Clinical trial NCT03436862
Conditions: Hodgkin Lymphoma
Keywords: Nivolumab Autologous Stem Cell Transplant Blood cancers
Sponsor: SCRI Development Innovations, LLC
Start date: 2018-05-23; Completion date: 2023-04-04
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase II single-arm open-label study of nivolumab as maintenance therapy after autologous stem cell transplantation in patients with Hodgkin lymphoma at risk of relapse or progression.

Detailed description:
The primary objective of this study is to evaluate safety and tolerability of nivolumab as maintenance therapy early after autologous stem cell transplant in patients with Hodgkin's Lymphoma (HL).

Eligible patients will receive nivolumab (240 mg IV) every 2 weeks (± 2 days as long as interval between doses is 12-16 days) starting 45-120 post-transplant for up to a maximum of 6 months of treatment. Response to treatment will be assessed 6 months and 1 year post-transplant using Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification.

Arms: arm 1: Patients will receive Nivolumab 240 mg by intravenous infusion (IV) starting Day 45-120 post-transplant (±10 days) every 2 weeks for up to a maximum of 6 months of treatment.
Interventions: intervention 1: Nivolumab
Intervention descriptions: intervention 1: Nivolumab 240 mg IV infusion over 60 minutes given every 2 weeks for up to 6 months.

Protocol documents:
Prot_SAP_000.pdf: 
 
C O N FI D E N TI A L  
T his d oc u me nt is c o nfi de nti al a n d is t he pr o perty of S ar a h C a n n o n Devel o p me nt I n n ov ati o ns,  L L C.  N o p art of t his 
d oc u me nt m ay be tr a ns mitte d, re pr o d uce d, p u blis he d, or use d by ot her pers o ns wit h o ut pri or writte n a ut h oriz ati o n 
fr o m S ar a h C a n n o n Devel o p me nt I n n ov ati o ns, L L C . 
B M T 2 4  
A P h ase II Si n gle Ar m St u d y of Ni v ol u m a b as M ai nte n a nce  Ther a p y after 
A ut ol o g o us S te m Cell T r a ns pl a nt ati o n i n P atie nts wit h H o d g ki n L y m p h o m a 
at R is k of R el a pse or P r o gressi o n 
S A R A H C A N N O N D E V E L O P M E N T 
I N N O V A TI O N S S T U D Y N U M B E R : 
 
B M T 2 4  
S T U D Y  D R U G:  
Ni v ol u ma b  
S P O N S O R:  
Sara h Ca n n o n De vel o p me nt I n n o vati o ns , L L C 
1 1 0 0 Dr. Marti n L . Ki n g Jr. Bl v d. , S uite 8 0 0 
Nas h ville, T N  3 7 2 0 3  
1- 8 4 4 -7 1 0 -6 1 5 7  
as ksara h @sara hca n n o n.c o m  
 
S T U D Y C H AI R : 
Carl os B ac hier, M D  
Sara h Ca n n o n Researc h I nstit ute   
1 1 0 0 Dr. Marti n L . Ki n g Jr. Bl v d. , S uite 8 0 0 
Nas h ville, T N  3 7 2 0 3  
1- 8 4 4 -7 1 0 -6 1 5 7  
 
D A T E FI N A L:  
0 6  J ul y 2 0 1 7  
A M E N D M E N T N U M B E R:  
1  
A M E N D M E N T D A T E:       
2 3 A u g ust 2 0 1 7  
A M E N D M E N T N U M B E R:  
2  
A M E N D M E N T D A T E:       
1 6 Oct o ber  2 0 1 7  
A M E N D M E N T N U M B E R:  
3  
A M E N D M E N T D A T E:       
2 3 Marc h  2 0 1 8  
A M E N D M E N T N U M B E R:  
4  
A M E N D M E N T D A T E:       
2 4  Se pte m ber  2 0 1 8  
A M E N D M E N T N U M B E R:  
5  
A M E N D M E N T D A T E:    
1 6 J a n uar y 2 0 1 9 
A M E N D M E N T N U M B E R:  
6  
A M E N D M E N T D A T E:    
0 7 Fe br uar y 2 0 2 0  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 of 6 9  
 
 
B M T 2 4  
A P h ase II Si n gle Ar m St u d y of Ni v ol u m a b as M ai nte n a nce  T her a p y after 
A ut ol o g o us Ste m C ell Tr a ns pl a nt ati o n i n P atie nts wit h H o d g ki n L y m p h o m a 
at Ris k of Rel a pse or Pr o gressi o n  
 
 T his cli nic al  st u d y s h all be c o n d ucte d i n c o m pli a nce wit h t he pr ot oc ol, as refere nce d herei n, a n d 
all a p plic a ble l oc al, n ati o n al, a n d i nter n ati o n al re g ul at or y re q uire me nts t o i ncl u de, b ut n ot be 
li mite d t o: 
•  
I nter n ati o n al C o u ncil f or  H ar m o nisati o n (I C H) G ui deli nes o n G o o d Cli nic al P r actice 
( G C P) 
•  
Et hic al pri nci ples t h at h a ve t heir ori gi ns i n t he Decl ar ati o n of Helsi n ki  
•  
F o o d a n d Dr u g A d mi nistr ati o n ( F D A) C o de of F e der al Re g ul ati o n ( C F R):  
o  
Title 2 1 C F R P art 5 0 & 4 5 C F R P art 4 6, Pr otecti o n of H u m a n S u bjects 
o  
Title 2 1 C F R P art 5 4, Fi n a nci al Discl os ure b y Cli nic al I n vesti g at ors  
o  
Title 2 1 C F R P art 5 6, I nstit uti o n al Re vie w B o ar ds  
o  
Title 2 1 C F R P art 3 1 2, I n vesti g ati o n al Ne w Dr u g A p plic ati o n 
o  
Titl e 4 5 C F R P arts 1 6 0, 1 6 2, a n d 1 6 4, He alt h I ns ur a nce P ort a bilit y a n d 
Acc o u nt a bilit y Act ( HI P A A)  
 
 
 
 
 
 
 
 
   
  
    
 
   
  
 
 
  
 
  
 
   
   
 
   
    
  
  
  
  
  
   
   
  
  
  
    
  
 
  
  
  
 
   
  
    
  
   
     
  
  
  
  
 
    
  
 
 
 
 


 
 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
Pa ge 3 of 6 9  
 
Cli nic al  St u d y  Si g n at ure A p pr o v al P a ge  
A P h ase II Si n gle Ar m St u d y of Ni v ol u m a b as M ai nte n a nce  T her a p y after 
A ut ol o g o us Ste m  Cell Tr a ns pl a nt ati o n i n P atie nts wit h H o d g ki n L y m p h o m a 
at Ris k of Rel a pse or Pr o gressi o n  
 
S A R A H C A N N O N D E V E L O P M E N T 
I N N O V A TI O N S S T U D Y N U M B E R : 
 
B M T 2 4  
S T U D Y  D R U G:  
Ni v ol u ma b   
D A T E FI N A L:  
0 6  J ul y 2 0 1 7 
A M E N D M E N T N U M B E R:  
1  
A M E N D M E N T D A T E:       
2 3 A u g ust 2 0 1 7  
A M E N D M E N T N U M B E R:  
2  
A M E N D M E N T D A T E:       
1 6 Oct o ber  2 0 1 7  
A M E N D M E N T N U M B E R:  
3  
A M E N D M E N T D A T E:       
2 3 Marc h  2 0 1 8  
A M E N D M E N T N U M B E R  
4  
A M E N D M E N T D A T E:   
2 4 Se pt e m ber  2 0 1 8  
A M E N D M E N T N U M B E R:  
5  
A M E N D M E N T D A T E:    
1 6  J a n uar y 2 0 1 9 
A M E N D M E N T N U M B E R:  
6  
A M E N D M E N T D A T E:    
0 7 Fe br uar y 2 0 2 0  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _         _ _ _ _ _ _ _ _ _ _ _ _ _ _  
St u d y C h ai r  
S ar a h C a n n o n Res e arc h I nstit ute  
St u d y C h ai r  Si g n at ure  
 
D ate  
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _         _ _ _ _ _ _ _ _ _ _ _ _ _ _  
S p o ns or Re pres e nt ati ve  
S ar a h C a n n o n De vel o p m e nt 
I n n o v ati o ns, L L C 
 
S ar a h C a n n o n De vel o p m e nt I n n o v ati o ns, 
L L C Re pres e nt ati ve Si g n at ure  
 
D ate  
 
 
 
 
 
 
 
 
0 2/ 1 2/ 2 0 2 0
0 9: 3 8 A M E S T
I a m a p pr o vi n g t hi s d o c u m e nt.
C arl o s  B a c hi er, M. D.
S h e et al  K h e d k ar, M. D., M S P H
I a m a p pr o vi n g t hi s
d o c u m e nt.
0 2/ 1 3/ 2 0 2 0
0 8: 5 1 A M E S T
02/13/2020
08:51 AM EST
I am approving this
document.
Sheetal  Khedkar, M.D., MSPH
Carlos  Bachier, M.D.
I am approving this document.
02/12/2020
09:38 AM EST


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 of 6 9  
 
 
Cli nic al St u d y Pri nci p al I n vesti g at or Si g n at ure F or m  
A P h ase II Si n gle Ar m St u d y of Ni v ol u m a b as M ai nte n a nce  T her a p y after 
A ut ol o g o us Ste m  Cell Tr a ns pl a nt ati o n i n P atie nts wit h H o d g ki n L y m p h o m a 
at Ris k of Rel a pse or Pr o gressi o n  
 
S A R A H C A N N O N D E V E L O P M E N T 
I N N O V A TI O N S S T U D Y N UM B E R:  
 
B M T 2 4  
D A T E FI N A L:  
0 6  J ul y 2 0 1 7 
A M E N D M E N T N U M B E R:  
1  
A M E N D M E N T D A T E:       
2 3 A u g ust 2 0 1 7  
A M E N D M E N T N U M B E R:  
2  
A M E N D M E N T D A T E:       
1 6 Oct o ber 2 0 1 7  
A M E N D M E N T N U M B E R:  
3  
A M E N D M E N T D A T E:       
2 3 Marc h  2 0 1 8  
A M E N D M E N T N U M B E R:  
4   
A M E N D M E N T D A T E:       
2 4 Se pte m ber  2 0 1 8  
A M E N D M E N T N U M B E R:  
5  
A M E N D M E N T D A T E:    
1 6  J a n uar y 2 0 1 9 
A M E N D M E N T N U M B E R:  
6  
A M E N D M E N T D A T E:    
0 7 Fe br uar y 2 0 2 0  
B y si g ni n g t his pr ot oc ol acce pta nce pa ge, I c o nfir m I ha ve rea d, u n dersta n d, a n d a gree t o c o n d uct t he 
st u d y i n acc or da nce wit h t he c urre nt pr ot oc ol. 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _            _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _     _ _ _ _ _ _ _  
P ri nci p al I n vesti g at or N a me  
( Please Pri nt) 
 
P ri nci p al I n vesti g at or Si g n at ure  
 
D ate  
 
Please retai n a c o p y of t his pa ge f or y o ur st u d y fil es a n d ret ur n t h e ori gi nal si g ne d a n d date d 
f or m t o: 
 
Sara h Ca n n o n De v el o p me nt I n n o v ati o ns , L L C 
1 1 0 0 Dr. Marti n L . Ki n g Jr. Bl v d., S uite 8 0 0 
At t n:  B M T 2 4  St u d y Tea m  
Nas h ville, T N 3 7 2 0 3 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 of 6 9  
 
B M T 2 4 S u m m ar y of C h a n ge  
 
A M E N D M E N T N U M B E R:  
6  
A M E N D M E N T D A T E:        0 7 Fe br uar y 2 0 2 0  
Secti o n 5. 0 St u d y Desi g n Fi ve of t he f ort y p atie nts t o be e nr olle d o n t he st u d y will be e nr olle d 
t o a c o ntr ol gr o u p. 
Secti o n 5. 4. 2 I m m u ne R ec o ver y  vers us C o ntr ol Gr o u p Secti o n a d de d t o detail st u d y sc h e d ule 
f or c o ntr ol patie nts. 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 of 6 9  
 
B M T 2 4  P R O T O C O L S Y N O P SI S  
Title of St u d y : 
A P hase II Si n gle Ar m St u d y of Ni v ol u ma b as Mai nte na nce  T hera p y after A ut ol o g o us Ste m  
C ell Tra ns pla ntati o n i n P atie nts wit h H o d g ki n L y m p h o ma at Ris k of Rela pse or Pr o gressi o n  
S ar a h C a n n o n 
De vel o p me nt 
I n n o v ati o ns St u d y  
N u m ber : 
B M T 2 4  
S p o ns or:  
Sara h Ca n n o n De vel o p me nt I n n o vati o ns , L L C –  Nas h ville , T N  
St u d y  D ur ati o n:  
T he t otal d urati o n of t he st u d y is pla n ne d t o be  4 years 
( 2 years e nr oll me nt a n d 2 years ma xi m u m f oll o w -u p).  
P h ase of St u d y :  II 
St u d y  Ce nter s: 
T his st u d y will be  c o n d ucte d at 6  st u d y sites. 
N u m ber of 
P atie nts:  
U p t o  4 0  patie nts are pla n ne d t o be e nr olle d i n t his st u d y: 3 5  will recei ve st u d y treat me nt a n d 
5 patie nts will recei ve sta n dar d-of -care pr oce d ures a n d treat me nt b ot h pre - a n d p ost-
tra ns pla nt. 
O bjecti ves:  
Pri m ar y O bjecti ve  
T he pri mar y o bj ecti ve of t his st u d y is t o:  
•  
E val uate safet y a n d t olera bilit y of ni v ol u ma b as mai nte na nc e earl y after a ut o l o g o us 
ste m cell tra ns pla nt ( A S C T) i n patie nts wit h H o d g ki n L y m p h o ma ( H L) 
Sec o n d ar y O bjecti ves  
T he sec o n dar y o bj ecti ve of t his st u d y is t o: 
•  
E val uate P F S at 1 2 m o nt hs  p ost -tra ns pla nt w he n ni v ol u ma b is a d mi nistere d as 
mai nte na nce i n patie nts wit h H L  after A S C T  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti ves of t his st u d y are t o:  
•  
C orrelate efficac y of ni v ol u ma b w he n gi ve n as mai nte na nce after A S C T  wit h 
pr o gra m me d cell deat h pr otei n -1 ( P D - 1) e x pressi o n a n d ot her i m m u ne effect or a n d 
re g ulat or y cells 
•  
C orrelate p ositr o n e missi o n t o m o gra p h y ( P E T )- c o m p ute d t o m o gra p h y ( C T ) 
ne gati vit y wit h P F S  
St u d y  Desi g n : 
T his is a P hase II si n gle -ar m o pe n -la bel st u d y of ni v ol u ma b as mai nte na nce  t hera p y after 
A S C T  i n patie nts wit h H L  at ris k of rela pse or pr o gressi o n.  
St u d y Dr u g s, 
D oses, a n d M o des 
of A d mi nistr ati o n:  
P atie nts will recei ve ni v ol u ma b ( 2 4 0  m g  I V) starti n g Da y 4 5 -1 8 0  p ost -tra ns pla nt (± 1 0 da ys) 
e ver y 2 wee ks f or u p t o a ma xi m u m of 6 m o nt hs of treat me nt.   Fi ve patie nts will recei ve 
sta n dar d-of -care treat me nt pre - a n d p o st-tra ns pla nt as a c o ntr ol gr o u p t o c o m pare i m m u ne 
rec o ver y. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 7 of 6 9  
 
 
B M T 2 4  PR O T O C O L S Y N O P SI S  
I ncl usi o n Criteri a: 
1.  P atie nts 1 8 years of a ge a n d ol der wit h H L  w h o ha ve recei ve d a ut o -H S C T i n t he pre vi o us 
4 5 -1 8 0  da ys.  
2.  C o m plete res p o nse ( C R), partial res p o nse ( P R) o r sta ble disease ( S D) t o sal va ge t hera p y 
pri or t o A S C T  
3.  Hi g h ris k of resi d ual H L p ost -A S C T, as deter mi ne d b y o ne  of t he f oll o wi n g:  
•  
P ositi ve P E T sca n defi ne d b y t he Dea u ville scale 3- 4 ( A p pe n di x C ) a n d wit hi n 2 
m o nt h s of start of hi g h-d ose c he m ot hera p y pri or t o A S C T  
•  
Refract or y t o fr o ntli ne t hera p y  
•  
Rela pse < 1 2 m o nt hs after fr o ntli ne t hera p y  
•  
Rela pse ≥1 2 m o nt hs after fr o ntli ne t hera p y wit h e xtra n o dal disease  
4.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) P erf or ma nc e Stat us sc ore of 0 -1 
( A p pe n di x A).  
5.  A de q uate he mat ol o gic f u ncti o n defi ne d as all of t he f oll o wi n g:  
-  
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1 0 0 0/ μ L  
-  
He m o gl o bi n ( H g b) ≥8 g/ d L (tr a nsf usi o ns t o reac h t his p oi nt are n ot per mitte d)  
-  
Platelets ≥5 0, 0 0 0/ µ L (tra nsf usi o n is n ot per mitte d)  
6.  A de q uate li ver f u ncti o n defi ne d as all of t he f oll o wi n g:  
-  
Ala ni ne a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase ( A S T) ≤2. 5 × t he 
u p per li mit of n or mal ( U L N)  
-  
T otal bilir u bi n ≤1. 5 × U L N ( u nless t he patie nt has Gra de 1 bilir u bi n ele vati o n d ue t o 
Gil bert disease or a si milar s y n dr o me i n v ol vi n g sl o w c o nj u gati o n of bilir u bi n)  
7.  A de q uate re nal f u ncti o n defi ne d as ser u m creati ni ne ≤1. 5 m g/ d L ( 1 3 3 μ m ol/ L).  
8.  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m or uri ne pre g na nc y test res ult 
wit hi n 7 2 h o urs pri or t o t he first d ose of ni v ol u ma b a n d m ust a gree t o f oll o w i nstr ucti o ns 
f or met h o d(s) of c o ntrace pti o n f or t he d urati o n of treat me nt wit h ni v ol u ma b a n d f or 
7 m o nt hs f oll o wi n g t heir last d ose of st u d y dr u g ( A p pe n di x C).  Fe males of n o n-
c hil d beari n g p ote ntial are t h os e w h o are p ost me n o pa usal gre ater t ha n 1 year or w h o ha ve 
ha d a bilateral t u bal li gati o n or h ysterect o m y.  
9.  Male patie nts wit h fe male part ners of c hil d beari n g p ote ntial a n d w o me n patie nts of 
c hil d beari n g p ote ntial are re q uire d t o use t w o f or ms of acce pt a ble  c o ntrace pti o n, i ncl u di n g 
o ne barrier met h o d, d uri n g t heir partici pati o n i n t he st u d y a n d f or 7 m o nt hs f oll o wi n g last 
d ose of st u d y dr u g.  Male pati e nts m ust als o refrai n fr o m d o nati n g s per m d uri n g t heir 
partici pati o n i n t he st u d y a n d f or 7  m o nt hs f oll o wi n g last d ose of st u d y dr u g ( A p pe n di x C).  
1 0.  Willi n g ness a n d a bilit y t o c o m pl y wit h st u d y a n d f oll o w -u p pr oce d ures.  
1 1.  A bilit y t o u n dersta n d t he nat ur e of t his st u d y a n d gi ve writte n i nf or me d c o nse nt.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 8 of 6 9  
 
B M T 2 4  P R O T O C O L S Y N O P SI S  
E xcl usi o n 
Criteri a:  
1.  P atie nts t hat ha ve recei ve d a n all o ge nic tra ns pla nt.  
2.  Pri or A S C T  or c urre nt t hera p y wit h ot her a nti -ne o plastic or i n vesti gati o nal a ge nts.  
3.  B est res p o nse of pr o gressi ve disease pri or t o A S C T  
4.  P atie nts wit h a n y a ut oi m m u ne disease or a hist or y of a ut oi m m u ne dise ase.  P atie nts wit h 
vitili g o, t y pe I dia betes mellit us, resi d ual h y p ot h yr oi dis m d ue t o a ut oi m m u ne c o n diti o n 
o nl y re q uiri n g h or m o ne re place me nt, ps oriasis n ot re q uiri n g s yste mic treat me nt, or 
c o n diti o ns n ot e x pecte d t o rec ur i n t he a bse nce of a n e xter nal tr i g ger are per mitte d t o 
e nr oll. 
5.  A n y c o n diti o n re q uiri n g s yste mic treat me nt wit h c ortic oster oi ds ( > 1 0 m g dail y pre d nis o ne 
e q ui vale nts) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys pri or t o first d ose of 
st u d y dr u g. I n hale d ster oi ds a n d a dre nal re place me nt ster oi d d oses > 1 0 m g dail y 
pre d nis o ne e q ui vale nts are per mitte d i n t he a bse nce of acti ve a ut oi m m u ne disease.  
6.  U se of a st u d y dr u g ≤2 1 da ys or 5 half-li ves ( w hic he ver is s h orter) pri or t o t he first d ose of 
ni v ol u ma b.  F or st u d y dr u gs f or w hic h 5 half -li ves is ≤2 1 da ys, a mi ni m u m of 1 0 da ys 
bet wee n ter mi nati o n of t he st u d y dr u g a n d a d mi nistrati o n of ni v ol u ma b is re q u ire d. 
7.  Wi de -fiel d ra di ot hera p y (i ncl u di n g t hera pe utic ra di ois ot o pes s uc h as str o nti u m 8 9) 
a d mi nistere d ≤2 8 da ys or li mit e d fiel d ra diati o n f or palliati o n ≤7 da ys pri or t o starti n g 
st u d y dr u g or has n ot rec o vere d fr o m si de effects of s uc h t hera p y.  
8.  Maj or s ur g ical pr oce d ures ≤2 8 da ys of be gi n ni n g st u d y dr u g, or mi n or s ur gical pr oce d ures 
≤7 da ys.  N o waiti n g re q uire d f oll o wi n g p ort -a-cat h place me nt.  
9.  Pre vi o usl y u ntreate d brai n metastases.  P atie nts w h o ha ve recei ve d ra diati o n or s ur ger y f or 
brai n metastases are e li gi ble if t hera p y was c o m plete d at least 2 wee ks pri or t o st u d y e ntr y 
a n d t here is n o e vi de nce of ce ntral ner v o us s yste m disease pr o gressi o n, mil d ne ur ol o gic 
s y m pt o ms, a n d n o re q uire me nt f or c hr o nic c ortic oster oi d t herap y.  
1 0.  Pre g na nt or lactati n g  
1 1.  Ac ute or c hr o nic li ver, re nal, or pa ncreatic disease.  
1 2.  U nc o ntr olle d dia betes mellit us  (fasti n g bl o o d gl uc ose > 2 5 0 m g/ d L). 
1 3.  A n y of t he f oll o wi n g car diac diseases c urre ntl y or wit hi n t he last 6 m o nt hs:  
-  
Left v e ntric ular ej ecti o n fracti o n ( L V E F) < 4 5 % as deter mi ne d b y m ult i ple g ate d 
ac q uisiti o n ( M U G A) sca n or ec h ocar di o gra m ( E C H O)  
-  
C orrecte d Q T ( Q T c ) i nter val > 4 8 0 ms o n scree ni n g electr ocar di o gra m ( E C G) 
-  
U nsta ble a n gi na pect oris  
-  
C o n gesti ve heart fail ure ( Ne w Y or k Heart Ass ociati o n ( N Y H A) ≥ Gra de 2 
[ A p pe n di x B])  
-  
Ac ute m y ocar di al i nfarcti o n  
-  
C o n d ucti o n a b n or malit y n ot c o ntr olle d wit h pace ma ker or me dicati o n  
-  
Si g nifica nt ve ntric ular or s u pra ve ntric ular arr h yt h mias ( patie nts wit h c hr o nic rate -
c o ntr olle d atrial fi brillati o n i n t he a bse nce of ot her car diac a b n or malities are eli gi ble)  
-  
Val v ular disease wit h si g nific a nt c o m pr o mise i n car diac f u ncti o n  
1 4.  I na de q uatel y c o ntr olle d h y pert e nsi o n (i.e., s yst olic bl o o d press ure [ S B P] > 1 8 0 m m H g or 
diast olic bl o o d press ure ( D B P) > 1 0 0 m m H g) ( patie nts wit h val ues a b o ve t hese le vels m ust 
ha ve t heir bl o o d  press ure [B P ] c o ntr olle d wit h me dicati o n pri or t o starti n g treat me nt).  
1 5.  Seri o us acti ve i nfecti o n at t he ti me of treat me nt or a n ot her s eri o us u n derl yi n g me dical 
c o n diti o n t hat w o ul d i m pair t he a bilit y of t he patie nt t o recei ve pr ot oc ol treat me nt.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 9 of 6 9  
 
