 1.   
D efi niti o n  of  A n al yti c  Visit  Wi n d o ws f o r  C A R  T  C ells i n  Bl o o d  
T a bl e   8- 1.  
A n al yti c  Visit  Wi n d o ws f o r  C A R  T  C ells  (i n  c o m bi n ati o n  wit h 
Rit u xi m a b)  i n  Bl o o d 
A n al yti c  Visit  
T a r g et  D a y  
Visit  Wi n d o w  
C o h o rt 1  
B as eli n e  
L e u k a p h er esis  
L e u k a p h er esis  
D a y  7  
7 
[ 4,  1 0] 
D a y  1 4  
1 4  
[ 1 1,  1 7] 
D a y  2 1  
2 1  
[ 1 8,  2 4] 
D a y  2 8  
2 8  
[ 2 5,  3 8] 
D a y  4 9  
4 9  
[ 3 9,  7 7] 
D a y  1 0 5  
1 0 5  
[ 7 8,  1 4 2] 
D a y  1 8 0  
1 8 0  
[ 1 4 3,  2 2 5] 
M o nt h  9  
2 7 0  
[ 2 2 6,  3 1 5] 
M o nt h  1 2  
3 6 0  
[ 3 1 6,  4 0 5] 
M o nt h  1 5  
4 5 0  
[ 4 0 6,  4 9 5] 
M o nt h  1 8  
5 4 0  
[ 4 9 6,  6 3 0] 
M o nt h  2 4  
7 2 0  
[ 6 3 1,  9 0 0] 
*  
W e  will  c o nti n u o usl y  m a k e  ass ess m e nts f or t h e  P K s a m pl es  at l at er ti m e  p oi nts  a c c or di n g t o t h e  pr ot o c ol.  


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  2 0  
 
2 5 J u n e  2 0 2 1  
8. 2.   
D efi niti o n  of  A n al yti c  Visit  Wi n d o ws f o r  Rit u xi m a b  i n  Bl o o d 
T a bl e   8- 2.  
A n al yti c  Visit  Wi n d o ws f o r  Rit u xi m a b  i n  Bl o o d 
A n al yti c  Visit  
T a r g et  D a y  
Visit  Wi n d o w  
C o h o rt 1  
B as eli n e  
- 5 
< =- 4 
D a y  2 1  
2 1  
[1 8 , 3 5 ] 
D a y  4 9  
4 9  
[ 36 , 6 3 ] 
D a y  7 7  
7 7  
[ 6 4,  9 1] 
D a y  1 0 5  
1 0 5  
[9 2 ,  1 1 9] 
D a y  1 3 3  
1 3 3  
[ 12 0 ,  ) 
 
8. 3.   
D efi niti o n  of  A n al yti c  Visit  Wi n d o ws f o r  C yt o ki n es i n  S e r u m  
T a bl e   8- 3.    
An al yti c  Visit  Wi n d o ws f o r  C yt o ki n es i n  S e r u m  
A n al yti c  Visit  
T a r g et  D a y  
Visit  Wi n d o w  
C o h o rt 1  
B as eli n e  
- 5 
< =- 5 
D a y  0  
0 
0 
D a y  1  
1 
[ 1,  2] 
D a y  3  
3 
[ 3,  4] 
D a y  5  
5 
[ 5,  6] 
D a y  7  
7  
[ 7,  1 0] 
D a y  1 4  
1 4  
[ 1 1,  1 7] 
D a y  2 1  
2 1  
[ 1 8,  2 4] 
D a y  2 8  
2 8  
[ 2 5,  3 8] 
D a y  4 9  
4 9  
[ 3 9,  1 0 5] 
 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  2 1  
 
2 5 J u n e  2 0 2 1  
8. 4.   
Usi n g  T r a p e z oi d al  R ul e t o  A p p r o xi m at e t h e  A r e a  u n d e r  t h e  C u r v e ( A U C) 
 
A U C ≈1
2 (𝑦𝑦0 + 𝑦𝑦1 ) ∙ Δ 𝑥𝑥 + 1
2 (𝑦𝑦1 + 𝑦𝑦2 ) ∙ Δ 𝑥𝑥 + 1
2 (𝑦𝑦2 + 𝑦𝑦3 ) ∙ Δ 𝑥𝑥 + ⋯  
 
 
 
 
  
 


A xi c a bt a g e n e  Cil ol e u c el  K T E - C1 9  
 
Tr a nsl ati o n al  St atisti c al  A n al ysis  Pl a n  
Kit e  P h ar m a, I n c.  
K T -U S -4 7 1 -0 1 1 4 ( Z U M A -1 4)  
Fi n al  
C O N FI D E N TI A L  
P a g e  2 2  
 
2 5 J u n e  2 0 2 1  
8. 5.   
S e r u m  C yt o ki n e  A n al y z e  
 
1   
C R P ( m g/ L)  
2   
C X C L 1 0 ( p g/ m L)  
3   
F erriti n ( n g/ m L)  
4   
Gr a n z y m e  B ( p g/ m L)  
5   
I C A M-1 ( n g/ m L)  
6   
I F N-g a m m a  ( p g/ m L) 
7   
I L-1  R A ( p g/ m L)  
8   
I L-1 0 ( p g/ m L)  
9   
I L-1 5 ( p g/ m L)  
1 0   
I L-2 ( p g/ m L)  
1 1   
I L-2  R  al p h a ( n g/ m L)  
1 2   
I L-6 ( p g/ m L)  
1 3   
I L-7 ( p g/ m L)  
1 4   
I L-8 ( p g/ m L)  
1 5   
T N F  al p h a ( p g/ m L)  
1 6   
V C A M -1 ( n g/ m L)  
1 7   
G M -C S F ( p g/ m L)  
1 8   
I C A M-1 ( p g/ m L)  
1 9   
I L-1 2  P 4 0  ( p g/ m L) 
2 0   
I L-1 7 ( p g/ m L)  
2 1   
I L-2  R  al p h a ( p g/ m L)  
2 2   
I L-4 ( p g/ m L)  
2 3   
I L-2 3 ( p g/ m L)  
2 4   
I L-5 ( p g/ m L  
2 5   
M D C ( p g/ m L)  
2 6   
M C P -1 ( p g/ m L)  
2 7   
M C P -4 ( p g/ m L)  
2 8   
MI P -1  al p h a ( p g/ m L)  
2 9   
S A A ( p g/ m L)  
3 0   
MI P -1  b et a ( p g/ m L)  
3 1   
V C A M -1 ( n g/ m L)  
3 2   
V C A M -1  ( p g/ m L) 
3 3   
V E G F ( p g/ m L)  
  
 

Prot_000.pdf: 


Axicabtagene Ciloleucel 
 
Clinical Protocol 
 
KT-US-471-0114 (ZUMA-14) 
Kite Pharma, Inc. 
CONFIDENTIAL 
Page 2 
18 May 2022 
SPONSOR AND INVESTIGATOR SIGNATURE PAGE 
KITE PHARMA, INC. 
2400 BROADWAY 
SANTA MONICA, CA 90404 
 
STUDY ACKNOWLEDGMENT 
 
A Phase 2 Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Axicabtagene 
Ciloleucel in Combination with Rituximab in Subjects with Refractory Large B-Cell Lymphoma 
(ZUMA-14) 
Amendment 5, 18 May 2022 
This protocol has been approved by Kite Pharma, Inc. The following signature documents this 
approval. 
Signature
Date
INVESTIGATOR STATEMENT 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated. 
I agree to comply with the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Harmonised Tripartite Guideline on Good Clinical 
Practice and applicable national or regional regulations and guidelines. I will provide all study 
personnel under my supervision copies of the protocol and access to all information provided by 
Kite Pharma, Inc. I will discuss this material with them to ensure that they are fully informed 
about the investigational product and the study. 
I agree and will ensure that financial disclosure statements will be completed by: 
 Me (including, if applicable, my spouse, legal partner, and dependent children) 
 Subinvestigators (including, if applicable, their spouse, legal partner, and dependent children) 
at the start of the study and for up to one year after the study is completed. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the conduct of the clinical investigation without prior written consent 
from Kite Pharma, Inc. 
Principal Investigator Name (Printed)
Signature
Date
Site Number
DocuSign Envelope ID: 81F156B9-6CB1-4EA9-B5DE-B7C5E87C6238
PPD
PPD


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 3
18 May 2022
PROTOCOL SYNOPSIS
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
Title:
A Phase 2 Open-Label, Multicenter Study Evaluating the Safety and 
Efficacy of Axicabtagene Ciloleucel in Combination With Rituximab 
in Subjects With Refractory Large B-Cell Lymphoma (ZUMA-14)  
Indication:
Refractory large B-cell lymphoma
Study Design:
This is a Phase 2 open-label, multicenter study evaluating the safety 
and efficacy of axicabtagene ciloleucel in combination with 
rituximab in subjects with refractory large B-cell lymphoma.

Rituximab (375 mg/m2) will be administered on Day –5, for 
1 dose. Fludarabine and cyclophosphamide conditioning will be 
administered on Day –5, Day –4, and Day –3.

Rituximab will also then be administered on Day 21 and will be 
continued for a total of 5 doses after axicabtagene ciloleucel 
infusion at 28-day intervals, for a total of 6 doses of rituximab.

A safety review team (SRT) will review safety data after the first 
6 subjects and again after the first 15 subjects have completed 
28 days of follow-up after axicabtagene ciloleucel infusion. The 
SRT will make recommendations on further study conduct and 
progression to expansion.

A second dosing strategy (Dose Level −1) will be to administer 
rituximab only after axicabtagene ciloleucel infusion. This dose 
level may be explored only if the planned dosing strategy 
(rituximab initiation concurrent with conditioning chemotherapy) 
has an unacceptable rate of toxicity.
For study requirements, refer to the schedule of assessments (SOAs).
Study Objectives: 
Primary Objective

To estimate the efficacy of axicabtagene ciloleucel in 
combination with rituximab, as measured by assessment of 
response rates, in adult subjects with relapsed/refractory large B-
cell lymphoma.


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 4
18 May 2022
Secondary Objectives

To estimate the safety of axicabtagene ciloleucel in combination 
with rituximab, as measured by assessment of adverse event (AE) 
rates, in adult subjects with relapsed/refractory large B-cell 
lymphoma.

To assess the efficacy of axicabtagene ciloleucel and rituximab, 
using additional efficacy endpoints.

To determine levels of axicabtagene ciloleucel expansion and 
persistence in blood (pharmacokinetics [PK]) using chimeric 
antigen receptor (CAR) T-cell polymerase chain reaction (PCR) 
assay, in combination with rituximab. 
Hypothesis:
No formal hypothesis will be tested in this study. The study is 
designed to evaluate safety and efficacy in subjects with refractory 
large B-cell lymphoma treated with axicabtagene ciloleucel in 
combination with rituximab.
Primary Endpoints:

Complete response rate; complete response (CR) per the 
International Working Group (IWG) Lugano Classification 
{Cheson 2014}, as determined by study investigators.
Secondary 
Endpoint(s):

Incidence of AEs and clinically significant changes in safety lab 
values

Objective response rate (ORR; CR + partial response [PR]) per 
the IWG Lugano Classification {Cheson 2014}, as determined by 
study investigators

Duration of response (DOR)

Progression-free survival (PFS) per the IWG Lugano 
Classification {Cheson 2014}, as determined by study 
investigators

Overall survival (OS)

PK (levels of axicabtagene ciloleucel in blood) 
Sample Size: 
Approximately 30 subjects
Study Eligibility:
Refer to Section 5 for a complete and detailed list of inclusion and 
exclusion criteria. 
CCI


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 5
18 May 2022
Treatment:
Conditioning Chemotherapy Treatment:

A conditioning chemotherapy regimen consisting of 
cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day 
will be administered for 3 days prior to axicabtagene ciloleucel 
infusion. Refer to Section 6 for chemotherapy treatment details.
Investigational Products:

Axicabtagene ciloleucel treatment consists of a single infusion of 
CAR transduced autologous T cells administered intravenously at 
a target dose of 2 x 106 anti-CD19 CAR T cells/kg. Refer to 
Section 6 and Section 7.8 for treatment details.

Rituximab treatment, as described in the Study Design.
Procedures:
As outlined in the SOAs, subjects will undergo the following 
procedures: collection of informed consent, medical history; physical 
examination; brain magnetic resonance imaging (MRI); neurological 
examination; Eastern Cooperative Oncology Group (ECOG) 
performance status; bone marrow biopsy and aspirate; disease 
staging, including a baseline positron emission tomography-
computed tomography (PET-CT) scan; and blood draws for lactate 
dehydrogenase levels, complete blood count (CBC), and serum 
chemistries. Subjects will also undergo baseline echocardiogram 
(ECHO) and electrocardiogram (ECG) assessments. Females of 
childbearing potential (FCBP) will undergo medically supervised 
urine or serum pregnancy tests.
Routinely throughout the conduct of the study, all subjects will be 
asked to report concomitant therapies, AEs, and subsequent 
lymphoma therapy. Subjects will undergo routine disease 
assessments as outlined in the SOAs.
For details for all study requirements, refer to Section 7 and the 
SOAs.
Safety Review Team 
(SRT):
An internal SRT, comprising the study sponsor medical monitor, 
drug safety physician, study statistician, and at least 1 active 
investigator, will meet after 6 subjects have completed their 28-day 
disease assessment and again after 15 subjects have completed their 
28-day disease assessment. The SRT will review ongoing safety data 
and will be chartered to make study conduct recommendations based 
on this analysis.


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 6
18 May 2022
Statistical 
Considerations:
No formal hypothesis will be tested in this study. The study is 
designed to evaluate safety and efficacy in subjects with 
relapsed/refractory large B-cell lymphoma treated with axicabtagene 
ciloleucel in combination with rituximab.
The primary efficacy analyses will be conducted on subjects treated 
with axicabtagene ciloleucel and at least 1 dose of rituximab after 
axicabtagene ciloleucel infusion, and safety analyses will be 
conducted on all subjects treated with axicabtagene ciloleucel.
The primary analysis will be conducted when the last subject has had 
the opportunity to be followed to the 6-month disease assessment.
The final analysis will occur when all subjects have had the 
opportunity to be followed for at least 24 months. Subjects treated 
with axicabtagene ciloleucel will be transitioned to the KT-US-982-
5968 study for the remainder of the 15-year Long-term Follow-up 
(LTFU) period. Descriptive estimates of key efficacy and safety 
analyses may be updated to assess the overall treatment profile.


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 7
18 May 2022
Figure 1.
Study Schema
Note: At the end of study KT-US-471-0114, subjects who received an infusion of axicabtagene ciloleucel will complete the remainder of the 15-year follow-up assessments in a 
separate long-term follow-up study, KT-US-982-5968. 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 8
18 May 2022
TABLE OF CONTENTS
SPONSOR AND INVESTIGATOR SIGNATURE PAGE............................................................................................2
PROTOCOL SYNOPSIS................................................................................................................................................3
TABLE OF CONTENTS................................................................................................................................................8
LIST OF IN-TEXT TABLES .......................................................................................................................................10
LIST OF IN-TEXT FIGURES......................................................................................................................................10
LIST OF ABBREVIATIONS.......................................................................................................................................11
1.
OBJECTIVES.......................................................................................................................................................14
1.1.
Primary Objective....................................................................................................................................14
1.2.
Secondary Objectives ..............................................................................................................................14
2.
DISEASE BACKGROUND ................................................................................................................................15
2.1.
Disease Background ................................................................................................................................15
2.2.
Axicabtagene Ciloleucel..........................................................................................................................16
2.3.
Prior Anti-CD19 CAR T-cell Study Designs and Results.......................................................................17
2.4.
Rituximab ................................................................................................................................................17
2.4.1.
Rationale for Anti-CD19 CAR T Cells in Combination with Rituximab .............................17
2.5.
Rationale for Combination Therapy........................................................................................................18
3.
STUDY DESIGN AND RATIONALE................................................................................................................19
3.1.
General Study Design..............................................................................................................................19
3.1.1.
Rituximab Dosing..................................................................................................................19
3.2.
Dosing Rationale .....................................................................................................................................20
3.2.1.
Rationale for Conditioning Chemotherapy ...........................................................................20
3.2.2.
Rationale for Axicabtagene Ciloleucel Dose ........................................................................20
3.2.3.
Rationale for Rituximab Dose...............................................................................................20
3.3.
Participating Sites....................................................................................................................................20
3.4.
Number of Subjects .................................................................................................................................20
3.5.
Replacement of Subjects .........................................................................................................................21
3.6.
Study Duration.........................................................................................................................................21
3.6.1.
Study Duration for Individual Subjects.................................................................................21
3.6.2.
Completion of Study..............................................................................................................21
4.
SUBJECT IDENTIFICATION ASSIGNMENT .................................................................................................22
5.
SUBJECT ELIGIBILITY.....................................................................................................................................23
5.1.
Inclusion Criteria.....................................................................................................................................23
5.2.
Exclusion Criteria....................................................................................................................................25
6.
PROTOCOL TREATMENT................................................................................................................................27
6.1.
Study Treatment ......................................................................................................................................27
6.1.1.
Leukapheresis........................................................................................................................27
6.1.2.
Conditioning Chemotherapy .................................................................................................27
6.1.3.
Axicabtagene Ciloleucel........................................................................................................28
6.1.4.
Rituximab ..............................................................................................................................28
6.1.5.
Concomitant Therapy ............................................................................................................29
6.1.6.
Excluded Medications ...........................................................................................................29
6.1.7.
Subsequent Therapy ..............................................................................................................30
CCI


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 9
18 May 2022
6.1.8.
Axicabtagene Ciloleucel Toxicity Management ...................................................................30
6.1.9.
Rituximab Toxicity Management..........................................................................................31
7.
STUDY PROCEDURES......................................................................................................................................32
7.1.
Informed Consent ....................................................................................................................................32
7.2.
Screening .................................................................................................................................................32
7.2.1.
Rescreening ...........................................................................................................................33
7.3.
Demographic Data...................................................................................................................................33
7.4.
Medical and Treatment History...............................................................................................................33
7.5.
Physical Exam, Vital Signs, and Performance Status .............................................................................33
7.5.1.
Cardiac Function ...................................................................................................................34
7.6.
Neurological Examination.......................................................................................................................34
7.7.
Disease Assessment.................................................................................................................................34
7.7.1.
Imaging..................................................................................................................................34
7.7.2.
Determination of Bone Marrow Involvement .......................................................................35
7.8.
Cell Collection and Axicabtagene Ciloleucel Study Treatment Schedule and Administration ..............35
7.8.1.
Leukapheresis........................................................................................................................35
7.8.2.
Rituximab Administration Prior to Axicabtagene Ciloleucel Infusion .................................36
7.8.3.
Conditioning Chemotherapy and Axicabtagene Ciloleucel Infusion....................................36
7.8.4.
Axicabtagene Ciloleucel Treatment Period...........................................................................40
7.8.5.
Rituximab Administration After Axicabtagene Ciloleucel Infusion.....................................41
7.9.
Laboratory ...............................................................................................................................................42
7.9.1.
Local Laboratory Analysis ....................................................................................................42
7.9.2.
Central Laboratory Analyses.................................................................................................42
7.10.
Post-treatment Assessment Period ..........................................................................................................45
7.11.
Long-term Follow-up Period...................................................................................................................45
7.12.
Post-study Care........................................................................................................................................46
8.
SUBJECT WITHDRAWAL ................................................................................................................................52
8.1.
Reasons for Removal from Treatment ....................................................................................................52
8.2.
Reasons for Removal from Study............................................................................................................53
9.
SAFETY REPORTING........................................................................................................................................54
9.1.
Adverse Events........................................................................................................................................54
9.2.
Reporting of Adverse Events...................................................................................................................54
9.2.1.
Reporting Abnormal Laboratory Findings ............................................................................56
9.3.
Definition of Serious Adverse Events .....................................................................................................56
9.4.
Reporting of Serious Adverse Events......................................................................................................57
9.5.
Reporting Deaths.....................................................................................................................................58
9.6.
Diagnosis Versus Signs and Symptoms ..................................................................................................58
9.7.
Instructions for Reporting Special Situations..........................................................................................58
9.8.
Hospitalization and Prolonged Hospitalization.......................................................................................60
9.9.
Abnormal Vital Sign Values ...................................................................................................................60
9.10.
Safety Review Team................................................................................................................................60
10.
STATISICAL CONSIDERATIONS....................................................................................................................61
10.1.
Hypothesis ...............................................................................................................................................61
10.2.
Study Endpoints.......................................................................................................................................61
10.2.1.
Primary Endpoint...................................................................................................................61
10.2.2.
Secondary Endpoints.............................................................................................................61
10.3.
Sample Size Considerations ....................................................................................................................62
10.4.
Access to Individual Subject Treatment Assignments ............................................................................62
10.5.
Interim Analysis and Early Stopping Guidelines ....................................................................................63
CCI


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 10
18 May 2022
10.6.
Analysis Subsets......................................................................................................................................63
10.7.
Planned Method of Analysis ...................................................................................................................63
10.7.1.
Complete Response Rate.......................................................................................................63
10.7.2.
Objective Response Rate.......................................................................................................63
10.7.3.
Duration of Response ............................................................................................................63
10.7.4.
Progression-free Survival ......................................................................................................64
10.7.5.
Overall Survival.....................................................................................................................64
10.7.6.
Safety.....................................................................................................................................64
10.7.7.
Pharmacokinetics...................................................................................................................64
10.7.8.
Long-term Data Analysis ......................................................................................................64
11.
REGULATORY OBLIGATIONS.......................................................................................................................65
11.1.
Independent Review Board/Independent Ethics Committee...................................................................65
11.2.
Subject Confidentiality............................................................................................................................65
11.3.
Investigator Signatory Obligations..........................................................................................................66
12.
PROTOCOL AMENDMENTS AND TERMINATION .....................................................................................67
13.
STUDY DOCUMENTATION AND ARCHIVING............................................................................................68
14.
STUDY MONITORING AND DATA COLLECTION......................................................................................69
15.
PUBLICATION ...................................................................................................................................................70
16.
REFERENCES.....................................................................................................................................................71
17.
APPENDICES......................................................................................................................................................74
Appendix 1.
International Working Group Lugano Classification ..............................................................75
Appendix 2.
Childbearing Potential and Birth Control................................................................................79
LIST OF IN-TEXT TABLES
Table 1.
Clinical Laboratory Parameters...............................................................................................42
Table 2.
Schedule of Assessments.........................................................................................................47
Table 3.
Long-term Follow-up Assessments for All Subjects...............................................................50
Table 4.
95% and 80% Exact Confidence Intervals Corresponding to Observed CR Rate 
After Treatment of 30 Subjects ...............................................................................................62
Table 5.
5-Point Scale (5PS)..................................................................................................................75
LIST OF IN-TEXT FIGURES
Figure 1.
Study Schema ............................................................................................................................7