E xcl usi o n 
Criteri a:  
1 6.  K n o w n dia g n osis of h u ma n i m m u n o deficie nc y vir us, he patitis B, or he patitis C.  T esti n g at 
baseli ne is n ot re q uire d.  
1 7.  Prese nce of ot her acti ve ca ncers, or hist or y of treat me nt f or i n vasi ve ca ncer ≤5 years.  
P atie nts wit h Sta ge I ca ncer w h o ha ve recei ve d defi niti ve l ocal treat me nt a n d are 
c o nsi dere d u nli kel y t o rec ur are eli gi ble.  All patie nts wit h pre vi o usl y treate d i n s it u 
carci n o ma (i.e., n o n -i n vasi ve) are eli gi ble, as are patie nts wit h hist or y of n o n-mela n o ma 
s ki n ca ncer. 
1 8.  Ps yc h ol o gical, fa milial, s oci ol o gical, or ge o gra p hical c o n diti o ns t hat d o n ot per mit 
c o m plia nce wit h t he pr ot oc ol.  
St atistic al 
M et h o d ol o g y:  
T he n ull  h y p ot hesis t o be teste d is t hat t he tr ue 1 2 -m o nt h P F S is 5 0 % a gai nst a t w o-si de d 
alter nati ve h y p ot hesis of a 7 0 % P F S rate.  T he 5 0 % 6 -m o nt h P F S rate was o btai ne d fr o m 
Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d Res p o nse Assess me nt of H o d g ki n a n d 
N o n -H o d g ki n L y m p h o ma: T he L u ga n o Classificati o n ( C hes o n et al. 2 0 1 4, see A p pe n di x F ).  A 
t w o-si de d, o ne-sa m ple l o g-ra n k test calc ulate d fr o m a sa m pl e of 3 6 e val ua ble s u bj ects ac hi e ves 
8 0. 3 % p o wer at a 0. 0 5 0 si g nifica nce le vel t o detect a n i m pr o ve me nt of 2 0 % i n 1 2 -m o nt h P F S.  
T h e pr o ba bilit y t hat a s u bj ect e x perie nces a n e ve nt d uri n g t he st u d y is 0. 4 5 7 9.  T he e x pecte d 
n u m ber of e ve nts d uri n g t he st u d y is 1 6.  It is ass u me d t hat t he s ur vi val ti me distri b uti o ns of 
b ot h gr o u ps are a p pr o xi mate d reas o na bl y well b y  t he W ei b ull distri b uti o n wit h a s ha pe 
para meter of 1. 0 0.  T hese pr o p orti o ns ass u me a n e nr oll me nt peri o d of 1 8 m o nt hs a n d a f oll o w -
u p peri o d of 1 2 m o nt hs after t he last s u bj ect is a d de d.  I n or der t o all o w f or a 1 0 % dr o p o ut rate, 
a t otal of 4 0 patie nts wil l be e nr olle d.  T he sa m ple size wa s calc ulate d usi n g P A S S versi o n 1 4. 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 0  of 6 9  
 
B M T 2 4  C O N T A C T I N F O R M A TI O N  
S ar a h C a n n o n De vel o p me nt  I n n o v ati o ns 
C o nt act I nf or m ati o n:  
Sara h Ca n n o n De vel o p me nt  I n n o vati o ns 
1 1 0 0 Dr. Marti n L . Ki n g Jr. Bl v d. , S uite 8 0 0 
Nas h ville, T N  3 7 2 0 3  
1- 8 4 4 -7 1 0 -6 1 5 7  
as ksara h @sara hca n n o n.c o m  
 
St u d y C h air : 
Carl os B ac hier, M D  
Sara h Ca n n o n Researc h I nstit ute  
1 1 0 0 Dr. Marti n L . Ki n g Jr. Bl v d. , S uite 8 0 0 
Nas h ville, T N  3 7 2 0 3  
1- 8 4 4 -7 1 0 -6 1 5 7  
as ksara h @sara hca n n o n.c o m  
 
S afet y De pt.  F a x #:  
S afet y De pt.  E m a il: 
1 -8 6 6 -8 0 7 -4 3 2 5  
C A N N. S A E @ S C RI -I n n o vati o ns.c o m 
Re g ul at or y P h o ne #  
Re g ul at or y E m ail:  
1 -8 4 4 -7 1 0 -6 1 5 7  
S C RI Re g ulat or y @ S C RI -I n n o vati o ns.c o m 
S ar a h C a n n o n De vel o p me nt  In n o v ati o ns  
E nr oll me nt P h o ne #:  
S ar a h C a n n o n De vel o p me nt  I n n o v ati o ns 
E nr oll me nt F a x #:  
S ar a h  C a n n o n De vel o p me nt I n n o v ati o ns 
E nr oll me nt E m ail : 
1 -8 4 4 -7 1 0 -6 1 5 7  
 
1- 8 6 6 -6 9 9 -0 2 5 8  
 
C A N N. S C RII n n o vati o ns E nr @scri -i n n o vati o ns.c o m 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 1  of 6 9  
 
LI S T O F A B B R E VI A TI O N S  
A E  
A d verse e ve nt  
A L P  
Al kali ne p h os p hatase  
A L T  ( S G P T) 
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil  c o u nt  
A S C T  
A ut ol o g o us ste m cell tra ns pla nt  
A S T ( S G O T) 
A s partate a mi n otra nsferase 
C B C  
C o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
cH L  
Classical H o d g ki n L y m p h o ma  
CI  
C o nfi de nce i nter val  
C M P  
C o m pre he nsi ve meta b olic pr ofile  
C R  
C o m plete res p o nse/re missi o n 
C R F  
Case re p ort for m  
C T  
C o m p ute d t o m o gra p h y  
E C G  
Electr ocar di o gra m  
E C O G   
Easter n C o o perati ve O nc ol o g y Gr o u p   
e C R F  
E lectr o nic case re p ort for m  
E F S  
E ve n t-free sur vi val  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
HI P A A  
Heal t h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
H L  
H o d g ki n L y m p h o ma  
H S C T  
He mat o p oietic ste m cell tra ns pla ntati o n 
I B 
I n vesti gat or B r oc h ure 
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or  Har m o ni sati o n  
I N R 
I nter nati o nal n or malize d rati o  
I R B 
I nstit uti o nal R e vie w B oar d  
I V 
I ntra ve n o usl y 
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
N S C L C  
N o n -s mall cell l u n g ca ncer 
O S  
O verall s ur vi val  
 
 
P D -1  
Pr o gra m me d cell deat h pr otei n -1  
P E T  
P ositr o n e missi o n t o m o gra p h y  
P F S  
Pr o gressi o n -free s ur vi val 
P HI  
P r otecte d healt h i nf or mati o n 
P K  
P har mac o ki netics  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 2  of 6 9  
 
 
LI S T O F A B B R E VI A TI O N S  (c o nti n ue d) 
P R  
P artial res p o nse/re missi o n  
R C C  
Re nal cell ca ncer  
S A E  
Seri o us a d verse e ve nt  
S A R  
S us pecte d a d verse reacti o n  
S D  
Sta ble disease  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
U L N  
U p per li mit of n or mal  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 3  of 6 9  
 
T A B L E O F C O N T E N T S  
1.  
I N T R O D U C TI O N ................................................................................................. 1 8 
1. 1  
Bac k gr o u n d ........................................................................................................... 1 8  
1. 2  
Treat me nt of Rela pse d or Refract or y H o d g ki n L y m p h o ma .................................. 1 8  
1. 3  
Pr o g n ostic Fact ors i n H o d g ki n L y m p h o ma........................................................... 1 8  
1. 4  
P ost-tra ns pla nt T hera p y f or H o d g ki n L y m p h o ma ................................................. 1 8  
1. 5  
Ni v ol u ma b ............................................................................................................. 1 9  
1. 5. 1  
Cli nical Efficac y  .................................................................................................... 1 9 
1. 5. 2  
Cli nical Safet y  ....................................................................................................... 2 0 
1. 6  
P D - 1 E x pressi o n i n H o d g ki n L y m p h o ma ............................................................. 2 0 
1. 7  
Rati o nale f or t he St u d y .......................................................................................... 2 1  
2.  
S T U D Y O BJ E C TI V E S  ......................................................................................... 2 1 
2. 1  
Pri mar y O bj ecti ve .................................................................................................. 2 1 
2. 2  
Sec o n dar y O bj ecti ves  ............................................................................................ 2 1 
2. 3  
E x pl orat or y O bjecti ves .......................................................................................... 2 1  
2. 4  
E n d p oi nts ............................................................................................................... 2 1  
2. 4. 1  
Safet y E n d p oi nts .................................................................................................... 2 1 
2. 4. 2  
Efficac y E n d p oi nt .................................................................................................. 2 2  
2. 4. 3  
A d diti o nal E n d p oi nt .............................................................................................. 2 2  
3.  
S T U D Y P A TI E N T P O P U L A TI O N A N D DI S C O N TI N U A TI O N  ...................... 2 2 
3. 1  
I n cl usi o n Criteria ................................................................................................... 2 2 
3. 2  
E x cl usi o n Criteria  .................................................................................................. 2 3 
3. 3  
Disc o nti n uati o n fr o m St u d y Treat me nt ................................................................. 2 5  
4.  
P A TI E N T R E GI S T R A TI O N  ................................................................................ 2 5 
5.  
S T U D Y D E SI G N  .................................................................................................. 2 6 
5. 1  
Treat me nt Pla n  ...................................................................................................... 2 6 
5. 1. 1  
Ni v ol u ma b ............................................................................................................. 2 6  
5. 2  
Treat me nt D ur ati o n ............................................................................................... 2 6  
5. 3  
C o nc o mita nt Me dicati o ns...................................................................................... 2 6  
5. 3. 1  
Per mitte d C o nc o mita nt Me dicati o ns  ..................................................................... 2 6 
5. 3. 2  
Pr o hi bite d C o nc o mita nt Me dicati o ns  .................................................................... 2 7 
5. 4  
C orrelati ve St u dies  ................................................................................................ 2 7 
5. 4. 1  
Bi o mar ker A nal ysis ............................................................................................... 2 7  
5. 4. 2  
I m m u ne Rec o ver y v ers us C o ntr ol Gr o u p .............................................................. 2 7 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 4  of 6 9  
 
5. 4. 3  
Ha n dli n g, St ora ge a n d D estr ucti o n of Bi ol o gical Sa m ples ................................... 2 7  
5. 4. 4  
Wit h dra wal of I nf or me d C o nse nt f or D o nate d Bi ol o gical Sa m ples ..................... 2 8  
6.  
D O S E M O DI FI C A TI O N S  .................................................................................... 2 8 
6. 1  
Ma na ge me n t of Ni v ol u ma b-Relate d A d v erse E v e nts  ........................................... 2 9 
6. 1. 1  
Ma na ge me nt of I nf usi o n- Relate d Reacti o ns  ......................................................... 2 9 
7.  
S T U D Y A S S E S S M E N T S A N D E V A L U A TI O N S  .............................................. 3 0 
7. 1  
O ver vie w  ............................................................................................................... 3 0 
7. 2  
Baseli ne St u d y Assess me nts  ................................................................................. 3 0 
7. 3  
St u d y Treat me nt A ssess me nts ............................................................................... 3 1 
7. 3. 1  
Da y 1 of Eac h C ycle ( ± 2 da ys as l o n g as i nter val b et wee n d oses is 1 2- 1 6 
da ys ) ...................................................................................................................... 3 1 
7. 4  
E n d of St u d y Tr eat me nt ........................................................................................ 3 1  
7. 5  
Res p o nse Assess me nt  ............................................................................................ 3 1 
7. 6  
F oll o w- u p .............................................................................................................. 3 2  
8.  
D R U G F O R M U L A TI O N, A V AI L A BI LI T Y, A D MI NI S T R A TI O N, A N D 
T O XI CI T Y I N F O R M A TI O N  ............................................................................... 3 2 
8. 1  
Ni v ol u ma b ............................................................................................................. 3 2  
8. 1. 1  
La b eli n g, Pac ka gi n g, S u p pl y, a n d St ora ge ............................................................ 3 2  
8. 1. 2  
Pre parati o n a n d A d mi nistrati o n of Ni v ol u ma b ..................................................... 3 2  
8. 1. 3  
Preca uti o ns a n d Ris ks Ass ociate d wit h Ni v ol u ma b .............................................. 3 2  
8. 2  
Acc o u nta bilit y f or All St u d y Dr u gs  ...................................................................... 3 2 
9.  
R E S P O N S E E V A L U A TI O N S  A N D M E A S U R E M E N T S  .................................. 3 3 
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................. 3 3 
1 0. 1  
Statistical Desi g n  ................................................................................................... 3 3 
1 0. 2  
Sa m ple Size C o nsi derati o ns .................................................................................. 3 3  
1 0. 3  
A nal ysis P o p ulati o n ............................................................................................... 3 3  
1 0. 4  
Data A nal ysis  ........................................................................................................ 3 4 
1 0. 4. 1  
De m o gra p hics a n d Baseli ne C haract eristics  ......................................................... 3 4 
1 0. 4. 2  
Efficac y A nal ysis  .................................................................................................. 3 4 
1 0. 4. 3  
Safet y A nal ysis  ...................................................................................................... 3 4 
1 0. 4. 4  
E x pl orat or y A nal ysis ............................................................................................. 3 5  
1 0. 5  
A nal ysis Ti me P oi nts ............................................................................................. 3 5 
1 0. 5. 1  
Fi nal A nal ysis  ........................................................................................................ 3 5 
1 0. 5. 2  
Pla n ne d I nteri m A nal ysis  ...................................................................................... 3 5 
1 1.  
S A F E T Y R E P O R TI N G A N D  A N A L Y S E S  ......................................................... 3 5 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 5  of 6 9  
 
1 1. 1  
Defi niti o ns  ............................................................................................................. 3 5 
1 1. 1. 1  
A d verse E v e nts  ...................................................................................................... 3 5 
1 1. 1. 2  
Seri o us A d verse E v e nt .......................................................................................... 3 6  
1 1. 1. 3  
A d verse Reacti o n  .................................................................................................. 3 6 
1 1. 1. 4  
S us pecte d A d vers e Reacti o n  ................................................................................. 3 6 
1 1. 1. 5  
Rec or di n g a n d Re p orti n g of A d vers e E ve nts ........................................................ 3 7  
1 1. 1. 6  
Assess me nt of A d vers e E ve nts .............................................................................. 3 8 
1 1. 2  
Seri o us A d verse E v e nt Re p orti n g b y I n vesti gat ors ............................................... 3 8  
1 1. 3  
Rec or di n g of A d v erse E v e nts a n d Seri o us A d vers e E ve nts .................................. 3 9  
1 1. 3. 1  
Dia g n osis vers us Si g ns a n d S y m pt o ms ................................................................. 3 9  
1 1. 3. 2  
Persiste nt or Rec urr e nt A d verse E ve nts  ................................................................ 3 9 
1 1. 3. 3  
A b n or mal La b or at or y Val ues ................................................................................ 3 9  
1 1. 3. 4  
Deat hs  .................................................................................................................... 4 0 
1 1. 3. 5  
H os pitalizati o n, Pr ol o n ge d H os pitalizati o n, or S ur ger y  ........................................ 4 0 
1 1. 3. 6  
Pre -E xisti n g Me dical C o n diti o ns  .......................................................................... 4 0 
1 1. 3. 7  
Ne w Ca ncers .......................................................................................................... 4 1 
1 1. 3. 8  
Pre g n a nc y, A b orti o n, a n d Birt h Defects/ C o n ge nital A n o malies  .......................... 4 1 
1 1. 3. 9  
Ni v ol u ma b O ver d ose ............................................................................................. 4 1  
1 1. 4  
S p o ns or Seri o us A d verse E ve nt Re p orti n g Re q uire me nts .................................... 4 1  
1 1. 4. 1  
S p o ns or Assess me nt of U ne x pecte d...................................................................... 4 2  
1 1. 4. 2  
S p o ns or Re p orti n g f or Cli nical St u dies U n der a n I n ve sti gati o nal N e w Dr u g 
A p plicati o n  ............................................................................................................ 4 2 
1 2.  
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  .................................... 4 2 
1 2. 1  
St u d y M o nit ori n g, A u diti n g, a n d I ns pecti n g ......................................................... 4 2  
1 3.  
E T HI C A L, FI N A N CI A L, A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ............ 4 3 
1 3. 1  
I nstit uti o nal Re vie w B oar d A p pr o val.................................................................... 4 3 
1 3. 2  
Re g ulat or y A p pr o val  ............................................................................................. 4 3 
1 3. 3  
I nf or me d C o nse nt .................................................................................................. 4 3 
1 3. 3. 1  
C o nfi de ntialit y  ....................................................................................................... 4 4 
1 3. 4  
Fi na ncial I nf or mati o n  ............................................................................................ 4 5 
1 4.  
R E S E A R C H R E T E N TI O N A N D D O C U M E N T A TI O N O F T H E S T U D Y  ........ 4 5 
1 4. 1  
A me n d me nts t o t he Pr ot oc ol ................................................................................. 4 5  
1 4. 2  
D oc u me ntati o n Re q uire d t o I nitiate t he St u d y  ...................................................... 4 6 
1 4. 3  
St u d y D oc u me ntati o n a n d St ora ge ........................................................................ 4 7  
1 4. 4  
Data C ollecti o n  ...................................................................................................... 4 8 
1 4. 5  
Discl os ure a n d P u blicati o n P olic y ......................................................................... 4 8  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 6  of 6 9  
 
1 5.  
R E F E R E N C E S ...................................................................................................... 5 0  
1 6.  
A P P E N DI C E S  ....................................................................................................... 5 2 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 7  of 6 9  
 
LI S T O F T A B L E S  
Ta ble 1  
D ose Le vel M o dificati o ns ........................................................................ 2 9  
LI S T O F A P P E N DI C E S  
A p pe n di x A:  
E C O G Perf or ma n ce Stat us Criteria  ......................................................... 5 2 
A p pe n di x B:  
Ne w Y or k Heart Ass ociati o n ( N Y H A) Classificati o n of Car diac 
Disease  ..................................................................................................... 5 3 
A p pe n di x C:  
Dea u ville 5 - p oi nt sc ori n g s yste m............................................................. 5 4 
A p pe n di x D:  
G ui deli nes f or Fe male Patie nts of C hil d beari n g P ote ntial a n d Fertile 
Male Patie nts  ............................................................................................ 5 5 
A p pe n di x E:  
Sc he d ule of Assess me nts  ......................................................................... 5 7 
A p pe n di x F:  
Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d Res p o nse 
Assess me nt of H o d g ki n a n d N o n- H o d g ki n L y m p h o ma: T he L u ga n o 
Classificati o n ............................................................................................ 5 9 
A p pe n di x G:  
Ma na ge me nt Al g orit h ms f or I m m u n o- O nc ol o g y A ge nts  ........................ 6 2 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 8  of 6 9  
 
1.  
IN T R O D U C TI O N  
1. 1  
B ac k gr o u n d 
H o d g ki n L y m p h o ma ( H L) is a ca n cer t h at arises fr o m ger mi nal ce nter or p ost -ger mi nal ce nter B 
cells.  T he diseas e has u ni q ue cell ular c o m p ositi o n disti n g uis hi n g it fr o m ot her B cell 
l y m p h o mas a n d c o nsists of s mall n u m bers of mali g na nt Ree d-Ster n ber g cells wit hi n a n e x te nsi ve 
b ut i neffecti ve i nfl a m mat or y a n d i m m u ne -cell i nfiltrate.  H o d g ki n L y m p h o ma acc o u nts f or 
a p pr o xi matel y 1 0 % of all l y m p h o mas, lea di n g t o a b o ut 8 5 0 0 ne w cas es a n d 1 1 2 0 deat hs 
a n n uall y i n t he U nite d States ( Sie gel et al.  2 0 1 6).  H o d g ki n L y m p h o ma has a bi m o dal a ge 
distri b uti o n c ur ve wit h a pea k i n y o u n g a d ults at a p pr o xi matel y 2 0 years of a ge a n d i n ol der 
a d ults ar o u n d a ge 6 5 ( Ries et al. 1 9 9 7 ).  M ost pati e nts affecte d b y t his disease are y o u n g a d ults. 
1. 2  
Tre at me nt of Rel a pse d or Refr act o r y H o d g ki n L y m p h o m a  
T he maj orit y of patie nts wit h H L are c ure d wit h c o m bi nati o n c he m ot hera p y a n d/ or ra diati o n 
t hera p y wit h c o m plete re missi o n attai ne d i n > 8 0 % of patie nts.  Hi g h- d ose t hera p y a n d 
a ut ol o g o us ste m cell tra ns pl a nt ( A S C T) are us e d as sta n dar d of care f or p atie nts wit h pri mar y 
resista nt or rec urr e nt H L .  W hile tra ns pla nt res ults i n a c ure f or s o me patie nts, m ore t ha n 5 0 % 
will e ve nt uall y r ela pse a n d die of t he disease ( Maj hail  et al. 2 0 0 6).  Pr o g n ostic fact ors ha v e bee n 
i de ntifie d t hat aff ect l o n g-ter m o utc o mes after tra ns pla nt f or patie nts wit h H o d g ki n diseas e.  
Ti me -t o-treat me nt f ail ure has bee n f o u n d t o b e a d v ersel y i nfl ue nce d b y a d v a nce d sta ge at 
dia g n osis, c o m ple me nt ar y r a di ot hera p y b ef ore A S C T, a s h ort first c o m plete res p o nse, a n d 
detecta ble disease at A S C T ( S ure da et al. 2 0 0 5 ).  Patie nts w h o pr o gress aft er A S C T ha ve li mite d 
t hera pe utic o pti o ns t o i m pr o ve t he o utc o me of t heir disease. 
1. 3  
Pr o g n osti c F act o rs i n H o d g ki n L y m p h o m a  
Pr o g n ostic fact ors ha v e b ee n i de ntifie d t hat affect l o n g- ter m o utc o me aft er tra ns pla nt f or patie nts 
wit h H o d g ki n diseas e.  P o or o utc o mes p ost- A S C T are ass o ciate d wit h t he prese nce of B 
s y m pt o ms, e xtra n o dal disease, a n d a less t ha n 1 2 m o nt h d urati o n of re missi o n after fr o ntli ne 
c he m ot hera p y.  Patie nts wit h i nter me diate or hi g h -ris k disease h a ve a 5-year e ve nt -free s ur vi val 
(E F S ) r ate of less t ha n 3 0 % c o m par e d t o 6 5 % t o 8 0 % f or patie nts wit h l o w-ris k disease 
(M os k o witz et al. 2 0 0 1 , Maj hail  et al. 2 0 0 6), (S ure da et al. 2 0 0 5 ).  Patie nts w h o pr o gress after 
A S C T ha ve li mite d t hera pe utic o pti o ns t o i m pr o ve t he o utc o me of t heir disease.  M ost rel a pses 
occ ur wit hi n t he first 2  years p ost - A S C T.  I ntr o d u ci n g a n o vel t hera p y t o pre ve nt diseas e 
pr o gressi o n a n d/ or r ela ps e i n i nter me diate - t o hi g h-ris k patie nts p ost- A S C T w o ul d be of be n efit 
f or t hese patie nts. 
1. 4  
P ost -tr a ns pl a nt T her a p y f or H o d g ki n L y m p h o m a  
B ase d o n d ata i n t he A E T H E R A trial, i n A u g ust 2 0 1 5 t he F D A a p pr o ve d bre nt u xi ma b ve d oti n 
f or t he p ost-a ut ol o g o us he mat o p oietic ste m cell tra ns pla ntati o n (a ut o-H S C T ) treat me nt of 
patie nts wit h classical H L at hi g h ris k of rela ps e or pr o gressi o n.  Pr o gressi o n -free s ur vi val (P F S ) 
i n t he bre nt u xi ma b ve d oti n ar m was 4 2. 9 m o nt hs c o m pare d t o 2 4. 1 m o nt hs i n t he place b o ar m 
(M os k o witz et al. 2 01 5 ).  W hile lea di n g t o a si g nifica nt i m pr o ve me nt i n P F S, disc o nti n uati o n of 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 1 9  of 6 9  
 
treat me nt d ue t o a d v erse e ve nts occ urre d i n o ver 3 0 % of patie nts pri maril y d ue t o peri p heral 
se ns or y a n d m ot or ne ur o pat hies (M os k o witz et al. 2 01 5 ).  T his i nt olera nce t o t he o nl y 
esta blis he d t hera p y t o pr e ve nt rela ps e de m o nstrat es t he nee d f or t he de v el o p me nt of n o vel 
treat me nt o pti o ns f or t hese patie nts. 
1. 5  
Ni v ol u m a b 
Ni v ol u ma b (als o ref err e d t o as B M S - 9 3 6 5 5 8 or M D X 1 1 0 6) is a h u ma n m o n ocl o nal a nti b o d y 
( H u M A b; i m m u n o gl o b uli n G 4 [I g G 4]-S 2 2 8 P) t hat tar gets t he pr o gra m me d deat h -1 ( P D -1)  
cl uster of diff ere ntiati o n 2 7 9 ( C D 2 7 9) cell s urface m e m bra ne rece pt or.  P D - 1 is a ne gati ve 
re g ulat or y m olec ul e e x presse d b y acti vat e d T a n d B l y m p h o c yt es (S har p e et al. 2 0 0 7 ).  Bi n di n g 
of P D -1 t o its  li ga n ds, pr o gr a m me d deat h-li ga n d 1 ( P D- L 1) a n d 2 ( P D- L 2), res ults i n t he d o w n-
re g ulati o n of l y m p h o c yte acti vati o n.  I n hi biti o n of t he i nteracti o n bet w ee n P D- 1 a n d its li ga n ds 
pr o m otes i m m u ne res p o nses a n d a nti ge n- s p ecific T-cell res p o ns es t o b ot h f orei g n a nti ge ns as 
well as  self- a nti ge ns.  Ni v ol u ma b is e x presse d i n C hi nese ha mster o var y ( C H O) cells a n d is 
pr o d uce d usi n g sta n dar d ma m malia n cell c ulti vati o n a n d c hr o mat o gra p hic p urificati o n 
tec h n ol o gi es.  T he  cli nical st u d y pr o d u ct is a sterile s ol uti o n f or pare nteral a d mi nistrati o n.  
T he p har mac o ki netics ( P K ), cli nical acti vit y, a n d safet y of ni v ol u ma b ha v e bee n assess e d i n 
s u bjects wit h n o n-s mall cell l u n g ca ncer ( N S C L C), mela n o ma, clear -cell re nal cell carci n o ma 
( R C C), a n d classical H o d g ki n L y m p h o ma (c H L) i n a d diti o n t o ot her t u m or t y pes.  Ni v ol u ma b 
m o n ot hera p y is a p pr o ve d i n m ulti ple c o u ntries, i ncl u di n g t he U S a n d E U, f or u nresecta ble or 
metastatic mela n o ma, pr e vi o usl y treate d metastati c N S C L C, a n d pre vi o usl y treate d a d v a nce d 
R C C . I n a d diti o n, ni v ol u ma b is als o a p pr o ve d f or t he treat me nt of c H L i n t he U S. 
1. 5. 1  
Cli nic al Effic ac y  
Ni v ol u ma b has de m o nstrate d d ura ble res p o nses e x cee di n g 6 m o nt hs as m o n ot hera p y a n d i n 
c o m bi nati o n wit h i pili m u ma b i n se veral t u m or t y p es , i ncl u di n g N S C L C, m ela n o ma, R C C, c H L, 
S C L C, gastric ca n cer, ur ot helial ca ncer, he p at ocell ular carci n o ma, a n d c ol orectal ca ncer .  I n 
c o nfir mat or y trials, ni v ol u ma b as m o n ot hera p y d e m o nstrate d a statisticall y si g nifica nt 
i m pr o ve me nt i n o verall s ur vi val (O S ) c o m pare d wit h t he c urre nt sta n dar d of care i n s u bjects wit h 
a d va nce d or metastatic N S C L C, u nr esecta ble or  m etastatic mela n o ma, a d va nce d  R C C, or 
s q ua m o us cell car ci n o ma of t he hea d a n d nec k (S C C H N ). 
1. 5. 1. 1  
Cli nic al Effic ac y i n H o d g ki n L y m p h o m a  
Ni v ol u ma b m o n ot hera p y has de m o nstrate d cli nical be nefit i n s u bjects wit h c H L w h o ha v e 
rela pse d or pr o gress e d, i ncl u di n g t h ose w h o recei ve d a ut ol o g o us h e mato p oietic ste m cell  
tra ns pla ntati o n a n d p ost-tra ns pla ntati o n bre nt u xi ma b ve d oti n, a n d has bee n a p pr o ve d f or use i n 
t he U S.  T w o st u dies e val uate d t he efficac y of ni v ol u ma b as a si n gl e a ge nt i n patie nts wit h c H L 
after f ail ure of a ut ol o g o us H S C T a n d p ost-tra ns pla ntati o n bre nt u xi ma b ve d oti n.  Patie nts 
recei v e d 2 4 0 m g of ni v ol u ma b a d mi nistere d i ntra v e n o usl y (I V) o v er 6 0 mi n utes e ver y 2 w ee ks 
u ntil disease pr o gressi o n, ma xi mal cli nical be nefit, or u nacce pta ble t o xicit y.  A c ycle  c o nsiste d 
of o ne d ose.  D os e re d u c ti o n was n ot per mitte d. 
Efficac y was e val uate d i n 9 5 patie nts  ( b ot h trials c o m bi ne d) w h o ha d recei ve d bre nt u xi ma b 
ve d oti n after f ail ure of a ut ol o g o us H S C T.  Res p o nse was assess e d usi n g  t h e Re vise d Res p o nse 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 0  of 6 9  
 
Criteria f or Mali g na nt L y m p h o ma ( C hes o n et al. 2 0 0 7 ).  Se ve n patie nts ( 7 %) ha d c o m plet e 
re missi o n ( C R) wit h a 9 5 % c o nfi de n ce i nter v al ( CI , [ 3, 1]) a n d 5 5 ( 5 8 %) patie nts ha d partial 
re missi o n ( P R) wit h a 9 5 % CI ( 4 7, 6 8).  T he o bj ecti ve res p o nse rate ( C R + P R) was 6 2 patie nts 
( 6 5 %).  Me dia n d urati o n of res p o nse ( D o R) was 8. 7 m o nt hs a n d me dia n ti me t o res p o nse w as 
2. 1 m o nt hs. 
1. 5. 2  
Cli nic al S af et y  
T he o ver all safet y e x peri e nce wit h ni v ol u ma b, as a m o n ot hera p y or i n c o m bi nati o n wit h ot her 
t hera pe utics, is bas e d o n e x perie nce i n a p pr o xi mately 1 2, 3 0 0 s u bjects treate d t o date.  F or 
m o n ot hera p y, t he saf et y pr ofile is si milar acr oss t u m or t y pes.  T h ere is n o patter n i n t he 
i nci de nce, se v erit y, or ca usalit y of a d v erse e ve nts ( A Es ) t o ni v ol u ma b d ose le vel.  I n P hase 3 
c o ntr olle d st u dies, t he saf et y pr ofile of ni v ol u ma b m o n ot hera p y is acce pta bl e i n t he c o nte xt of 
t he o bser ve d cli nical efficac y a n d ma na gea ble usi n g esta blis he d s afet y g ui deli nes.  Cli nicall y 
rele va nt A Es t y pical of sti m ulati o n of t he i m m u ne s yste m were i nfre q ue nt a n d ma na gea bl e b y 
dela yi n g or st o p pi n g ni v ol u ma b treat me nt a n d ti mel y i m m u n os u p pressi v e t hera p y or ot her 
s u p p orti ve car e. 
1. 5. 2. 1  
Re n al a n d He p atic I m p air me nt  
T he eff ect of re nal i m pair me nt o n t he cleara nce ( C L ) of ni v ol u ma b w as e v al uate d i n s u bjects 
wit h mil d  (gl o mer ular filtrati o n rate  [G F R ] < 9 0 a n d ≥6 0 m L/ mi n/ 1. 7 3 m 2; n = 3 7 9), m o derate 
( G F R < 6 0 a n d ≥3 0 m L/ mi n/ 1. 7 3 m2; n = 1 7 9), or se vere ( G F R < 3 0 a n d ≥1 5 m L/ mi n/ 1. 7 3 m 2; 
n = 2) re n al i m pair me nt c o m pare d t o  s u bjects wit h n or mal re nal f u n cti o n ( G F R ≥9 0 m L/ mi n/ 1. 7 3 
m 2; n = 3 4 2) i n t he p o p ulati o n p har mac o ki netic (P P K ) a nal ysis.  N o  cli nicall y i m p orta nt 
differe n ces i n t he C L of ni v ol u ma b were f o u n d b et wee n s u bjects wit h mil d or m o derate re nal 
i m pair me nt a n d s u bjects wit h n or mal re nal f u n cti o n.  Data fr o m s u bjects wit h  se vere re nal 
i m pair me nt are to o li mite d t o dra w c o n cl usi o ns o n t his p o p ulati o n. 
T he eff ect of h e patic i m p air me nt o n t he C L of ni v ol u ma b was e val uat e d i n s u bjects wit h mil d  
he patic i m pair me nt (t otal bilir u bi n 1. 0 t o 1. 5 ti mes u p per li mit of n or mal [ U L N ] or as p artate 
a mi n otra nsfer ase [ A S T ] > U L N as d efi ne d usi n g t he  Nati o nal Ca ncer I nstit ute [ N CI] criteria of 
he patic d ysf u ncti o n; n = 9 2) c o m par e d t o s u bjects wit h n or mal he patic f u n cti o n (t otal bilir u bi n 
a n d A S T ≤ U L N; n = 8 0 4) i n t he p o p ulati o n P K a nal yses.  N o cli nicall y i m p orta nt differe nc es i n 
t he C L of ni v ol u ma b w er e f o u n d bet wee n s u bjects wit h mil d he patic i m pair me nt a n d n or mal 
he patic f u ncti o n.  Ni v ol u ma b has n ot bee n st u die d i n s u bjects wit h m o derate (t otal bilir u bi n > 1. 5 
t o 3 ti mes U L N a n d a n y A S T) or se vere he p atic i m pair me nt (t otal bilir u bi n > 3 ti mes U L N a n d 
a n y A S T).  
1. 6  
P D -1 E x pressi o n i n H o d g ki n L y m p h o m a  
St u dies ha ve f o u n d hi g h e x pressi o n of P D- L 1 i n H L  (R oe mer et al  2 0 1 6).  Pr o gra m me d cell 
deat h pr otei n 1 ( P D - 1) bl oc ka de wit h ni v ol u ma b i n cli nical trials e nr olli n g hea vil y pre-treate d 
H L p atie nts ha ve r es ulte d i n res p o nse rat es i n o ver 8 5 % of patie nts ( A nsell  et al. 2 01 5 ).  T he 
m ost c o m m o n dr u g- r elat e d A Es were r as h a n d decreas e d platelet c o u nt wit h 9 % of patie nts 
disc o nti n ui n g d ue t o t o xic eff ects (A ns ell  et al. 2 0 1 5 ).  Data de m o nstrati n g t he t olera bilit y a n d 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 1  of 6 9  
 
efficac y of P D -1 i n hi biti o n i n H L p atie nts ma ke ni v ol u ma b a pr o misi n g t h era p y t o e v al uate i n 
t he p ost-tra ns pla nt setti n g. 
1. 7  
R ati o n ale f or t he St u d y  
T he mali g n a nt Ree d - Ster n ber g cells f o u n d i n H L  ha ve bee n f o u n d t o o vere x press P D- 1 (Gree n  et 
al. 2 0 1 0 ).  Ni v ol u ma b, a n a nti b o d y directe d a gai nst P D - 1, has bee n w ell -t olerate d a n d 
efficaci o us i n t his patie nt p o p ulati o n ( A nsell  et al. 2 01 5 ).  We pr o p ose t o st u d y ni v ol u ma b 
mai nte na nce  t hera p y p ost-A S C T  i n H o d g ki n disease t o see if it is well-t olerate d w he n gi ve n as 
earl y mai nte na n ce t hera p y.  M os k o witz et al. 2 0 1 0  c o n d ucte d a st u d y t o i de ntif y pr o g n ostic 
fact ors f or patie nts wit h r ela pse d or r efract or y H L recei vi n g tra ns pla nt.  I n t his a nal ysis of 
1 5 3 patie nts, it was f o u n d t hat f u ncti o nal i ma gi n g stat us bef ore A S C T was t he o nl y fact or 
si g nifica nt f or E F S  a n d O S a n d clearl y i de ntifi e d a p o o r ris k p o p ulati o n ( 5 year E F S 3 1 % a n d 
7 5 % f or FI - p ositi ve a n d ne gati ve patie nts res pecti vel y).  T his st u d y ai ms t o e nr oll hi g h -ris k 
patie nts as defi ne d b y t his ma n uscri pt t o recei ve ni v ol u ma b t hera p y as c o ns oli dati o n t hera p y 
p ost-tra ns pla nt.  We are als o e x pl ori n g if P F S ca n be pr ol o n ge d i n hi g h- ris k H L p atie nts 
c o m pare d t o hist orical pl ace b o c o ntr ols re p ort e d i n ot her st u dies.  
2.  
S T U D Y  OB J E C TI V E S  
2. 1  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve of t his st u d y is t o: 
•  E val uate saf et y a n d t oler a bilit y of ni v ol u ma b as mai n te na nce t hera p y earl y after A S C T  i n 
patie nts wit h H L  
2. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ve  of t his st u d y is t o: 
•  E val uate P F S at 1 2 m o nt hs p ost-tra ns pla nt w he n ni v ol u ma b is a d mi nistere d as 
mai nte na nce t hera p y i n p atie nts wit h H L  after A S C T  
2. 3  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti v es of t his st u d y are t o: 
•  C orrelate efficac y of ni v ol u ma b w he n gi ve n as m ai nte na nce t hera p y after A S C T  wit h 
P D - 1 e x pressi o n a n d ot her i m m u ne effect or a n d re g ul at or y cells  
•  C orrelat e p ositr o n e missi o n t o m o gra p h y ( P E T )-c o m pute d t o m o gra p h y ( C T ) ne gati vit y 
wit h P F S  
2. 4  
E n d p oi nts  
2. 4. 1  
S af et y E n d p oi nts  
•  T y pe, i n ci de nce, se verit y, seri o us ness, a n d relate d ness of A E s 
•  La b orat or y a b n or malities  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 2  of 6 9  
 
•  A Es  lea di n g t o disc o nti n uati o n 
2. 4. 2  
Effic ac y E n d p oi nt 
•  Pr o gr essi o n- fr ee s ur vi val 
2. 4. 3  
A d diti o n al E n d p oi nt  
•  P E T - C T ne gati vit y at 1 year p ost-tra ns pla nt 
3.  
S T U D Y  P A TI E N T P O P U L A TI O N A N D D I S C O N TI N U A TI O N 
3. 1  
I ncl usi o n Criteri a 
Patie nts w h o will recei ve st u d y dr u g m ust meet t h e f oll o wi n g criteria i n or der t o be i ncl u de d i n 
t he researc h st u d y: 
1.  Patie nts 1 8  y ears of a ge a n d ol der wit h H L  w h o ha ve recei ve d a ut o- H S C T i n t he pre vi o us 
4 5- 1 8 0 da ys . 
2.  C o m ple te res p o nse (C R ), partial res p o nse ( P R ) or sta ble disease (S D ) t o sal va ge t hera p y 
pri or t o A S C T 
3.  H i g h ris k of resi d ual H L p ost-A S C T , as deter mi ne d b y 1 of t h e f oll o wi n g: 
•  P ositi ve P E T sca n  defi ne d b y t he D ea u ville scale 3- 4 (A p pe n di x C ) a n d wit hi n 2 
m o nt hs of start of hi g h- d ose c he m ot hera p y  pri or t o A S C T 
•  Refract or y t o fr o ntli ne t h era p y  
•  Rela pse < 1 2 m o nt hs after fr o ntli ne t hera p y 
•  Rela pse ≥1 2 m o nt hs after fr o ntli ne t h era p y wit h e xtra n o dal disease  
4.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us sc ore of 0 - 1 
( Ap pe n di x A ). 
5.  A d e q uate h e mat ol o gi c  f u ncti o n defi ne d as all of t he f oll o wi n g: 
-  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥10 0 0/ μ L  
-  He m o gl o bi n (H g b) ≥8 g/ d L  (tra nsfusi o ns t o reac h t his p oi nt are n ot per mitte d)  
-  Plate lets ≥5 0 , 0 0 0/ µ L (tra nsf usi o n is n ot per mitte d) 
6.  A de q uate li ver f u ncti o n defi ne d as all of t he f oll o wi n g: 
-  A la ni ne a mi n otra nsf eras e (A L T) a n d as partate a mi n otra nsferas e ( A S T) ≤2. 5 ×  t he 
u p per li mit of n or mal ( U L N) 
-  T otal bilir u bi n ≤1. 5  ×  U L N ( u nless t he patie nt has Gra de 1 bilir u bi n ele v ati o n d ue 
t o Gil bert disease or a si milar s y n dr o me i n v ol vi n g sl o w c o nj u gati o n of bilir u bi n) 
7.  A de q uate r e nal f u n cti o n defi ne d as ser u m creati ni ne ≤1. 5 m g/ d L ( 1 3 3 μ m ol/ L)  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 3  of 6 9  
 