Axicabtagene Ciloleucel
Clinical Protocol
KT-US-471-0114 (ZUMA-14)
Kite Pharma, Inc.
CONFIDENTIAL
Page 11
18 May 2022
LIST OF ABBREVIATIONS
ABC
Activated B-cell
ADCC
Antibody-dependent cell mediated cytotoxicity
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aRMMs
Additional Risk Minimization Measures
ASCT
Autologous stem cell transplant
AST
Aspartate aminotransferase
AUC
Area under the curve
CAR
Chimeric antigen receptor 
CBC
Complete blood count
CDC
Complement-dependent cytotoxicity
CLL
Chronic lymphocytic leukemia
CMV
Cytomegalovirus
CNS
Central nervous system
CR
Complete response/remission
CrCl
Creatinine clearance
CRF
Case report form
CRO
Contract Research Organization
CRP
C-reactive protein
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria For Adverse Events
CTEP
Cancer Therapy Evaluation Program
DLBCL
Diffuse large B-cell lymphoma
DOR
Duration of response
DVT
Deep vein thrombosis
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
FAS
Full analysis set
FCBP
Female of childbearing potential
FDA
Food and Drug Administration
FL
Follicular lymphoma


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GCP
Good Clinical Practice
GCB
Germinal center B-cell
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HEENT
Head, ears, eyes, nose, and throat
HGBCL
High-grade B-cell lymphoma
HIV
Human immunodeficiency virus
HLH
Hemophagocytic lymphohistiocytosis
IB
Investigator’s Brochure
IC
Investigator’s choice
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICU
Intensive care unit
ID
Identification
IDSA
Infectious Diseases Society of America
IEC
Independent Ethics Committee
IFN
Interferon
IHC
Immunohistochemistry
IL
Interleukin
IMiD
Immunomodulatory drug
IP
Investigational product
IPM
Investigational Product Manual
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IV
Intravenous
IWG
International Working Group
LTFU
Long-term follow-up
LTFU study
Long term follow study, KT-US-982-5968
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody
mITT
Modified intent-to-treat
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NK
Natural killer
NPT
Nasopharyngeal-throat
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell


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PCR
Polymerase chain reaction
PD
Progressive disease
PET-CT
Positron emission tomography-computed tomography
PFS
Progression-free survival
PK
Pharmacokinetics
PMBCL
Primary mediastinal large B-cell lymphoma
PO
Taken orally
PR
Partial response/remission
qPCR
Quantitative polymerase chain reaction
RCR 
Replication-competent retrovirus
REMS
Risk Evaluation and Mitigation Strategy
RMP
Risk Management Plan
SAE
Serious adverse event
scFv
Single-chain variable fragment
SCT
Stem cell transplant
SD
Stable disease
SmPC
Summary of product characteristics
SOA
Schedule of assessment
SPM
Secondary primary malignancy
SRT
Safety review team
SSAP
Supplementary statistical analysis plan
TEAE
Treatment-emergent adverse event
TLS
Tumor lysis syndrome
TNF
Tumor necrosis factor
UA
Urinalysis
ULN
Upper limit of normal
US
United States
USPI
United States Prescribing Information
UTI
Urinary tract infection
WBC
White blood cell


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1.
OBJECTIVES
1.1.
Primary Objective

To estimate the efficacy of axicabtagene ciloleucel in combination with rituximab, as 
measured by assessment of response rates, in adult subjects with relapsed/refractory large B-
cell lymphoma
1.2.
Secondary Objectives

To estimate the safety of axicabtagene ciloleucel in combination with rituximab, as measured 
by assessment of adverse event (AE) rates, in adult subjects with relapsed/refractory large B-
cell lymphoma

To assess the efficacy of axicabtagene ciloleucel and rituximab, using additional efficacy 
endpoints

To determine levels of axicabtagene ciloleucel expansion and persistence in blood 
(pharmacokinetics [PK]) using chimeric antigen receptor (CAR) T-cell polymerase chain 
reaction (PCR) assay, in combination with rituximab
CCI


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2.
DISEASE BACKGROUND
2.1.
Disease Background
Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers originating in 
B lymphocytes, T lymphocytes, or natural killer (NK) cells. In the United States (US), B-cell 
lymphomas represent 80% to 85% of NHL cases reported {American Cancer Society 2019}. In 
2018, approximately 74,680 new cases of NHL and over 19,000 deaths related to the disease 
were estimated to occur. NHL is the most prevalent hematological malignancy and is the seventh 
most common new cancer among men and women. It accounts for 4.3% of all new cancer cases 
and approximately 3% of deaths related to cancer {Noone 2017}.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL, accounting for 
approximately 30% of NHL cases {Chaganti 2016, Morton 2006, Sehn 2015}. There are 
approximately 22,000 new diagnoses of DLBCL in the US each year. In the past 2 decades, 
progress has been made in understanding the biological heterogeneity of DLBCL and in 
improving survival with combinations of chemotherapy and immunotherapy. The addition of 
rituximab into combination therapies for DLBCL, such as R-CHOP (rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone), has greatly improved patient 
outcomes. However, first-line R-CHOP has been associated with a 10-year progression-free 
survival (PFS) of < 40% {Coiffier 2010}. Patients with chemotherapy-refractory DLBCL have a 
particularly dire prognosis {Flowers 2010}.
SCHOLAR-1, a large multicenter, patient-level, retrospective study, examined outcomes of 
refractory DLBCL using pooled data from 2 randomized Phase 3 clinical trials (the Lymphoma 
Academic Research Organization CORAL study and Canadian Cancer Trials Group study 
LY.12) and 2 observational cohorts (MD Anderson Cancer Center and University of Iowa/Mayo 
Clinic Lymphoma Specialized Program of Research Excellence). For the study, refractory 
DLBCL was defined as progressive disease (PD) or stable disease (SD) as the best response at 
any point during chemotherapy (> 4 cycles of first-line or 2 cycles of later-line therapy) or 
relapsed within ≤ 12 months of autologous stem cell transplantation (ASCT). The study 
highlighted the poor prognosis of patients affected with refractory DLBCL, finding an objective 
response rate (ORR) to the next line of therapy of 26% (complete response [CR] rate, 7%) and a 
median overall survival (OS) of only 6.3 months {Crump 2017}.
These discouraging results demonstrate that new treatment options are needed for patients whose 
tumors have demonstrated a lack of response to chemotherapy. The recently approved 
anti-CD19 CAR products are a promising treatment option for patients with relapsed or 
refractory large B-cell lymphoma who have no other curative alternatives.


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2.2.
Axicabtagene Ciloleucel
Axicabtagene ciloleucel is a CD19-directed genetically modified autologous T-cell 
immunotherapy. For this therapy, a patient’s T cells are genetically modified to produce a CAR 
protein, allowing the T cells to identify and eliminate CD19-expressing normal and malignant 
cells. CD19 is expressed by most B-cell malignancies {Leonard 2001, Olejniczak 2006, 
Rodriguez 1994, Uckun 1988}, as well as normal B lymphocytes in peripheral blood and spleen, 
but not by granulocytes, monocytes, platelets, erythrocytes, and T lymphocytes {Uckun 1988}. 
Briefly, the anti-CD19 CAR transgene comprises the following key domains: 1) an extracellular 
anti-human CD19 single-chain variable region fragment (scFv) derived from the monoclonal 
antibody (mAb) FMC63, 2) the partial extracellular domain and complete transmembrane and 
intracellular signaling domains of human CD28, and 3) the cytoplasmic portion of human CD3ζ 
that includes the signaling domain {Nicholson 1997}. Following CAR engagement with CD19+ 
target cells, the CD3ζ domain activates a downstream signaling cascade that leads to T-cell 
activation, proliferation, and acquisition of effector function.
On 18 October 2017, the US Food and Drug Administration (FDA) approved axicabtagene 
ciloleucel for the treatment of adult patients with relapsed or refractory large B-cell lymphoma 
after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, primary 
mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and 
DLBCL arising from follicular lymphoma (FL) {YESCARTA 2017}.
On 23 August 2018, the European Medicines Agency (EMA) approved axicabtagene ciloleucel 
for the treatment of adult patients with relapsed or refractory DLBCL and PMBCL after 2 or 
more lines of systemic therapy.
FDA and EMA approvals were based on ZUMA-1, a single-arm, multicenter study of 108 adult 
subjects with relapsed or refractory aggressive large B-cell NHL. The ORR among these subjects 
was 82%, and the CR rate was 58%. At a median follow-up of 15.4 months, 42% of subjects 
remained in ongoing response, highlighting the durability of responses achieved with 
axicabtagene ciloleucel over time. Median OS was not reached, and 56% of subjects remained 
alive {Neelapu 2017}. The most common Grade 3 or higher AEs (incidence of ≥ 10%) included 
febrile neutropenia, fever, cytokine release syndrome (CRS), encephalopathy, infections 
(pathogen unspecified), hypotension, hypoxia, and lung infections. Serious adverse reactions 
occurred in 52% of subjects and included, but were not limited to, encephalopathy, fever, febrile 
neutropenia, and serious infections. Fatal cases of CRS and neurologic toxicity occurred. FDA 
approved axicabtagene ciloleucel with a Risk Evaluation and Mitigation Strategy (REMS) 
{YESCARTA 2017}. EMA approved axicabtagene ciloleucel with additional Risk Minimization 
Measures (aRMMs) as part of the Risk Management Plan (RMP).
The dose of axicabtagene ciloleucel is a single intravenous (IV) infusion with a target of 
2 x 106 CAR-positive viable T cells per kg body weight (maximum dose of 2 x 108 CAR T cells), 
preceded by cyclophosphamide and fludarabine lymphodepleting chemotherapy {Yescarta 2018, 
YESCARTA 2017}. Additional details regarding the mechanism of action and clinical results of 
axicabtagene ciloleucel can be found in the Investigator’s Brochure (IB).


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Despite the success of axicabtagene ciloleucel, about 60% of patients have primary or secondary 
resistance to axicabtagene ciloleucel therapy; therefore, additional strategies are needed to 
further improve outcomes for patients with relapsed or refractory DLBCL.
2.3.
Prior Anti-CD19 CAR T-cell Study Designs and Results
Refer to the current axicabtagene ciloleucel IB for the most current anti-CD19 CAR T-cell non-
clinical and clinical information.
2.4.
Rituximab
Rituximab (RITUXAN®) is a chimeric IgG1 mAb against CD20, a receptor expressed on the 
surface of B cells {Perez-Callejo 2015}. Rituximab is approved in the US for the treatment of 
NHL, including previously untreated DLBCL; CD20-positive NHL, in combination with CHOP 
or other anthracycline-based chemotherapy regimens; CD20-positive chronic lymphocytic 
leukemia (CLL), in combination with fludarabine and cyclophosphamide; rheumatoid arthritis, in 
combination with methotrexate; granulomatosis with polyangiitis and microscopic polyangiitis, 
in combination with glucocorticoids; and pemphigus vulgaris {MabThera 2019, RITUXAN 
2018}. The boxed warnings for rituximab include fatal infusion reactions, severe mucocutaneous 
reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
R-CHOP is the current standard of care for first-line treatment for DLBCL {Flowers 2010}. 
Although more effective than chemotherapy alone, first-line R-CHOP only results in long-term 
disease remission in < 40% of subjects {Coiffier 2010}. Thus, 60% or more of all subjects with 
large B-cell lymphoma may have relapsed or refractory disease.
In NHL, rituximab has 3 main mechanisms of action after binding to CD20: antibody-dependent 
cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and induction 
of apoptosis in healthy and malignant B cells {Marshall 2017, Perez-Callejo 2015, RITUXAN 
2018}.
2.4.1.
Rationale for Anti-CD19 CAR T Cells in Combination with Rituximab
The use of anti-CD20 rituximab in conjunction with CAR T cells has been explored preclinically 
to determine whether a dual-targeting approach could improve the response rate for lymphoma 
treatment. Mihara and colleagues studied the effect of rituximab and anti-CD19 CAR T cells on 
mice inoculated with HT-luciferase cells (a cell line derived from B-NHL cells) {Mihara 2010}. 
The study demonstrated that rituximab augmented the tumor-suppressing effect of anti-CD19 
CAR T cells on B-NHL cells in vitro and in vivo with few side effects. In addition, Rufener and 
colleagues studied the effect of rituximab concentrations on the activity of anti-CD20 CAR T 
cells in vitro and in vivo and found more tumors were eradicated in mice that received rituximab 
plus CAR T cells versus rituximab alone or CAR T cells alone {Rufener 2016}. Thus, in 
adoptive tumor models in immunodeficient mice, rituximab could augment CAR T-cell 
antitumor activity.


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The use of anti-CD20 rituximab in conjunction with CAR T cells has not been studied clinically 
for lymphoma treatment. To explore whether unexpected safety findings might occur with this 
combination, an ad hoc analysis of ZUMA-1, the pivotal study for axicabtagene ciloleucel, was 
performed comparing the 64 subjects with rituximab in their last prior line of therapy with the 
108 subjects in the total study population. Rituximab levels in these subjects are expected to be 
low because the median duration from receiving rituximab in the last line of therapy to CAR 
T-cell infusion was approximately 9 weeks, and rituximab terminal half-life is 3 weeks; thus, 
levels are expected to be less than 1/8 or 1/16 of peak. Still, the proportion of subjects with 
Grade 3 or higher CRS and Grade 3 or higher neurological toxicities was consistent between 
subjects with rituximab in their last prior line of therapy (8% and 31%, respectively) compared 
with the subjects in the total study population (12% and 31%, respectively).
2.5.
Rationale for Combination Therapy
Previous clinical trial experience with axicabtagene ciloleucel in the same patient population 
(ZUMA-1) demonstrated an ORR of 82% and a CR rate of 58% at the updated analysis after a 
median follow-up of 15.4 months {Neelapu 2017}. Ongoing responses were seen in 42% of 
subjects, of whom 40% were in ongoing CR. Among the 58% of subjects who were not in 
ongoing response at the 12-month follow-up, 18% of subjects demonstrated primary resistance to 
therapy (did not achieve partial response [PR] or CR), and 40% of subjects achieved an objective 
response and later progressed or died. Possible mechanisms of resistance to axicabtagene 
ciloleucel are hypothesized to be suboptimal CAR T-cell expansion {Neelapu 2017}, an 
exclusionary tumor microenvironment {Rossi 2018}, and CD19 target antigen loss {Neelapu 
2017}.
Further, it was also observed in ZUMA-1 that 23 of 60 subjects with either a PR (11 of 35) or SD 
(12 of 25) at the first tumor assessment (1 month after axicabtagene ciloleucel infusion) 
subsequently achieved CR up to 15 months after infusion without additional therapy. In addition, 
peak expansion and area under the blood concentration vs time curve (AUC) from Day 0 to 
Day 28 (AUC0-28) were associated with response. Therefore, combination strategies that either 
increase proliferation, expansion, and persistence of CAR T cells or prevent activation--induced 
cell death (AICD) of CAR T cells may improve clinical outcomes seen with anti-CD19 CAR 
T-cell therapy.
This study will utilize a combination strategy to improve the clinical efficacy of axicabtagene 
ciloleucel. ZUMA-14 will use a dual-targeting approach to target CD20 with rituximab and 
CD19 with axicabtagene ciloleucel to augment the anti-B-cell activity and potentially mitigate 
loss of efficacy due to loss of CD19 antigen.


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3.
STUDY DESIGN AND RATIONALE
3.1.
General Study Design
Study KT-US-471-0114 (ZUMA-14) is a Phase 2, open-label, multicenter study evaluating the 
safety and efficacy of axicabtagene ciloleucel in combination with rituximab in subjects with 
relapsed/refractory large B-cell lymphoma.
Study candidates will be adults with recurrent large B-cell lymphoma who are refractory to prior 
chemotherapy or have had ASCT. They must have at least 1 measurable lesion and meet multiple 
organ function criteria. Approximately 30 subjects will be enrolled and treated using an 
interactive response technology (IRT) system to dispense rituximab. Six subjects will be enrolled 
for an initial safety evaluation, followed by safety review team (SRT) review, prior to expansion.
At the end of ZUMA-14, subjects who received an infusion of axicabtagene ciloleucel will 
complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up 
(LTFU) study, KT-US-982-5968.
3.1.1.
Rituximab Dosing
Subjects will receive a planned dose of rituximab on Day –5 and conditioning chemotherapy 
with fludarabine and cyclophosphamide on Day –5, Day –4, and Day –3. After 2 days of rest on 
Day –2 and Day –1, subjects will receive axicabtagene ciloleucel, administered at a target dose 
of 2 x 106 anti-CD19 CAR T cells/kg on Day 0. Subjects will also receive rituximab for 
5 additional doses at 28-day intervals beginning on Day 21 after axicabtagene ciloleucel 
infusion.
A second dosing strategy (Dose Level −1) will be to administer rituximab only after 
axicabtagene ciloleucel infusion. This dose level may be explored only if the planned dosing 
strategy (rituximab initiation concurrent with conditioning chemotherapy) has an unacceptable 
rate of toxicity.
An internal SRT, comprising the study sponsor medical monitor, drug safety physician, study 
statistician, and at least 1 active investigator, will meet after 6 subjects have completed their 28-
day disease assessment and then again after 15 subjects have completed their 28-day disease 
assessment. The SRT will review safety data and will be chartered to make study conduct 
recommendations based on this analysis.
For study requirements assigned to each study period, refer to the schedule of assessments 
(SOAs) in Table 2 and Table 3.
A study schema is described in Figure 1.


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3.2.
Dosing Rationale
3.2.1.
Rationale for Conditioning Chemotherapy
Increasing levels of lymphodepleting chemotherapy correlates with clinical responses to adoptive 
cell therapy {Dudley 2008}. Specifically, there appears to be a link between adequate 
lymphodepletion and adoptively transferred T-cell expansion and function in preclinical models, 
which demonstrate that the depth and duration of lymphodepletion correlate with antitumor 
activity of the adoptively transferred tumor-specific CD8+ T cells {Gattinoni 2005}. 
Lymphodepletion may function by eradicating cytokine sinks for the transferred cells, 
eliminating T regulatory cells, or enhancing antigen-presenting cell activation {Klebanoff 2005}. 
Cyclophosphamide and fludarabine combination is a potent lymphodepleting regimen. 
Cyclophosphamide (500 mg/m2/day) and fludarabine (30 mg/m2/day) are both given for 
3 consecutive days. This combination has been studied in subjects with B-cell malignancies and 
was tolerated by this population {Kochenderfer 2017, O'Brien 2001}. Cyclophosphamide and 
fludarabine combination treatment was also used in the ZUMA-1 study {Locke 2017, Neelapu 
2017}.
3.2.2.
Rationale for Axicabtagene Ciloleucel Dose
The rationale for the axicabtagene ciloleucel dose in this study is based on the aggregate safety 
and efficacy data compiled from ZUMA-1, as outlined in the IB, US Prescribing Information 
(USPI), and summary of product characteristics (SmPC). Based on the favorable benefit/risk 
ratio seen in ZUMA-1, axicabtagene ciloleucel will be administered at a target dose of 
2 x 106 anti-CD19 CAR T cells/kg, but subjects may be dosed at a minimum of 
1 x 106 anti-CD19 CAR T cells/kg. For subjects weighing > 100 kg, a maximum flat dose of 
axicabtagene ciloleucel at 2 x 108 anti-CD19 CAR T cells will be administered.
3.2.3.
Rationale for Rituximab Dose
Standard lymphoma dose rituximab will be used per rituximab package insert: 375 mg/m2 IV. 
The schedule will be every 28 days for a total of 6 doses. The first dose will be given on the day 
conditioning chemotherapy starts (Day –5).
3.3.
Participating Sites
Approximately 15 centers located in the US will participate in this study. During the conduct of 
the study, additional regions, countries, or sites may be added as necessary.
3.4.
Number of Subjects
Participants in this study will be referred to as “subjects.” It is anticipated that up to 
approximately 30 subjects will be enrolled and treated in this study.


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3.5.
Replacement of Subjects
Subjects may continue to be enrolled until the specified approximate number of subjects are 
dosed with axicabtagene ciloleucel and at least 1 dose of rituximab after axicabtagene ciloleucel 
infusion. Subjects who have not received the target dose of axicabtagene ciloleucel will be 
retained in the analyses of disposition and safety, where appropriate (see Section 10.6).
3.6.
Study Duration
3.6.1.
Study Duration for Individual Subjects
The duration of participation for individual subjects will vary depending on a subject’s screening 
requirements, response to treatment, survival, and timing of transition to the separate LTFU 
study, KT-US-982-5968 (discussed in Sections 3.6.2. and 7.11.).
For a subject who completes participation in this study and also completes the LTFU period in 
the separate LTFU study, the entire duration of a subject’s participation in both studies will be up 
to approximately 15 years from the time of the initial infusion of axicabtagene ciloleucel. The 
need for prolonged follow-up is based on the potential persistence of gene transfer vectors in 
treated subjects, and need to understand and mitigate the potential risks of delayed onset AEs 
that could be the potential consequence of this emerging technology.
3.6.2.
Completion of Study
Completion of the study is defined as the time at which the last subject has had the opportunity to 
be followed for at least 24 months, is considered lost to follow-up, withdraws consent, or dies. 
Upon activation of the LTFU study, KT‑US-982-5968, at the subject’s study site, the subject will 
be offered the opportunity to complete LTFU assessments under the KT-US-982-5968 protocol.


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4.
SUBJECT IDENTIFICATION ASSIGNMENT
Each subject who enters the screening period, which starts when the subject signs the informed 
consent form (ICF), will receive a unique subject identification (ID) number. This number will 
be used to identify the subject throughout the study and must be used on all study documentation 
related to the subject. The subject ID number will never be changed even if the subject is 
rescreened.
After study eligibility has been confirmed, subjects will receive axicabtagene ciloleucel in 
combination with rituximab.


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5.
SUBJECT ELIGIBILITY
5.1.
Inclusion Criteria
101)
Histologically proven large B-cell lymphoma, including the following types defined by 
{Swerdlow 2016}:

DLBCL not otherwise specified (germinal center B-cell [GCB]/activated B-cell 
[ABC] types)

PMBCL

DLBCL arising from FL

HGBCL with or without MYC and BCL2 and/or BCL6 rearrangements

Intravascular large B-cell lymphoma

T-cell/histiocyte rich large B-cell lymphoma

DLBCL associated with chronic inflammation

Primary cutaneous DLBCL, leg type

Epstein-Barr virus (EBV) + DLBCL
102)
Chemotherapy-refractory disease, defined as one or more of the following:

No response to first-line therapy (primary refractory disease); subjects who are 
intolerant to first-line therapy are excluded
PD as best response to first-line therapy
SD as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of 
R-CHOP) with SD duration no longer than 6 months from last dose of therapy

No response to second or greater lines of therapy
PD as best response to most recent therapy regimen
SD as best response after at least 2 cycles of last line of therapy with SD duration 
no longer than 6 months from last dose of therapy
or


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
Refractory after ASCT
Disease progression or relapsed ≤ 12 months after ASCT (must have 
biopsy-proven recurrence in relapsed subjects)
If salvage therapy is given after ASCT, the subject must have had no response to 
or relapsed after the last line of therapy.
103)
At least 1 measurable lesion according to the International Working Group (IWG) 
Lugano Classification {Cheson 2014}. Lesions that have been previously irradiated will 
be considered measurable only if progression has been documented following completion 
of radiation therapy.
104)
Subjects must have received adequate prior therapy, including at a minimum:

Anti-CD20 mAb

An anthracycline-containing chemotherapy regimen
105)
No evidence, suspicion, and/or history of central nervous system (CNS) involvement of 
lymphoma or detectable cerebrospinal fluid (CSF) malignant cells or brain metastases
106)
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior 
systemic therapy at the time the subject is planned for leukapheresis
107)
Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities, such as alopecia)
108)
Age 18 or older
109)
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
110)
Absolute neutrophil count (ANC) ≥ 1000/μL. Growth factor 7 days prior to screening is 
not allowed to meet ANC eligibility criteria.
111)
Platelet count ≥ 75,000/μL. Transfusion 7 days prior to screening is not allowed to meet 
platelet eligibility criteria.
112)
Absolute lymphocyte count ≥ 100/μL
113)
Adequate renal, hepatic, pulmonary, and cardiac function defined as:

Creatinine clearance (CrCl; as estimated by Cockcroft Gault) ≥ 60 mL/min

Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5 upper 
limit of normal (ULN)

Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert’s syndrome


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
Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion

No clinically significant pleural effusion

Baseline oxygen saturation > 92% on room air
114)
Females of childbearing potential (FCBP)* must have medically supervised negative 
serum or urine pregnancy tests with a sensitivity of at least 25 mIU/mL. 
A female is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.
115)
FCBP must agree to practice highly effective forms of birth control until at least 
6 months after lymphodepleting chemotherapy, 6 months after axicabtagene ciloleucel, or 
12 months after rituximab dosing, whichever is longer, and must also agree to routine 
pregnancy testing as described in the schedule of assessments. Methods of highly 
effective birth control are defined in Appendix 2.
5.2.
Exclusion Criteria
201)
Known CD19 negative or CD20 negative tumor
202)
History of Richter’s transformation of CLL
203)
Prior CAR therapy or other genetically modified T-cell therapy
204)
Hypersensitivity to rituximab or any excipients of rituximab
205)
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides
206)
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled or 
requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and 
uncomplicated bacterial pharyngitis are permitted if responding to active treatment and 
after consultation with the sponsor’s medical monitor.
207)
History of human immunodeficiency virus (HIV) infection or acute or chronic hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infection. Subjects with history of hepatitis 
infection must have cleared their infection as determined by standard serological and 
genetic testing per current Infectious Diseases Society of America (IDSA) guidelines or 
applicable country guidelines.


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208)
Presence of any in-dwelling line or drain (eg, percutaneous nephrostomy tube, 
in-dwelling Foley catheter, biliary drain, or pleural/peritoneal/pericardial catheter). 
Dedicated central venous access catheters, such as a Port-a-Cath or Hickman catheter, are 
permitted.
209)
History or presence of CNS disorder, such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, progressive multifocal 
leukoencephalopathy, or any autoimmune disease with CNS involvement
210)
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
211)
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, heart 
failure requiring use of digoxin or other drug for rate control, or other clinically 
significant cardiac disease within 12 months of enrollment
212)
Requirement for urgent therapy due to tumor mass effects (eg, blood vessel compression, 
bowel obstruction, or transmural gastric involvement)
213)
Primary immunodeficiency
214)
History of autoimmune disease (eg, Crohn’s, rheumatoid arthritis, systemic lupus) resulting 
in end organ injury or requiring systemic immunosuppression/systemic disease modifying 
agents within the last 2 years. Subjects with a history of autoimmune-related hypothyroidism 
on a stable dose of thyroid replacement hormone and subjects with controlled type 1 
diabetes mellitus on a stable insulin regimen may be eligible for this study.
215)
History of deep vein thrombosis (DVT) or pulmonary embolism within the last 6 months
216)
Any medical condition likely to interfere with assessment of safety or efficacy of study 
treatment
217)
Live vaccine ≤ 6 weeks prior to planned start of conditioning chemotherapy
218)
Women who are breastfeeding
219)
History of malignancy other than nonmelanoma skin cancer in situ (eg, cervix, bladder, 
breast) or low-grade (Gleason ≤ 6) prostate cancer or surveillance without any plans for 
treatment, unless disease-free for at least 3 years
220)
ASCT within 6 weeks of planned enrollment
221)
Prior organ transplantation, including prior allogeneic stem cell transplant (SCT)
222)
Prior CD19 targeted therapy
223)
In the investigator’s judgment, the subject is unlikely to complete all protocol-required 
study visits or procedures, including follow-up visits, or comply with the study 
requirements for participation.


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6.
PROTOCOL TREATMENT
6.1.
Study Treatment
6.1.1.
Leukapheresis
Leukapheresis refers to the procedure for collecting peripheral blood mononuclear cells 
(PBMCs) that are used to manufacture the subject-specific axicabtagene ciloleucel treatment.
Subjects will undergo leukapheresis to obtain T cells for the manufacturing of axicabtagene 
ciloleucel. Leukapheresed cells obtained at participating centers will be shipped to the sponsor’s 
manufacturing facility as described in the Investigational Product Manual (IPM).
6.1.2.
Conditioning Chemotherapy
Conditioning chemotherapy refers to fludarabine and cyclophosphamide used for 
lymphodepletion before administration of axicabtagene ciloleucel.
Conditioning chemotherapy will be supplied by the investigative site unless otherwise noted.
Refer to the current product label for guidance on packaging, storage, preparation, 
administration, and toxicity management associated with the administration of chemotherapy 
agents.
6.1.2.1.
Fludarabine
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose. Fludarabine is a purine 
antagonist antimetabolite.
Refer to the most recent version of the package insert for specific details surrounding the 
administration of fludarabine.
6.1.2.2.
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard derivative that acts as an alkylating agent following 
conversion to active metabolites in the liver and has potent immunosuppressive activity. The 
serum half-life after IV administration ranges from 3 to 12 hours; the drug and/or its metabolites 
can be detected in the serum for up to 72 hours after administration.
Refer to the current version of the package insert for specific details associated with the 
administration of cyclophosphamide.


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6.1.2.3.
Mesna
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by chemotherapy. 
The active ingredient in mesna is a synthetic sulfhydryl compound designated as 
sodium-2-mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2.
Mesna should be administered per institutional guidelines. Refer to the current version of the 
package insert for specific details surrounding the administration of mesna.
6.1.3.
Axicabtagene Ciloleucel
Axicabtagene ciloleucel is supplied cryopreserved in cryostorage bags. The product in the bag is 
slightly cloudy and cream to yellow color. The cryostorage bag containing axicabtagene 
ciloleucel arrives frozen in a liquid nitrogen dry shipper. The bag must be stored in a vapor phase 
of liquid nitrogen and remain frozen until the subject is ready for treatment to assure that viable 
live autologous cells are administered to the subject. Several inactive ingredients are added to the 
product to assure viability and stability of the live cells through the freezing, thawing, and 
infusion process.
Axicabtagene ciloleucel is a subject-specific product. The product is labelled per local 
regulations with the subject’s unique subject ID number assigned at the time of screening. Upon 
receipt, verification that the product and subject-specific labels match the subject’s information 
(eg, subject ID number) is essential. Do not infuse the product if the information on the 
subject-specific label does not match the intended subject. The volume of axicabtagene 
ciloleucel infused, the thaw start/stop time, and axicabtagene ciloleucel administration start/stop 
time will all be noted in the subject medical record. The product must not be thawed until the 
subject is ready for the infusion. Refer to the IPM for details and instructions on storage, 
thawing, and administration of axicabtagene ciloleucel.
There have been no instances of accidental overdose of subjects in this program to date. In case 
of accidental overdose, treatment should be supportive. Corticosteroid therapy may be 
considered if any dose is associated with severe toxicity. Toxicity management guidelines are 
found in the current product IB and should be consulted.
If any problems related to the use of axicabtagene ciloleucel or any products that support the 
management of axicabtagene ciloleucel (eg, cryostorage bags, subject ID labels) are identified, 
research staff should report the problem per the instructions in the IPM.
6.1.4.
Rituximab
6.1.4.1.
Formulation, Packaging, and Handling
Rituximab drug product may be supplied in clear glass vials at a 10-mg/mL (100 mg/vial and 
500 mg/vial) concentration as sterile solution for IV administration. Refer to the package insert 
for additional information.


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6.1.4.2.
Dosage and Administration
Rituximab dosage is 375 mg/m2, the standard approved dose for NHL. Rituximab will be 
administered as an IV infusion per institutional guidelines. Refer to the package insert for 
additional information.
6.1.5.
Concomitant Therapy
Concomitant therapy refers to treatment that subjects receive during the conduct of the study.
During the course of the study, investigators may prescribe any concomitant therapies deemed 
necessary to provide adequate supportive care except those medications listed in Section 6.1.6.
All concomitant therapies, including medications, intubation, dialysis, oxygen, and blood 
products, will be recorded.
For subjects who receive axicabtagene ciloleucel treatment:

Concomitant therapies will be recorded from the date of the informed consent until 30 days 
after the final rituximab infusion, or for 3 months after completing treatment with 
axicabtagene ciloleucel (whichever is longer).

After the post-treatment follow-up, targeted concomitant therapies will be recorded for either 
24 months after axicabtagene ciloleucel infusion or until disease progression, whichever 
occurs first. Targeted concomitant therapies include immunoglobulins (eg, gammaglobulin), 
immunosuppressive drugs, anti-infective drugs, and vaccinations.
For subjects who are enrolled but not dosed with axicabtagene ciloleucel, concomitant therapies 
will be recorded from the date of the informed consent until 30 days after the last study-specific 
procedure has occurred (eg, leukapheresis, conditioning chemotherapy) or until the initiation of 
new anticancer therapy, whichever occurs first.
For subjects who are not enrolled (eg, screen failure), concomitant therapies related to any 
SAE(s) will be recorded.
Specific concomitant therapy collection requirements and instructions are included in the case 
report form (CRF) completion guidelines.
6.1.6.
Excluded Medications
Excluded medications refer to treatment that is not to be administered, unless otherwise 
specified, during the conduct of the study.
Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent doses of 
other corticosteroids) and other immunosuppressive drugs must be avoided for 7 days before 
leukapheresis and 5 days before axicabtagene ciloleucel administration.


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Systemic corticosteroids may not be administered as premedication to subjects for whom 
computed tomography (CT) scans with contrast are contraindicated (ie, subjects with contrast 
allergy or impaired renal clearance). Such subjects should undergo noncontrast CT scans instead.
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
axicabtagene ciloleucel administration unless used to manage axicabtagene ciloleucel-related 
toxicities. Other medications, such as nonsteroidal anti-inflammatory agents, that might interfere 
with the evaluation of axicabtagene ciloleucel should also be avoided for the same period unless 
medically necessary.
Therapeutic doses of systemic anticoagulants, such as unfractionated heparin and low-molecular 
weight heparin, should be avoided, when possible, anytime subjects are at risk of bleeding due to 
thrombocytopenia.
Treatments for lymphoma, such as chemotherapy, immunotherapy, targeted agents, radiation, 
and high-dose corticosteroids (other than those defined/allowed in this protocol) and other 
investigational agents, are prohibited, except those outlined in the protocol (rituximab) and as 
needed for treatment of disease progression after axicabtagene ciloleucel infusion.
If permissibility of a specific medication/treatment is in question, contact the sponsor’s medical 
monitor (contact information located on title page of this protocol).
6.1.7.
Subsequent Therapy
Subsequent therapy refers to treatment administered after axicabtagene ciloleucel infusion that is 
necessary to treat a subject’s disease.
Subsequent therapy, such as non-study specified chemotherapy, immunotherapy, targeted agents, 
SCT, or radiation therapy, administered after axicabtagene ciloleucel infusion that is necessary to 
treat a subject’s disease will be recorded for all subjects until one of the following happens: the 
subject transitions to the LTFU study, KT-US-982-5968, is considered lost to follow-up, 
withdraws consent, or dies.
If a subject achieves a CR as best response and subsequently progresses, sites are strongly 
encouraged to collect a biopsy confirming disease progression.
For subjects who are enrolled but do not receive axicabtagene ciloleucel infusion, any additional 
anticancer therapy will also be collected until subject completes the LTFU period, is considered 
lost to follow-up, withdraws consent, or dies.
6.1.8.
Axicabtagene Ciloleucel Toxicity Management
To date, the following risks have been identified with axicabtagene ciloleucel: CRS, neurologic 
events, infections, hypogammaglobulinemia, and cytopenias. Refer to the current axicabtagene 
ciloleucel IB for details regarding these events and management guidance.


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As the safety experience with axicabtagene ciloleucel increases, the management guidance may 
be updated. Therefore, it is important to always refer to the most current version of the 
axicabtagene ciloleucel IB for guidance regarding managing axicabtagene ciloleucel-related 
toxicities. Additional information and management recommendations regarding important 
potential risks associated with axicabtagene ciloleucel, as well as possible complications 
associated with malignancy and cancer treatment, can also be found in the IB.
6.1.9.
Rituximab Toxicity Management
While rituximab is widely used and most subjects will have been treated with rituximab multiple 
times, it may still cause AEs. Rituximab has warnings for infusion reactions, severe 
mucocutaneous reactions, hepatitis B reactivation, progressive multifocal leukoencephalopathy, 
tumor lysis syndrome (TLS), infection, cardiovascular adverse reactions, renal toxicity, bowel 
obstruction and perforation, and embryo-fetal toxicity.
Refer to the current rituximab package insert for details regarding toxicity management 
guidance.


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7.
STUDY PROCEDURES
Research staff should refer to the SOA Table 2 and Table 3 for an outline of the procedures 
required.
The visit schedule is calculated from axicabtagene ciloleucel infusion on study Day 0.
An overview of study assessments/procedures is outlined in the following sections. Refer to the 
CRF completion guidelines for data collection requirements and best practices for documentation 
of study procedures.
7.1.
Informed Consent
Before a subject participates in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequately explaining the study design, 
anticipated benefits, and potential risks. Subjects should sign the most current Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) approved ICF before any 
study-specific activity or procedure is performed.
The consent process and the subject’s agreement or refusal to participate in the study must be 
documented in the subject’s medical records. If the subject agrees to participate, the ICF must be 
signed and dated by both the subject and the person who conducted the informed consent 
discussion. The original signed ICF will be retained in accordance with institution policy and 
IRB/IEC requirements, and a copy of the ICF will be provided to the subject.
All subjects who are enrolled into the study should be re-consented with any updated version of 
the IRB/IEC-approved ICF if the new version is relevant to their participation.
7.2.
Screening
Investigative sites will maintain a log of all screened subjects who were reviewed and evaluated 
for study participation. Information collected in the screening log should include limited 
information, such as the date of screening, date the subject was enrolled, or the reason for why 
the subject failed screening.
The screening period begins on the date the subject signs the IRB/IEC-approved ICF and 
continues through confirmation of eligibility into the study. Informed consent must be obtained 
before completion of any non-standard of care study-specific procedures. Procedures that are 
part of standard of care are not considered study-specific and, therefore, may be performed 
before obtaining consent and used to confirm eligibility provided they occur within the time 
allowance outlined below and in the SOA.
After written informed consent has been obtained, Kite Pharma will assign a screening number 
to the subject, as described in Section 4.


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Refer to Section 7.2.1 for the study procedures for subjects who rescreen into the study. Only 
subjects who meet the eligibility criteria listed in Section 5 will be enrolled into the study. If at 
any time before enrollment the subject fails to meet the eligibility criteria, the subject should be 
designated as a screen failure, and the reasons for failing screening should also be recorded.
Refer to the SOA (Table 2) for a list of study procedures to be completed during the screening 
period.
7.2.1.
Rescreening
Subjects who are unable to complete or meet the eligibility criteria during the 28-day screening 
period will be permitted to rescreen one time. Subjects will retain the same subject ID number 
assigned at the original screening. If rescreening occurs within 28 days of the signing of the 
original informed consent, it is only necessary to perform the procedure(s)/assessment(s) that did 
not originally meet the eligibility criteria; all other initial screening procedures/assessments do 
not need to be repeated. If rescreening occurs, or leukapheresis is delayed more than 28 days 
from the signing of the original informed consent, subjects must be reconsented and repeat all 
screening procedures/assessments.
7.3.
Demographic Data
Demographic data will be collected for each subject as per country and local regulations and 
guidelines. Where applicable, demographic data will include sex, year of birth, race, ethnicity, 
and country of enrollment with the intent to assess the possible association of demographics with 
subject safety and treatment effectiveness.
7.4.
Medical and Treatment History
Relevant medical history before the start of AE reporting will be collected. Relevant medical 
history is defined as data on the subject’s current medical condition that would be typically 
shared in a referral letter. In addition to the medical history, all history related to the subject’s 
disease, treatment, and response to treatment will be collected and must date back to the original 
diagnosis. All findings will be recorded in the CRFs.
For subjects who are being referred from another clinic or institution to the participating research 
center, copies of the subject’s chart should be obtained.
7.5.
Physical Exam, Vital Signs, and Performance Status
Physical exams will be performed during screening and at times noted in the SOA. All physical 
exam changes noted in subsequent exams when compared to the baseline exam will be reported 
as AEs.
Vital signs, including blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature, will be monitored and recorded at screening and at times outlined in the SOA. In 
addition to the time points outlined in the SOA, it is recommended that vital signs are monitored 
during and after study treatment as clinically indicated.


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Performance status as measured by the ECOG scale will be performed to quantify the subject’s 
general well-being and ability to perform activities of daily life.
7.5.1.
Cardiac Function
Each subject’s cardiac function, as measured by left ventricular ejection fraction (LVEF), will be 
assessed during the screening period to confirm study eligibility. Absence of pericardial effusion 
will also be confirmed, per study eligibility criteria. Both LVEF and pericardial effusion will be 
assessed by echocardiogram (ECHO) before study entrance. An ECHO that was performed after 
the subject’s last chemotherapy treatment may also be used to confirm eligibility, provided that it 
occurred ≤ 28 days before signing the consent.
To establish a baseline, a 12-lead electrocardiogram (ECG) will also be performed during the 
screening period.
7.6.
Neurological Examination
A neurological examination will be performed, and any of the following abnormalities will be 
recorded: level of consciousness, orientation, vision, cranial nerves and brain stem functions, 
pyramidal and extra pyramidal motor system, reflexes, muscle tone and trophic findings, 
coordination, sensory system, and neuropsychological findings (eg, speech, cognition, and 
emotion).
A neurological examination should be done before axicabtagene ciloleucel infusion on treatment 
Day 0, on treatment Day 1, and on every other day during the observation period, which must 
last a minimum of 7 days unless otherwise required by country regulatory agencies.
Subjects will be specifically asked about changes in neurological status since the previous 
neurological examination, as noted in the SOA (see Table 2).
7.7.
Disease Assessment
Subjects will be evaluated for disease response by the site investigator at times indicated in the 
SOA. Disease assessments will be evaluated per the IWG Lugano Classification {Cheson 2014}; 
refer to Appendix 1. Flow cytometric, molecular, or cytogenetic studies will not be used to 
determine response.
7.7.1.
Imaging
7.7.1.1.
Imaging at Baseline
Each subject will undergo a screening brain magnetic resonance imaging (MRI) during the 
screening period of the study to rule out CNS metastasis. If an MRI is contraindicated, then a 
brain CT scan may be performed instead.
To confirm eligibility and/or to establish a baseline, positron emission tomography-computed 
tomography (PET-CT) scans of the neck, chest, abdomen, and pelvis, along with the appropriate 


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imaging of all other sites of disease, are required at screening. PET-CT performed after the 
subject’s last line of therapy and prior to signing the consent may be used for confirmation of 
eligibility if within 28 days prior to enrollment and no other anticancer treatment has been 
administered. If PET-CT is performed > 28 days prior to enrollment, the PET-CT scan must be 
repeated to establish a new baseline. PET-CT should be performed as close to enrollment as 
possible.
7.7.1.2.
Post-treatment Response Assessment
The first planned post-treatment PET-CT tumor assessment will occur at Day 28.
PET-CTs will continue at time points outlined in the SOA through Month 24 or until disease 
progression, whichever comes first. If the subject’s disease has not progressed by Month 24, 
disease assessments will continue to be performed per standard of care for imaging assessment of 
large B-cell lymphoma. Subjects with symptoms suggestive of disease progression should be 
evaluated for progression at the time symptoms occur even if this requires an unscheduled visit. 
If the subject has started subsequent anticancer therapy, then imaging assessments will no longer 
be required per protocol.
7.7.2.
Determination of Bone Marrow Involvement
A subject’s bone marrow involvement should be confirmed by the baseline PET-CT or bone 
marrow biopsy and aspirate prior to the start of conditioning chemotherapy.
If there is evidence of baseline bone marrow involvement and follow-up PET-CT is not 
available, if there are unexplained cytopenias, or if there is any other suspicion of bone marrow 
involvement, a bone marrow aspirate and biopsy will be performed in subjects who are being 
assessed for CR to confirm complete response. The bone marrow aspirate and biopsy must show 
no evidence of disease by morphology, or if indeterminate by morphology, it must be negative 
by immunohistochemistry (IHC). Refer to Appendix 1 for treatment response assessment 
requirements per the IWG Lugano Classification {Cheson 2014}.
Bone marrow aspirate/biopsy should also be considered to evaluate hemophagocytic 
lymphohistiocytosis (HLH) as indicated. Refer to the current axicabtagene ciloleucel IB (section 
on “Hemophagocytic Lymphohistiocytosis in the Setting of CRS”) for additional information.
7.8.
Cell Collection and Axicabtagene Ciloleucel Study Treatment Schedule and 
Administration
7.8.1.
Leukapheresis
The leukapheresis visit should occur within approximately 5 days of eligibility confirmation. 
Subjects must remain eligible per the eligibility criteria outlined in Section 5 prior to the start of 
leukapheresis. If any screening assessments or procedures are repeated between confirmation of 
eligibility and the start of leukapheresis and results are outside the eligibility criteria listed in 
Section 5, contact the sponsor’s medical monitor (contact information located on title page of 
this protocol) prior to proceeding with leukapheresis.