8.  Fe males o f c hil d beari n g p ote ntial m ust ha ve a ne gati ve ser u m or uri n e pre g na nc y test 
res ult wit hi n 72 h o urs pri or t o t he first d ose of ni v ol u ma b a n d m ust a gree t o f oll o w 
i nstr ucti o ns f or met h o d(s) of c o ntrace pti o n f or t h e d urati o n of treat me nt wit h ni v ol u ma b 
a n d f or 7 m o nt hs f oll o wi n g t heir last d ose of st u d y dr u g (A p pe n di x D ).  Fe males of n o n-
c hil d beari n g p ote ntial ar e t h ose w h o are p ost me n o pa usal greater t ha n 1 year or w h o ha v e 
ha d a bilater al t u bal li gati o n or h ysterect o m y.  
9.  Male patie nts wit h fe m al e part ners of c hil d beari n g p ote ntial a n d w o me n p atie nts of 
c hil d beari n g p ote ntial ar e re q uire d t o use t w o f or ms of acce pt a ble  c o ntrace pti o n, 
i ncl u di n g o ne b arrier met h o d, d uri n g t heir p artici p ati o n i n t he st u d y a n d f or 7 m o nt hs 
f oll o wi n g last d ose of st u d y dr u g .  M ale patie nts m ust als o refrai n fr o m d o nati n g s per m 
d uri n g t heir p artici pati o n i n t he st u d y a n d f or 7 m o nt hs f oll o wi n g last d ose of st u d y dr u g 
(A p pe n di x D ). 
1 0.  Willi n g ness a n d a bilit y t o c o m pl y wit h  st u d y a n d f oll o w- u p pr oce d ures. 
1 1.  A bilit y t o u n d ersta n d t he nat ure of t his st u d y a nd gi ve writte n i nf or me d c o nse nt. 
3. 2  
E xcl usi o n Criteri a  
Patie nts  w h o will recei ve st u d y dr u g w h o meet a n y of t he f oll o wi n g criteri a will be e x cl u de d 
fr o m st u d y e ntr y:  
1.  P atie nts t hat ha ve recei ve d a n all o ge nic tra ns pl a nt 
2.  Pri or all o ge n eic ste m cell tra ns pla nt  or c urre nt t hera p y wit h ot her a nti- ne o pl astic or 
i nvesti gati o nal a ge nts  
3.  B est res p o ns e of pr o gressi ve disease pri or t o A S C T 
4.  P atie nts wit h a n y a ut oi m m u ne disease or a hist or y of a ut oi m m u ne di sease.  Patie nts  wit h 
vitili g o, t y pe I di a betes mellit us, resi d ual h y p ot h yr oi dis m d ue t o a ut oi m m u ne c o n diti o n 
o nl y re q uiri n g h or m o ne r e place m e nt, ps oriasis n ot re q uiri n g s yst e mic treat me nt, or 
c o n diti o ns n ot e x pecte d t o rec ur i n t he a bse nce of a n e xter nal tri g ger are per mitte d t o 
e nr oll. 
5.  A n y c o n diti o n re q uiri n g syste mic treat me nt wit h c ortic oster oi ds ( > 1 0 m g dail y 
pr e d nis o ne e q ui val e nts) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys pri or t o 
first d ose of st u d y dr u g.  I n h ale d ster oi ds a n d a dre nal re place me nt ster oi d d oses > 1 0 m g 
dail y pr e d nis o ne e q ui val e nts are p er mitte d i n t he a bse nce of acti ve a ut oi m m u ne disease.  
6.  U se of a st u d y dr u g  ≤2 1 da ys or 5 half -li ves ( w hic he ver is s h orter) pri or t o t he first d ose 
of ni v ol u ma b.  F or st u d y dr u gs f or w hic h 5 h alf- li ves is ≤2 1 da ys, a mi ni m u m of 1 0  da ys 
bet wee n ter mi nati o n of t he s t u d y dr u g a n d a d mi nistrati o n of ni v ol u ma b is re q uire d. 
7.  Wi de-fiel d ra di ot hera p y (i ncl u di n g t hera pe utic ra di ois ot o pes s uc h as str o nti u m 8 9) 
a d mi nistere d ≤2 8 da ys or li mite d fiel d ra diati o n f or palliati o n ≤7 da ys pri or t o starti n g 
st u d y dr u g or h as n ot rec o vere d fr o m si de effects of s uc h t hera p y. 
8.  Maj or s ur gical pr o ce d ur es ≤2 8 da ys of b e gi n ni n g st u d y dr u g, or mi n or s ur gical 
pr oce d ur es ≤7 da ys.  N o waiti n g re q uire d f oll o wi n g p ort -a-cat h place me nt.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 4  of 6 9  
 
9.  Pre vi o usl y u ntre ate d br ai n metastases.  Patie nts w h o ha ve recei ve d ra diati o n or s ur ger y 
f or brai n metast ases ar e eli gi ble if t hera p y was c o m plete d at least 2 wee ks pri or t o st u d y 
e ntr y a n d t her e is n o e vi d e nce of ce ntral ner v o us s yste m diseas e pr o gressi o n, mil d 
ne ur ol o gi c s y m pt o ms, a n d n o re q uire me nt f or c hr o nic c ortic oster oi d t hera p y. 
1 0.  Pre g n a nt or lact ati n g  
1 1.  Ac ute or c hr o nic li ver, re nal, or pa ncreatic disease . 
1 2.  U nc o ntr olle d dia betes m ellit us  (fasti n g bl o o d gl u c ose > 2 5 0 m g/ d L). 
1 3.  A n y of t he f oll o wi n g car diac diseases c urre ntl y  or wit hi n t he last 6 m o nt hs:  
-  Left v e ntric ular ejecti o n fracti o n ( L V E F) < 4 5 % as deter mi ne d b y m ulti ple g at e d 
ac q uisiti o n ( M U G A) sca n or ec h ocar di o gra m ( E C H O) 
-  C orrecte d Q T ( Q T c ) i nter val > 4 8 0 ms o n scree ni n g el ectr ocar di o gra m ( E C G ) 
-  U nsta ble a n gi na pect oris  
-  C o n gesti ve heart f ail ure ( Ne w Y or k Heart Ass ociati o n ( N Y H A ) ≥ Gra de 2 
[A p pe n di x B ]) 
-  Ac ute m y ocar dial i nfar cti o n  
-  C o n d ucti o n a b n or malit y n ot c o ntr olle d wit h pace ma ker or me di cati o n 
-  Si g nifica nt ve ntri c ular or s u pra ve ntric ular arr h yt h mias ( p atie nts wit h c hr o nic rate -
c o ntr olle d atrial fi brillati o n i n t he a bse nce of ot her car di ac a b n or malities are 
eli gi ble)  
-  Val v ular diseas e wit h si g nifica nt c o m pr o mise i n car diac f u ncti o n  
1 4.  In a de q uat el y c o ntr olle d h y p erte nsi o n (i.e., s yst olic bl o o d press ure [ S B P] > 1 8 0 m m H g or 
di ast olic bl o o d press ure [ D B P ] > 1 0 0 m m H g) ( pati e nts wit h val ues a b o ve t h ese le vels 
m ust ha ve t heir bl o o d press ure [ B P ] c o ntr olle d wit h me dicati o n pri or t o starti n g 
treat me nt). 
1 5.  S eri o us acti ve i nfecti o n at t he ti me of treat me nt, or a n ot her seri o us u n d erl yi n g me dical 
c o n diti o n t hat w o ul d i m pair t he a bilit y of t he patie nt t o recei ve pr ot oc ol treat me nt . 
1 6.  K n o w n dia g n osis of h u ma n i m m u n o deficie nc y vir us, he patitis B, or he p atitis C.  Testi n g 
at baseli ne is n ot re q uir e d.  
1 7.  Prese nce of ot her acti ve ca ncers, or hist or y of treat me nt f or i n vasi ve ca n cer  ≤5 years.  
Patie nts wit h S ta ge I ca n cer w h o h a ve recei ve d defi niti ve l ocal treat me nt a n d are 
c o nsi dere d u nli kel y t o rec ur ar e eli gi ble.  All patie nts wit h pre vi o usl y treate d i n sit u 
carci n o ma (i.e. , n o n-i n vasi ve) are eli gi ble, as are p atie nts wit h hist or y of n o n-mela n o ma 
s ki n ca ncer. 
1 8.  Ps yc h ol o gical, f a milial, s oci ol o gical, or ge o gra p hi cal c o n diti o ns t hat d o n ot per mit 
c o m plia nce wit h t he pr ot oc ol. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 5  of 6 9  
 
3. 3  
Disc o nti n u ati o n f r o m St u d y  Tre at me nt  
Patie nts will be disc o nti n ue d fr o m st u d y treat me nt f or a n y of t he f oll o wi ng reas o ns:  
•  
Disease pr o gressi o n  
•  
Irre v ersi ble or i nt oler a ble t o xicit y or a b n or mal la b orat or y val ues t h o u g ht t o be relate d t o 
dr u g t o xicit y 
•  
C o n diti o ns re q uiri n g t her a pe utic i nter ve nti o n n ot per mitte d b y t he pr ot oc ol 
•  
I nterc urre nt ill ness (t his will be at t he I n vesti gat or’s discreti o n) 
•  
I n a bilit y of t he p atie nt t o c o m pl y wit h st u d y re q uire me nts 
•  
Patie nt re q uests t o disc o nti n ue treat me nt  
•  
Patie nt wit h dra ws c o nse nt fr o m t he st u d y 
•  
N o n -c o m plia nce/l ost t o f oll o w - u p 
•  
Pre g n a nc y  
After disc o nti n uati o n fr o m pr ot oc ol treat me nt, patie nts m ust be f oll o we d f or A Es f or 1 0 0 d a ys  
after t heir l ast d ose of ni v ol u ma b.  All ne w A Es o cc urri n g d uri n g t his peri o d m ust be re p orte d 
a n d f oll o we d u ntil res ol uti o n, u nless, i n t he o pi ni o n of t he I n vesti gat or, t hes e val ues are n ot 
li kel y t o i m pr o ve, beca us e of t he u n derl yi n g disease.  I n t his case, t he I n vesti gat or m ust rec or d 
his or her reas o ni n g f or t his decisi o n i n t he patie nts’ me dical rec or ds. 
All patie nts w h o ha ve Gr a de 3 or 4 la b orat or y a b n or malities ( per N ati o nal Ca ncer I nstit ute 
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts [ N CI C T C A E] v 4. 0 3 ) at t he ti me of 
disc o nti n uati o n m ust be f oll o we d u ntil t he la b orat or y v al ues ha v e ret ur n e d t o Gra de 1 or 2, 
u nless it is, i n t he o pi ni o n of t he I n vesti gat or, n ot li kel y t hat t hese v al ues are t o i m pr o ve.  I n t his 
case, t he I n vesti gat or m ust rec or d his or h er reas o ni n g f or m a ki n g t his decisi o n i n t he patie nts’ 
me dical rec or ds.  
4.  
P A TI E N T R E GI S T R A TI O N  
T he patie nt m ust willi n gl y c o ns e nt after bei n g i nf or me d of t he pr o ce d ures t o be f oll o we d, 
e x peri me ntal nat ure  of t h e treat me nt, p ote ntial be n efits, treat me nt alter n ati ves, si de  effects, ris ks , 
a n d disc o mf orts.  I nstit uti o nal Re vie w B o ar d (I R B) a p pr o val of t his pr ot o c ol a n d c o nse nt f or m is 
re q uire d.  Eli gi ble patie nts w h o wis h t o partici pate i n t he st u d y will be e nr olle d i nt o t he st u d y. 
Re gistrati o n m ust occ ur pri or t o t he i nitiati o n of pr ot oc ol t hera p y.  Patie nts eli gi ble t o partici p ate 
i n t he st u d y ma y be e nr olle d t hr o u g h t he Sara h Ca n n o n De vel o p me nt I n n o v ati o ns Ce ntral 
E nr oll me nt Des k.  T he e nr oll me nt des k ma y b e reac he d b y calli n g ( 8 4 4) 7 1 0- 6 1 5 7.  Re gistrati o n 
ma y b e d o ne: 1) via fa x ( 8 6 6) 6 9 9- 0 2 5 8 M o n da y t hr o u g h Fri da y, 8: 3 0 a. m. t o 4: 3 0 p. m., Ce ntral 
Sta n dar d Ti me , or 2) via e mail at C A N N. S C RII n n o vati o ns E nr @scri-i n n o v ati o ns.c o m.  Patie nt 
re gistrati o n will be co nfir me d via e mail wit hi n 2 4  h o urs or b y t he ne xt b usi ness day.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 6  of 6 9  
 
5.  
S T U D Y  DE SI G N  
T his is a P hase II  si n gle- ar m o pe n- la b el st u d y of ni v ol u ma b as mai nte na nce  t hera p y after 
a ut ol o g o us ste m cell tra ns pla ntati o n i n patie nts wit h H L  at ris k of rela ps e or pr o gressi o n . 
Patie nts will recei ve ni v ol u ma b ( 2 4 0 m g  I V) e v er y 2 wee ks ( ± 2  d a ys  as l o n g as i nter val bet w ee n 
d oses is 1 2- 1 6 da ys) starti n g 4 5- 1 8 0 d a ys p ost-tra ns pla nt f or u p t o a ma xi m u m of 6 m o nt hs of 
treat me nt.  T o c o m pare i m m u ne rec o ver y, a c o ntr ol gr o u p of 5 p atients will  recei ve st a n dar d- of-
care pr oce d ures a n d treat me nt b ot h pre- a n d p ost-tra ns pla nt.  Res p o nse t o treat me nt f or p atie nts 
recei vi n g st u d y dr u g will be assesse d  6 m o nt hs a n d 1 year p ost-tra ns pla nt usi n g t he 
Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d  Res p o nse Assess me nt of H o d g ki n a n d 
N o n - H o d g ki n L y m p h o m a: T he L u ga n o Classificati o n (C hes o n et al. 2 0 1 4 , see A p pe n di x F ). 
T he pla n ne d e nr oll me nt f or t his st u d y is 4 0 patie nts: 3 5 patie nts  recei vi n g st u d y dr u g a n d 5 
patie nts will recei ve sta n dar d - of-care pr o ce d ures a n d treat me nt b ot h pre- a n d p ost-tra ns pla nt. 
5. 1  
Tre at me nt Pl a n  
5. 1. 1  
Ni v ol u m a b 
Ni v ol u ma b :  2 4 0 m g  I V Da y 1  of e v er y c ycle (e v er y 2 wee ks ) 
5. 2  
Tre at me nt D ur ati o n  
St u d y treat me nt c o nsists of a ma xi m u m of 6 m o nt hs of treat me nt.  Patie nts m ust recei ve at least 
2 c ycles of ni v ol u ma b t o be e val ua bl e f or efficac y. 
5. 3  
C o nc o mit a nt Me dic ati o ns  
Patie nts  w h o recei v e st u d y dr u g will be i nstr ucte d n ot t o ta ke a n y a d diti o nal me dicati o ns d uri n g 
t he c o urse of t h e st u d y wit h o ut pri or c o ns ultati o n wit h t he researc h tea m.  At eac h visit, t he 
patie nt will be as ke d a b o ut a n y n e w me dicati o ns he /s he is ta ki n g or h as ta k e n after t he start of 
t he st u d y dr u g. 
5. 3. 1  
Per mitte d C o nc o mit a nt Me dic ati o ns  
Pre me dicati o n wit h a nti -e metics is all o we d  acc or di n g to sta n dar d practice g ui deli nes.  
Me dicati o ns ma y be a d mi nistere d f or mai nte n a nce of e xisti n g c o n diti o ns pri or t o st u d y 
e nr oll me nt or f or a ne w c o n diti o n t hat de vel o ps w hile o n st u d y , i ncl u di n g b ut n ot li mite d t o t he 
f oll o wi n g: 
•  Patie nts are per mi tte d t he use of t o pical, oc ular, i ntra-artic ular, i ntra n asal, a n d 
i n halati o nal c ortic oster oi ds ( wit h mi ni mal s yste mi c a bs or pti o n).  A dre nal re place m e nt 
ster oi d d oses ≤1 0 m g d ail y pre d nis o n e are per mitt e d.  A brief (less t ha n 3 wee ks) c o urse 
of c ortic oster o i ds f or pr o p h yla xis  (e. g., c o ntrast d ye aller g y) or f or treat me nt of n o n-
a ut oi m m u ne c o n diti o ns (e. g. , d ela ye d-t y p e h y perse nsiti vit y reacti o n ca use d b y a c o ntact 
aller ge n) is per mitte d.  Ster oi d treat me nt s pecifie d as ≤1 6 m g de x a met has o n e b y m o ut h 
(P O ) dail y t a per e d i n ≤4 wee ks is all o we d o nl y f or t he treat me nt of brai n e de ma.  
Ot her me dicati o ns c o nsi d ere d necessar y f or t h e patie nt’s safet y a n d well -bei n g ma y b e gi ve n at 
t he discreti o n of t he In v esti gat or wit h t he e x ce pti o n of t h ose liste d i n Secti o n  5. 3. 2 . 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 7  of 6 9  
 
5. 3. 2  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
T he f oll o wi n g tr eat me nts are pr o hi bite d f or patie nts recei vi n g st u d y dr u g w hile i n t his st u d y:  
•  N o ot her i n vesti gati o nal t hera p y s h o ul d be gi ve n t o patie nts.  N o a ntica ncer a ge nts ot her 
t ha n t he st u d y me dicati o ns s h o ul d be gi ve n t o patie nts.  If s u c h a ge nts are re q uire d f or a 
patie nt, t he n t he patie nt m ust first be wit h dra w n fr o m t he st u d y.  
•  I m m u n os u p pr essi ve a ge nts (e x ce pt t o treat a dr u g-relate d A E ) 
•  I m m u n os u p pr essi ve d oses of s yste mic c ortic oster oi ds (e x ce pt as state d i n Secti o n 5. 3. 1 ) 
5. 4  
C orrel ati v e St u dies  
5. 4. 1  
Bi o m ar ker A n al ysis 
Ma n dat or y p eri p heral b l o o d sa m ples will be c ollecte d fr o m patie nts recei vi n g st u d y dr u g at 
C ycle 1 Da y 1, C ycle 2 Da y 1, C ycle 3 D a y 1, e n d of treat me nt ( E O T  [ 6 m o nt hs]), a n d 1 year 
after t he first d ose of ni v ol u ma b f or fl o w c yt o metric a nal ysis of P D-1 e x pressi o n  of circ ulati n g 
i m m u ne cell s u bsets, i ncl u di n g l y m p h oi d ( C D 4, C D 8, Tre g, N K, B) a n d m yel oi d cells 
( m o n oc yt es, M D S Cs), a n d e x pressi o n of ot her c hec k p oi nt rece pt ors, s uc h as L A G- 3, TI M- 3 
TI GI T, or a g o nists s uc h as I C O S, GI T R, O X- 4 0.  T hese sa m ples will be la bele d wit h a u ni q ue 
st u d y i de ntifier a n d s u bject c o de i n or der t o mai ntai n patie nt c o nfi de ntialit y.  T hes e sa m ples ha v e 
n o cli nical val ue a n d will be use d f or researc h o nl y.  I nf or mati o n o n c ollecti o n, p r ocessi n g 
st ora ge a n d s hi p me nt f or cells a n d plas ma/ser u m will be i n t he la b orat or y ma n ual. 
5. 4. 2  
I m m u ne R ec o v er y vers us C o ntr ol Gr o u p 
C orrelati ve st u dies will c o m pare i m m u ne rec o ver y f or 5 patie nts u n der g oi n g a ut ol o g o us ste m 
cell tra ns pla nt f or H L  b ut n ot recei vi n g ni v ol u ma b (c o ntr ol) wit h patie nts recei vi n g ni v ol u ma b as 
mai nte na nce t hera p y  (treat me nt).  All pre - a n d p ost-tra ns pla nt pr oce d ures i n t he c o ntr ol gr o u p 
will be acc or di n g t o sta n dar d - of-care as d eter mi n e d b y t h eir treati n g p h ysi cia n.  W he n c o m plete 
bl o o d c o u nt ( C B C) a n d c o m pre he nsi ve meta b olic pr ofili n g ( C M P) pa n els are c ollect e d res ults 
will be e ntere d i nt o t he el ectr o nic case re p ort f or m (e C R F) as p art of t he st u d y rec or d.  Bl o o d 
sa m ples i n c o ntr ol patie nts are t o be c ollecte d at:  
•  Bet wee n da ys 4 5- 1 8 0 aft er a ut ol o g o us ste m cell tra ns pla nt 
•  E ver y 2 - 4 w ee ks ( ± 5 d a ys) w hile recei vi n g st u d y treat me nt bas e d o n sta n dar d- of-car e 
sc he d ule 
•  At 6 m o nt hs ( ± 7 da ys) fr o m first sa m ple, a n d 
•  At 1 year ( ± 7 d a ys)  fr o m first sa m ple. 
5. 4. 3  
H a n dli n g, St or a ge a n d D estr ucti o n of B i ol o gic al S a m ples  
O nce testi n g has bee n c o m plete d, sa m ples will be st ore d f or a n a d diti o nal year be y o n d st u d y 
c o m pleti o n.  At t his ti me sa m ples will ha ve all i de ntifiers re m o ve d a n d destr o ye d.  Sa m ples will 
be t ha we d, d ec o nta mi nat e d, s oli difie d, a ut ocla ve d, a n d t he n place d i nt o t he pr o per bi o hazar d 
waste c o ntai ner f or f urt h er dis p osal. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 8  of 6 9  
 
5. 4. 4  
Wit h dr a w al of I nf or me d C o nse nt f or D o n ate d Bi ol o gic al S a m ples  
If a patie nt wit h dr a ws c o nse nt t o t he use of ma n dator y bi ol o gical sa m ples, t he n t he sa m ples will 
be dis p ose d of/ destr o ye d, a n d t he acti o n d oc u m e nte d.  If sa m ples are alrea d y a n al ys e d , Sara h 
Ca n n o n De vel o p me nt I n n o vati o ns is n ot o bli ge d t o destr o y t h e res ults of t his researc h. 
As c ollecti o n of t hese bi ol o gi cal sa m ples is a m a n dat or y p art of t he st u d y, t he patie nt ma y n ot 
c o nti n ue i n t he st u d y.  
6.  
D O S E M O DI FI C A TI O N S  
If t o xicit y o cc urs, t he t o xicit y will be gra d e d utilizi n g t he N CI C T C A E v 4. 0 3 
(htt ps://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3/ C T C A E _ 4. 0 3 _ 2 0 1 0 - 0 6-
1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df ), a n d a p pr o priate s u p p orti ve care treat me nt will be a d mi nistere d 
t o decrease t he si g ns a n d s y m pt o ms t here of. 
T here will be n o d ose re d ucti o n of ni v ol u ma b; h o we ver, treat me nt dela ys are all o we d.  If t he 
t o xicit y d oes n ot res ol ve t o N CI C T C A E ≤ Gra de 1 after 2 8 d a ys, t he n t he patie nt s h o ul d be 
wit h dra w n fr o m t he st u d y a n d o bs er ve d u ntil res ol uti o n of t he t o xicit y. 
T he d ose m o di ficati o ns t o be use d i n t his st u d y are prese nt e d i n Ta ble 1 . 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 2 9  of 6 9  
 