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Before leukapheresis commences, the below criteria must be met:

No evidence or suspicion of an infection

Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent 
doses of other corticosteroids) and other immunosuppressive drugs must be avoided for 
7 days prior to leukapheresis
If criteria are not met, leukapheresis must be delayed until the event resolves. If leukapheresis is 
delayed more than 5 days after eligibility confirmation, baseline complete blood count (CBC) 
with differential and chemistry panel must be repeated. If results are outside the eligibility 
criteria listed in Section 5, contact the medical monitor (contact information located on title page 
of this protocol) prior to proceeding with leukapheresis.
After a subject commences leukapheresis and is entered in the IRT system, the subject will be 
considered enrolled into the study.
After the above criteria are met, mononuclear cells will be obtained by leukapheresis (12 to 15 L 
apheresis with a goal to target approximately 5 x 109 to 10 x 109 mononuclear cells). The 
leukapheresed cells are then packaged for expedited shipment to the manufacturing facility as 
described in the IPM.
Refer to the SOA Table 2 for a list of study procedures to be completed on the leukapheresis 
collection day and as outlined in the SOA.
7.8.1.1.
Pregnancy Testing
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 
25 mIU/mL must be performed for FCBP This requirement includes FCBP who practice 
absolute and continuous abstinence. 
7.8.2.
Rituximab Administration Prior to Axicabtagene Ciloleucel Infusion
Rituximab (375 mg/m2) will be administered via IV on Day –5.
7.8.3.
Conditioning Chemotherapy and Axicabtagene Ciloleucel Infusion
Administration of CAR T cells to subjects with ongoing infection or inflammation, even if such 
processes are asymptomatic, increases the risk of high-grade and fatal toxicity. All efforts should 
be made to rule out such conditions prior to cell infusion.
Signs, symptoms, or abnormal laboratory results attributed to the malignancy (eg, tumor fever, 
elevated C-reactive protein [CRP]) are diagnoses of exclusion that require a documented workup 
to establish.
Conditioning chemotherapy and axicabtagene ciloleucel infusion should only be initiated when it 
is reasonably assured that cell infusion can safely proceed.


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Refer to Section 7.8.3.3 for work-up requirements for potential infectious and/or inflammatory 
states.
7.8.3.1.
Requirements for Initiating Conditioning Chemotherapy
If any of the following criteria are met prior to the initiation of conditioning chemotherapy, the 
workup listed in Section 7.8.3.3 must be performed to determine the potential cause if there is no 
identified source of infection.

Temperature > 38°C within 72 hours of conditioning chemotherapy

CRP > 100 mg/L anytime between enrollment and start of conditioning chemotherapy

White blood cell (WBC) count or WBC differential concerning for infectious process 
between enrollment and start of conditioning chemotherapy (eg, WBC > 20,000/μL, rapidly 
increasing WBC, or differential with high percentage of segments/bands)
Additionally:

If any screening assessments or procedures are repeated between confirmation of eligibility 
and the start of conditioning chemotherapy and results are outside the eligibility criteria listed 
in Section 5, then the condition must resolve before proceeding with conditioning 
chemotherapy.

Complete history and physical exam, including head, ears, eyes, nose, and throat (HEENT) 
and cardiac, vascular, respiratory, gastrointestinal, integumentary, and neurological systems, 
must not reveal evidence of infection/inflammation.

The subject must not have received systemic antimicrobials for the treatment of a known or 
suspected infection within 48 hours before conditioning chemotherapy (prophylactic use of 
antimicrobials is allowed).

Treatment course of any antimicrobials given for known or suspected antecedent infection 
should be complete as per infectious disease service consult (if applicable) recommendation 
before stopping or switching to prophylactic antimicrobials.

If a subject is confirmed to have an infectious process for which antimicrobials are not 
available (eg, viral pneumonia), the infection must be clinically resolved, as determined by 
the investigator in consultation with infectious disease service consult (if applicable).

Most recently collected blood, urine, or other body fluid cultures must show no growth for at 
least 48 hours, and any other infectious workup performed (eg, bacterial, viral serologies, 
PCR, stool studies, imaging studies) must be negative. If there is clinical suspicion for an 
infection for which cultures are unlikely to be positive within 48 hours (eg, fungal infection), 
adequate time must be allowed for cultures to become positive.


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After the above criteria are met, then the subject can proceed with conditioning chemotherapy.
7.8.3.2.
Requirements for Initiating Axicabtagene Ciloleucel Infusion
If any of the following criteria are met prior to the initiation of axicabtagene ciloleucel infusion, 
then the workup listed in Section 7.8.3.3 must be performed to determine the potential cause if 
there is no identified source of infection.

Temperature > 38°C within 72 hours of axicabtagene ciloleucel infusion

CRP > 100 mg/L anytime between enrollment and start of axicabtagene ciloleucel infusion

WBC count or WBC differential concerning for infectious process between enrollment and 
start of axicabtagene ciloleucel infusion (eg, WBC > 20,000/μL, rapidly increasing WBC, or 
differential with high percentage of segments/bands)
Additionally:

If any screening assessments or procedures are repeated between confirmation of eligibility 
and the start of axicabtagene ciloleucel infusion and results are outside the eligibility criteria 
listed in Section 5, then the condition must resolve prior to proceeding with axicabtagene 
ciloleucel infusion (except for peripheral blood cell counts that have been impacted by 
conditioning chemotherapy).

Complete history and physical exam, including HEENT and cardiac, vascular, respiratory, 
gastrointestinal, integumentary, and neurological systems, must not reveal evidence of 
infection/inflammation.

The subject must not have received systemic antimicrobials for the treatment of a known or 
suspected infection within 48 hours before axicabtagene ciloleucel infusion (prophylactic use 
of antimicrobials is allowed).

Treatment course of any antimicrobials given for known or suspected antecedent infection 
should be complete as per infectious disease service consult (if applicable) recommendation 
before stopping or switching to prophylactic antimicrobials.

If a subject is confirmed to have an infectious process for which antimicrobials are not 
available (eg, viral pneumonia), the infection must be clinically resolved, as determined by 
the investigator in consultation with the infectious disease service consult (if applicable).

Most recently collected blood, urine, or other body fluid cultures must show no growth for at 
least 48 hours, and any other infectious workup performed (eg, bacterial, viral serologies, 
PCR, stool studies, imaging studies) must be negative. If there is clinical suspicion for an 
infection for which cultures are unlikely to be positive within 48 hours (eg, fungal infection), 
adequate time must be allowed for cultures to become positive.


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After the above criteria are met, then the subject can proceed with administration of axicabtagene 
ciloleucel.
If the axicabtagene ciloleucel infusion is delayed > 2 weeks, protocol-specified conditioning 
chemotherapy must be repeated.
7.8.3.3.
Requirements to Work Up Potential Infectious and/or Inflammatory States
In the absence of an identified source of infection (eg, line infection, pneumonia on chest x-ray), 
the minimum workup to be performed before administration of conditioning chemotherapy 
and/or axicabtagene ciloleucel consists of:

Call Kite medical monitor

Infectious disease service consult

CT imaging of the chest, abdomen, and pelvis with IV contrast. If there is a medical 
contraindication to contrast, then non-contrast CT is allowed.

The following must be performed (before the initiation of antimicrobials if clinically 
feasible):
Blood cultures (aerobic and anaerobic x 2 bottles each) and urinalysis (UA) and urine 
culture. Deep/induced sputum culture if clinically indicated.
All in-dwelling lines, such as central venous catheters, should be examined for any signs 
of infection, and additional cultures should be drawn from the line.
Nasopharyngeal-throat (NPT) swab or equivalent assay for viral infection, such as 
influenza A/B (including H1N1), parainfluenza 1/2/3, adenovirus, respiratory syncytial 
virus, coronavirus, metapneumovirus
Collection of fungal cultures and markers as appropriate (eg, galactomannan, fungitell)
Collection of appropriate serum viral studies (eg, cytomegalovirus [CMV])

If a CNS process is suspected, appropriate brain imaging and subsequent lumbar puncture 
with cytology, culture, Gram stain, and viral PCR should be performed.

Any additional sign- or symptom-directed investigation should be performed as clinically 
indicated.
Before proceeding with conditioning chemotherapy or axicabtagene ciloleucel infusion, the 
above workup must not suggest the presence of an active infection, and all requirements for 
conditioning chemotherapy and axicabtagene ciloleucel infusion must be satisfied.


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If the above workup was triggered due to CRP > 100 mg/L, CRP should be repeated, and if CRP 
continues to increase significantly, evaluation should be performed for any other potential 
infectious or inflammatory condition not previously evaluated.
7.8.3.4.
Conditioning Chemotherapy Administration (Day –5 through Day –3 Prior to 
Axicabtagene Ciloleucel Infusion)
Subjects will receive a conditioning chemotherapy regimen consisting of cyclophosphamide and 
fludarabine. The first dose of conditioning chemotherapy will be designated as Day –5. Subjects 
will initiate conditioning chemotherapy with cyclophosphamide and fludarabine beginning on 
Day –5 and through Day –3, with 2 rest days (Day –2 and Day –1) before receiving axicabtagene 
ciloleucel. The 3-day conditioning chemotherapy regimen will be administered in an outpatient 
setting.
The 3-day conditioning chemotherapy regimen of cyclophosphamide and fludarabine will be 
administered in accordance with the following daily dosing instructions:

IV hydration with a balanced crystalloid, according to institutional guidelines, prior to 
administration of cyclophosphamide on the day of infusion

Cyclophosphamide 500 mg/m2 IV over 60 minutes (± 15 minutes) followed by

Fludarabine 30 mg/m2 IV over 30 minutes (± 15 minutes) followed by

Additional IV hydration with a balanced crystalloid, according to institutional guidelines, to 
be administered upon completion of infusion

Mesna should be administered per institutional guidelines.
Subjects should be instructed to drink plenty of liquids (approximately 2 L/24 hours) during 
chemotherapy and throughout the 24-hour period after chemotherapy. In general, subjects should 
be kept well-hydrated but closely monitored to prevent fluid overload.
Refer to the SOA Table 2 for a listing of study procedures to be completed during the 
conditioning chemotherapy period.
7.8.4.
Axicabtagene Ciloleucel Treatment Period
7.8.4.1.
Axicabtagene Ciloleucel Premedication Dosing
Prior to axicabtagene ciloleucel infusion, the following medications should be administered 
approximately 1 hour before infusion. Alternatives to the following recommendations should be 
discussed with the medical monitor.

Acetaminophen (paracetamol) 500 to 1,000 mg PO or equivalent

Diphenhydramine 12.5 to 25 mg administered either orally or via IV or equivalent


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7.8.4.2.
Axicabtagene Ciloleucel Administration Day 0
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility, followed by 
daily monitoring at a healthcare facility for at least 7 days, unless otherwise required by country 
regulatory agencies, to monitor for signs and symptoms of CRS and neurologic toxicities. 
Alternatively, subjects may be hospitalized to receive their axicabtagene ciloleucel infusion and 
be observed for CRS and neurologic toxicities in the hospital setting, if deemed appropriate by 
the investigator.
If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel-related non-hematological toxicities resolve to ≤ Grade 1 or return to 
baseline. Subjects may be discharged with non-critical and clinically stable or improving 
toxicities (eg, renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator. 
Subjects should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, 
hypotension, hypoxia, or ongoing neurologic events > Grade 1, or if deemed necessary by the 
investigator.
If a subject is discharged from the hospital or healthcare facility between Days 8 and 13, the 
subject’s next scheduled assessments are on Day 14. Subjects should be instructed to remain 
within proximity of the clinical study site for at least 4 weeks following axicabtagene ciloleucel 
infusion. Subjects should be advised to refrain from driving and engaging in hazardous 
occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 
8 weeks following axicabtagene ciloleucel infusion. Subjects and their family 
members/caregivers should be educated on potential CRS and neurologic symptoms, such as 
fever, dyspnea, confusion, aphasia, dysphasia, somnolence, encephalopathy, ataxia, or tremor. 
Subjects or their family members/caregivers should be instructed to immediately contact the 
treating investigator or seek immediate medical attention if any of these symptoms develop.
Refer to the SOA (Table 2) for a list of study procedures to be completed during the 
axicabtagene ciloleucel treatment period.
Central venous access, such as a port or a peripherally inserted catheter, is required for the 
administration of axicabtagene ciloleucel. Catheter care, per institutional guidelines, should be 
followed. Materials and instructions for the thawing, timing, and administration of axicabtagene 
ciloleucel are outlined in the IPM. Vital signs should be measured during and after axicabtagene 
ciloleucel treatment (see Section 7.5).
Research sites should follow institutional guidelines for the infusion of cell products.
7.8.5.
Rituximab Administration After Axicabtagene Ciloleucel Infusion
Rituximab (375 mg/m2) will be administered via IV on Day 21 and will be continued at 28-day 
intervals for a total of 5 doses after axicabtagene ciloleucel infusion.


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7.9.
Laboratory
7.9.1.
Local Laboratory Analysis
Assessments listed in Table 1 will be performed at the local laboratory at the time points 
indicated in the SOA. Additional samples (eg, blood, urine, CSF, tissue) may be collected as 
needed for further safety testing.
Table 1.
Clinical Laboratory Parameters
Serum Chemistries
Hematology
Other
Albumin
ALT/GPT
ALP
AST/GOP
Bicarbonate total (if applicable)
Bilirubin direct
Bilirubin total
BUN or ureaa
Calcium total
Chloride
Creatinine
Creatinine clearance
Glucose
Inorganic phosphorus
LDH
Magnesium total
Potassium
Sodium
Uric acidb 
CBC with differentialb
CRP
Ferritin
Pregnancy test
Abbreviations:  ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea 
nitrogen; CBC, complete blood count; CRP, C-reactive protein; GOP, serum glutamic-oxaloacetic transaminase; GPT, serum 
glutamic-pyruvic transaminase;  LDH, lactate dehydrogenase.
a
If BUN test cannot be analyzed by the Local Laboratory, urea should be analyzed.
b
Per institutional guidelines.
7.9.2.
Central Laboratory Analyses
Biomarker analysis will be performed on blood, CSF, and tumor samples to evaluate PK and 
pharmacodynamics markers for axicabtagene ciloleucel in combination with rituximab. 
Prognostic markers for aggressive NHL and related to the tumor immune environment may also 
be evaluated.
Clinical biospecimens (eg, tumor tissue, bone marrow, complete blood, CSF, or other bodily 
fluids) will be sent from clinical study centers to the central laboratory for sample processing, 
accessioning, and distribution to specialty laboratories or Kite. Samples will be obtained at the 
time points indicated in the SOA. Additional samples (eg, complete blood, urine, CSF, tissue) 
may be collected as needed for further safety testing.




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7.9.2.2.
PK and Pharmacodynamics
PK and pharmacodynamics analyses will be performed on blood (levels of anti-CD19 CAR 
T cells) or serum (cytokines and rituximab PK) at the intervals outlined in the SOA to evaluate 
predictive markers for the efficacy and safety of axicabtagene ciloleucel. The following 
cytokines and chemokines may be included in the panel: homeostatic, pro-inflammatory and 
immune modulating cytokines IL-2, IL-6, IL-10, IL-12p40/p70, IL-15, IL-17a, TNF-α, IFN-γ, 
and granulocyte-macrophage colony-stimulating factor (GM-CSF); acute phase reactants, such 
as CRP; chemokines IL-8, monocyte chemoattractant protein (MCP)-1 and macrophage 
inflammatory protein (MIP)-1α, and interferon-inducible protein (IP)-10; and HLH-related 
markers ferritin and interleukin-2 receptor alpha (IL-2Rα).
CSF samples and additional subject samples (eg, pleural fluid) will be collected at baseline and 
at time points after infusion as outlined in the SOA to enable evaluation of inflammatory 
cytokines and chemokine levels for determination of PK, pharmacodynamics, and presence of 
CAR T cells and other immune cell subsets. CSF draws and additional subject samples will be 
obtained from subjects who develop Grade 2 or higher neurologic events for evaluation of 
inflammatory cytokine and chemokine levels and presence of anti-CD19 CAR T cells. As 
applicable, lymphocyte populations residing in the CSF or other subject samples may also be 
monitored for the purpose of understanding the safety profile of axicabtagene ciloleucel.
7.9.2.3.
Product Characteristics
In addition, baseline leukapheresis and final axicabtagene ciloleucel samples will be banked and 
may be analyzed by immunophenotyping, quantitative polymerase chain reaction (qPCR), and/or 
gene expression profiling
 
Samples of apheresis material or final product will be retained and tested by the sponsor or 
specialty laboratory for the purpose of understanding the mechanism of action and safety profile 
of axicabtagene ciloleucel.
7.9.2.4.
RCR Testing
Axicabtagene ciloleucel comprises T cells transduced with a γ-retroviral vector; hence, there is a 
theoretical risk for RCR developing in exposed subjects. RCR testing will occur at the following 
time points: baseline, Day 105, Day 180, and Month 12. Thereafter, samples will be collected 
yearly and held for up to 15 years from the last patient dosed. If a subject tests positive for RCR 
at any time point within the first year, samples will continue to be collected and tested yearly for 
CCI
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up to 15 years from the last patient dosed or as clinically indicated. If secondary malignancies 
emerge, RCR testing will also be performed following diagnosis. Additional information is 
provided in the current axicabtagene ciloleucel IB.
7.10.
Post-treatment Assessment Period
After completing study treatment, all subjects will return to the clinic for post-treatment 
follow-up visits.
If a subject does not respond to treatment at any time during the post-treatment assessment 
period, then the subject will continue to undergo the post-treatment follow-up procedures per the 
SOA and then be followed for survival and disease outcomes in the LTFU portion of the study 
starting with the Month 9 visit (see Table 3).
Refer to the SOA (Table 2) for a list of study procedures and disease assessments to be 
completed during the post-treatment follow-up period.
7.11.
Long-term Follow-up Period
All enrolled and treated subjects will be followed in the LTFU period for safety analysis, 
survival, and disease status, if applicable. Subjects will begin the LTFU period at the Month 9 
visit. Subjects who did not respond to axicabtagene ciloleucel treatment may receive off-protocol 
therapy but will continue to be followed for disease assessments (if progression was not 
documented), subsequent anti-cancer therapy, and survival. If the subject has started a 
subsequent anti-cancer therapy, then imaging assessments will no longer be required per 
protocol.
Subjects may also be contacted by telephone to confirm survival status and subsequent 
anticancer therapy use. If the subject fails to return to the clinic for a scheduled protocol-specific 
visit, sites will need to make 2 attempts, using both the telephone and either mail or email, to 
contact the subject. Sites must document both attempts to contact the subject. If the subject does 
not respond within 1 month after the second contact, then the subject will be considered lost to 
follow-up, and no additional contact will be required.
Refer to the SOA (Table 3) for a list of study procedures and disease assessments to be 
completed during the LTFU period.
Subjects who are enrolled/leukapheresed, but either did not receive axicabtagene ciloleucel 
treatment or received axicabtagene ciloleucel treatment and progressed, will be followed in the 
LTFU period and undergo the following assessments at the time points outlined in the SOA:

Subsequent therapy for the treatment of NHL

Survival status

Disease assessment per protocol


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
AE/SAE per Section 9

All subjects who received an infusion of axicabtagene ciloleucel will be provided the 
opportunity to transition to a separate LTFU study, KT-US-982-5968, where they will be 
monitored for occurrence of late-onset targeted AEs/SAEs suspected to be possibly related to 
axicabtagene ciloleucel as defined in KT-US-982-5968, presence of RCR, and/or insertional 
mutagenesis for up to 15 years from the time of axicabtagene ciloleucel infusion. In KT-US-
982-5968, subjects will continue assessments at timepoints contiguous with the LTFU 
timepoints in this study. 
7.12.
Post-study Care
Kite will not provide additional care for study subjects after their participation in the study has 
ended.


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Table 2.
Schedule of Assessments
Procedures
Screening
Leukapheresis
Conditioning Chemotherapy
Axicabtagene 
Ciloleucel
Post-treatment Follow-up
Day
Within 
28 days of 
enrollment
Within 
approx. 5 days 
after 
confirming 
eligibility
D-5
D-4
D-3
D-2
D-1
D0
D1 to 
D14n
D21 
(± 3 
days)
D28 
(± 3 
days)
D49
(± 3 
days)
D77
(± 3 
days)
D105
(± 14 
days)
D133
(± 14 
days)
D180
(± 14 days)
Leukapheresis 
Xj
Rituximab 
administrationk
X
X
X
X
X
X
Fludarabine/ 
Cyclophosphamide
X
X
X
Axicabtagene 
ciloleucel IV 
infusion 
X
Medical history 
X
ECOG 
performance status
X
ECG 12-lead
X
ECHO
Xa
Brain MRI
X
Weight (plus height 
at screening)
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
Neurological 
examination
X
Xb
Days 
0, 1, 3, 
5, 7b
X
X
Vital signs (BP, 
HR, O2 sat, temp, 
and RR)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Procedures
Screening
Leukapheresis
Conditioning Chemotherapy
Axicabtagene 
Ciloleucel
Post-treatment Follow-up
Day
Within 
28 days of 
enrollment
Within 
approx. 5 days 
after 
confirming 
eligibility
D-5
D-4
D-3
D-2
D-1
D0
D1 to 
D14n
D21 
(± 3 
days)
D28 
(± 3 
days)
D49
(± 3 
days)
D77
(± 3 
days)
D105
(± 14 
days)
D133
(± 14 
days)
D180
(± 14 days)
Pregnancy test 
(serum or urine)
X
X
X 
X
X
Lumbar punctured
X
Xd
PET-CT disease 
assessment
Xe
X
X
X
Tumor biopsy
Xf
Day 5 
+/- 2df
Blood draw for 
rituximab PKg
X
X
X
X
X
X
Blood draw for 
chemistry panel
X
X
X
X
X
X
X
X
X
X
X
Central CBC 
w/differential
X
Day 7, 
14
X
X
X
X
X
Blood draw for 
CBC w/differential
X
X
X
X
X
X
X
X
X
X
X
Blood draw for 
CRP, ferritin
X
X
X
Blood draw for 
PBMC, serum, 
plasma (central 
lab)h
X
X
X
Day 1, 
3, 5, 7, 
14
X
X
X
X
X
AEs/Concomitant 
medicationsi
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE, adverse event; approx., approximately; BP, blood pressure; BSA, body surface area; CAR, chimeric antigen receptor; CBC, complete blood count; CR, 
complete response; CRP, C-reactive protein; CRS, cytokine release syndrome; CSF, cerebrospinal fluid; D, day; ECG, electrocardiogram; ECHO, echocardiogram; ECOG, Eastern 
Cooperative Oncology Group; FFPE, formalin-fixed paraffin-embedded; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, heart rate; 
IRT, interactive response technology; IV, intravenous; MRD, minimal residual disease; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cell; PET-CT, 
positron emission tomography-computed tomography; PK, pharmacokinetics; QOD, every other day; RCR, replication-competent retrovirus; RR, respiratory rate; SAE, serious 
adverse event; sat, saturation; temp, temperature


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a
ECHO performed following the subject’s last chemotherapy treatment and within 28 days before signing the consent may be used for confirmation of eligibility.
b
As clinically indicated thereafter.
c
It is recommended that vital signs are monitored during and after axicabtagene ciloleucel treatment and as clinically indicated.
d
Lumbar puncture: For subjects with neurologic symptoms at screening, a lumbar puncture will be performed at screening to confirm eligibility. For subjects with new onset 
Grade 2 or higher neurologic symptoms after axicabtagene ciloleucel infusion, a lumbar puncture will be performed to assess cerebrospinal fluid (CSF) if there are no 
contraindications. If possible, opening pressure should be measured and recorded in the subject’s site chart.
e
PET-CT (neck-chest-abdomen-pelvis)/disease assessment: PET-CT performed following the subject’s last line of therapy and prior to signing the informed consent may be 
used for confirmation of eligibility if within 28 days prior to enrollment, and no other anticancer treatment has been administered.
f
Sites are required to submit archival samples at screening as formalin-fixed paraffin-embedded (FFPE) tumor block(s) or 30 unstained slides. Archived samples will be 
submitted to the central laboratory after eligibility has been confirmed and prior to leukapheresis. If archival material is unavailable or insufficient at screening, a fresh tumor 
sample is required to be collected and submitted prior to leukapheresis. 
 If a 
subject achieves a CR as best response and subsequently progresses, sites are strongly encouraged to collect a biopsy confirming disease progression.
g
Blood draw for rituximab PK should be collected immediately before each rituximab infusion and between 15 minutes and 3 hours after each rituximab infusion.
h
Blood draws for PBMCs, serum, and plasma: Blood draw for PBMCs includes the analysis of anti-CD19 CAR T cells and replication-competent retrovirus (RCR); blood 
draw for serum includes the analysis of cytokines; blood draw for plasma includes analysis of minimal residual disease (MRD). If, following discharge from initial 
hospitalization, the subject is subsequently re-admitted to the hospital with any axicabtagene ciloleucel-related AEs, blood samples for PBMC and serum will be collected on 
day of admission, then weekly, and on day of discharge. If the subject experiences a Grade 3 or higher axicabtagene ciloleucel-related toxicity, such as Grade 3 CRS or 
neurologic toxicities, 1 additional blood draw for serum will be taken at the time of the Grade 3 or higher axicabtagene ciloleucel-related toxicity and upon resolution of the 
event. If subjects develop secondary malignancies, a blood draw for PBMCs will also be scheduled and performed after diagnosis and sent to the central laboratory for RCR 
analysis.
i
SAE and concomitant medication reporting begins after signing of the informed consent. AE reporting begins after enrollment.
j
Lab draws can be performed 24 hours prior to the leukapheresis. 
k
Weight taken on the leukapheresis day will be used to calculate the BSA for the rituximab dosage and will be entered into IRT. This dose will remain consistent for all 
rituximab infusions unless a significant weight change is seen.
n.
If a subject is discharged from the hospital or healthcare facility between Days 8 and 13, the subject’s next scheduled assessments are on Day 14.
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4
Targeted AEs/SAEs will be collected for 15 years or until disease progression (whichever occurs first). All subjects treated with axicabtagene ciloleucel must have SPMs 
reported for 15 years following treatment.
5
Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occurs first).
6
Subsequent therapy administered after axicabtagene ciloleucel infusion for a subject’s disease, such as non-study specified chemotherapy, immunotherapy, targeted agents, as 
well as stem cell transplant and radiation therapy, must be collected until subject completes the long-term follow-up period, is considered lost to follow-up, withdraws 
consent, or dies. Subjects may be contacted by telephone to collect information about subsequent therapy for NHL and to assess survival status.
7
In the event of PD, subject will begin the long-term follow-up period after completion of the post-treatment follow-up visits and be assessed for survival status, subsequent 
therapy for the treatment of NHL, disease assessments as indicated in footnote 2, AEs/SAEs as indicated in footnote 4, and concomitant medications as indicated in 
footnote 5.
8.
At the end of the KT-US-471-0114 study, subjects who have received an infusion of axicabtagene ciloleucel will have the opportunity to transition to the LTFU study,KT-US-
982-5968, after providing signed consent, to complete the remainder of the 15-year LTFU period.


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8.
SUBJECT WITHDRAWAL
Subjects have the right to withdraw from the study at any time and for any reason without 
prejudice to their future medical care by the physician or at the institution.
Subjects can decline to continue to receive study-required treatment and/or other 
protocol-required procedures at any time during the study while continuing to participate in the 
study. This is referred to as partial withdrawal of consent.
If partial withdrawal of consent occurs, the investigator must discuss with the subject the 
appropriate process for discontinuation from the study investigational product (IP) or other 
protocol-required therapies and must also discuss options for continued participation, completion 
of procedures, and the associated data collection as outlined in the SOA. The level of follow-up 
and method of communication should also be discussed between the research staff and the 
subject and documented in the source documents.
Withdrawal of full consent from a study means that the subject does not wish to receive further 
protocol-required therapy, undergo procedures, and continue participating in study follow-up.  
Subject data collected up until withdrawal of consent will be retained and included in the 
analysis of the study. Publicly available data (death records) can be included after withdrawal of 
consent if local regulations permit. The investigator is to discuss with the subject appropriate 
procedures for withdrawal from the study.
As part of the study, sites may be asked to conduct searches of public records, such as those 
establishing survival status, if available, to obtain survival data for any subject for whom the 
survival status is not known. Sites may be asked to also retrieve autopsy reports to confirm status 
of disease at the time of death.
The investigator and/or sponsor can also decide to withdraw a subject from the IP and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time before study 
completion.
8.1.
Reasons for Removal from Treatment
Reasons for removal from protocol-required IPs or procedures include any of the following:

AEs

Subject request

Product not available

Lost to follow-up

Death


Axicabtagene Ciloleucel
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
Decision by sponsor

Progressive Disease

Pregnancy
8.2.
Reasons for Removal from Study
Reasons for removal of a subject from the study are as follows:

Subject withdrawal of consent from further follow-up

Investigator decision

Lost to follow-up

Death

Termination of the study by the sponsor

Other (eg. Non-compliance; refusal to consent to the KT-US-982-5968 study)


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9.
SAFETY REPORTING
9.1.
Adverse Events
An AE is defined as any untoward medical occurrence in a clinical trial subject. The event does 
not necessarily have a relationship with study treatment. The investigator is responsible for 
ensuring that any AEs observed by the investigator or reported by the subject are recorded in the 
subject’s medical record. The definition of AEs includes worsening of a pre-existing medical 
condition. Worsening indicates that the pre-existing medical condition has increased in severity, 
frequency, and/or duration or has an association with a worse outcome. When recording such 
events, provide descriptions that the pre-existing condition has changed (eg, more frequent 
headaches for a subject with pre-existing headaches, or blood pressure is now increased in a 
subject with pre-existing hypertension).
A pre-existing condition that has not worsened during the study or involves an intervention, such 
as elective cosmetic surgery or a medical procedure while on study, is not considered an AE.
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical 
procedures that were planned before study participation are not considered AEs. Hospitalization 
for study treatment infusions or precautionary measures per institutional policy are not 
considered AEs.
The term “disease progression,” as assessed by measurement of malignant lesions on radiographs 
or other methods, should not be reported as an AE. Death due to disease progression should be 
reported using the primary tumor type (eg, B-cell lymphoma).
When an AE or SAE is due to the disease under investigation, it is necessary to report the signs 
and symptoms. Worsening of signs and symptoms of the malignancy under study should also be 
reported as AEs in the appropriate section of the CRF.
The investigator’s clinical judgment is used to determine whether a subject is to be removed 
from treatment due to an AE. If a subject requests to withdraw from protocol-required therapies 
or the study because of an AE, then the subject should undergo the procedures outlined in the 
Day 105 visit of the SOA.
9.2.
Reporting of Adverse Events
The investigator is responsible for reporting all AEs observed by the investigator or reported by 
the subject that occur after enrollment through 30 days after completing the final dose of 
rituximab or 3 months after the axicabtagene ciloleucel infusion, whichever is longer. For 
subjects who are enrolled (ie, leukapheresed) but do not receive rituximab or axicabtagene 
ciloleucel, the AE reporting period ends 30 days after the last study-specific procedure (eg, 
leukapheresis, conditioning chemotherapy).


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For subjects who are dosed (ie, receive rituximab or axicabtagene ciloleucel), all AEs will be 
recorded from the date of enrollment through 30 days after last dose of rituximab or 3 months 
after the axicabtagene ciloleucel infusion, whichever is longer. If a subject has disease 
progression prior to Month 3 and does not receive another anticancer therapy, only related AEs 
will be collected through 3 months after axicabtagene ciloleucel infusion.
After Month 3, only targeted AEs will be recorded from Month 3 through 15 years after 
axicabtagene ciloleucel infusion or disease progression, whichever occurs first. Targeted AEs 
include cytopenias, infection, thromboembolic events, autoimmune disorders, 
hypogammaglobulinemia, and SPMs. All subjects treated with axicabtagene ciloleucel must have 
SPMs reported for 15 years following treatment.
The investigator is expected to follow reported AEs until stabilization or resolution.
The investigator must provide the following information regarding the AEs being reported:

AE diagnosis or syndrome (if not known, signs or symptoms)

Dates of onset and resolution

Severity

Assessment of relatedness to IP, lymphodepleting chemotherapy, or study procedures

Action taken
The AE grading scale used will be the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. A copy of the grading scale can be 
downloaded from the Cancer Therapy Evaluation Program (CTEP) home page 
(http://ctep.cancer.gov). The severity of CRS events will be graded using a modification of the 
system proposed by Lee and colleagues {Lee 2014} as outlined in the axicabtagene ciloleucel 
IB.
In reviewing AEs, investigators must assess whether the AE is possibly related to 
1) axicabtagene ciloleucel, 2) rituximab, 3) conditioning chemotherapy, 4) any protocol-required 
study procedure or treatment, 5) disease progression, 6) concurrent disease, 7) concomitant 
medication, or 8) other. The relationship is indicated by a yes or no response and entered into the 
CRF. A “yes” response should indicate that there is evidence to suggest a causal relationship 
between the study treatment or procedure and the AE. Additional relevant data with respect to 
describing the AE will be collected in the CRFs.
The investigator is expected to follow reported AEs until stabilization or resolution. If a subject 
begins a new anticancer therapy, the AE reporting period for non-SAEs ends at the time the new 
treatment is started.


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9.2.1.
Reporting Abnormal Laboratory Findings
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a clinically significant change from the 
subject’s baseline values. In general, abnormal laboratory findings without clinical significance 
(based on the investigator’s judgment) are not to be recorded as AEs. However, abnormal 
laboratory findings that result in new or worsening clinical sequelae, or that require therapy or 
adjustment in current therapy, are considered AEs. Where applicable, clinical sequelae (not the 
laboratory abnormality) are to be recorded as the AE.
An abnormal laboratory test result must be reported as an AE if it is a change from baseline and 
meets any of the following criteria:

Associated with clinical symptoms

Results in a medical intervention (eg, potassium supplementation for hypokalemia or iron 
replacement therapy for anemia) or a change in concomitant therapy

Clinically significant in the investigator’s judgment
9.3.
Definition of Serious Adverse Events
An SAE is defined as an AE (as defined in Section 9.1) that meets at least 1 of the following 
serious criteria:

Fatal

Life-threatening (places the subject at immediate risk of death)

Requires inpatient hospitalization or prolongation of existing hospitalization

An AE would meet the criterion of “requires hospitalization” if the event necessitated an 
admission to a healthcare facility (eg, overnight stay).
Events that require an escalation of care when the subject is already hospitalized should 
be recorded as an SAE.
Examples of such events include movement from routine care in the hospital to the 
intensive care unit (ICU) or if that event resulted in a prolongation of the existing planned 
hospitalization.

Results in persistent or significant disability/incapacity

Congenital anomaly/birth defect

Other medically important serious event


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If an investigator considers an event to be clinically important, but it does not meet any of the 
serious criteria, the event could be classified as an SAE with the criterion of “other medically 
important serious event.”

The following events must be submitted as SAEs:
CRS events Grade 3 or higher
Neurologic events Grade 3 or higher
All events of cerebral edema
All events of hemophagocytic lymphohistiocytosis/macrophage activation syndrome
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an AE 
according to NCI CTCAE version 5.0 criteria; the event itself may be of relatively minor medical 
significance and, therefore, may not meet the seriousness criteria. Severity and seriousness need 
to be independently assessed for each AE recorded on the eCRF.
9.4.
Reporting of Serious Adverse Events
The investigator is responsible for reporting all SAEs observed by the investigator or reported by 
the subject that occur after signing of the informed consent through 30 days after completing 
final dose of rituximab or 3 months after the axicabtagene ciloleucel infusion, whichever is 
longer. After this follow-up period is completed, only targeted SAEs will be reported. Targeted 
SAEs are defined as and include neurological, hematological, infections, autoimmune disorders, 
and SPMs that occur up to 15 years or until disease progression. In addition, all subjects treated 
with axicabtagene ciloleucel must have SPMs reported for 15 years following treatment. 
SAEs that the investigator assesses as related to axicabtagene ciloleucel or rituximab should be 
reported regardless of the time period.
SPMs must be reported as SAEs regardless of when they occur and regardless of their 
relationship to the study treatments/procedures.
For subjects who screen-fail or are enrolled, but do not receive axicabtagene ciloleucel, the 
reporting period for SAEs ends 30 days after the last study-specific procedure (eg, screen 
procedure, leukapheresis, lymphodepleting chemotherapy, administration of rituximab).
All SAEs must be submitted to Kite Pharma via the eSAE system within 24 hours of the 
investigator’s knowledge of the event. If the eSAE system is unavailable (eg, system outage), 
then the SAE must be submitted using the SAE Report Form and sent via email to the SAE 
Reporting mailbox: 
Following completion of ZUMA-14, any relevant information on ongoing SAEs must be 
submitted to Kite Pharma within 24 hours of the investigator’s knowledge of the event using the 
paper SAE Report Form and sent via e-mail to the SAE Reporting mailbox: 
PPD
PPD


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Subsequently, all SAEs will be reported to the health authorities per local reporting guidelines.
Disease progression of the malignancy is not considered an AE. However, signs and symptoms 
of disease progression may be recorded as AEs or SAEs and indicated as being due to disease 
progression within the CRF. If the malignancy has a fatal outcome before 24 months, then the 
event “B-cell lymphoma” must be recorded as an SAE with the outcome being fatal.
Death must be reported if it occurs during the SAE reporting period, irrespective of any 
intervening treatment.
Any death occurring after enrollment and before the post-treatment follow-up period, regardless 
of attribution to treatment, requires expedited reporting within 24 hours. Any death occurring 
after the post-treatment follow-up period requires expedited reporting within 24 hours only if it is 
considered related to treatment.
9.5.
Reporting Deaths
Deaths that occur during the protocol-specified AE reporting period that are attributed by the 
investigator solely to progression of underlying lymphoma should be recorded as SAEs with the 
preferred term “B-cell lymphoma” and must be reported immediately to the sponsor. Death is an 
outcome and not a distinct event. The event or condition that caused or contributed to the fatal 
outcome should be recorded on the AE form. However, every effort should be made to capture 
the established cause of death, which may become available later on (eg, after autopsy). Deaths 
during the post-study survival follow-up due to underlying cancer should be recorded only on the 
Survival Status CRF.
9.6.
Diagnosis Versus Signs and Symptoms
For AEs, a diagnosis (if known) rather than individual signs and symptoms should be recorded 
on the AE form. The exception is for CRS where both the diagnosis and signs and symptoms will 
be captured on the CRF AE form. For signs and symptoms of the underlying cancer, the signs 
and symptoms should be captured. However, on the AE form, the investigator should state that 
these signs and symptoms are due to the underlying disease.
9.7.
Instructions for Reporting Special Situations
There is no relevant clinical experience with axicabtagene ciloleucel in pregnant or lactating 
women, and animal reproductive studies have not been performed. FCBP must have a negative 
pregnancy test before leukapheresis and before conditioning chemotherapy because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus. FCBP should be 
monitored according to local and country-specific regulations. This experimental therapy should 
not be administered to pregnant women or women who are breastfeeding.
Female subjects and female partners of male subjects are recommended to use highly effective 
methods of contraception (method must achieve an annual failure rate of < 1%) for at least 
6 months after lymphodepleting chemotherapy, 6 months after axicabtagene ciloleucel dosing, or 


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12 months after rituximab dosing, whichever is longer. Male subjects are recommended not to 
father a child for 6 months after lymphodepleting chemotherapy or axicabtagene ciloleucel 
dosing, whichever is longer.
Any pregnancy in a female subject enrolled into the study must be reported, regardless of the 
time after axicabtagene ciloleucel infusion. If the pregnancy occurs in a female partner of a male 
subject within 6 months after completing lymphodepleting chemotherapy or the administration 
of axicabtagene ciloleucel, whichever is longer, the pregnancy must be reported. All such 
pregnancies must be reported to Kite Pharmacovigilance and Epidemiology (PVE) using the 
Pregnancy Report Form within 24 hours after becoming aware of the pregnancy. Information 
regarding the pregnancy and/or the outcome will be requested by the sponsor. Pregnancy report 
forms should be reported to Kite PVE at 
 or 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. Any premature termination of pregnancy (eg, a spontaneous 
abortion, an induced therapeutic abortion due to complications or other medical reasons) must be 
reported as an SAE within 24 hours. The underlying medical reason for this procedure should be 
recorded as the AE term. Any SAE occurring as an adverse pregnancy outcome post study must 
be reported to Kite PVE.
The pregnant subject or subject partner should receive appropriate monitoring and care until the 
conclusion of the pregnancy. The outcome should be reported to Kite PVE using the pregnancy 
outcome report form. If the end of the pregnancy occurs after the study has been completed, the 
outcome should be reported directly to Kite PVE.
Pregnancies of female partners of male study subjects exposed to axicabtagene ciloleucel or 
other study drugs must also be reported, and relevant information should be submitted within 24 
hours to Kite PVE using the pregnancy and pregnancy outcome forms. If the end of the 
pregnancy occurs after the study has been completed, the outcome should be reported directly to 
Kite PVE.
If a lactation case occurs in a female subject in the study, the lactation case must be reported to 
Kite PVE within 24 hours after the investigator’s awareness of the event using the Special 
Situations Reporting Form. In addition to reporting a lactation case during the study, 
investigators should monitor for pregnancy and lactation cases throughout the long term follow 
up period. Report the lactation case and Special Situations report forms to Kite PVE at 
 or 
 
PPD
PPD
PPD
PPD


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9.8.
Hospitalization and Prolonged Hospitalization
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE as described in Section 9.4.
The following hospitalization scenarios are not considered to be SAEs:

Hospitalization for palliative care or hospice care

Planned hospitalization required by the protocol (eg, for monitoring of the subject or to 
perform an efficacy measurement for the study)

Planned hospitalization for a pre-existing condition

Hospitalization due to progression of the underlying cancer
9.9.
Abnormal Vital Sign Values
Not all vital sign abnormalities qualify as an AE. A vital sign result must be reported as an AE if 
it is a change from baseline and meets any of the following criteria:

Accompanied by clinical symptoms

Results in a medical intervention or a change in concomitant therapy

Clinically significant in the investigator’s judgment
It is the investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should be 
classified as an AE. However, if a clinically significant vital sign abnormality is a sign of a 
disease or syndrome (eg, high blood pressure), only the diagnosis (ie, hypertension) should be 
recorded on the CRF.
9.10.
Safety Review Team
The internal SRT comprises the study sponsor medical monitor, drug safety physician, study 
statistician, and at least 1 active study investigator. As part of its oversight, the SRT will assess 
safety criteria to make recommendations on dosing with rituximab, determine pause of 
enrollment, decide when to move forward with the expansion phase, and consider any other 
study conduct-related changes. The SRT will meet and review the safety data after 6 subjects 
have completed their 28-day disease assessment and again after 15 subjects have completed their 
28-day disease assessment. The details for these criteria and for the function of the SRT are 
found in the SRT charter.


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10.
STATISICAL CONSIDERATIONS
10.1.
Hypothesis
No formal hypothesis will be tested in this study. The study is designed to estimate the CR rate 
in subjects with large B-cell lymphoma treated with axicabtagene ciloleucel in combination with 
rituximab.
10.2.
Study Endpoints
10.2.1.
Primary Endpoint
Complete response rate (CR per the IWG Lugano Classification {Cheson 2014}), as determined 
by the study investigators.
10.2.2.
Secondary Endpoints

Incidence of AEs and clinically significant changes in safety lab values

ORR is defined as the incidence of either a CR or a PR per IWG Lugano Classification 
{Cheson 2014}, as determined by study investigators. All subjects who do not meet the 
criteria for an objective response by the analysis data cutoff date will be considered 
nonresponders.