T a ble 1 
D ose Le vel M o dific ati o ns  
A d verse Reacti o n  
Se verit y *  
D ose M o dificati o n  
C olitis  
Gra de 2 diarr hea or c olitis  
Wit h h ol d d ose
a 
Gra de 3 diarr hea or c olitis  
Wit h h ol d d ose
a 
Gra de 4 diarr hea or c olitis  
P er ma ne ntl y disc o nti n ue  
P ne u m o nitis  
Gra de 2  
Wi t h h ol d d osea 
Gra de 3 or 4  
P er ma ne ntl y disc o nti n ue  
He patitis  
A S T or A L T  > 3 a n d u p t o 5 ×  t he 
U L N or t otal bilir u bi n > 1. 5 a n d u p t o 
3 ×  t he U L N 
Wit h h ol d d ose
a 
A S T or A L T > 5 ×  t he U L N or t otal 
bilir u bi n > 3 ×  t he U L N 
P er ma ne ntl y disc o nti n ue  
H y p o p h ysitis  
Gra de 2 or 3  
Wit h h ol d d ose
a 
Gra de 4  
P er ma ne ntl y disc o nti n ue  
A dre nal  
I ns ufficie nc y 
Gra de 2  
Wit h h ol d d ose
a 
Gra de 3 or 4  
P er ma ne ntl y disc o nti n ue  
T y pe 1 Dia betes  
Mellit us  
Gra de 3 h y per gl yce mia  
Wit h h ol d d ose
a 
Gra de 4 h y per gl yce mia  
P er ma ne ntl y disc o nti n u e  
Ne p hritis a n d Re nal  
D ysf u ncti o n  
Ser u m creati ni ne > 2. 5  a n d u p t o 6 ×  
t he U L N 
Wit h h ol d d ose
a 
Ser u m creati ni ne > 6 ×  t he U L N 
P er ma ne ntl y disc o nti n ue  
Ras h  
Gra de 3  
Wit h h ol d d ose
a 
Gra de 4  
P er ma ne ntl y disc o nti n ue  
E nce p halitis  
Ne w -o nset m o derate or se vere 
ne ur ol o gic si g ns or s y m pt o ms  
Wit h h ol d d ose
a 
I m m u ne-me diate d e nce p halitis  
P er ma ne ntl y disc o nti n ue  
Ot her  
Ot her Gra de 3 a d verse reacti o n  
First occ urre nce  
Rec urre nce of sa me Gra de 3 a d verse 
reacti o ns 
 
Wit h h ol d d ose
a 
P er ma ne ntl y disc o nti n ue  
Life -t hreate ni ng or Gra de 4 a d verse 
reacti o n 
P er ma ne ntl y disc o nti n ue  
Re q uire me nt f or 1 0 m g per da y or 
greater pre d nis o ne or e q ui vale nt f or 
m ore t ha n 1 2 wee ks  
P er ma ne ntl y disc o nti n ue  
P ersiste nt Gra de 2 or 3 a d verse 
reacti o ns lasti n g 1 2 wee ks or l o n ger 
P er ma ne ntl y disc o nti n ue  
* T o xicit y was gra de d per N CI C T C A E v. 4 . 0 3. 
a Res u me treat me nt w he n a d verse reacti o n ret ur ns t o Gra de 0 or 1.  
6. 1  
M a n a ge me nt of Ni v ol u m a b- R el ate d A d verse E ve nts  
M a na ge me nt al g orit h ms f or t he f oll o wi n g ni v ol u ma b-relat e d A Es  are l ocate d i n A p pe n di x G  – 
gastr oi ntesti nal, r e nal, p ul m o nar y, h e patic, e n d o cri n o pat h y, s ki n, a n d n e ur ol o gical.   
6. 1. 1  
M a n a ge me nt of I nf usi o n - Rel ate d R e a cti o ns  
Ni v ol u ma b ca n ca use se v ere i nf usi o n r eacti o ns, w hic h ha ve bee n re p orte d i n less t ha n 1 % of 
patie nts i n  cli nical trials.  Disc o nti n ue ni v ol u ma b i n patie nts wit h Gra de 3 or 4 i nf usi o n 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 0  of 6 9  
 
reacti o ns.  I nterr u pt or sl o w t he rate of i nf usi o n i n patie nts wit h Gra de 1 or 2 i nf usi o n reacti o ns.  
F or ma na ge me nt of i nf usi o n- relate d si de effects, refer t o i nstit uti o nal g ui deli nes. 
7.  
S T U D Y  A S S E S S M E N T S A N D E V A L U A TI O N S  
7. 1  
O ver vie w  
All patie nts s h o ul d visit t he st u d y ce nter o n t h e da ys s pecifie d wit hi n t his pr ot oc ol.  T he 
c o m plete Sc he d ule of Assess me nts f or t his st u d y is s h o w n i n A p pe n di x E .  T he baseli ne p h ysical 
e x a mi nati o n, me dical hist or y, E C O G P S, c o m plet e bl o o d c o u nt ( C B C) wit h  differe ntial a n d 
platelets, c o m pre h e nsi ve meta b olic pr ofile ( C M P ), a n d pr ot hr o m bi n ti me ( P T )/partial 
t hr o m b o plasti n ti me (P T T )/I nt er nati o nal N or malize d Rati o (I N R) s h o ul d b e d o ne ≤7 da ys pri or 
t o i nitiati o n of treat me nt.  A pre g na n c y test m ust be perf or me d wit hi n 7 2 h o urs of C ycl e 1 Da y 1.  
P E T -C T  sca ns s h o ul d be perf or me d ≤6 wee ks  pri or t o i nitiati o n of treat me nt.  E C G a n d researc h 
sa m ples s h o ul d be perf or me d ≤2 8 da ys pri or t o i nitiati o n of st u d y treat me nt.  
7. 2  
B aseli ne  St u d y Assess me nts  
T he f oll o wi n g i nf or mati o n will be c ollecte d a n d pr oce d ures will be perf or me d f or eac h p atie nt at 
scree ni n g: 
•  Writte n i nf or me d c o nse nt pri or t o a n y ot h er st u d y- relate d pr oce d ures ( ≤2 8 da ys pri or t o 
i nitiati o n of treat me nt) 
•  Me dical hist or y  
o  Pri or s yste mic t her a p y a n d ra di ot hera p y f or H L  
o  Res ults of pre- tra ns pla nt P E T-C T (if d o ne) 
•  P h ysical e x a mi nati o n, meas ure m e nts of hei g ht (first visit), wei g ht, a n d vital si g ns (resti n g 
heart r ate, B P, r es pirat or y r ate, a n d oral te m perat ure)  
•  E C O G perf or ma nce stat us (see A p p e n di x A ) 
•  1 2- lea d E C G 
•  C o nc o mita nt me dicati o n re vie w  
•  C B C wit h 3 -part differe ntial a n d platelets  
•  C M P t o i ncl u de: gl uc ose, bl o o d urea nitr o ge n ( B U N), creati ni ne, s o di u m, p otassi u m, 
c hl ori de, cal ci u m, car b o n di o xi de ( C O 2), al kali ne p h os p hatase (A L P ), A S T, A L T , t otal 
bilir u bi n, t otal pr otei n, a n d al b u mi n 
•  C oa g ulati o n a n al ysis:  P T/I N R /P T T  
•  Ser u m or uri ne pr e g na nc y test ( m ust be perf or m e d wit hi n 7 2  h o urs of C ycle 1 Da y 1) 
•  P E T -C T  sca ns ≤6 wee ks pri or t o i nitiati o n of st u d y treat me nt 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 1  of 6 9  
 
•  B o ne marr o w bi o ps y, o nl y if t here is pri or e vi d e nce of b o ne marr o w i n v ol v e me nt.  If 
b o ne marr o w bi o ps y n ee ds t o be re peate d, it s h o ul d be d o ne ≤2 8 da ys pri or t o i nitiati o n 
of st u d y tr eat me nt . 
7. 3  
St u d y Tre at me n t Assess me nts 
7. 3. 1  
D a y 1 of E ac h C ycle  (± 2  d a ys as l o n g as i nter v al bet w ee n d oses is 1 2- 1 6 d a ys) 
•  P h ysical e x a mi nati o n, i ncl u di n g meas ure me nt of wei g ht a n d vital si g ns  
•  E C O G perf or ma nce stat us  
•  A E assess me nt  
•  C o nc o mita nt me dicati o n re vie w  
•  C B C, i ncl u di n g 3- p art diff er e ntial a n d platelets  
•  C M P  
•  Pre - d ose researc h bl o o d sa m ple f or c orrelati ve a n al ysis ( C y cle 1 D a y 1, C ycle 2 D a y 1, 
a n d C ycle 3 D a y 1 o nl y ) 
7. 4  
E n d of St u d y  Tre at me nt  
After wit h dra wal fr o m or c o m pleti o n of pr ot oc ol treat me nt, patie nts m ust be f oll o we d f or A Es 
f or 1 0 0 cal e n dar d a ys aft er t he last d ose of st u d y dr u g.  T h e f oll o wi n g assess me nts will be 
perf or me d : 
•  P h ysical e x a mi nati o n, i ncl u di n g meas ure me nt of wei g ht a n d vital si g ns  
•  E C O G perf or ma nce stat us  
•  A E assess me nt  
•  C o nc o mita nt me dicati o n re vie w  
•  C B C, i ncl u di n g 3- p art differ e ntial a n d platelets  
•  C M P  
•  Ser u m or uri ne pr e g na nc y test 
•  Researc h bl o o d s a m ple f or c orr elati ve a n al ysis  
7. 5  
Res p o nse Assess me nt  
Patie nts s h o ul d ha ve P E T- C T sca ns d o ne p er i nstit uti o n sta n dar d of care.  P E T- C T sca ns are 
re q uire d 1- 3 m o nt hs p ost-A S C T pr i or t o i nitiati o n of t hera p y, 6 m o nt hs p ost- A S C T,  a n d 1 year 
p ost- A S C T.   If t here is pri or e vi de nce of b o ne marr o w i n v ol ve me nt, patie nts s h o ul d als o ha ve 
b o ne marr o w bi o ps y p erf or me d if i n C R at t hese sta gi n g visits t o d oc u me nt res p o nse. 
Patie nts disc o nti n ui n g t hera p y earl y r ecei vi n g > 6 c ycles wit h meas ura ble disease at bas eli ne are 
rec o m me n de d t o h a ve a n E O T P E T- C T.  Patie nts e n di n g treat me nt earl y nee d t o ha ve a P E T -C T  
at 1 year p ost-A S C T  u nless patie nt pr o gresses or st arts a ne w t h era p y. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 2  of 6 9  
 
7. 6  
F oll o w- u p  
Patie n ts will be f oll o we d e ver y m o nt h ( ± 1 wee k ) f or 3 m o nt hs a n d t he n e ver y 3 m o nt hs 
t hereafter fr o m t he date of last d ose of ni v ol u ma b f or u p t o 2 years.  A res earc h bl o o d sa m ple 
will be ta ke n 1 year aft er t he first d ose of ni v ol u ma b.  A p h o ne call ma y be use d t o assess 
s ur vi val a n d t o rec or d i nitiati o n of a n alter nati ve f or m of treat me nt f or l y m p h o ma after res p o nse 
assess me nt at 1 year p ost -A S C T . 
8.  
D R U G F O R M U L A TI O N , A V AI L A BI LI T Y, A D MI NI S T R A TI O N, A N D 
T O XI CI T Y I N F O R M A TI O N  
8. 1  
Ni v ol u m a b 
 
I n vesti g ati o n al Pr o d uct 
D os a ge F or m a n d Stre n gt h 
M a n uf act urer  
Ni v ol u ma b  
1 0 0 m g/ 1 0 m L ( 1 0 m g/ m L)  
Brist ol -M yers S q ui b b  
 
8. 1. 1  
L a beli n g, P ac k a gi n g, S u p pl y, a n d St or a ge 
Ni v ol u ma b will be s u p plie d i n 1 0- cc t y pe I fli nt gl ass vials wit h b ut yl r u b ber st o p pers a n d seale d 
wit h al u mi n u m seals  b y Brist ol- M yers S q ui b b. 
St ore u n der refri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F).  Pr otect fr o m li g ht b y st ori n g i n t he 
ori gi nal pac ka ge u ntil ti me of use.  D o n ot freeze or s ha ke. 
All st u d y dr u gs m ust be ke pt i n a sec ure place u n der a p pr o priate st ora ge c o n diti o ns.  St ora ge 
c o n diti o ns f or ni v ol u ma b are i ncl u de d o n t h e i n vesti gati o nal pr o d uct la b el. 
Sara h Ca n n o n De v el o p me nt I n n o v ati o ns m ust be gra nte d access o n reas o n a ble re q u est t o c hec k 
dr u g st or a ge, dis pe nsi n g pr oce d ur es, a n d acc o u nta bilit y rec or ds. 
8. 1. 2  
Pre p ar ati o n a n d A d mi nistr ati o n of Ni v ol u m a b 
Ni v ol u ma b is a d mi nistere d as a n I V i nf usi o n o ver 6 0 mi n utes.  
Pre parati o n a n d a d mi nistrati o n i nstr ucti o ns will be pr o vi de d i n t he ni v ol u ma b I n v esti gat or ’s 
Br oc h ure (I B).  
8. 1. 3  
Prec a uti o ns a n d Ris ks Ass oci ate d wit h Ni v ol u m a b 
Preca uti o ns a n d ris ks are l ocate d i n t he ni v ol u ma b I B.  Ma n a ge me nt of ni v ol u ma b-relate d A Es is 
pr o vi de d i n A p pe n di x G . 
8. 2  
Acc o u nt a bilit y f or All St u d y D r u gs 
T he P ri nci pal In vesti gat or  (PI, or desi g nee) is res p o nsi ble f or acc o u nta bilit y of all use d a n d 
u n use d st u d y dr u g s u p pli es at t he site. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 3  of 6 9  
 
All st u d y dr u g i n ve nt ories m ust be ma de a vaila ble f or i ns pecti o n b y t he S p o ns or or its 
re pres e ntati ves a n d r e g ul at or y a ge n c y i ns pect ors u p o n re q uest. 
At t he e n d of t he st u d y , all Sara h Ca n n o n De vel o p me nt I nn o v ati o ns Dr u g Acc o u nta bilit y Rec or d 
F or m(s) will be c o m plete d b y t he site a n d s e nt t o t he Sara h Ca n n o n D e vel o p me nt I n n o v ati o ns 
Re g ulat or y De part me nt .  St u d y dr u g  s u p plies m ust n ot be destr o ye d u nless pri or a p pr o val h as 
bee n gra nt e d b y t he S p o ns or or its r e pres e ntati ve.  Please c o ntact Sara h Ca n n o n De vel o p me nt 
I n n o v ati o ns re gar di n g dis p osal of a n y st u d y dr u g. 
9.  
R E S P O N S E E V A L U A TI O N S A N D M E A S U R E M E N T S  
L y m p h o ma pr o gressi o n will be assesse d usi n g t he Rec o m me n dati o ns f or I nitial E val uati o n, 
Sta gi n g, a n d  Res p o nse As sess me nt of H o d g ki n a n d N o n- H o d g ki n L y m p h o ma: T he L u ga n o 
Classificati o n  (C hes o n et al. 2 0 1 4 , see A p p e n di x F ).  Pr o gressi o n will be assesse d  6 m o nt hs 
p ost- A S C T a n d 1 year p ost- A S C T . 
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 0. 1  
St atistic al Desi g n  
T his is a m ultice nter, o pe n -la bel, P hase II st u d y of ni v ol u ma b as mai nte na n ce  t hera p y aft er 
A S C T  i n patie nts wit h H L  at ris k of rela ps e or pr o gressi o n.  T he pri mar y, s ec o n dar y a n d 
e x pl orat or y o bjecti ves a n d e n d p oi nts are f o u n d i n S ecti o n 2 . 
1 0. 2  
S a m ple Size C o nsi der ati o ns  
T he n ull h y p ot hesis t o be teste d is t hat t he tr ue 1 2-m o nt h P F S is 5 0 % a gai nst a t w o -si de d 
alter nati ve h y p ot hesis of a 7 0 % P F S rate .  T he 5 0 % 6 - m o nt h P F S rate w as o btai ne d fr o m t he 
Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d Res p o nse Assess me nt of H o d g ki n a n d 
N o n - H o d g ki n L y m p h o m a: T he L u ga n o Classificati o n (C hes o n et al. 2 0 1 4 , see A p pe n di x F ).  A 
t w o-si de d, o ne-sa m ple l o g-ra n k test calc ulate d fr o m a sa m ple of 3 6 e v al ua ble s u bjects ac hie v es 
8 0. 3 % p o wer at a 0. 0 5 0 si g nifica n ce le v el t o detect a n i m pr o ve me nt of 2 0 % i n 1 2- m o nt h P F S. 
T he pr o ba bilit y t h at a s u bject  e x perie nces a n e ve nt d uri n g t he st u d y is 0. 4 5 7 9.  T he e x pecte d 
n u m ber of e v e nts d uri n g t he st u d y is 1 6.  It is ass u me d t hat t he s ur vi val ti me distri b uti o ns of b ot h 
gr o u ps are a p pr o xi mate d  reas o na bl y w ell b y t h e Wei b ull distri b uti o n wit h a s ha pe para meter of 
1. 0 0.  T hese pr o p orti o ns ass u me a n e nr oll me nt peri o d of 1 8 m o nt hs a n d a f oll o w- u p peri o d of 1 2 
m o nt hs after t he last s u bject is a d de d.  I n or der t o all o w f or a 1 0 % dr o p o ut rate, a t otal of 4 0 
patie nts will be e nr olle d.  T he sa m ple size was calc ulate d usi n g P A S S versi o n 1 4. 
1 0. 3  
A n al ysis P o p ul ati o n 
T he f oll o wi n g a nal ysis p o p ulati o ns will be use d: 
•  F ull A nal ysis Set ( F A S) is defi ne d as all s u bjects w h o ha ve recei v e d at least o ne d ose of 
st u d y me dicati o n. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 4  of 6 9  
 
•  Efficac y -E val u a ble P o p ulati o n ( E F F) is defi ne d as all s u bjects recei vi n g at least t w o 
c ycles of st u d y me dicati o n.  
•  Safet y P o p ulati o n ( S A F) is defi ne d as all patie nts w h o ha ve recei v e d at least o ne d ose of 
st u d y treat me nt.  T his p o p ulati o n will be use d f or t he safet y a n al ysis. 
1 0. 4  
D at a A n al ysis 
Descri pti ve statistics, i ncl u di n g mea n, me di a n, sta n dar d de viati o ns a n d ra n ges f or all c o nti n u o us 
m eas ures will be ta b ulat e d a n d re p ort e d.  Perce nta ges a n d fre q ue nci es f or all cate g orical 
meas ures will als o be pr ese nte d.  Ti me -t o-e v e nts e n d p oi nts will be re p orte d usi n g K a pl a n-Meier 
esti mates, wit h 9 5 %  a CI  f or me dia n ti me t o e ve nt. 
1 0. 4. 1  
D e m o gr a p hics a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d baseli n e disease c har acteristics will be s u m marize d.  Data t o be ta b ulate d will 
i ncl u de de m o gra p hic feat ures s uc h as a ge, se x a n d race, as well as disease-s pecific 
c haracteristics.  
T he n u m ber a n d p erce nta ges of patie nts scr ee ne d, ra n d o mize d, treate d, c o m plete d t he 
treat me nt/st u d y a n d wit h dra w n fr o m treat me nt/st u d y f or a n y reas o ns will b e prese nt e d. 
1 0. 4. 2  
Effic ac y A n al ysis 
T he pri mar y  efficac y a n al ysis will be perf or me d usi n g t he F A S .  Se nsiti vit y a n al ys es will be 
pe rf or me d usi n g the Effi cac y - E val ua ble P o p ulati o n ( E F F). 
•  P r o gr essi o n- Fr ee S ur vi val ( P F S), defi ne d as t he ti me fr o m t he first da y of st u d y dr u g 
a d mi nistrati o n ( Da y 1) t o disease pr o gressi o n as d efi ne d b y t he Rec o m me n dati o ns f or 
I nitial E val uati o n, Sta gi n g, a n d Res p o ns e Assess me nt of H o d g ki n a n d N o n- H o d g ki n 
L y m p h o ma: T he L u ga n o Classificati o n  (C hes o n et al. 2 0 1 4 , see A p pe n di x F ), or d eat h o n 
st u d y.  Patie nts w h o ar e ali ve a n d free fr o m diseas e pr o gressi o n will be ce ns ore d at t he 
date of last t u m or assess me nt.  
F or P F S Ka pl a n -Meier c ur ves will be ge nerate d a n d t he me dia n ti me t o e ve nt a n d t he ass oci ate d 
9 5 % CI  b e pr o vi de d.  K a pla n -M eier esti mat es will als o be pr o d uce d f or t he f oll o wi n g s pecifie d 
ti me p oi nts: 1 2 m o nt hs a n d 2 4 m o nt hs.  T he hazar d rati o a n d t he 9 5 % CI f or t hese e n d p oi nts 
bet wee n t he t w o tr eat me nt gr o u ps will be calc ulat e d.  
1 0. 4. 3  
S af et y A n al ysis 
Safet y will be assesse d t hr o u g h t he a nal ysis of t he re p orte d i nci d e nce of treat me nt -e mer ge nt 
A Es.  Treat me nt -e mer ge nt A Es are t h ose wit h a n o nset o n or after t he i nitiati o n of t hera p y, a n d 
will be gr a de d acc or di n g t o N CI C T C A E v 4. 0 3.  A c o p y of C T C A E sc ori n g s yste m ma y be 
d o w nl oa de d fr o m: htt ps://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3/ C T C A E _ 4. 0 3 _ 2 0 1 0 - 0 6-
1 4 _ Q uic k Refere nce _ 8. 5 x 1 1. p df.  
T he A Es will be c o de d usi n g Me dical Dicti o nar y f or Re g ulat or y A cti vities ( Me d D R A), a n d 
s u m marize d usi n g s yste m or ga n class a n d preferre d ter m f or all patie nts i n t he Safet y P o p ulati o n.  
I n a d diti o n, s u m maries of seri o us a d verse e v e nts (S A Es ), A Es lea di n g t o treat me nt 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 5  of 6 9  
 
disc o nti n uati o n, A Es b y ma xi m u m N CI C T C A E gra de, a n d A Es rel ate d t o st u d y treat me nt will 
als o be prese nt e d.  
Ot her saf et y e n d p oi nts i ncl u di n g la b or at or y res ults a n d vital si g ns will be s u m marize d f or all 
patie nts i n t he Safet y P o p ulati o n. 
C o nc o mita nt me dicati o ns will be  liste d a n d s u m marize d a n d c o de d usi n g t h e W orl d Healt h 
Or ga nizati o n -Dr u g Dicti o nar y.  
1 0. 4. 4  
E x pl or at or y A n al ysis 
T he sc o pe a n d details of t he e x pl orat or y a nal ysis, i ncl u di n g c orrelati ve bi o mar ker a nal ysis, will 
be detaile d i n t he Statistical A nal ysis Pla n ( S A P).  
1 0. 5  
A n al ysis Ti me P oi nts  
1 0. 5. 1  
Fi n al A n al ysis  
T he fi nal a n al ysis of t he st u d y will occ ur w he n all e nr olle d s u bjects ha v e recei ve d at least 2 
c ycles of ni v ol u ma b a n d ha ve c o m plete d 1 2 m o nt h p ost- A S C T disease ass ess me nt . 
1 0. 5. 2  
Pl a n ne d I nteri m A n a l ysis 
T here is n o pla n ne d i nteri m a nal ysis f or t his st u d y. 
1 1.  
S A F E T Y R E P O R TI N G A N D  A N A L Y S E S  
Safet y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g pr ot o c ol- defi n e d A Es a n d S A Es, 
meas ure me nt of pr ot oc ol- s pecifie d h e mat ol o g y, cli nical c he mistr y, a n d ot h er pr ot oc ol- s p ecifie d 
tests i n t he e C R Fs t hat ar e dee me d critical t o t he s afet y e v al uati o n of t he st u d y dr u g. 
T he PI  is r es p o nsi ble f or rec o g nizi n g a n d re p orti n g A Es t o t he Sara h Ca n n o n De vel o p me nt 
I n n o v ati o ns Safet y De p art me nt (see Secti o n 1 1. 2 ).  It is t he S p o ns or’s res p o nsi bilit y t o re p ort 
rele va nt S A Es t o t he a p plica ble l ocal, nati o nal, or i nter nati o nal re g ul at or y b o dies.  I n a d diti o n, 
I n v esti gat ors m ust re p ort S A Es a n d f oll o w- u p i nf or mati o n t o t heir res p o nsi ble I R B acc or di n g t o 
t he p olicies of t hat I R B.  
T he PI  is als o res p o nsi ble f or e ns uri n g t h at e ver y staff me m ber i n v ol ve d i n t he st u d y is fa miliar 
wit h t he c o nte nt of t his secti o n. 
1 1. 1  
Defi niti o ns  
1 1. 1. 1  
A d verse E ve nts  
A d verse e ve nt mea ns a n y u nt o war d me dical o cc urre nce a ss oci ate d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g- relate d.  A n A E  ca n b e a n y u nfa v ora ble a n d u ni nte n d e d 
si g n (e. g., a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p oraril y ass o ciate d wit h t he 
use of a dr u g, wit h o ut a n y j u d g me nt a b o ut ca usalit y.   A n A E  ca n arise wit h a n y us e of t he dr u g 
(e. g., off-la bel use, us e i n c o m bi nati o n wit h a n ot her dr u g) a n d wit h a n y r o ut e of a d mi nistrati o n, 
f or m ulati o n, d ose or i ncl u di n g o ver d ose. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 6  of 6 9  
 
1 1. 1. 2  
Seri o us A d verse E ve nt  
A n A E or a s us pecte d a d verse re a cti o n ( S A R) is c o nsi dere d “seri o us ” if it res ults i n a n y of 
t he f oll o wi n g o utc o mes: 
•  De at h  
•  A lif e -t hre ate ni n g A E 
•  I n p atie nt h os pit aliz ati o n of at le ast 2 4- h o urs or pr ol o n g ati o n of e xisti n g 
h os pit aliz ati o n 
•  A persiste nt or si g nific a nt i nc a p acit y or s u bst a nti al disr u pti o n of t he a bilit y t o 
c o n d uct n or m al lif e f u ncti o ns  
•  A c o n ge nit al a n o m al y/ birt h defect 
I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w h e n, base d u p o n a p pr o priate me dical j u d g m e nt, t he y 
ma y je o p ar dize t he patie nt or s u bject a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t his defi niti o n.  E x a m ples of s uc h me dical e v e nts i ncl u de aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, bl o o d d yscrasias 
or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g de pe n de n c y or dr u g 
a b use.  
It is i m p orta nt t o disti n g uis h bet wee n “s eri o us” a n d “se vere” A E, as t he ter ms are n ot 
s y n o n y m o us.  Se verit y is a meas ur e of i nte nsit y; h o we ver, a n A E of s e vere i nte nsit y n ee d n ot 
necessaril y b e c o nsi der e d seri o us.  Seri o us ness ser ves as t he g ui de f or defi ni n g re g ul at or y 
re p orti n g o bli gati o ns.  “ Seri o us” is a r e g ulat or y defi niti o n a n d is base d o n patie nt/e ve nt o utc o me 
or acti o n us uall y ass ociat e d wit h e ve nts t hat p ose a t hreat t o a p atie nt’s life or vital f u ncti o ns.  
F or e x a m ple, na usea w hi c h persists f or se v eral h o urs ma y b e c o nsi dere d se vere na us ea, b ut ma y 
n ot be c o nsi dere d a n S A E.  O n t he ot her ha n d, a str o ke w hic h res ults i n o nl y a li mite d de gree of 
disa bilit y ma y b e c o nsi dere d o nl y a mil d str o ke, b ut w o ul d be c o nsi dere d a n S A E.  Se verit y a n d 
seri o us ness s h o ul d be i n de pe n de ntl y assess e d w he n rec or di n g A Es o n t he e C R F a n d S A Es o n t he 
S A E Re p ort F or m. 
1 1. 1. 3  
A d verse R e acti o n  
A n a d vers e reacti o n mea ns a n y A E  ca us e d b y a dr u g.  A d v erse reacti o ns are a s u bset of all S A Rs  
w here t here is a reas o n t o c o ncl u de t hat t he dr u g ca use d t he e v e nt.  
1 1. 1. 4  
S us pecte d A d verse Re a cti o n  
S us pecte d a d verse r eacti o n mea ns a n y A E  f or w hic h t here is a reas o n a ble p ossi bilit y t hat t he 
dr u g ca use d t h e A E .  Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest a ca us al 
relati o ns hi p bet wee n t h e dr u g a n d t he A E .  A n S A R  i m plies a lesser de gree of cert ai nt y a b o ut 
ca usalit y t h a n A E , w hic h mea ns a n y A E  ca use d b y a dr u g.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 7  of 6 9  
 
1 1. 1. 5  
Rec or di n g a n d Re p orti n g of A d verse E ve nts  
Rec or di n g of A d verse E ve nts  
All A Es fr o m a n y patie nt t hat occ ur d uri n g t he c o urse of t he researc h st u d y will be rec or d e d i n 
t he e C R F, a n d t he I n v esti gat or will gi ve his or h er o pi ni o n as t o t he relati o ns hi p of t he A E t o t he 
st u d y dr u g tr eat me nt (i.e., w het her t he e ve nt is rel ate d or u nrelate d t o st u d y dr u g a d mi nistrati o n). 
All A Es s h o ul d be d oc u me nte d.  A descri pti o n of t he e ve nt, i ncl u di n g its date of o nset a n d 
res ol uti o n, w het her it c o nstit utes a S A E or n ot, a n y acti o n ta ke n (e. g., c ha n ges t o st u d y 
treat me nt), a n d o ut c o me, s h o ul d be pr o vi de d, al o n g wit h t he In v esti gat or’s assess me nt of 
ca usalit y (i.e., t he r elati o ns hi p t o t he st u d y treat m e nt[s]).  F or a n A E t o be a s us pecte d treat me nt-
relate d e v e nt t here s h o ul d be at least a reas o n a ble p ossi bilit y of a ca us al rel ati o ns hi p bet wee n t he 
pr ot oc ol treat me nt a n d t h e A E.  A d verse e v e nts will be gra de d acc or di n g t o t he N CI C T C A E 
v 4. 0 3, a n d c ha n ges will be d oc u me nte d. 
If t he A E is seri o us, it s h oul d be re p orte d i m me di atel y t o t he Sara h Ca n n o n De vel o p me nt 
I n n o v ati o ns Safet y De p art me nt.  Ot her u nt o war d e ve nts occ urri n g i n t he fra me w or k of a cli nical 
st u d y ar e t o be r ec or d e d as A Es (i.e., A Es t hat o cc ur pri or t o assi g n me nt of st u d y treat me nt t hat 
are r elate d t o a pr ot oc ol- ma n date d i nter ve nti o n, i ncl u di n g i n vasi ve pr oce d ures s uc h as bi o psies, 
me dicati o n was h o ut, or n o treat me nt r u n- i n). 
A n y cli nicall y si g nifica nt si g ns a n d s y m pt o ms; a b n or mal test fi n di n gs; c h a n ges i n p h ysical 
e x a mi nati o n; h y p erse nsiti v it y; a n d ot her meas ure me nts t hat occ ur will be re p orte d as a n A E, a n d 
c ollecte d o n t he r ele va nt e C R F scree n.  
Test fi n di n gs will be r e p orte d as a n A E if: t he test res ult re q uires a n a dj ust me nt i n t he st u d y 
dr u g(s) or disc o nti n uati o n of treat me nt, a n d/ or t e st fi n di n gs re q uire a d diti o nal testi n g or s ur gi cal 
i nter ve nti o n, a test res ult or fi n di n g is ass o ciate d wit h acc o m pa n yi n g s y m pt o ms, or a test res ult is 
c o nsi dere d t o be a n A E b y t he I n v esti gat or. 
Re p orti n g Peri o d f or A d verse E ve nts  
All A Es , re gar dl ess of seri o us ness or relati o ns hi p t o ni v ol u ma b treat me nt (calle d st u d y 
treat me nt), s pa n ni n g fr o m t he start of st u d y treat me nt u ntil 1 0 0 cale n dar d a ys after 
disc o nti n uati o n or c o m pleti o n of st u d y treat me nt as defi ne d b y t he cli nical st u d y f or t h at patie nt, 
are t o be rec or de d o n t he c orres p o n di n g scree n(s) i ncl u de d i n t he e C R F. 
All A Es res ulti n g i n disc o nti n uati o n fr o m t he st u d y s h o ul d be f oll o w e d u ntil res ol uti o n or 
sta bilizati o n.  All ne w A Es occ urri n g d uri n g t his peri o d m ust be re p ort e d a n d f oll o we d u ntil 
res ol uti o n u nless, i n t he o pi ni o n of t he In v esti gat or, t he A E or la b orat or y a b n or malit y/ies are n ot 
li kel y t o i m pr o ve beca us e of t he u n derl yi n g disease.  I n t his case, t he I n vesti gat ors m ust rec or d 
his or her reas o ni n g f or t his decisi o n i n t he patie nt’s me dical rec or d. 
After 1 0 0 da ys f oll o wi n g t he c o m pleti o n of pr ot oc ol-s pecific treat me nt or disc o nti n uati o n, o nl y 
A Es, S A Es, or deat hs ass esse d b y t he I n v esti gat or as treat me nt -relate d are t o be re p ort e d. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 8  of 6 9  
 
1 1. 1. 6  
Assess me nt of A d verse E ve nts  
All A Es a n d S A Es w het h er v ol u nteer e d b y t he pati e nt, disc o vere d b y st u d y pers o n nel d uri n g 
q uesti o ni n g, or det ecte d t hr o u g h p h ysical e x a mi nati o n, la b orat or y test, or ot her mea ns will be 
re p orte d a p pr o priat el y.  Eac h r e p orte d A E or S A E will be descri be d b y its d urati o n (i.e., start a n d 
e n d dates), r e g ulat or y seri o us ness criteria if a p plica ble, s us pecte d relati o ns hi p t o t he st u d y dr u g 
(see f oll o wi n g g ui da nce), a n d acti o ns ta ke n. 
T o e ns ure c o nsiste n c y of A E a n d S A E ca us alit y assess me nts, I n v esti gat ors s h o ul d a p pl y t he 
f oll o wi n g ge n eral g ui deline:  
Y E S:   T here is a pla usi bl e te m p oral relati o ns hi p bet wee n t he o ns et of t he A E a n d 
a d mi nistrati o n of t he st u d y me dicati o n, a n d t he A E ca n n ot be rea dil y e x plai ne d b y t he 
patie nt’s cli nical state, i nterc urre nt ill ness, or c o nc o mita nt t hera pies, a n d/ or t he A E 
f oll o ws a k n o w n patter n of res p o nse t o t he st u d y dr u g, a n d/ or t he A E a bat es or res ol ves 
u p o n disc o nti n uati o n of t he st u d y dr u g or d ose re d ucti o n a n d, if a p plica ble, rea p pears 
u p o n re- c h alle n ge.  
N O:   E vi de nce e xists t hat t he A E has a n eti ol o g y ot her t ha n t he st u d y dr u g (e. g., pre-
e xisti n g me dical c o n diti o n, u n derl yi n g disease, i nt erc urre nt ill ness, or c o n c o mita nt 
me dicati o n), a n d/ or t he A E has n o pla usi ble te m p oral relati o ns hi p t o st u d y dr u g 
a d mi nistrati o n (e. g., ca n cer dia g n ose d 2 d a ys after first d ose o f st u d y dr u g). 
1 1. 2  
Seri o us A d verse E ve nt Re p orti n g b y I n vesti g at ors  
A d verse e ve nts classifie d b y t he tr eati n g I n vesti gat or as seri o us re q uire e x pe diti o us ha n dli n g a n d 
re p orti n g t o t he Sara h Ca n n o n De vel o p me nt I n n o v ati o ns Safet y De part me nt i n or der t o c o m pl y 
wi t h re g ul at or y re q uire m e nts.  Deter mi nati o n of life-t hreate ni n g or seri o us is base d o n t he 
o pi ni o n of eit her t he S p o ns or or t he I n vesti gat or. 
Seri o us A Es ma y o cc ur at a n y ti me fr o m t he start of st u d y treat me nt t hr o u g h  1 0 0 da ys after t he 
last st u d y treat me nt.  T h e S ar a h C a n n o n De vel o p me nt  I n n o v ati o ns S afet y De p art me nt m ust 
be n otifie d of all S A Es, re g ar dless of c a us alit y, wit hi n 2 4 h o urs of t he first k n o wle d ge of t he 
e ve nt b y t he tre ati n g p h ysici a n or rese arc h pers o n nel.  
T o re p ort a S A E, t he S A E Re p ort F or m s h o ul d be c o m plete d wit h t he necessar y i nf or mati o n. 
T he S A E re p ort s h o ul d b e se nt t o t he Sara h Ca n n o n De vel o p me nt I n n o vati o ns Safet y 
De part me nt via fa x or e mail usi n g t he usi n g t h e f oll o wi n g c o ntact i nf or mati o n ( d uri n g b ot h 
b usi ness a n d n o n- b usi ness h o urs): 
Sara h Ca n n o n De v el o p me nt I n n o v ati o ns Safet y D e part me nt  
Safet y De pt. Fa x #:      1 - 8 6 6- 8 0 7- 4 3 2 5 
Safet y De pt. E mail:      C A N N. S A E @ S C RI -I n n o v ati o ns.c o m 
Tra ns missi o n of t he S A E re p ort s h o ul d be c o nfir me d b y t h e site pers o n nel s u b mitti n g t he re p ort. 
F oll o w- u p i nf or mati o n f or S A Es a n d i nf or mati o n o n n o n-seri o us A Es t hat bec o me seri o us s h o ul d 
als o be re p ort e d t o t he Sara h Ca n n o n De v el o p me nt I n n o vati o ns Safet y De p art me nt as s o o n as it 
is a vaila ble; t hese r e p orts s h o ul d be s u b mitte d usi n g t he Sara h Ca n n o n D e vel o p me nt I n n o vati o ns 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 3 9  of 6 9  
 
S A E Re p ort F or m.  T he detaile d S A E re p orti n g pr ocess will be pr o vi de d t o t he sites i n t he S A E 
re p orti n g g ui deli nes c o nt ai ne d i n t he st u d y refere n ce ma n ual. 
I n v esti gat ors m ust re p ort S A Es a n d f oll o w- u p i nf or mati o n t o t heir res p o nsi ble I R B accor di n g t o 
t he p olicies of t he res p o nsi ble I R B. 
1 1. 3  
Rec or di n g of A d verse E ve nts a n d Seri o us A d verse E ve nts  
1 1. 3. 1  
Di a g n osis vers us Si g ns a n d S y m pt o ms 
All A Es s h o ul d be rec or d e d i n di vi d uall y i n t he patie nt’s o w n w or ds ( v er bati m) u nless, i n t he 
o pi ni o n of t he PI  or d esi g nate d p h ysicia n, t he A Es c o nstit ute c o m p o ne nts of a rec o g nize d 
c o n diti o n, disease, or s y n dr o me.  I n t he latter cas e, t he c o n diti o n, disease, or s y n dr o me s h o ul d b e 
na me d rat her t ha n eac h i n di vi d ual si g n or s y m pt o m.  If a c o nstellati o n of si g ns a n d/ or s y m pt o ms 
ca n n ot be me dicall y c har acterize d as a si n gle di a g n osis or s y n dr o me at t he ti me of re p orti n g, 
eac h i n di vi d ual e v e nt s h o ul d be rec or de d as a n A E or S A E as a p pr o priate o n t he rele va nt f or m(s) 
( S A E Re p ort F or m a n d/ or A E e C R F scree n).  If a dia g n osis is s ubse q ue ntl y esta blis he d, it s h o ul d 
be re p ort e d as f oll o w- u p i nf or mati o n bec o mes  a v aila ble.  If a dia g n osis is d eter mi ne d s u bse q ue nt 
t o t he re p orti n g of t he c o nstellati o n of s y m pt o ms, t he si g ns/s y m pt o ms s h o ul d be u p date d t o 
reflect t he dia g n osis. 
Pr o gr essi o n of mali g n a nc y (i ncl u di n g fatal o utc o m es), if d oc u me nte d b y us e of a p pr o priate 
met h o d (f or e x a m ple, as per L u ga n o C lassificati o n [C hes o n et al. 2 0 1 4 , see A p pe n di x F ]), s h o ul d 
n ot be re p orte d as a n S A E. 
1 1. 3. 2  
Pe rsiste nt or Rec u rre nt A d verse E ve nts  
A persiste nt A E is o ne t h at e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n patie nt e val uati o n 
ti me p oi nts.  S uc h e ve nts s h o ul d o nl y be rec or d e d o nce o n t he S A E Re p ort F or m a n d/ or t he A E 
e C R F scree n.  If a persiste nt A E bec o mes m ore se vere or l esse ns i n se verit y, it s h o ul d be 
rec or d e d o n a se p ar ate S A E Re p ort F or m a n d/ or A E e C R F scree n. 
A rec urre nt A E is o n e t hat occ urs a n d res ol ves b et wee n patie nt e v al uati o n ti me p oi nts a n d 
s u bse q ue ntl y rec urs.  All rec urre nt A Es s h o ul d be rec or d e d o n a n S A E Re p ort F or m a n d/ or A E 
e C R F scree n.  
1 1. 3. 3  
A b n or m al L a b or at or y V al ues 
If a n a b n or mal la b or at or y val u e or vital si g n is ass ociate d wit h cli nical si g ns a n d/ or s y m pt o ms, 
t he si g n or s y m pt o m s h o ul d be re p orte d as a n A E or S A E, a n d t he ass oci ate d la b orat or y v al ue or 
vital si g n s h o ul d be c o nsi dere d a d diti o nal i nf or m ati o n t hat m ust be c ollecte d o n t he rele va nt 
e C R F scree n.  If t h e la b orat or y a b n or m alit y is a si g n of a diseas e or s y n dr o me, o nl y t he dia g n osis 
nee ds t o be r ec or d e d o n t he S A E Re p ort F or m or A E e C R F scree n.  
A b n or mal la b orat or y v al ues will be re p orte d as a n A E if: t he la b orat or y res ult re q uires a n 
a dj ust me nt i n t he st u d y dr u g(s) or disc o nti n uati o n of treat me nt, a n d/ or l a b orat or y fi n di n gs 
re q uire a d diti o nal testi n g or s ur gical i nter v e ntio n, a la b orat or y res ult or fi n di n g is ass ociate d wit h 
acc o m pa n yi n g s y m pt o ms, or a la b or at or y res ult is c o nsi dere d t o be a n A E b y t he I n v esti gat or. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 0  of 6 9  
 