Duration of response (DOR): Among subjects who experience an objective response, DOR is 
defined as the date of their first objective response to disease progression per IWG Lugano 
Classification {Cheson 2014}, as determined by study investigators, or death from any cause. 
Subjects not meeting the criteria for progression or death by the analysis data cutoff date will 
be censored at their last evaluable disease assessment date, and their response will be noted 
as ongoing. Subjects who receive additional anticancer therapy in the absence of documented 
progression will be censored at the last evaluable disease assessment prior to the additional 
therapy. Subjects who receive an SCT in the absence of documented progression will be 
censored at the last evaluable disease assessment prior to the date of the SCT. A sensitivity 
analysis will be conducted in which disease assessments obtained after SCT while in 
axicabtagene ciloleucel-induced remission are included in the derivation of DOR.

PFS is defined as the time from the axicabtagene ciloleucel infusion date to the date of 
disease progression per IWG Lugano Classification {Cheson 2014}, as determined by study 
investigators, or death from any cause. Subjects not meeting the criteria for progression or 
death by the analysis data cutoff date will be censored at their last evaluable disease 
assessment date. The PFS for subjects who undergo SCT while in remission will be censored 
at the last evaluable disease assessment prior to the date of SCT; the PFS for subjects who 
undergo other new anticancer therapies in the absence of documented relapse will be 
censored at the last evaluable disease assessment prior to the new anticancer therapies. A 
sensitivity analysis will be conducted in which disease assessments obtained after SCT while 
in axicabtagene ciloleucel-induced remission are included in the derivation of PFS.


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
OS is defined as the time from axicabtagene ciloleucel infusion to the date of death. Subjects 
who have not died by the analysis data cutoff date will be censored at their last date known as 
alive or the data cutoff date, whichever is earlier.

PK is defined as levels of axicabtagene ciloleucel in blood.
10.3.
Sample Size Considerations
This study uses a single-arm design to estimate the true CR rate in subjects with large B-cell 
lymphoma treated with axicabtagene ciloleucel in combination with rituximab. The anticipated 
enrollment in this study is approximately 30 subjects. With a total sample size of 30 subjects at a 
given dosing schedule, an observed CR rate of 70% will yield an 80% confidence intervals for 
the response rate with a maximum half-width no greater than 13%, corresponding to a lower 
limit of at least 57%. This target CR rate, and the lower limit of the 80% confidence interval for 
the CR rate, is meaningful because it would represent a significant improvement in the response 
rate for the subjects with large B-cell lymphoma over existing therapies.
Additional assumptions and corresponding 2-sided 95% and 80% exact confidence intervals are 
provided in Table 4.
Table 4.
95% and 80% Exact Confidence Intervals Corresponding to 
Observed CR Rate After Treatment of 30 Subjects 
Subjects with CR
Observed CR Rate
95% Confidence Interval
80% Confidence Interval
15
50%
[31%, 69%]
[37%, 63%]
18
60%
[41%, 77%]
[47%, 72%]
21
70%
[51%, 85%]
[57%, 81%]
24
80%
[61%, 92%]
[68%, 89%]
27
90%
[73%, 98%]
[79%, 96%]
Abbreviations: CR, complete response.
10.4.
Access to Individual Subject Treatment Assignments
This is an open-label combination study; subjects and investigators will be aware of treatment 
received. Data handling procedures for the study will be devised to reduce potential sources of 
bias and maintain the validity and credibility of the study. These procedures will be outlined in 
the study statistical plan.
CCI


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10.5.
Interim Analysis and Early Stopping Guidelines
Formal interim analyses of efficacy are not planned for the early trial stopping purpose. The team 
will review the interim safety data per the SRT charter.
10.6.
Analysis Subsets
In this study, subjects are to be dosed at a target of 2 x 106 (1.0 x 106 to 2.4 x 106) anti-CD19 
CAR T cells/kg. A minimum dose of 1 x 106 anti-CD19 CAR T cells/kg may be administered. 
For subjects weighing > 100 kg, a maximum flat dose of 2 x 108 anti-CD19 CAR T cells will be 
administered. Subjects are considered to have received the target dose if they receive at least 
1 x 106 anti-CD19 CAR T cells/kg.
Full analysis set (FAS): The FAS will consist of all enrolled subjects and will be used for the 
summary of subject disposition.
Modified intent-to-treat (mITT) set: The mITT set will consist of all subjects enrolled and treated 
with axicabtagene ciloleucel and at least 1 dose of rituximab after axicabtagene ciloleucel 
infusion. This analysis set will be used for all efficacy analyses.
Safety set: The safety set is defined as all subjects treated with any dose of axicabtagene 
ciloleucel.
10.7.
Planned Method of Analysis
The primary analysis will be performed when the last treated subject in the mITT set has had the 
opportunity to be evaluated for response at 6 months. The final analysis will occur when all 
subjects have completed at least 24 months of follow-up. Additional analyses of safety and 
efficacy may occur at any time after the primary analysis.
Subjects will be transitioned to the KT-US-982-5968 study for the remainder of the 15-year 
LTFU period. Descriptive estimates of key efficacy and safety analyses may be updated to assess 
the overall treatment profile.
10.7.1.
Complete Response Rate
The incidence of CR and exact 2-sided 95% confidence intervals will be generated.
10.7.2.
Objective Response Rate
The incidence of ORR and exact 2-sided 95% confidence intervals will be generated.
10.7.3.
Duration of Response
Kaplan-Meier estimates and 2-sided 95% confidence intervals will be generated for DOR. 
Estimates of the proportion of subjects alive and in response at 3-month intervals will be 
provided.




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11.
REGULATORY OBLIGATIONS
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki

Applicable International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines

Applicable laws and regulations
11.1.
Independent Review Board/Independent Ethics Committee
A copy of the protocol, ICF, and any additional subject or trial information, such as subject 
recruitment materials, must be submitted to each site’s respective IRB/IEC for approval. After 
approval is obtained from the IRB/IEC, all documents must be provided to the key sponsor 
contact before subject recruitment can begin.
The investigator must also receive IRB/IEC approval for all protocol and ICF changes or 
amendments. Investigators must ensure that ongoing/continuous IRB/IEC approval (ie, annual 
approval) is provided throughout the conduct of the study. Copies of IRB/IEC approval are to be 
forwarded to the key sponsor contact for archiving.
During the course of the study, investigators are to submit site-specific and study SAEs 
(provided to the site by the key sponsor contact), along with any protocol deviations, to their 
IRB/IEC in accordance with their respective IRB/IEC policies.
11.2.
Subject Confidentiality
Subject confidentiality must be maintained within all material that is submitted to the key 
sponsor contact. The following rules are to be applied:

Subjects will be identified by a unique ID number.

Date of birth or year of birth/age at time of enrollment will be reported according to local 
laws and regulations.
For reporting of SAEs, subjects will be identified by their respective subject ID number, initials, 
and date of birth or year of birth (as per their local reporting requirements for both initials and 
date of birth).
Per country-specific regulations and ICH/GCP guidelines, investigators and institutions are 
required to permit authorization to the sponsor, Contract Research Organization (CRO), 
IRB/IEC, and regulatory agencies to subject’s original source documents for verification of study 
data. The investigator is responsible for informing potential subjects that such individuals will 
have access to their medical records, which include personal information.


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11.3.
Investigator Signatory Obligations
Each Clinical Study Report (CSR) will be signed by the coordinating investigator. The 
coordinating investigator will be identified by Kite Pharma under the following criteria:

Is a recognized expert in the disease setting

Provided significant contributions to the design or analysis of study data

Participates in the study and enrolled a high number of eligible subjects


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12.
PROTOCOL AMENDMENTS AND TERMINATION
If the protocol is amended, the investigator’s agreement with the amendment and the IRB/IEC 
approval of the amendment must be obtained. Documentation acknowledging approval from 
both parties is to be submitted to the key sponsor contact.
Both Kite Pharma and the investigator reserve the right to terminate the investigator’s 
participation in the study as per the terms of the agreement in the study contract. The investigator 
is to provide written communication to the IRB/IEC regarding either the trial completion or early 
termination and provide the CRO with a copy of the correspondence.
Kite Pharma reserves the unilateral right, at its sole discretion, to determine whether to 
manufacture axicabtagene ciloleucel and provide it to sites and subjects after the completion of 
the study.


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13.
STUDY DOCUMENTATION AND ARCHIVING
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. The individuals authorized to fulfill these responsibilities should be outlined and 
included in the Delegation of Authority Form.
Source documents are original documents, data, and records for which the study data are 
collected and verified. Examples of such source documents may include, but are not limited to, 
hospital records and patient charts; laboratory, pharmacy, radiology records; subject diaries; 
microfiches; correspondence; and death registries. CRF entries may be considered as source data 
if the site of the original data collection is not available. However, the use of the CRFs as source 
documentation is not recommended as a routine practice.
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system of all subject records that are readily retrieved to be monitored and/or audited at 
any time by the key sponsor contact, health authorities, and IRB/IECs. The filing system will 
include at minimum:

Subject content, including ICFs and subject ID lists

Protocols and protocol amendments, IB, copies of pre-study documentation, and all IRB/IEC 
and sponsor communication

Proof of receipt, experimental treatment flow records, and experimental product-related 
correspondence
Original source documents supporting entries into CRFs must be maintained at the site and 
readily available upon request. No study documents should be discarded without prior written 
agreement between Kite Pharma and the investigator. If storage is no longer available to archive 
source documents or if source documents must be moved to an alternative location, the research 
staff should notify the key sponsor contact before shipping the documents.


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14.
STUDY MONITORING AND DATA COLLECTION
The key sponsor contact, monitors, auditors, or regulatory inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and verifying 
source documents and records must also assure that subject confidentiality is respected.
The monitor is responsible for source document verification of CRF data at regular intervals 
during the study. Protocol adherence and accuracy and consistency of study conduct and data 
collection with respect to local regulations will be confirmed. Monitors will have access to 
subject records as identified in Section 13.
By signing the investigator’s agreement, the investigator agrees to cooperate with the monitor to 
address and resolve issues identified during monitoring visits.
In accordance with ICH/GCP and the audit plan, a site may be chosen for a site audit. A site 
audit would include, but is not limited to, an inspection of the facility(ies), review of subject- and 
study-related records, and compliance with protocol requirements as well as ICH/GCP and 
applicable regulatory policies.
All data will be collected in an electronic CRF system. All entries must be completed in English, 
and concomitant therapies should be identified by trade names. For additional details related to 
the completion of CRFs, refer to the CRF completion guidelines.


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15.
PUBLICATION
Authorship of publications from data generated in KT-US-471-0114 will be determined based on 
the uniform requirements for manuscripts submitted to biomedical journals (as outlined in the 
International Committee of Medical Journal Editors December 2013), which states that 
authorship should be based on:

Substantial contributions to the conception or design of the work, acquisition of data, 
analysis, or interpretation of data for the work; and

Drafting the article or revising it critically for important intellectual content; and

Final approval of the version to be published; and

Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated or resolved
When a large, multicenter group has conducted the work, the group should identify the 
individual who accepts direct responsibility for the manuscript. This individual should fully meet 
the criteria for authorship defined above.
Funding, collection of data, or general supervision of the research alone or in combination does 
not qualify an individual for authorship.
Any publication, in any form, that is derived from this study must be submitted to Kite Pharma 
for review and approval. The study contract among the institution, principal investigator, and 
Kite or its delegate will outline the requirements for publication review.


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REFERENCES
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of imaging in the staging and response assessment of lymphoma: consensus of the 
International Conference on Malignant Lymphomas Imaging Working Group. J 
Clin Oncol 2014;32 (27):3048-58.
Chaganti S, Illidge T, Barrington S, McKay P, Linton K, Cwynarski K, et al. Guidelines for the 
management of diffuse large B-cell lymphoma. Br J Haematol 2016;174 (1):43-
56.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32 (27):3059-68.
Clinical Trials Facilitation Group (CTFG). Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials. Final Version. 15 September.  2014.
Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al. Long-term 
outcome of patients in the LNH-98.5 trial, the first randomized study comparing 
rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by 
the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 2010;116 (12):2040-5.
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in 
refractory diffuse large B-cell lymphoma: results from the international 
SCHOLAR-1 study. Blood 2017;130 (16):1800-8.
Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy 
for patients with metastatic melanoma: evaluation of intensive myeloablative 
chemoradiation preparative regimens. J Clin Oncol 2008;26 (32):5233-9.
Flowers CR, Sinha R, Vose JM. Improving outcomes for patients with diffuse large B-cell 
lymphoma. CA Cancer J Clin 2010;60 (6):393-408.
Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of 
homeostatic cytokine sinks by lymphodepletion enhances the efficacy of 
adoptively transferred tumor-specific CD8+ T cells. J Exp Med 2005;202 (7):907-
12.
Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen 
presenters: how lymphodepletion enhances T cell-mediated tumor 
immunotherapy. Trends Immunol 2005;26 (2):111-7.


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Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, et al. Lymphoma Remissions 
Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With 
High Serum Interleukin-15 Levels. J Clin Oncol 2017;35 (16):1803-13.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood 2014;124 
(2):188-95.
Leonard JP, Schattner EJ, Coleman M. Biology and management of mantle cell lymphoma. Curr 
Opin Oncol 2001;13 (5):342-7.
Locke FL, Westin JR, Miklos DB, Herrara AF, Jacobson CA, Lee J, et al. Phase 1 Results from 
ZUMA-6: Axicabtagene Ciloleucel (axi-cel; KTE-C19) in Combination with 
Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell 
Lymphoma (DLBCL). Blood 2017;130 (Suppl 1):2826-.
MabThera, Roche Products Limited. MabThera 100 mg Concentrate for Solution for Infusion. 
Summary of Product Characteristics. Welwyn Garden City, United Kingdom. 
Revised: 30 July.  2019:
Marshall MJE, Stopforth RJ, Cragg MS. Therapeutic Antibodies: What Have We Learnt from 
Targeting CD20 and Where Are We Going? Frontiers in immunology 
2017;8:1245.
Mihara K, Yanagihara K, Takigahira M, Kitanaka A, Imai C, Bhattacharyya J, et al. Synergistic 
and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 
chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin 
lymphoma. Br J Haematol 2010;151 (1):37-46.
Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the United States, 1992-2001. Blood 
2006;107 (1):265-76.
Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene 
Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J 
Med 2017;377 (26):2531-44.
Nicholson IC, Lenton KA, Little DJ, Decorso T, Lee FT, Scott AM, et al. Construction and 
characterisation of a functional CD19 specific single chain Fv fragment for 
immunotherapy of B lineage leukaemia and lymphoma. Mol Immunol 1997;34 
(16-17):1157-65.
Noone A, Howlader N, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics 
Review, 1975-2015. National Cancer Institute. Bethesda, MD, 
https://seer.cancer.gov/csr/1975_2015/, based on November 2017 SEER data 
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O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, et al. Results of the 
fludarabine and cyclophosphamide combination regimen in chronic lymphocytic 
leukemia. J Clin Oncol 2001;19 (5):1414-20.
Olejniczak SH, Stewart CC, Donohue K, Czuczman MS. A quantitative exploration of surface 
antigen expression in common B-cell malignancies using flow cytometry. 
Immunol Invest 2006;35 (1):93-114.
Perez-Callejo D, Gonzalez-Rincon J, Sanchez A, Provencio M, Sanchez-Beato M. Action and 
Resistance of Monoclonal CD20 Antibodies Therapy in B-cell Non-Hodgkin 
Lymphomas. Cancer Treat Rev 2015;41:680-9.
RITUXAN, Genentech Inc. RITUXAN® (rituximab) injection, for intravenous use. US 
Prescribing Information. South San Francisco, CA. Revised: June.  2018:
Rodriguez J, Pugh WC, Romaguera JE, Cabanillas F. Primary mediastinal large cell lymphoma. 
Hematological Oncology 1994;12 (4):175-84.
Rossi JM, Galon J, Turcan S, Danan C, Locke FL, Neelapu SS, et al. Characteristics of the 
pretreatment tumor microenvironment may influence clinical response in patients 
with refractory large B cell lymphoma treated with axicabtagene ciloleucel (axi-
cel) in the pivotal ZUMA-1 [Abstract LB-016/16]. American Association for 
Cnacer Research (AACR); 2018 14-18 April; Chicago, Illinois. 
Rufener GA, Press OW, Olsen P, Lee SY, Jensen MC, Gopal AK, et al. Preserved Activity of 
CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of 
Rituximab. Cancer Immunol Res 2016;4 (6):509-19.
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of 
clinical and biologic heterogeneity. Blood 2015;125 (1):22-32.
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the 
World Health Organization classification of lymphoid neoplasms. Blood 
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on Expression and Function of CD19 Surface Determinant by Using B43 
Monoclonal Antibody and the Clinical Potential of Anti-CD19 Immunotoxins. 
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Summary of Product Characteristics. Holborn, London, UK. Available at: 
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17.
APPENDICES
Appendix 1.
International Working Group Lugano Classification
Appendix 2.
Childbearing Potential and Birth Control


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Appendix 1.
International Working Group Lugano Classification
Refer to the imaging manual and {Cheson 2014} for details of assessment.
Table 5.
5-Point Scale (5PS)
Score 
Description
1 
No uptake above background 
2 
Uptake ≤  mediastinum 
3 
Uptake > mediastinum but ≤ liver 
4 
Uptake moderately higher than liver 
5 
Uptake markedly higher than liver and/or new lesions
X 
New areas of uptake unlikely to be related to lymphoma 
Source: {Barrington 2014}
Complete Remission
Complete Metabolic Response (CMR) for Positron Emission Tomography-Computed 
Tomography (PET-CT)-based Response
The designation of CMR requires all of the following:

A 5PS (5-point scale) score of 1, 2, or 3, with or without a residual mass
In Waldeyer’s ring or extranodal sites with high physiologic uptake or with activation 
within spleen or marrow, uptake may be greater than normal mediastinum and/or liver. In 
this circumstance, CMR may be inferred if uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if the tissue has high physiologic uptake.

No new sites of disease should be observed.

No evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow
Complete Radiologic Response (CRR) for Computed Tomography (CT)-based Response
The designation of CRR requires all of the following:

Target nodes/nodal masses must regress to ≤ 1.5 cm in longest transverse diameter of a lesion 
(LDi)

No extralymphatic sites of disease

Absent nonmeasured lesion


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
Organ enlargement regress to normal

No new sites of disease should be observed.

Bone marrow normal by morphology; if indeterminate, immunohistochemistry (IHC) 
negative
Partial Remission
Partial Metabolic Response (PMR) for PET-CT-based Response
The designation of PMR requires all of the following:

A 5PS score of 4 or 5, with reduced uptake compared to baseline (screening), and residual 
mass(es) of any size

Note:
At interim, these findings suggest responding disease.
At end of treatment (EOT), these findings suggest residual disease.

No new sites of disease should be observed.

Residual uptake higher than uptake in normal bone marrow, but reduced compared with 
baseline (diffuse uptake compatible with reactive changes from chemotherapy allowed)
If there are persistent focal changes in the marrow in the context of a nodal response, 
consideration should be given to further evaluation with magnetic resonance imaging (MRI) or 
biopsy or an interval scan.
Partial Radiologic Response (PRR) for CT-based Response
The designation of PRR requires all of the following:

≥ 50% decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 target 
measurable nodes and extranodal sites
When a lesion is too small to measure on CT, assign 5 mm x 5 mm as the default value.
When no longer visible, 0 x 0 mm
For a node > 5 mm x 5 mm, but smaller than normal, use actual measurement for 
calculation.


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
Absent/normal, regressed, but no increase of nonmeasured lesions

Spleen must have regressed by > 50% in length beyond normal

No new sites of disease should be observed.
Stable Disease
No Metabolic Response (NMR) for PET-CT-based Response
The designation of NMR requires all of the following:

A 5PS score of 4 or 5, with no significant change in FDG uptake, compared to baseline 
(screening) at an interim time point or EOT

No new sites of disease should be observed.

No change from baseline in bone marrow
Stable Radiologic Disease (SRD) for CT-based Response
The designation of SRD requires all of the following:

< 50% decrease from baseline in the SPD of up to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive disease are met

No increase consistent with progression in nonmeasured lesion and organ enlargement

No new sites of disease should be observed.
Progressive Disease
Progressive Metabolic Disease (PMD) for PET-CT-based Response
The designation of PMD requires at least 1 of the following:

A 5PS score of 4 or 5 with an increase in intensity of uptake from baseline and/or

New FDG-avid foci consistent with lymphoma at interim or EOT assessment

New FDG-avid foci consistent with lymphoma rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of new lesions, biopsy or interval scan may be 
considered.

New or recurrent FDG-avid foci in bone marrow


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Progressive Radiologic Disease (PRD) for CT-based Response
The designation of PRD requires at least 1 of the following:

An individual node/lesion must be abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from cross product of LDi and perpendicular diameter (PPD) nadir 
and
An increase in LDi or SDi (shortest axis perpendicular to the LDi) from nadir
■
0.5 cm for lesions ≤ 2 cm
■
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the splenic length must increase by > 50% of the extent of 
its prior increase beyond baseline (eg, a 15-cm spleen must increase to > 16 cm). If no 
prior splenomegaly, must increase by at least 2 cm from baseline
New or recurrent splenomegaly

New or clear progression of pre-existing nonmeasured lesions

New lesion
Regrowth of previously resolved lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in any axis; if < 1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to lymphoma.
Assessable disease of any size unequivocally attributable to lymphoma

New or recurrent bone marrow involvement


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Appendix 2.
Childbearing Potential and Birth Control
This study will follow the recommendations from the Clinical Trial Facilitation Group (CTFG) 
{Clinical Trials Facilitation Group (CTFG) 2014}, as described below. 
A. Definition of Childbearing Potential
A female is considered of childbearing potential (ie, fertile) following menarche and until 
becoming postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
For the purpose of this study, a man is considered fertile after puberty unless permanently sterile 
by bilateral orchidectomy.
B. Birth Control Methods That May Be Considered as Highly Effective
Birth control methods that may be considered as highly effective must achieve an annual failure 
rate of less than 1% when used consistently and correctly.1 

Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation2:
Oral
Intravaginal
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation2:
Oral
Injectable
1  2014 clinical trial facilitation and coordination group contraception guidance.
2  Hormonal contraception may be susceptible to interaction with the investigational product, which may reduce the 
efficacy of the contraception method.