1 1. 3. 4  
De at hs  
Deat hs t hat occ ur d uri n g t he pr ot oc ol-s pecifie d A E re p orti n g peri o d t hat are attri b ute d b y t he 
I n v estigat or s olel y t o pr o gr essi o n of disease will be rec or de d o n t he “ St u d y Disc o nti n uati o n” 
e C R F scree n.  All ot her o n st u d y deat hs, re gar dless of attri b uti o n, will be rec or de d o n a n S A E 
Re p ort F or m a n d e x pe diti o usl y re p orte d t o t he Sara h Ca n n o n De v el o p me nt I n no v ati o ns Safet y 
De part me nt.  
W he n rec or di n g a S A E wit h a n o utc o me of deat h, t he e ve nt or c o n diti o n t hat ca use d or 
c o ntri b ute d t o t he fatal o utc o me s h o ul d be rec or d e d as t he si n gle me dical c o nce pt o n t he S A E 
Re p ort F or m a n d A d vers e E ve nt scr ee n of t h e e C R F.  If t he ca use of deat h is u n k n o w n a n d 
ca n n ot be as cert ai ne d at t he ti me of re p orti n g, rec or d “ Deat h N O S” ( N ot Ot her wise S pecifie d) o n 
t he e C R F A d verse E ve nt scree n.  D uri n g p ost-st u d y s ur vi val f oll o w- u p, deat hs attri b ute d t o 
pr o gressi o n of diseas e will be rec or d e d o nl y o n t he “ After Pr o gressi ve Disease F oll o w-U p” 
e C R F scree n.  
1 1. 3. 5  
H os pit aliz ati o n, Pr ol o n ge d H os pit aliz ati o n, or S ur ger y 
A n y A E t hat res ults i n h os pitalizati o n of > 2 4 h o urs or pr ol o n gati o n of pre- e xisti n g 
h os pitalizati o n s h o ul d be d oc u me nte d a n d re p o rte d as a n S A E u nless s pecificall y i nstr u cte d 
ot her wise i n t his pr ot oc ol.  T here are s o me h os pitalizati o ns t hat d o n ot re q uire re p orti n g as a n 
S A E.  
Treat me nt wit hi n or a d missi o n t o t he f oll o wi n g facilities is n ot c o nsi dere d t o meet t he criteri a of 
“i n patie nt h os pitalizati o n” (alt h o u g h if a n y ot her S A E criteria are met, t he e ve nt m ust still be 
treate d as a n S A E a n d i m me diatel y re p orte d): 
•  E mer ge nc y d e part me nt or emer ge nc y r o o m 
•  O ut patie nt or sa me - d a y s ur ger y u nits 
•  O bser vati o n or s h ort-st a y u nit 
•  Re ha bilitati o n facilit y  
•  H os pice or s kille d n ursi n g f acilit y  
•  N ursi n g h o mes, c ust o dial care or res pite care facilit y 
H os pitalizati o n d uri n g t he st u d y f or a pre- pla n n e d s ur gical or me dical pr oce d ure ( o n e w hic h w as 
pla n ne d pri or t o e ntr y i n t he st u d y) d o es n ot re q uire re p ort i n g as an S A E t o t he Sara h Ca n n o n 
De vel o p me nt I n n o vati o ns Safet y De part me nt.  
1 1. 3. 6  
Pre -E xisti n g Me dic al C o n diti o ns  
A pre - e xisti n g me dical c o n diti o n is o ne t hat is prese nt at t he start of t he st u d y.  S uc h c o n diti o ns 
s h o ul d be rec or de d o n t h e Ge neral Me dical Hist or y e C R F s cree n.  A pre-e xisti n g me dical 
c o n diti o n s h o ul d be rec or de d as a n A E or S A E o nl y if t he fre q u e nc y, se v erit y, or c h aracter of t he 
c o n diti o n w orse ns d uri n g t he st u d y.  W he n rec or di n g s uc h e ve nts o n a n S A E Re p ort F or m a n d/ or 
A E  e C R F scr ee n, it is i m p orta nt t o c o n ve y t he c o n ce pt t hat t he pre-e xisti n g c o n diti o n has 
c ha n ge d b y i ncl u di n g a p plica ble descri pt ors. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 1  of 6 9  
 
1 1. 3. 7  
Ne w C a ncers  
T he de vel o p me nt of a ne w pri mar y ca ncer s h o ul d be re gar de d as a n A E a n d will ge nerall y meet 
at least o ne of t he s eri o us ness criteria (see Secti o n  1 1. 1. 2 ).  Ne w pri mar y ca ncers are t h ose t hat 
are n ot t he pri mar y reas o n f or t he a d mi nistrati o n of t he st u d y treat me nt a n d ha ve de v el o pe d aft er 
t he i ncl usi o n of t he patie nt i nt o t he st u d y.  T h e y d o n ot i ncl u de metastases of t he ori gi nal ca n cer.  
S y m pt o ms of met astasis or t he metastasis itself s h o ul d n ot be re p orte d as a n A E/ S A E, as t he y are 
c o nsi dere d t o be disease pr o gressi o n. 
1 1. 3. 8  
Pre g n a nc y, A b orti o n, a n d Birt h Defects/ C o n ge nit al A n o m alies  
If a patie nt b ec o mes pr e g na nt while e nr olle d i n t he st u d y, a Pre g n a nc y F or m (a pa per re p ort 
f or m, n ot a vaila ble wit hi n t he e C R F) s h o ul d be c o m plete d a n d fa x e d t o t he Sara h Ca n n o n 
De vel o p me nt I n n o vati o ns Safet y De part me nt.  T h e Sara h Ca n n o n D e vel o p me nt I n n o v ati o ns 
Safet y De part me nt s h o ul d be n otifie d e x pe diti o usl y, irres pecti ve of w het h er or n ot it meets t he 
criteria f or e x pe dite d re p orti n g.  A b orti o ns (s p o nt a ne o us, acci de ntal, or t h era pe utic) m ust als o be 
re p orte d t o Sar a h Ca n n o n De vel o p me nt I n n o vati o ns Safet y De part me nt.  
If a f e male part ner of a m ale patie nt bec o m es pre g na nt d uri n g t he m ale pati e nt’s partici pati o n i n 
t his st u d y, t his m ust be re p orte d t o t he Sara h Ca n n o n De vel o p me nt I n n o vati o ns Safet y 
De part me nt i m me diatel y.  E ver y eff ort s h o ul d be ma de t o f oll o w t he pre g n a nc y f or t h e fi n al 
pre g na nc y o ut c o me. 
C o n ge nital a n o malies/ birt h defects al w a ys meet S A E criteria a n d s h o ul d t heref ore be 
e x pe diti o usl y r e p orte d as a n S A E usi n g t he pre vi o usl y descri be d pr o cess f or S A E re p orti n g.  A 
Pre g n a nc y F or m s h o ul d als o ha ve bee n pre vi o usl y c o m plet e d, a n d will nee d t o be u p date d t o 
reflect t he o utc o me of t h e pre g na n c y. 
1 1. 3. 9  
Ni v ol u m a b O ver d ose  
S y m pt o matic a n d n o n-s y m pt o matic o ver d ose m ust be re p orte d i n t he e C R F.  A n y acci d e ntal or 
i nte nti o nal o ver d ose wit h t he st u d y treat me nt t hat is s y m pt o matic, e ve n if n ot f ulfilli n g a 
seri o us ness criteri o n, is t o be re p ort e d t o t he Sara h Ca n n o n De vel o p me nt I n n o vati o ns Safet y 
De part me nt n o gr eater t ha n 2 4 h o urs fr o m first k n o wle d ge of t he e ve nt usi n g t he c orres p o n di n g 
scree ns i n t he e C R F a n d f oll o wi n g t he sa m e pr ocess descri be d f or S A E re p orti n g (see 
Secti o n  1 1. 2 ) if t he o ver d ose is s y m pt o matic. 
F or i nf or m ati o n o n h o w t o ma na ge a n o v er d ose of ni v ol u ma b , see t he I B. 
1 1. 4  
S p o ns or Seri o us A d verse E ve nt Re p orti n g Re q uire me nts  
Sara h Ca n n o n De v el o p me nt I n n o v ati o ns Safet y D e part me nt will f or w ar d S A E i nf or mati o n t o 
B M S Gl o bal P har mac o vi gila nce  at W orl d wi de. Safet y @ b ms .c o m wit hi n 1 b usi ness da y of Sara h 
Ca n n o n De vel o p me nt I n n o vati o ns Safet y De part me nt pers o n nel bec o mi n g a ware of t he S A E. 
Sara h Ca n n o n De v el o p m e nt I n n o v ati o ns is res p o nsi ble f or re p orti n g rele va nt S A Es t o t he 
c o m pete nt a ut h orit y, ot her a p plica bl e re g ulat or y a ut h orities, a n d partici pati n g I n v esti gat ors, i n 
acc or d a nce wit h I nter n ati o nal C o u ncil f or Har m o nisati o n ( I C H) g ui deli nes a n d F D A re g ulati o ns . 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 2  of 6 9  
 
1 1. 4. 1  
S p o ns or Assess me nt of U ne x pecte d  
T he S p o ns or is res p o nsi ble f or assessi n g a n A E  or s us pecte d A E as “ u ne x pecte d .” 
A n A E  or S A R is c o nsi dere d “ u n e x pecte d” w h e n t he f oll o wi n g c o n diti o ns occ ur: 
•  E ve nt(s) is n ot me nti o ne d i n t he I B ( or c urre nt U S Pac ka ge I nsert [ U S PI]) 
•  E ve nt(s) is n ot liste d at t he s pecificit y or s e verit y t hat has bee n o bser ve d 
•  A n e ve nt(s) is n ot c o nsist e nt wit h t he Ge neral I n vesti gati ve Pla n or i n t he c urre nt 
a p plicati o n 
•  I n cl u des A Es or S A R t hat ma y be a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he 
st u d y dr u g, or t h at occ ur wit h me m bers of t he dr u g cl ass, b ut t hat ha ve pre vi o usl y bee n 
o bser ve d u n der i n vesti gati o n 
W he n a p plica ble, a n u n e x pecte d A E ma y als o a p pl y t o a n e v e nt t hat is n ot liste d i n t he c urre nt 
U S PI or a n e ve nt t hat ma y be m e nti o ne d i n t he U S PI, b ut differs fr o m t he e ve nt beca us e of 
gr eater se verit y or s p ecifi cit y.  
K n o w n as S us pecte d U n e x pecte d Seri o us A d vers e Reacti o ns ( S U S A R), t h ese e ve nts s us pecte d 
( b y t he I n vesti gat or or S p o ns or) t o be rel ate d t o t he st u d y dr u g, are u ne x pecte d ( n ot liste d i n t he 
I B), are s eri o us (as d efi n e d b y t h e pr ot oc ol) a n d re q uire e x pe die nt s u b missi o n t o rele va nt healt h 
a ut h orities wit hi n 7 da ys (fatal or lif e -t hreate ni n g e ve nt) or 1 5 d a ys (all seri o us e ve nts), or as 
defi ne d b y la w.  T h e ter m S U S A R is  use d pri maril y i n t he re p orti n g of e ve nts t o re g ulat or y 
a ut h orities.  
E x pecte d A Es are t h ose e ve nts t hat are liste d or c h aract erize d i n t he Pac ka ge I nsert or c urre nt I B.  
1 1. 4. 2  
S p o ns or Re p orti n g f or Cli nic al St u dies U n der a n I n vesti g ati o n al Ne w Dr u g 
A p plic ati o n  
A ll writte n i n vesti gati o nal ne w dr u g (I N D) Safet y Re p orts s u b mitte d t o t he F D A b y t he Sara h 
Ca n n o n De vel o p me nt I n n o vati o ns Safet y De part me nt m ust als o be fa x e d t o p har mace utical 
c o m pa n y(ies) t hat are s u p p orti n g t he st u d y wit h eit her f u n di n g or dr u g s u p pl y: 
B M S Gl o bal P har mac o vi gila nce 
B M S Safet y S A E Fa x #: 6 0 9 - 8 1 8- 3 8 0 4 
W orl d wi de. Safet y @ b ms . c o m 
1 2.  
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  
1 2. 1  
St u d y M o nit ori n g, A u diti n g, a n d I ns pecti n g  
T he In vesti gat or will per mit st u d y -relate d m o nit ori n g, q ualit y a u dits, a n d i ns pecti o ns b y t he 
S p o ns or or its re prese nt ati ve(s), g o ver n m e nt re g ul at or y a ut h orities, a n d t he I R B/ E C of all 
st u d y-r elate d d oc u m e nts (e. g., s o urce d oc u me nts, re g ulat or y d oc u m e nts, data c ollecti o n 
i nstr u me nts, case re p ort f or ms).  T he In v esti gat or will e ns ure t he ca p a bilit y f or i ns pecti o ns of 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 3  of 6 9  
 
a p plica ble st u d y-r elate d f acilities.  T he In vesti gat or will e ns ure t hat t he st u d y m o nit or or a n y 
ot her c o m plia nce or Q ualit y Ass ura n ce re vie w er is gi ve n access t o all st u d y -relate d d o c u me nts 
a n d st u d y- relate d facilities. 
At t he S p o ns or’s discreti o n, S o urce D oc u m e nt Verificati o n ( S D V) ma y b e perf or me d o n all data 
ite ms or a perce nta ge t h ere of. 
Partici pati o n as a n In vesti gat or i n t his st u d y i m plies t he acce pta n ce of p ote ntial i ns pecti o n b y 
g o ver n me nt re g ul at or y a ut h orities, t he S p o n s or or its re prese ntati ve(s). 
1 3.  
E T HI C A L, FI N A N CI A L, A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
T his resear c h st u d y will be c o n d ucte d acc or di n g t o t he sta n dar ds of G o o d Cli nical Practice 
( G C P) o utli ne d i n t he I C H E 6 Tri partite G ui deli n e a n d C F R Title 2 1 part 3 1 2, a p plica b le 
g o ver n me nt re g ul ati o ns, i nstit uti o nal researc h p olicies a n d pr o ce d ures a n d a n y ot h er l ocal 
a p plica ble r e g ulat or y r e q uire me nt(s).  
1 3. 1  
I nstit uti o n al Re vie w B o ar d A p pr o v al 
T he cli nical st u d y pr ot oc ol, i nf or me d c o nse nt f or m ( I C F), I B, a v aila ble safet y i nf or matio n, 
patie nt d oc u me nts (e. g., st u d y diar y), patie nt recr uit me nt pr oce d ures (e. g., a d vertise me nts), 
i nf or mati o n a b o ut pa y me nts (i.e., PI  p a y m e nts) a n d c o m pe nsati o n a vaila ble t o t he patie nts a n d 
d oc u me ntati o n e vi de nci n g t he PI ’s q u alificati o ns s h o ul d be s u b mitte d t o t he I R B f or et hical 
re vie w a n d a p pr o v al if re q uire d b y l o cal re g ulati o ns, pri or t o t he st u d y start. 
T he PI / S p o ns or a n d/ or d esi g nee will f oll o w all necessar y re g ulati o ns t o e ns ure a p pr o priate, 
i nitial, a n d o n- g oi n g , I R B st u d y re vie w.  T he PI / S p o ns or (as a p pr o pri ate) m ust s u b mit a n d, 
w here n ecess ar y, o btai n a p pr o val fr o m t he I R B f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d 
c ha n ges t o t he i nf or m e d c o nse nt d oc u me nt.  I n v esti gat ors will be a d vise d b y t he S p o ns or or 
desi g nee w het h er a n a me n d me nt is c o nsi dere d s u bsta ntial or n o n-s u bsta ntial a n d w het her it 
re q uires s u b missi o n f or a p pr o val or n otificati o n o nl y t o a n I R B. 
Safet y u p dates f or ni v ol u ma b will be pre pare d b y t he S p o ns or or its re pres e ntati ve as re q uire d, 
f or distri b uti o n t o t he I n v esti gat or(s) a n d s ub missi o n t o t he rele va nt I R B. 
1 3. 2  
Re g ul at or y A p pr o v al 
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or will e ns ure all le gal as pects are c o vere d, a n d 
a p pr o val of t he a p pr o pri ate re g ulat or y b o dies o btai ne d, pri or t o st u d y i nitiati o n.  If re q uire d, t he 
S p o ns or will als o e ns ure t hat t he i m ple me ntati o n of s u bsta ntial a me n d me nt s t o t he pr ot oc ol a n d 
ot her rele v a nt st u d y d o c u me nts ha p pe n o nl y after a p pr o val b y t he rele va nt re g ulat or y a ut h orities. 
1 3. 3  
I nf or me d C o nse nt 
I nf or me d c o ns e nt is a pr o cess b y w hic h a p atie nt v ol u ntaril y c o nfir ms his or her willi n g ness t o 
partici pate i n a p artic ular st u d y aft er ha vi n g bee n i nf or me d of all as p ects of t he st u d y t hat are 
rele va nt t o t he patie nt's d ecisi o n t o partici pate.  I nf or me d c o nse nt is d oc u me nte d b y mea ns of a 
writte n, si g ne d, a n d date d I C F. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 4  of 6 9  
 
T he I C F will be s u b mitte d f or a p pr o v al t o t he I R B t hat is res p o nsi ble f or re vie w a n d a p pr o val of 
t he st u d y.  Eac h c o nse nt f or m m ust i ncl u de all of t he rele v a nt ele me nts c urre ntl y re q uire d b y t he 
F D A, as well as l ocal c o u nt y a ut h orit y or state re g u lati o ns a n d nati o nal re q uire me nts. 
Bef ore r ecr uit me nt a n d e nr oll me nt i nt o t he st u d y, eac h pr os p ecti ve ca n di date will be gi ve n a f ull 
e x pla nati o n of t he resear c h st u d y.  O n ce t he esse ntial i nf or mati o n has bee n pr o vi de d t o t he 
pr os pecti ve ca n di date, a n d t he I n v esti gat or is s ure t hat t he i n di vi d ual ca n di date u n dersta n ds t he 
i m plicati o ns of partici pati n g i n t his researc h st u d y, t he ca n di date will be as ke d t o gi ve c o nse nt t o 
partici pate i n t he st u d y b y si g ni n g a n I C F.  A n otati o n t hat writte n i nf or me d c o nse nt has bee n 
o btai ne d will be ma de i n t he patie nt’s me dical rec or d.  A c o p y of t he I C F, t o i ncl u de t he patie nt’s 
si g nat ur e, will be pr o vi de d b y t he In vesti gat or t o t he patie nt.  
If a n a m e n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y desi g n or t he p ote ntial ris ks t o t he 
patie nts, t he patie nt’s c o nse nt t o c o nti n ue partici pati o n i n t he st u d y s h o ul d b e o btai ne d. 
1 3. 3. 1  
C o nfi de nti alit y  
1 3. 3. 1. 1  P ati e nt C o nfi de nti alit y  
C o nfi de ntialit y of patie nt’s pers o nal dat a will be pr otecte d i n acc or d a nce wit h t he Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6 ( HI P A A).  HI P A A re g ulati o ns re q uire t hat, 
i n or der t o partici pat e i n t he st u d y, a patie nt m ust si g n a n a ut h orizati o n f or m f or t he st u d y t hat he 
or s he has bee n i nf or me d of f oll o wi n g: 
•  W hat pr otecte d healt h i nf or mati o n ( P HI) will be c ollecte d fr o m patie nts i n t his st u d y 
•  W h o will ha ve access t o t hat i nf or mati o n a n d w h y 
•  W h o will use or discl ose t hat i nf or mati o n  
•  T hat healt h i nf or mati o n ma y b e f urt her discl ose d b y t he reci pie nts of t he i nf or mati o n a n d 
t hat if t he i nf or mati o n is discl ose d t he i nf or mati o n ma y n o l o n ger be pr ot ecte d b y fe deral 
or state pri vac y l a ws  
•  T he i nf or mati o n c ollect e d a b o ut t he researc h st u d y will be ke pt se p arate fr o m t he 
patie nt’s me dical r ec or ds, b ut t he patie nt will be a ble t o o btai n t he researc h rec or ds after 
t he c o ncl usi o n of t he st u d y 
•  W het her t he a ut h orizati o n c o ntai ns a n e x pirati o n date 
•  T he ri g hts of a r esearc h p atie nt t o re v o ke his or her a ut h orizati o n 
I n t he e ve nt t hat a p atie nt re v o kes a ut h orizati o n t o c ollect or use his or h er P HI, t he I n vesti gat or, 
b y r e g ulati o n, retai ns t he a bilit y t o use all i nf or mati o n c ollecte d pri or t o t he re v ocati o n of p atie nt 
a ut h orizati o n.  F or patie nts t hat ha ve re v o k e d a ut h orizati o n t o c ollect or use P HI, atte m pts s h o ul d 
be ma de t o o btai n per missi o n t o c ollect at least vital stat us (i.e., t hat t he patie nt is ali ve) at t he 
e n d of t heir sc h e d ule d st u d y peri o d. 
I n c o m plia nce wit h I C H G C P g ui deli nes a n d a p plica ble parts of 2 1 C F R it is a re q uire me nt t hat 
t he I n v esti gat or a n d i nstit uti o n per mit a ut h orize d re prese nt ati ves of t he S p o ns or, t he re g ulat or y 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 5  of 6 9  
 
a ut h orities a n d t he I R B direct access t o re vie w t he patie nt’s ori gi n al me dical rec or ds at t he site 
f or verifi cati o n of st u d y-r elate d pr oce d ures a n d dat a. 
Meas ures t o pr ot ect c o nfi de ntialit y i ncl u de: o nl y a u ni q ue st u d y n u m ber will i de ntif y patie nts i n 
t he e C R F or ot her d o c u m e nts s u b mitte d t o t he S p o ns or.  T his i nf or mati o n, t o get h er wit h t he 
patie nt’s date of birt h, will be use d i n t he data bas e f or patie nt i de ntificati o n.  Patie nt na mes or 
a d dresses will n ot be e nt ere d i n t he e C R F.  N o  material beari n g a patie nt’s na me will be ke pt o n 
file b y S p o ns or.  Patie nts will be i nf or me d of t heir ri g hts wit hi n t he I C F. 
1 3. 3. 1. 2  I n vesti g at or a n d St aff I nf or m ati o n 
Pers o nal data of t he I n vesti gat ors a n d s u b-I n vesti gat ors m a y be i ncl u de d i n t he Sara h Ca n n o n 
De vel o p me nt I n n o vati o ns data base, a n d s hall be treate d i n c o m plia nce wit h all a p plica ble la ws 
a n d re g ulati o ns.  W he n arc hi vi n g or pr ocessi n g p ers o nal data pertai ni n g t o t he I n vesti gat or or 
s u b-I n vesti gat or, Sar a h Ca n n o n De vel o p me nt I n n o vati o ns s hall ta ke all a p pr o priate meas ures t o 
safe g uar d a n d pr e ve nt access t o t his data b y a n y u na ut h orize d part y. 
1 3. 4  
Fi n a nci al I nf or m ati o n 
T he fi na nces f or t his cli nical st u d y will be s u bject t o a se parate writte n a gree me nt bet wee n t he 
Sara h Ca n n o n De v el o p me nt  I n n o v ati o ns, L L C a n d a p plica ble parties.  A n y I n v esti gat or fi na n cial 
discl os ures as a p plica bl e t o 2 1 C F R Part 5 4 s hall be a p pr o pri atel y pr o vi de d. 
1 4.  
R E S E A R C H R E T E N TI O N A N D D O C U M E N T A TI O N O F T H E S T U D Y  
1 4. 1  
A me n d me nts t o t he Pr ot oc ol  
A me n d me nts t o t he pr ot oc ol s hall be pla n ne d, d oc u me nte d , a n d si g n at ure-a ut h orize d pri or t o 
i m ple me ntati o n. 
If a n a m e n d me nt t o t he pr ot oc ol is re q uire d, t he a me n d me nt will be ori gi n ate d a n d d oc u m e nte d 
b y t he S p o ns or or its r e pr ese ntati ves .  All a me n d m e nts re q uire re vie w a n d a p pr o val of all 
p har mace utical c o m pa ni es a n d t he PI  s u p p orti n g t he st u d y.  T h e writte n a m e n d me nt m ust be 
re vie we d a n d a p pr o ve d b y t he S p o ns or, a n d s u b mitte d t o t he I R B at t he In v esti gat or’s facilit y f or 
t he b oar d’s a p pr o val. 
A me n d me nts s pecificall y i n v ol vi n g c ha n ge t o st u d y desi g n, ris k t o patie nt, i ncreas e t o d osi n g or 
e x p os ure, patie nt n u m ber i ncreas e, a d diti o n or re m o val of ne w tests or pr oce d ures, s hall be 
re vie we d a n d a p pr o ve d b y t he I R B of rec or d f or  t h e I n vesti gat or’s facilit y. 
T he a me n d me nt will be s u b mitte d f or mall y t o t he F D A or ot h er re g ulat or y a ut h orities b y t he 
S p o ns or as a p plica ble, a n d I R B a p pr o v al o btai ne d, a n d s pecificall y w he n a n i ncreas e t o d osi n g or 
patie nt e x p os ure a n d/ or p atie nt n u m ber has bee n pr o p ose d; or, w he n t h e a d diti o n or re m o val of 
a n I n vesti gat or is necessitate d.  
Ite ms r e q uiri n g a pr ot o c ol a me n d me nt a p pr o val fr o m  I R B a n d/ or F D A or ot her re g ulat or y 
a ut h orities i ncl u des, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  C ha n ge t o st u d y desi g n  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 6  of 6 9  
 