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Implantable3
Intrauterine device (IUD)3
Intrauterine hormone-releasing system (IUS)3
Bilateral tubal occlusion3
Vasectomized partner3,4
Sexual abstinence5
Unacceptable Birth Control Methods
Birth control methods that are unacceptable include periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM). A female condom and a male condom should not be used 
together.
3  Contraception methods that in the context of this guidance are considered to have low user dependency.
4  Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success.
5  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
Sponsor:
Kite Pharma, Inc.
2400 Broadway
Santa Monica, CA 90404
United States of America
Company Code:
KTE-C19
Axicabtagene ciloleucel
USAN Name:
Rituximab
Protocol
A Phase 2 Open-Label, Multicenter Study Evaluating the Safety and 
Efficacy of Axicabtagene Ciloleucel in Combination with   Rituximab  in 
Subjects with Refractory Large B-Cell Lymphoma (ZUMA-14)  
Version Number:
2.0
Release Date:
11 November 2020
Replaces Previous Version(s):
1.0 (22 January 2019)
CONFIDENTIALITY NOTICE
This document contains confidential information of Kite Pharma Inc., a wholly owned subsidiary 
of Gilead Sciences, Inc.    This document must not be disclosed to anyone other than the site 
research staff and members of the institutional review board/independent ethics committee, a 
scientific review board, or an equivalent.  The information in this document cannot be used for 
any purpose other than the conduct of the clinical investigation without the prior written consent 
of Kite Pharma, Inc.  Questions regarding how this document should be used or the conduct of 
the clinical trial should be directed to the key sponsor contacts.


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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN ...............................................................................................................................1
TABLE OF CONTENTS................................................................................................................................................2
LIST OF TABLES..........................................................................................................................................................3
LIST OF FIGURES ........................................................................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.................................................................................4
1.
INTRODUCTION..................................................................................................................................................5
2.
OBJECTIVES.........................................................................................................................................................6
3.
STUDY DESIGN...................................................................................................................................................7
3.1.
Overview ...................................................................................................................................................7
3.2.
Hypothesis .................................................................................................................................................7
3.3.
Sample Size Consideration........................................................................................................................8
4.
STUDY ENDPOINTS AND COVARIATES........................................................................................................9
4.1.
Endpoints...................................................................................................................................................9
4.1.1.
Primary Endpoint.....................................................................................................................9
4.1.2.
Secondary Endpoints...............................................................................................................9
4.2.
Subgroups and Covariates .........................................................................................................................9
5.
DEFINITIONS .....................................................................................................................................................11
5.1.
General ....................................................................................................................................................11
5.2.
Safety.......................................................................................................................................................12
5.3.
Efficacy....................................................................................................................................................14
6.
ANALYSIS SETS................................................................................................................................................16
6.1.
Modified Intent-to-treat Analysis Set......................................................................................................16
6.2.
Safety Analysis Set..................................................................................................................................16
6.3.
Full Analysis Set......................................................................................................................................16
7.
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES....................................................................17
7.1.
Safety Interim Analysis ...........................................................................................................................17
8.
DATA SCREENING AND ACCEPTANCE.......................................................................................................18
8.1.
General Principles ...................................................................................................................................18
8.2.
Electronic Transfer and Archiving of Data .............................................................................................18
8.3.
Handling of Missing and Incomplete Data..............................................................................................18
8.3.1.
Efficacy..................................................................................................................................18
8.3.2.
Safety.....................................................................................................................................18
8.4.
Detection of Bias .....................................................................................................................................18
8.5.
Outliers ....................................................................................................................................................18
8.6.
Distributional Characteristics ..................................................................................................................19
8.7.
Validation and Configuration Management ............................................................................................19
9.
STATISTICAL METHODS OF ANALYSIS......................................................................................................20
9.1.
General Principles ...................................................................................................................................20
9.2.
Subject Accountability ............................................................................................................................20
9.3.
Important Protocol Deviations ................................................................................................................20
9.4.
Demographic and Baseline Characteristics.............................................................................................20
9.5.
Efficacy Analyses....................................................................................................................................21


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9.5.1.
Complete Response and Objective Response........................................................................21
9.5.2.
Duration of Response ............................................................................................................22
9.5.3.
Progression Free Survival......................................................................................................22
9.5.4.
Overall Survival.....................................................................................................................22
9.5.5.
Tumor Burden .......................................................................................................................22
9.6.
Safety Analyses .......................................................................................................................................22
9.6.1.
Adverse Events......................................................................................................................23
9.6.2.
Laboratory Test Results.........................................................................................................23
9.6.3.
Anti-axicabtagene Ciloleucel Antibodies..............................................................................23
9.6.4.
Replication Competent Retrovirus ........................................................................................23
9.7.
Exposure to Study Treatments and Product Characteristics....................................................................24
9.8.
Exposure to Concomitant Medications and Procedures..........................................................................24
9.9.
Subsequent Anti-Cancer Therapy............................................................................................................24
9.10.
Duration Metrics......................................................................................................................................24
9.11.
Axicabtagene Ciloleucel Delivery Time .................................................................................................25
9.12.
Pharmacokinetics.....................................................................................................................................25
10.
CHANGES FROM PROTOCOL SPECIFIED ANALYSES..............................................................................26
11.
REFERENCES.....................................................................................................................................................27
12.
APPENDICES......................................................................................................................................................28
Appendix 1.
Conventions for Clinical Data That Require Imputation for Partial or Missing Dates ...........29
Appendix 2.
Derivation of Time to Event Endpoints...................................................................................31
Appendix 3.
Derivation of Last date known to be alive...............................................................................34
LIST OF TABLES
Table 1.
95% and 80% Exact Confidence Intervals for Observed CR Rate based on 30 
Subjects......................................................................................................................................8
Table 2.
Imputation Rules for Partial or Missing Start Dates................................................................29
Table 3.
Primary Analysis of DOR........................................................................................................31
Table 4.
Sensitivity Analysis of DOR ...................................................................................................32
Table 5.
Primary Analysis of PFS .........................................................................................................32
Table 6.
Sensitivity Analysis of PFS .....................................................................................................33
Table 7.
Imputation Rule of OS Event/Censoring Date ........................................................................33
LIST OF FIGURES
Figure 1.
Study Schema ............................................................................................................................7
CCI-


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ADaM
Analysis data model
AE
Adverse event
ASCT
Autologous stem cell transplant
BSA
Body surface area
CAR
Chimeric antigen receptor
CR
Complete response 
CRF
Case report form
CRS
Cytokine release syndrome
CTCAE
Common terminology criteria for adverse event
DLBCL 
Diffuse large B-cell lymphoma
DOR
Duration of response 
ECOG
Eastern Cooperative Oncology Group
HLGT
High-level group term
IPD
Important protocol deviation
IPI
International Prognostic Index 
IWG
International Working Group 
MedDRA
Medical Dictionary for Regulatory Activities
MST
MedDRA search term 
mITT
Modified intent-to-treat 
NHL
Non-Hodgkin lymphoma
ORR
Objective response rate 
PD
Progressive disease 
PFS
Progression-free survival 
PR
Partial response
PT
Preferred term
RCR
Replication-competent retrovirus
OS
Overall survival 
SAE
Serious adverse event
SAP
Statistical analysis plan
SCT
Stem cell transplant
SD
Stable disease
SDTM
Study data tabulation model 
SMQ
Standardized MedDRA query 
SOC
System organ class
SPD
Sum of the product of the diameters 
SRT
Safety review team
TEAE
Treatment-emergent adverse event
WHO
World Health Organization


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Statistical Analysis Plan
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1.
INTRODUCTION
This statistical analysis plan (SAP) sets forth prospectively the details of statistical analyses that 
are outlined in protocol KT-US-471-0114 entitled “A Phase 2 Open-Label, Multicenter Study 
Evaluating the Safety and Efficacy of Axicabtagene Ciloleucel in Combination with Rituximab   
in Subjects with Refractory Large B-Cell Lymphoma (ZUMA-14)” dated 08 July 2020. This 
document was updated from Version 1.0 to 2.0 as the Lenalidomide cohort was discontinued per 
Protocol Amendment 4.


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2.
OBJECTIVES
The primary objective of the analyses is to estimate the efficacy of axicabtagene ciloleucel in 
combination with rituximab as measured by assessment of response rates in adult subjects with 
relapsed/refractory large B-cell lymphoma.  
Secondary objectives of the analyses outlined herein are:

To estimate the safety of axicabtagene ciloleucel in combination with rituximab as measured 
by assessment of adverse event (AE) rates in adult subjects with relapsed/refractory large 
B-cell lymphoma.  

To assess the efficacy of axicabtagene ciloleucel in combination with rituximab using 
additional efficacy endpoints.

To determine levels of axicabtagene ciloleucel expansion and persistence in blood using 
chimeric antigen receptor (CAR) T-cell polymerase chain reaction (PCR) assay 
(pharmacokinetics [PK]), in combination with  rituximab   .


KT-US-471-0114 
Statistical Analysis Plan 
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3_ 
STUDY DESIGN 
3.1. 
Overview 
This is a phase 2, open-label, single ann, multicenter study evaluating the safety and efficacy of 
axicabtagene ciloleucel in combination with rituximab in subjects with relapsed/refracto1y large 
B-Cell lymphoma. 
Approximately 30 subjects will receive a planned dose of rituximab -
and conditioning 
chemotherapy with fludarabine and cyclophosphamide on Day -5, -4, and-3. After 2 days of 
rest on Day - 2 and Day -1, subjects will receive axicabtagene ciloleucel, administered at ~et 
dose of2 x 106 anti-CD19 CART cells/kg on ~bjects will also receive rituximab-
at 28-da intervals beginning- after axicabtagene ciloleucel infusion 
. A second dosing strategy (Dose Level -1) will be to 
administer rituximab only after axicabtagene ciloleucel infusion. This dose level may be 
explored only if the planned dosing strategy (rituximab initiation concunent with conditioning 
chemotherapy) has an unacceptable rate of toxicity. 
Further details on study procedures can be found in the study protocol. A study schema is 
presented in Figure 1. 
Figure 1. 
Study Schema 
Axicabtag;ene Ciloleucel 
Administration 
0. 
:::> 1 
0 
,----------, 
Conditioning Chemotherapy 
Fhid.vaba,c JOm~1/day. 
Cyclopbosphlllnidc $00 mpm11day 
Da -5 
Da -4 
Da -3 
Abbreviations: CAR, chimeric amigen receptor; IV, intravenous 
3.2. 
Hypothesis 
A sblglc infil!;ion of CAR 
tranSduc«t aurolo,:oll.$ T Cd$ 
odmiwstttcd IV 11 a •~ dose o 
2 X trf 11111i-CDl9 CART «llslk$ 
Da 0 
.----P-os-t--T-re-at-m-en-,-A-ss-es-sru- en-ts---. 
i3 
2 
3 
No fonnal hypothesis will be tested in this study. The study is designed to estimate the complete 
response (CR) rate in subjects with relapsed/refracto1y large B-cell lymphoma treated with 
axicabtagene ciloleucel in combination with rituximab. 
CONFIDENTIAL 
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29 Janua1y 2021 


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3.3.
Sample Size Consideration
The anticipated enrollment in this study is approximately 30 subjects. With a total sample size of 
30 subjects at a given dosing schedule, an observed CR rate of 70% will yield an 80% 
confidence intervals for the response rate with a maximum half width no greater than 13%, 
corresponding to a lower limit of at least 57%. This target CR rate, and the lower limit of the 
80% confidence interval for the CR rate, is meaningful because it would represent a significant 
improvement in the response rate for the subjects with relapsed/refractory large B-cell lymphoma 
over existing therapies
Additional assumptions and corresponding two-sided 95% and 80% exact confidence intervals 
are provided in Table 1.   
Table 1.
95% and 80% Exact Confidence Intervals for Observed CR Rate 
based on 30 Subjects
Subjects with CR
Observed CR Rate
95% Confidence 
Interval
80% Confidence 
Interval
15
50%
[31%, 69%]
[37%, 63%]
18
60%
[41%, 77%]
[47%, 72%]
21
70%
[51%, 85%]
[57%, 81%]
24
80%
[61%, 92%]
[68%, 89%]
27
90%
[73%, 98%]
[79%, 96%]


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4.
STUDY ENDPOINTS AND COVARIATES
4.1.
Endpoints
4.1.1.
Primary Endpoint
Complete response rate (complete response [CR] per the International Working Group (IWG) 
Lugano Classification {Cheson 2014}, as determined by the study investigators.
4.1.2.
Secondary Endpoints

Incidence of AEs and clinically significant changes in safety lab values

Objective Response Rate (ORR; CR + partial response [PR]) per the IWG Lugano 
Classification {Cheson 2014}, as determined by study investigators

Duration of Response (DOR) per the IWG Lugano Classification {Cheson 2014}, as 
determined by study investigators 

Progression Free Survival (PFS) per the IWG Lugano Classification {Cheson 2014}, as 
determined by study investigators 

Overall Survival (OS)

Pharmacokinetics (PK): Levels of axicabtagene ciloleucel in blood
4.2.
Subgroups and Covariates
The following variables may be used to examine efficacy results in subgroups or covariate 
analyses, as well as safety analyses. Analyses might be subject to restrictions due to small 
sample size.

Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 

Age at baseline  (<65 years,  ≥65 years) 

Race

Gender

Histologically proven Diffuse large B-cell lymphoma (DLBCL) type  

Cell of origin

 Double/Triple hit status


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
Disease stage at study entry  

International Prognostic Index (IPI) total score at baseline  

Refractory subgroup  

Number of prior chemotherapy regimens (1, 2-3, ≥ 4)

Bulky disease (at least one lesion 10 cm in diameter))  

Tumor burden at baseline, as measured by the sum of the product of the diameters (SPD) of 
target lesions at baseline (≤ median vs. > median value)


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5.
DEFINITIONS
5.1.
General
Study enrollment: Study enrollment occurs when a subject is confirmed to be eligible for the 
study, and   commences leukapheresis. 
Study Day 0: Defined as the day the subject receives the axicabtagene ciloleucel infusion. The 
day prior to Day 0 will be study Day -1. Any days prior Day 0 will be sequential and negative 
integer-valued. 
Baseline: Defined as the last non-missing value measured on or prior to conditioning 
chemotherapy, unless specified otherwise. 
Refractory Subgroup at Baseline: 
Chemotherapy-refractory disease is defined as one or more of the following:

Primary refractory disease
Progressive disease (PD) as best response to first-line therapy 
Stable disease (SD) as best response after at least 4 cycles of first-line therapy 
(e.g., 4 cycles of R-CHOP) with SD duration no longer than 6 months from last dose of 
therapy 

Refractory to second or greater lines of therapy 
PD as best response to most recent therapy regimen
SD as best response after at least 2 cycles of last line of therapy with SD duration no 
longer than 6 months from last dose of therapy 

Refractory post-autologous stem cell transplantation (ASCT)
Disease progression or relapsed ≤ 12 months after ASCT (must have biopsy proven 
recurrence in relapsed subjects)
If salvage therapy is given post-ASCT, the subject must have had no response to or 
relapsed after the last line of therapy
In case a subject may meet the criteria for multiple refractory subgroups, this subject will be 
assigned to the subgroup based on the hierarchy of priority of Refractory post ASCT > 
Refractory to second or greater lines of therapy > Primary refractory disease.  


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5.2.
Safety
Treatment-emergent adverse event (TEAE):  Any worsening of a pre-existing medical 
condition that occurs on or after axicabtagene ciloleucel infusion or any adverse event with onset 
on or after axicabtagene ciloleucel infusion. 
Deaths: Any death occurring after the leukapheresis up through the end of study.  
Adverse events of interest: The following AEs are of interest for the treatments of axicabtagene 
ciloleucel in combination with   rituximab:  
Identified risks: 

Cytokine-release syndrome (CRS) 

Neurologic toxicity

Cytopenias 

Infections

Hypogammaglobulinemia
Potential risks: 

Secondary malignancy

Replication competent retrovirus (RCR)

Immunogenicity (anti-axicabtagene ciloleucel antibodies)

Autoimmune disorders

Bone marrow failure
CRS: CRS is identified via collection of the syndrome on a case report from (CRF) specifically 
designed to collect CRS. Specific individual symptoms of CRS (eg, fever) collected on the AE 
log are coded using Medical Dictionary for Regulatory Activities (MedDRA) and linked to the 
corresponding CRS episode. Individual symptoms of CRS are graded per the latest version of 
Common Terminology Criteria for Adverse Events (CTCAE), and CRS as a syndrome is graded 
per modified Lee criteria {Lee 2014}. In the modified grading scale, neurologic AEs are not 
reported as part of the CRS syndrome as they will be reported separately with the neurologic 
events category and graded per the latest version of CTCAE v5.0.


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Neurologic toxicity: Neurologic adverse events are identified with a search strategy based on 
known neurologic toxicities associated with anti-CD19 immunotherapy {Topp 2015}.  The 
search strategy focuses on central nervous system toxicity, without regard to temporal 
relationship or concomitant conditions (e.g. CRS).   Additionally, the MedDRA system organ 
classes (SOCs) of Psychiatric Disorders and Nervous System Disorders will be reviewed for 
additional events; these events will then be evaluated for potential inclusion as neurologic AEs.
Cytopenias:  Cytopenias (neutropenia, anemia, or thrombocytopenia) are identified as: 

Neutropenia is identified using the latest version of the MedDRA search term (MST) 
documented prior to each analysis.

Anemia (including aplastic anemia) is identified using the standardized MedDRA query 
(SMQ) haematopoietic erythropenia (broad search).

Thrombocytopenia is identified using the SMQ haematopoietic thrombocytopenia (narrow 
search). 
Subjects with cytopenias present on or after Day 30 post axicabtagene ciloleucel infusion will be 
summarized separately by cell lineage.
Infections:  Infections are identified as AEs within the MedDRA SOC of Infections and 
Infestations that occur after treatment with axicabtagene ciloleucel. Subtypes of infections are 
identified using MedDRA high level group terms (HLGT) that capture events of: 

Bacterial infection, encompassing the MedDRA HLGTs of 
Bacterial infectious disorders 
Chlamydial infectious disorders

Viral infection, encompassing the MedDRA HLGT of viral infectious disorders

Opportunistic infections, encompassing the MedDRA HLGTs of 
Fungal infectious disorders
Mycobacterial infectious disorders

Other infections, encompassing the MedDRA HLGT of Infections – pathogen unspecified 
Hypogammaglobulinemia: Hypogammaglobulinemia will be identified using a MST search 
strategy defined by Kite.  


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Secondary malignancy:  Secondary malignancies are identified via collection on a case report 
form in which the investigator classifies the event as a secondary malignancy.  Additionally, 
adverse events that are coded into the SOC of Neoplasms benign, malignant, and unspecified 
(including cysts and polyps) with the exception of preferred terms containing “B-cell” or 
“B cell” and “Lymphoma”  will be reviewed to identify other potential events.  
Immunogenicity (anti-axicabtagene ciloleucel antibodies): Immunogenicity will be identified 
for subjects who have treatment emergent anti-axicabtagene ciloleucel antibody and have 
developed any AE belonging to the SMQ of anaphylactic reaction and the SMQ of 
hypersensitivity.  The narrow version of these 2 SMQs will be used.  
Autoimmune disorders: Autoimmune disorders are identified via collection on a case report 
form in which the investigator classifies the event as an autoimmune disorder. Additionally, 
adverse events that are coded into the MedDRA high level group term of auto-immune disorders 
within the immune system disorders system organ class (SOC) will be reviewed to identify other 
potential events.
Bone marrow failure:  Bone marrow failure will be identified using the narrow SMQ of 
haematopoietic cytopenias affecting more than one type of blood test.
Study day of onset of event/syndrome: Study day of onset of an event/syndrome is defined as 
the study day of the first occurrence of the event/syndrome. Study day of Onset of Grade 3 or 
Higher Events/Syndromes are defined in the same way, but restricted to Grade 3 or higher 
events/syndromes.
Study day of resolution of an event/syndrome: Study day of resolution of an event/syndrome 
is the last study day the event is present. If multiple events occur after axicabtagene ciloleucel 
infusion, the study day of resolution is the last day of the multiple events presented. Study day of 
resolution will not be calculated for events that are ongoing at the time of the data cutoff date or 
death.  
Duration of an AE of interest: The duration of an AE of interest may be derived only among 
subjects for whom all events of the class have resolved by the analysis data cutoff date. The 
duration is defined as the time from the earliest onset date of the AEs in the event class of 
interest through the resolution date of the last AEs in the event class, regardless of the gaps of the 
days between multiple events, ie, the resolution date of the last AE in the event class – the start 
date of the first AE in the event class + 1.  
The cumulative dose of rituximab is defined as the sum of all doses (in mg/m2) administered 
across the treatment period including Day -5 dosing.
5.3.
Efficacy
Complete Response Rate (CR rate):  The proportion of subjects with a CR after treatment with 
axicabtagene ciloleucel and   rituximab   and prior to any subsequent anti-lymphoma therapy. 
Subjects who do not meet the criteria for CR by the analysis cutoff date will be considered non-
CR. The derivation of this endpoint will only include response assessments obtained after at least 


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one dose of  rituximab   administration after axicabtagene ciloleucel infusion, and prior to any 
subsequent therapies for non-Hodgkin lymphoma (NHL) (including stem cell transplant [SCT] ).  
Responses will be assessed per the Lugano Classification {Cheson 2014}, as determined by the 
study investigators.
Objective Response Rate (ORR):  The proportion of subjects with a CR or PR   after treatment 
with axicabtagene ciloleucel and   rituximab   and prior to any subsequent anti-lymphoma 
therapy. Subjects who do not meet the criteria for objective response by the analysis cutoff date 
will be considered non-responders.  The derivation of this endpoint will only include response 
assessments obtained after at least one dose of rituximab   administration after axicabtagene 
ciloleucel infusion, and prior to any subsequent therapies for NHL (including SCT).  Responses 
will be assessed per the Lugano Classification {Cheson 2014}, as determined by the study 
investigators. 
Duration of response (DOR): DOR is defined only for subjects who experience an objective 
response (CR or PR) and is the time from the first objective response to disease progression per 
the Lugano Classification {Cheson 2014} as determined by study investigators or death due to 
any reason. Subjects not meeting the criteria for progression or death by the analysis data cutoff 
date will be censored at their last evaluable disease assessment date and their response will be 
noted as ongoing. Subjects who receive additional anti-cancer therapy in the absence of 
documented progression will be censored at the last evaluable disease assessment prior to the 
additional therapy. Subjects who receive an SCT in the absence of documented progression will 
be censored at the last evaluable disease assessment prior to the date of the SCT. A sensitivity 
analysis will be conducted in which disease assessments obtained after SCT  while in 
axicabtagene ciloleucel induced remission are included in the derivation of DOR. Additional 
details on the derivation of DOR are provided in Appendix 2. 
Progression-free Survival (PFS): PFS is defined as the time from the axicabtagene ciloleucel 
infusion date to the date of disease progression per the Lugano Classification {Cheson 2014} as 
determined by study investigators or death from any cause. Subjects not meeting the criteria for 
progression or death by the analysis data cutoff date will be censored at their last evaluable 
disease assessment date. The PFS for subjects who undergo SCT while in remission will be 
censored at the last evaluable disease assessment prior to the date of SCT; the PFS for subjects 
who undergo other new anti-cancer therapies in the absence of documented relapse will be 
censored at the last evaluable disease assessment prior to the new anti-cancer therapies. A 
sensitivity analysis will be conducted in which disease assessments obtained after SCT while in 
axicabtagene ciloleucel induced remission are included in the derivation of PFS. Additional 
details on the derivation of PFS are provided in Appendix 2.
Overall Survival (OS): OS is defined as the time from the axicabtagene ciloleucel infusion to 
the date of death. Subjects who have not died by the analysis data cutoff date will be censored at 
their last date known to be alive or the data cutoff date, whichever is earlier.  Further details on 
the derivation of OS and the specific data modules that will be used to derive the last date known 
to be alive are provided in Appendix 2.   


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6.
ANALYSIS SETS
The following analyses sets are defined for this study.
6.1.
Modified Intent-to-treat Analysis Set
Modified intent-to-treat (mITT) analysis set consists of all subjects enrolled and treated with the 
target dose of axicabtagene ciloleucel at 2 x 106 (1.0 x 106 to 2.4 x 106 ) anti CD19 CAR T 
cells/kg, and at least one dose of rituximab   after axicabtagene ciloleucel infusion. Subjects are 
considered to have received the target dose if they receive at least 1 x 106 anti-CD19 CAR T 
cells/kg. This analysis set will be used for all efficacy analyses. 
6.2.
Safety Analysis Set
Safety analysis set consists of all subjects treated with any dose of axicabtagene ciloleucel.
6.3.
Full Analysis Set
Full analysis set consists of all enrolled subjects (i.e. commences leukapheresis) and will be used 
for summaries of subject disposition.


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7.
INTERIM ANALYSIS AND EARLY STOPPING GUIDELINES
Formal interim analysis of efficacy is not planned for the early trial stopping purpose. 
7.1.
Safety Interim Analysis
An internal safety review team (SRT), comprising the study sponsor medical monitor, drug 
safety physician, study statistician, and at least 1 active investigator, will meet after 6 subjects  
have completed their 28-day disease assessment and again after 15 subjects have completed their 
28-day disease assessment. The SRT will review ongoing safety data and will be chartered to 
make study conduct recommendations based on an analysis of benefit vs. risk.


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8.
DATA SCREENING AND ACCEPTANCE
8.1.
General Principles
The database will be subject to the edit checks outlined in the Data Management Plan and 
additional manual data reviews defined by the study team. Data inconsistencies will be reviewed 
and resolved before the database snapshot for the primary analysis and the final database lock.
8.2.
Electronic Transfer and Archiving of Data
The Medidata Rave system will be used to collect the data in this study. Raw data extracted from 
Medidata Rave will be archived prior to further dataset creation, maintenance, and analysis. 
Datasets (raw data, study data tabulation model [SDTM] data, and/or analysis data model 
[ADaM] data) for planned analyses will be archived. Any additional unplanned analyses that 
occur after the primary analysis and prior to the final analysis will also be archived. Key data 
external to the clinical study database will be included in the relevant SDTM and ADaM 
modules when the external data are available.
8.3.
Handling of Missing and Incomplete Data
8.3.1.
Efficacy
The method for handling missing data is described in the definition for each efficacy endpoint. 
Every effort will be made to obtain complete dates for deaths. In the event of a partial or missing 
death date and the corresponding censoring date for survival, the algorithm in Appendix 1 
(Section 12) will be used.
8.3.2.
Safety
Partial AE start dates will be imputed. If dates are missing or incomplete for adverse event start 
dates, the algorithm defined in Appendix 1 (Section 12) will be used. Completely missing death 
dates or death dates with only a year reported will not be imputed.
8.4.
Detection of Bias
A listing of subjects with important protocol deviations (IPDs) will be generated. The deviations 
included in this list will include, but not be limited to, violations of eligibility criteria and use of 
exclusionary medication during the study. Lack of protocol compliance will be evaluated by 
summarizing the subject incidence of IPDs. High rates of IPDs may indicate bias.
8.5.
Outliers
Descriptive statistics may be used to identify potential outliers in any key variables analyzed. 
Suspected outliers will be included in all analyses unless there is sufficient scientific justification 
to exclude them.


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8.6.
Distributional Characteristics
The Clopper-Pearson (an exact interval) method is used to generate 95% CI for the CR rate. This 
method assumes that individual subject responses are independent with binomial distribution. 
While the Clopper-Pearson interval provides adequate coverage probability, it is commonly 
wider than necessary {Brown 2002}, leading to overly conservative estimates of the lower bound 
of response rate.
8.7.
Validation and Configuration Management
Programs for the development of the SDTM and ADaM datasets and the generation of the tables, 
figures, and listings will be developed and maintained according to Kite Pharma’s Standard 
Operating Procedures (SOPs) if applicable. The software and version used to generate analyses 
will be indicated in the archived documentation.


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9.
STATISTICAL METHODS OF ANALYSIS
9.1.
General Principles
The primary efficacy analysis will be performed when the last treated subject in the mITT set has 
had the opportunity to be evaluated for the 6-month disease assessment. The final analysis will 
occur when all subjects have completed the study.  Additional analyses for additional internal 
review or publication may occur after the primary analysis.
9.2.
Subject Accountability
The number of subjects screened, enrolled, treated with conditioning chemotherapy, treated with 
investigational treatments will be summarized. The reasons for discontinuing treatment and 
discontinuing study will be summarized.
Summaries of actual and potential follow-up time from axicabtagene ciloleucel infusion will be 
provided. Actual follow-up time is defined as time from the first dose of axicabtagene ciloleucel 
to the date of death or the last date known alive, and calculated as date of death or the last date 
known alive - axicabtagene ciloleucel infusion date + 1. Potential follow-up time is defined as 
the time from the axicabtagene ciloleucel infusion to the data cutoff date for the analysis, and 
calculated as data cutoff date - axicabtagene ciloleucel infusion date + 1. 
The number of subjects enrolled by site will be summarized.
The number of subjects in each analysis set along with reasons for exclusion will be provided if 
data are available.
9.3.
Important Protocol Deviations
The clinical study team will define IPD categories and review all potential IPDs at minimum, 
prior to the database snapshot for the primary efficacy analysis. Important protocol deviations 
will be categorized by deviation type (eg, entry eligibility, use of excluded medication). The 
subject incidence of IPDs will be summarized overall and by deviation category.
9.4.
Demographic and Baseline Characteristics
Statistics and frequencies for the following demographic and baseline characteristics will be 
tabulated:

Age (in years) at baseline and by category (< 65, ≥ 65)

Sex

Ethnicity and race

Weight at leukapheresis


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
ECOG performance status at baseline

Number of prior chemotherapy regimens and best overall response to the last prior regimen

Prior ASCT and best overall response corresponding to the ASCT

Refractory subgroup

Tumor burden, as measured by the SPD of selected nodes or lesions at baseline

Disease stage at study entry (I, II, III, IV)

Cell of origin

Histologically proven DLBCL type

Disease extent (presence of B symptoms, S [splenic involvement], E [extranodal disease], 
X [bulky disease], bone marrow involvement) as determined by the investigator at screening

Double/Triple Hit Status

IPI total score at baseline
9.5.
Efficacy Analyses
Efficacy analyses will be conducted on the mITT analysis set, and the investigator assessment of 
disease status per the IWG Lugano Classification {Cheson 2014} will be used for disease 
response related analyses. 
9.5.1.
Complete Response and Objective Response
9.5.1.1.
Analyses of Response Rate
The subject incidence of CR and objective response (CR+PR) will be calculated. Two-sided 95% 
Confidence Intervals will be generated using the Clopper-Pearson (an exact interval) method.
The number and percentage of subjects who initially do not attain CR and who subsequently 
attain a CR will be summarized. 
9.5.1.2.
Subgroup Analyses 
The response rates and exact 2-sided 95% confidence intervals will be generated for subgroups 
of the mITT analysis set based on but not limited to the covariates defined in Section 4.2. A 
forest plot of the proportion of responders for each of these groups will be generated.


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9.5.2.
Duration of Response
The Kaplan-Meier approach will be used to estimate DOR. The number of subjects censored and 
the reasons for censoring will be summarized. The reverse Kaplan-Meier approach {Schemper 
1996} will be used to estimate the follow-up time for DOR.    
DOR may be summarized in subgroups defined by the best response attained on study.
9.5.3.
Progression Free Survival 
Kaplan-Meier plots, estimates and 2-sided 95% confidence intervals will be generated for PFS.  
Estimates of the proportion of subjects alive and progression-free at 3 month intervals will be 
provided.  The number of subjects censored or having events, and the reasons for censoring or 
type of events (PD or death) will be summarized. 
PFS may be summarized in subgroups defined by the best response attained on study.
9.5.4.
Overall Survival
The analysis of overall survival will use the same methods as the analysis of PFS. The reverse 
Kaplan-Meier approach {Schemper 1996} will be used to estimate the follow up time for overall 
survival. 
OS may be summarized in subgroups defined by the best response attained on study.
9.5.5.
Tumor Burden
The change in tumor burden, as measured by the SPD of the selected lesions, from baseline to 
post-baseline nadir will be summarized in absolute numbers (mm2) and percentage.  A graphical 
summary of this change will be presented in a vertical bar chart with each subject’s change from 
baseline to nadir displayed as a vertical bar, with color coding that indicates best response 
attained (“waterfall” plot).  Summary statistics will be provided for this change. Data collected 
after new anti-cancer therapy (including SCT) will not be included for the analyses.
9.6.
Safety Analyses
Safety analyses will be conducted on the safety analysis set. The primary analysis of safety data 
will summarize all TEAEs and laboratory values. 
AEs will be coded with the latest version of MedDRA. The severity of adverse events will be 
graded using the latest version of National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE). The incidence and severity of Cytokine release syndrome (CRS) 
will be graded using a revised CRS grading scale developed by Lee and colleagues {Lee 2014}. 
Individual symptoms associated with CRS will be graded per the latest version of CTCAE.
Subjects enrolled, but not received investigational treatments, will be followed for AEs for 30 
days after the last study procedure. AEs reported in these subjects will be archived in the study 
database and available in SDTM and ADaM datasets, but will not be tabulated in adverse event 
summaries.


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9.6.1.
Adverse Events 
The subject incidence of the following AEs will be tabulated: 

Summary of adverse events (any, worst severity, serious, related) 

All TEAEs by SOC and preferred term (PT)

All serious adverse events (SAEs) by SOC and PT

All leukapheresis/conditioning chemotherapy/ axicabtagene ciloleucel and/or rituximab 
related AEs/SAEs 

All Grade 3 or higher TEAEs 

All Grade 3 or higher axicabtagene ciloleucel and/or rituximab related TEAEs  

TEAEs of interest, including identified risks and potential risks 

Other clinically important adverse reactions 

Death (through the long term follow-up and treatment related SAEs)
Summary statistics for the study day of onset, the study day of resolution, and the duration of 
AEs of interest will be provided. A subject listing of deaths and SAEs (including narratives) will 
be provided by overall and by treatment period. 
Subgroup analyses of AEs may be generated using the covariates listed in Section 4.2 if 
applicable.
9.6.2.
Laboratory Test Results 
Laboratory results will be graded according to the latest version of CTCAE.   The incidence of 
worst grade CTCAE at post-baseline for selected analytes will be  summarized.
9.6.3.
Anti-axicabtagene Ciloleucel Antibodies 
The subject incidence of any anti-axicabtagene ciloleucel antibodies will be tabulated. For 
subjects testing positive for antibodies, the persistence of the antibody over time will be 
summarized.
9.6.4.
Replication Competent Retrovirus   
The subject incidence of RCR detected in blood samples will be tabulated overall and by 
assessment time. The persistence of RCR over time will be summarized


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9.7.
Exposure to Study Treatments and Product Characteristics
Summary statistics and subject listings will be provided for the following:

Total body surface area (BSA)-adjusted dose of cyclophosphamide 

Total BSA-adjusted dose of fludarabine 

Weight-adjusted dose of axicabtagene ciloleucel    

Total CAR T cells of the axicabtagene ciloleucel infusion 

Total T cells of the axicabtagene ciloleucel infusion 

Transduction percentage 

Ratio of CD4 and CD8 T cells 

Percentages of T cell memory phenotypes 

Interferon gamma (IFN-γ) production in co-cultures of axicabtagene ciloleucel product

Number of infusion and cumulative dose of rituximab
9.8.
Exposure to Concomitant Medications and Procedures
The subject incidence of concomitant medications will be provided and summarized by 
medication category (general, immunosuppressive, anti-infective, vasopressor, corticosteroid, 
and tocilizumab) and World Health Organization (WHO) Drug coded term. The subject 
incidence of procedures will be tabulated.
9.9.
Subsequent Anti-Cancer Therapy
The incidence and type (by WHO Drug coded term and categories) of subsequent anti-cancer 
therapy and stem cell transplant (autologous, allogeneic) will be summarized. 
9.10.
Duration Metrics 
Summary statistics will be provided for the following durations:

Days from leukapheresis to commencement of conditioning chemotherapy

Days from leukapheresis to administration of axicabtagene ciloleucel 

Days from conditioning chemotherapy to administration of axicabtagene ciloleucel 

Duration of hospitalization for the axicabtagene ciloleucel infusion


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9.11.
Axicabtagene Ciloleucel Delivery Time
Summary statistics will be provided for the following delivery time:

Days from leukapheresis to axicabtagene ciloleucel release 

Days from leukapheresis to delivery of axicabtagene ciloleucel at study site among dosed 
subjects
9.12.
Pharmacokinetics
Refer to separate PK/PD SAP.
CCI-


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10.
CHANGES FROM PROTOCOL SPECIFIED ANALYSES
Not applicable.


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11.
REFERENCES
Brown LD, Cai TT, DasGupta A. Confidence Intervals for a Binomial Proportion and 
Asymptotic Expansions. The Annals of Statistics 2002;30 (1):160-201.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014;32 (27):3059-68.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the 
diagnosis and management of cytokine release syndrome. Blood 2014;124 
(2):188-95.
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials 1996;17 (4):343-6.
Topp MS, Gokbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity 
of blinatumomab for adult patients with relapsed or refractory B-precursor acute 
lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 
2015;16 (1):57-66.


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12.
APPENDICES
Appendix 1.
Conventions for Clinical Data That Require Imputation for Partial or Missing Dates
Appendix 2.
Derivation of Time to Event Endpoints
Appendix 3.
Derivation of Last date known to be alive


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Appendix 1.
Conventions for Clinical Data That Require Imputation for Partial or 
Missing Dates
The following data will be imputed using the algorithm shown in Table 2 below:

Adverse event start dates 

Deaths (please see exceptions below) 

Concomitant start dates
Table 2.
Imputation Rules for Partial or Missing Start Dates
Stop Date
Complete:  
yyyymmdd
Partial:  yyyymm
Partial:  yyyy
Start Date
< day 0
≥ day 0
< day 0 
yyyymm
≥ day 0
yyyymm
< day 0 
yyyy
≥ day 0
yyyy
Missing
= day 0
yyyymm
1
1
n/a
1
1
Partial
yyyymm
≠ day 0
yyyymm
2
2
2
2
2
2
2
= day 0
yyyy
1
1
n/a
1
1
Partial
yyyy
≠ day 0 
yyyy
3
3
3
3
3
3
3
Missing
4
1
4
1
4
1
1
1 = impute the date of day 0
2 = impute the first of the month
3 = impute January 1 of the year
4 = impute January 1 of the stop year
Note:  if the start date imputation leads to a start date that is after the stop date, then do not impute the start date.
Imputation rules for partial or missing death dates:
1. If death year and month are available but day is missing:

If mmyyyy for the last contact date = mmyyyy for death date, set death date to the day after 
the last date known to be alive.

If mmyyyy for the last date known to be alive < mmyyyy for death date, set death date to the 
first day of the death month.

If mmyyyy for last date known to be alive > mmyyyy for death date, data error and do not 
impute.


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2. If both month and day are missing for death date or a death date is completely missing, do 
not impute and censor the subject survival time at the last date known to be alive.
Imputation rules for original date of diagnosis: 
1. If year and month are available but day is missing, then impute the first day of the month.  
2. If year is available but month and day are missing, then impute January 1 of the year.


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Appendix 2.
Derivation of Time to Event Endpoints 
The derivations of Duration of Response (DOR), Progression-free Survival (PFS), and Overall 
Survival (OS) are provided below. 
Duration of Response 
Table 3.
Primary Analysis of DOR
Circumstance
Event / Censored
Date of Event / Censoring
Disease progression prior to initiation of new anti-
cancer therapy (including SCT) , and prior to data 
cutoff for analysis 
Event
Progression date
Death without disease progression and without new 
anti-cancer therapy (including SCT)  prior to data 
cutoff for analysis
Event
Death date
New anti-cancer therapy (including SCT)  started 
before disease progression or death, and prior to 
data cutoff for analysis
Censored
Date of last evaluable disease 
assessment prior to initiation of 
new therapy or SCT, whichever 
is earlier.
Disease progression or death documented after data 
cutoff for analysis 
Censored
Date of last evaluable disease 
assessment prior to data cutoff 
for analysis
Remain in response without new anti-cancer 
therapy (including SCT)  through the 
discontinuation of  study, and prior to data cutoff 
for analysis 
Censored
Date of last evaluable disease 
assessment prior  to the 
discontinuation of study, or 
prior to data cutoff for analysis, 
whichever earlier


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Table 4.
Sensitivity Analysis of DOR
Circumstance*
Event / Censored
Date of Event / Censoring
Disease progression after initiation of SCT, but 
prior to other new anti-cancer therapy 
Event
Progression date
Death after  SCT without disease progression or 
other new anti-cancer therapy 
Event
Death date
Remain in response after SCT without other new 
anti-cancer therapy  
Censored
Last evaluable disease 
assessment date
Remain in response after SCT prior to other 
initiated new anti-cancer therapy
Censored
Last evaluable disease 
assessment prior to other 
initiated new anti-cancer 
therapy
Death without disease progression and without new 
anti-cancer therapy (including SCT)  prior to data 
cutoff for analysis 
Censored
Last evaluable disease 
assessment date before death 
date
*For data from SCT after axicabtagene ciloleucel infusion. For all the other circumstances, follow the imputation rules described 
in Table 3.
Progression-free Survival (PFS):  
Table 5.
Primary Analysis of PFS
Circumstance
Event / Censored
Date of Event / Censoring
Disease progression prior to initiation of 
new anti-cancer therapy (including SCT) , 
or prior to the data cutoff for analysis 
Event
Progression date
Death without disease progression and 
without new anti-cancer therapy (including 
SCT) prior to the data cutoff for analysis
Event
Death date
New anti-cancer therapy (including SCT) 
started before disease progression or death, 
or prior to the data cutoff for analysis 
Censored
Date of last evaluable disease assessment 
prior to initiation of new therapy or SCT, 
whichever is earlier
Disease progression or death documented 
after data cutoff for analysis
Censored
Date of last evaluable disease assessment 
prior to data cutoff for analysis
No disease progression through the 
discontinuation of study, or prior to data 
cutoff for analysis 
Censored
Date of last evaluable disease assessment 
prior to the discontinuation of study, or 
prior to data cutoff for analysis, whichever 
is earlier
No disease assessment done after 
axicabtagene ciloleucel infusion by the 
cutoff date
Censored 
 Axicabtagene ciloleucel infusion date


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Table 6.
Sensitivity Analysis of PFS
Circumstance*
Event / Censored
Date of Event / Censoring
Disease progression after initiation of SCT, 
but prior to other new anti-cancer therapy 
Event
Progression date
Death after  SCT without disease 
progression or other new anti-cancer 
therapy 
Event
Death date
Remain no disease progression after SCT 
without other new anti-cancer therapy  
Censored
Last evaluable disease assessment date
Remain no disease progression after SCT 
prior to other initiated new anti-cancer 
therapy
Censored
Last evaluable disease assessment prior to 
other initiated new anti-cancer therapy
*For data from SCT after axicabtagene ciloleucel infusion. For all the other circumstances, follow the imputation rules described 
in Table 5.
Overall Survival (OS):  
Table 7.
Imputation Rule of OS Event/Censoring Date
Circumstance
Event / Censored
Date of Event / Censoring
Death before data cutoff date for analysis
Event
Date of death
Death after data cutoff date for analysis
Censored
Data cutoff date
Known to be alive after data cutoff date for 
analysis
Censored
Data cutoff date
Alive up through the discontinuation of 
study, or data cutoff date and no further 
information available afterwards   
Censored
Last date known to be alive date up 
through the date of discontinuation of 
study, or data cutoff date, whichever 
is earlier


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Appendix 3.
Derivation of Last date known to be alive
The last date known to be alive will be derived by obtaining the maximum complete date among 
the following data modules, and more date points may be considered based on actual data 
collected:

Leukapheresis date

Conditioning chemo admin date

Axicabtagene ciloleucel infusion date

 Rituximab infusion date

CT scan date

PET scan date

Target lesion assessment date

Non-target lesion assessment date

New lesion assessment date

Disease response assessment date

Long term follow up subject status date where status = ‘alive’

End of treatment disposition where status is not equal to death or lost to follow up

End of post-treatment assessment period where status is not equal to death or lost to follow 
up

End of study data where end of study reason is not equal to death or lost to follow up