•  Ris k t o patie nt 
•  I n crease t o d ose or patie nt e x p os ure t o dr u g 
•  Patie nt n u m ber i ncrea se 
•  A d diti o n or re m o val of tests a n d / or pr oce d ures  
•  A d diti o n/re m o val of a ne w I n vesti gat or  
It s h o ul d be f urt her n ote d t hat, if a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y 
desi g n or t h e p ote ntial ris ks t o t he patie nts, t heir c o nse nt t o c o nti n ue partici pati o n i n t he st u d y 
s h o ul d be o btai ne d. 
1 4. 2  
D oc u me nt ati o n Re q uire d t o I niti ate t he St u d y  
Bef ore t he st u d y ma y b e gi n  certai n d oc u me nt ati o n re q uire d b y F D A re g ul ati o ns a n d I C H G C P  
m ust be pr o vi de d b y t h e I n v esti gat or.  T he re q uire d d oc u me ntati o n s h o ul d be s u b mitte d t o: 
Sara h Ca n n o n De v el o p me nt I n n o v ati o ns 
Re g ulat or y De part me nt  
1 1 0 0 Dr. Marti n L.  Ki n g Jr. Bl v d., S uite 8 0 0 
Nas h ville, T N  3 7 2 0 3 
D oc u me nts at a mi ni m u m re q uire d t o be gi n a st u d y i n t he U S i ncl u de, b ut are n ot li mite d t o, t he 
f oll o wi n g: 
•  A si g nat ur e-a ut h orize d pr ot oc ol a n d c o ntract 
•  A c o p y of t he official I R B a p pr o v al of t he st u d y a n d t he I R B me m bers list  
•  C urre nt C urric ula Vita e f or t he PI  a n d a n y s u b-I n v esti gat or(s) w h o will be i n v ol ve d i n t he 
st u d y 
•  I n dicati o n of a p pr o priate accr e ditati o n f or a n y l a b orat ories t o be use d i n t h e st u d y a n d a 
c o p y of t he n or mal r a n ges f or tests t o be perf or me d b y t hat la b orat or y 
•  Ori gi nal F or m F D A 1 5 7 2 ( State me nt of I n vesti gat or), a p pr o pri atel y c o m pl ete d a n d 
si g ne d 
•  A c o p y of t he I R B- a p pr o ve d c o nse nt f or m (a n d patie nt i nf or mati o n s heet, if a p plica ble) 
c o ntai ni n g p er missi o n f or a u dit b y re prese ntati ves of Sara h Ca n n o n D e vel o p me nt 
I n n o v ati o ns, t he I R B, a n d t he F D A a n d ot her re g ulat or y a ge nci es (as a p plica ble)  
•  Fi na ncial discl os ur e f or ms f or all I n vesti gat ors liste d o n F or m F D A 1 5 7 2 (if a p plica ble) 
•  Site q ualificati o n re p orts, w here a p plica ble  
•  Verificati o n of PI  acce pt a bilit y fr o m l ocal a n d/ or nati o nal de bar me nt list(s)  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 7  of 6 9  
 
1 4. 3  
St u d y  D oc u me nt ati o n a n d St or a ge 
T he PI  m ust mai ntai n a list of a p pr o priatel y q u alifie d pers o ns t o w h o m he/s he has dele gate d 
st u d y d uties a n d s h o ul d e ns ure t hat all pers o ns assisti n g i n t he c o n d uct of t h e st u d y are i nf or me d 
of t heir o bli gati o ns.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n t he eC R Fs are 
t o be i ncl u de d o n t his d oc u me nt.  All e ntries i n t he patie nt’s e C R F are t o b e s u p p orte d b y s o urce 
d oc u me ntati o n w her e a p pr o priate. 
S o urce d oc u me nts are t h e ori gi n al d oc u me nts, dat a, rec or ds, a n d certifie d c o pies of ori gi nal 
rec or ds of cli nical fi n di n gs, o bser vati o ns, a n d acti vities fr o m w hic h t h e patie nt’s e C R F data are 
o btai ne d.  T hese ca n i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical a n d office c h arts, 
la b orat or y, me dic o-tec h nical de part me nt a n d p har mac y rec or ds, diari es, micr ofic h es, E C G 
traces, c o pies or tra ns cri pti o ns certifie d after verificati o n as bei n g acc urate a n d c o m plete, 
p h ot o gra p hic ne gati ves, micr ofil m or ma g n etic m e dia, X-ra ys, a n d c orres p o n de nce. 
T he PI  a n d eac h st u d y staff me m ber is res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s yste m (e. g., re g ul at or y bi n der or In vesti gat or st u d y file [I S F]) of all st u d y-
relate d ( esse ntial) d oc u m e ntati o n, s uita ble f or i ns p ecti o n at a n y ti me b y re prese ntati ves fr o m t he 
S p o ns or a n d/ or a p plica bl e re g ulat or y a ut h orities.  T he I S F m ust c o nsist of t h ose d oc u me nts t hat 
i n di vi d uall y or c ollecti vel y per mit e v al uati o n of t he c o n d uct of t he st u d y a n d t he q ualit y of t he 
data pr o d uce d.  T he I S F s h o ul d c o ntai n as a mi ni m u m all rele va nt d oc u me nts a n d 
c orres p o n d e nce as o utli ne d i n I C H G C P Secti o n 8 a n d 2 1 C F R Part 3 1 2. 5 7, i ncl u di n g ke y 
d oc u me nts s uc h as t he I B a n d a n y a me n d m e nts, pr ot oc ol a n d a n y a me n d m e nts, si g ne d I C Fs, 
c o pies of c o m plete d e C R Fs, I R B a p pr o val d o c u me nts, patie nt i de ntificati o n lists, e nr oll me nt 
l o gs, dele gati o n of a ut h orit y l o g, staff q ualifi cati o n d oc u me nts, la b orat or y n or mal ra n ges, rec or ds 
relati n g t o t he st u d y dr u g i ncl u di n g acc o u nta bilit y rec or ds.  Dr u g acc o u nta bilit y rec or ds s h o ul d, 
at a mi ni m u m, c o ntai n i nf or mati o n re gar di n g recei pt, s hi p me nt, a n d dis p ositi o n.  Eac h f or m of 
dr u g acc o u nt a bilit y r ec or d, at a m i ni m u m, s h o ul d c o ntai n PI  n a me, date dr u g s hi p pe d/recei v e d, 
date, q ua ntit y a n d batc h/ c o de, or l ot n u m ber f or i de ntit y of eac h s hi p me nt.  I n a d diti o n, all 
ori gi nal s o ur ce d oc u m e nts s u p p orti n g e ntries i n t h e e C R F m ust be mai ntai n e d a n d be rea dil y 
a vaila ble.  
T he S p o ns or s hall mai ntai n a de q uate i n vesti gati o n al pr o d uct rec or ds a n d fi na ncial i nterest 
rec or ds as per 2 1 C F R Part 5 4. 6 a n d Part 3 1 2. 5 7 f or n o less t ha n 2 years aft er t he last mar k eti n g 
a p plicati o n has bee n a p pr o ve d b y t h e F D A; or, i n t he e ve nt t hat t he mar keti n g a p plicati o n has n ot 
bee n a p pr o v e d b y t he F D A, f or n o less t ha n 2 years after t he last s hi p me nt / deli ver y of t he dr u g 
f or i n vesti gati o nal use is disc o nti n ue d a n d t he F D A has bee n n otifie d of t he disc o nti n uati o n. 
T he I R B s h all mai ntai n a de q uate d o c u m e ntati o n / rec or ds of I R B acti vities as per 2 1 C F R Part 
5 6. 1 1 5 f or at least 3 years after c o m pleti o n of t h e researc h. 
T he I n vesti gat or s hall mai ntai n a de q uate rec or ds of dr u g dis p ositi o n, case hist ories, a n d a n y 
ot her st u d y- relat e d rec or ds as per 2 1 C F R Part 3 1 2. 6 2 f or n o less t ha n 2 years after t he last 
mar keti n g a p plicati o n has bee n a p pr o v e d b y t he F D A; or, i n t he e ve nt t hat t he mar keti n g 
a p plicati o n has n ot bee n a p pr o ve d b y t he F D A, f or n o less t ha n 2 years after t he last s hi p me nt / 
deli ver y of t he dr u g f or i n vesti gati o nal use is disc o nti n ue d a n d t he F D A has bee n n otifie d of t he 
disc o nti n uati o n. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 8  of 6 9  
 
T o e na ble e v al uati o ns a n d/ or a u dits fr o m re g ulat or y a ut h orities or fr o m t he S p o ns or or its 
re pres e ntati ve, t he I n v esti gat or a d diti o nall y a grees t o kee p rec or ds, i ncl u di n g t he i de ntit y of all 
partici pati n g p atie nts (s ufficie nt i nf or mati o n t o li n k rec or ds e. g., eC R Fs, m e dical rec or ds), all 
ori gi nal, si g ne d I C Fs, a n d c o pies of all e C R Fs, S A E Re p orti n g f or ms, s o urce d oc u m e nts, 
detaile d rec or ds of tr eat me nt dis p ositi o n, a n d relate d esse ntial re g ulat or y d oc u me nts.  T he 
d oc u me nts liste d a b o ve m ust be retai ne d b y t he I n vesti gat or f or as l o n g as nee de d t o c o m pl y wit h 
nati o nal a n d i nter nati o nal re g ulati o ns ( ge nerall y 2 years after disc o nti n ui n g cli nical de vel o p me nt 
or after  t h e last mar keti n g a p pr o val).  S p o ns or will n otif y t he In v esti gat or(s)/i nstit uti o ns(s) w he n 
t he st u d y-relate d rec or ds are n o l o n ger re q uire d. 
If t he I n vesti gat or rel ocat es, retires, or f or a n y reas o n wit h dra ws fr o m t he st u d y, b ot h t he 
S p o ns or a n d its re prese nt ati ve s h o ul d be pr os pecti vel y n otifie d.  T h e st u d y rec or ds m ust be 
tra nsferre d t o a n acce pta ble desi g n ee, s uc h as a n ot her I n vesti gat or, a n ot her i nstit uti o n, or t o t he 
S p o ns or .  T he I n vesti gat or m ust o btai n t he S p o ns or’s writte n per missi o n bef ore dis p osi n g of a n y 
rec or ds, e ve n if r ete nti o n re q uire me nts ha v e bee n met.  All st u d y files will be mai ntai ne d b y t he 
S p o ns or ( Sara h Ca n n o n De vel o p me nt I n n o vati o ns) t hr o u g h o ut t he st u d y, a n d w ill be hel d b y t he 
S p o ns or at t he c o ncl usi o n of t he st u d y. 
1 4. 4  
D at a C ollecti o n 
T he st u d y eC R F is t he pri mar y d ata c ollecti o n i nstr u me nt f or t he st u d y.  Case re p ort f or ms will 
be c o m plete d usi n g t he E n glis h la n g ua ge a n d s h o ul d be ke pt c urre nt t o e na ble t he S p o ns or t o 
re vie w t he p atie nts’ stat us t hr o u g h o ut t he c o urse of t he st u d y. 
I n or der t o mai ntai n c o nfi de ntialit y, o nl y st u d y n u m ber, patie nt n u m ber, a n d year  of birt h will 
i de ntif y t he p atie nt i n t he e C R F.  If t he p atie nt’s n a me a p pears o n a n y ot h er d oc u me nt (e. g., 
la b orat or y r e p ort), it m ust be o bliterate d o n t he c o p y of t he d oc u me nt t o be s u p plie d t o Sara h 
Ca n n o n De vel o p me nt I n n o vati o ns a n d re place d i nstea d wit h t he patie nt n u m ber a n d patie nt’s 
i nitials.  T he In vesti gat or will mai ntai n a pers o nal patie nt i de ntificati o n list ( patie nt n u m bers wit h 
c orres p o n di n g p atie nt i de ntifiers) t o e na ble rec or ds t o be i de ntifie d a n d verifie d as a ut he ntic.  
Patie nt data/i nf or mati o n will be ke pt c o nfi de ntial, a n d will be ma na ge d acc or di n g t o a p plica ble 
l ocal, state, a n d f e der al r e g ul ati o ns. 
All data re q uest e d i n t he e C R F m ust be s u p p orte d b y a n d b e c o nsiste nt wit h t he patie nt’s s o urce 
d oc u me ntati o n.  All missi n g data m ust be e x plai ne d.  W he n a re q uire d l a b orat or y t est, 
assess me nt, or e v al uati o n has n ot bee n d o ne or a n “ U n k n o w n” b o x is n ot a n o pti o n o n t he e C R F, 
a n ote s h o ul d be cr eate d verif yi n g t hat t he fiel d w as “ N ot D o ne” or “ U n k n o w n. ”  F or a n y e ntr y 
err ors ma d e, t he err or(s) m ust be c orrecte d, a n d a n ote e x plai ni n g t he reas o n f or c ha n ge s h o ul d 
be pr o vi de d. 
T he In vesti gat or will electr o nicall y si g n a n d date t he patie nt e C R F case b o o k i n dicati n g t ha t t he 
data i n t he eC R F has b ee n assesse d.  Eac h c o m plete d e C R F will be si g n e d a n d date d b y t he PI , 
o nce all data f or t hat pati e nt is fi nal.  
1 4. 5  
Discl os ure a n d P u blic ati o n P olic y  
All i nf or mati o n pr o vi de d re gar di n g t he st u d y , as well as all i nf or mati o n c ollecte d/ d oc u me nte d 
d uri n g t he c o urse of t he st u d y, will be re gar d e d as c o nfi de ntial.  T he S p o ns or reser ves t he ri g ht 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 4 9  of 6 9  
 
t o release liter at ure p u bli cati o ns base d o n t he res ults of t he st u d y.  Res ults fr o m t he st u d y will be 
p u blis he d/ prese nte d as p er t he S p o ns or’s p u b licati o n pr ocess.  
I n cl usi o n of t he I n vesti gat or i n t he a ut h ors hi p of a n y m ultice nter p u blicati o n will be base d u p o n 
s u bsta ntial c o ntri b uti o n t o t he desi g n, a nal ysis, i nter pret ati o n of data, drafti n g a n d/ or criticall y 
re visi n g a n y ma n uscri pt(s) deri ve d fr o m t he st u d y.  T he I n vesti gat or ac k n o wle d ges t hat t he st u d y 
is part of a m ultice nter st u d y a n d a grees t hat a n y p u blicati o n b y t he I n v esti gat or of t he res ults of 
t he st u d y c o n d u cte d at r esearc h site s h all n ot be ma de bef ore t he first m ultice nter  p u blicati o n.  I n 
t he e ve nt t her e is n o m ultice nter p u blicati o n wit hi n fiftee n ( 1 5) m o nt hs after t he st u d y h as bee n 
c o m plete d or ter mi nate d at all st u d y sites, a n d all data has bee n recei ve d, t he I n vesti gat or s hall 
ha ve t he ri g ht t o p u blis h its res ults fr o m t he st u d y , su bject  t o t he n otice re q uire me nts descri b e d 
herei n a n d s u bject t o ac k n o wle d ge me nt of t he S p o ns or as a p pr o priate.  I n v esti gat or s h all pr o vi de 
t he S p o ns or t hirt y ( 3 0) d a ys t o r e vie w a ma n uscri pt or a n y p oster prese ntati o n, a bstract or ot her 
writte n or oral m aterial w hic h descri bes t he res ults of t he st u d y f or t he p ur p ose o nl y of 
deter mi ni n g if a n y c o nfi d e ntial or pate nta ble i nf or mati o n is discl ose d t here b y.  If t he S p o ns or 
re q uests i n writi n g, t h e I n vesti gat or s h all wit h h ol d a n y p u blicati o n or pres e ntati o n a n a d diti o nal 
si xt y ( 6 0) d a ys s ol el y t o per mit t he S p o ns or t o see k pate nt pr otecti o n a n d t o re m o ve a n y Sara h 
Ca n n o n De vel o p me nt I n n o vati o ns C o nfi de ntial I nf or mati o n fr o m all p u blicati o ns.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 0  of 6 9  
 
1 5.  
R E F E R E N C E S  
A nsell  et al. 2 0 1 5 
A nsell S M, Les o k hi n A M, B orr ell o I, et al. P D-1 Bl oc ka d e wit h ni v ol u ma b i n r ela pse d or 
refr act or y H o d g ki n’s l y m p h o ma. N E n gl J Me d. 2 0 1 5; 3 7 2( 4): 3 1 1- 1 9. 
C hes o n et al. 2 0 0 7 
C hes o n B D, Pfist ner B, J u wei d M E, et al. Re vise d res p o nse criteria f or m ali g na nt l y m p h o ma. 
J Cli n O nc ol. 2 0 0 7; 2 5( 5): 5 7 9- 8 6. 
C hes o n et al. 2 0 1 4 
C hes o n B D, Fis her RI , Barri n gt o n S F , et al. Rec o m me n dati o ns f or i nitial e val uati o n, s ta gi n g, a n d 
res p o nse ass ess me nt of H o d g ki n a n d n o n-H o d g ki n  l y m p h o m a: the L u ga n o classificati o n. J Cli n 
O nc ol. 2 0 1 4; 3 2( 2 7): 3 0 5 9- 6 7.  
Gree n  et al. 2 0 1 0 
Gre e n M R , M o nti S, R o di g SJ, et al. I nte grati ve a n al ysis re v eals selecti ve 9 p 2 4. 1 a m plificati o n, 
i ncreas e d P D- 1 li ga n d e x pressi o n, a n d f urt h er i n d ucti o n via J A K 2 i n n o d ular scler osi n g H o d g ki n 
l y m p h o ma a n d pri mar y me diasti nal lar ge B-cell l y m p h o ma. Bl o o d. 2 0 1 0( 1 7); 1 1 6: 3 2 6 8- 7 7. 
M aj h ail et al. 2 0 0 6 
Maj hail N S, Weis d orf DJ, Def or T E, et al. L o n g-ter m res ults of a ut ol o g o us ste m cell 
tra ns pla ntati o n f or pri mar y refract or y or rel a pse d H o d g ki n’s l y m p h o ma. Bi ol Bl o o d Marr o w 
Tra ns pla nt. 2 0 0 6; 1 2( 1 0): 1 0 6 5- 7 2. 
M os k o witz et  al. 2 0 0 1 
M os k o witz C H , Ni mer SD , Zele netz AD, et al. A 2 -ste p c o m pre h e nsi ve hi g h- d os e 
c he m ora di ot hera p y sec o n d- li ne pr o gra m f or rel a pse d a n d refract or y H o d g ki n disease: a nal ysis b y 
i nte nt t o treat a n d de vel o p me nt of a pr o g n ostic m o del. Bl o o d. 2 0 0 1; 9 7( 3): 61 6- 2 3. 
M os k o witz et al. 2 0 1 0 
M os k o witz AJ , Ya hal o m J , Ke walra ma ni  T, et al. Pretra ns pla ntati o n f u ncti o nal i ma gi n g pre dicts 
o utc o me f oll o wi n g a ut ol o g o us ste m cell tra ns pla ntati o n f or rela ps e d a n d refract or y H o d g ki n 
l y m p h o ma. Bl o o d. 2 0 1 0; 1 1 6( 2 3): 4 9 3 4- 7. 
M os k o witz  et al. 2 0 1 5 
M os k o witz C H, Na de ma nee A, Masszi  T, et al. Bre nt u xi ma b ve d oti n as c o ns oli dati o n t hera p y 
after a ut ol o g o us ste m- cell tra ns pla ntati o n i n patie nts wit h H o d g ki n's l y m p h o ma at ris k of rel a pse 
or pr o gressi o n ( A E T H E R A): a ra n d o mise d, d o u ble- bli n d, place b o-c o ntr olle d, p hase 3 trial. 
La n cet . 2 0 1 5; 3 8 5( 9 9 8 0): 1 8 5 3- 6 2. 
Ries et al. 1 9 9 7 
Ries L A, K os ar y C L, Ha n ke y B F, et al. ( E ds). S E E R ca ncer statistics re vie w: 1 9 7 3- 1 9 9 4, NI H 
p u bl n o. 9 7- 2 7 8 9, Nati o nal Ca ncer I nstit ute, Bet hes da 1 9 9 7.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 1  of 6 9  
 
R oe mer et al . 2 0 1 6 
R oe mer M, A d va ni R H, Li g o n A H, et al. P D- L 1 a n d P D-L 2 g e netic alterati o ns d efi ne classical 
H o d g ki n l y m p h o ma a n d p re dict o utc o me. J Cli n O nc ol. 2 0 1 6; 3 4( 2 3): 2 6 9 0- 7. 
S h ar pe et al. 2 0 0 7 
S har pe A H, W herr y EJ, A h me d R, et al. T he f u n cti o n of pr o gra m me d cell deat h 1 a n d its li ga n ds 
i n re g ul ati n g a ut oi m m u nit y a n d i nf ecti o n. Nat I m m u n ol . 2 0 0 7; 8( 3): 2 3 9- 4 5. 
Sie gel et al.  2 0 1 6 
Sie gel R L, Miller K D, J e mal A. Ca ncer statistics, 2 0 1 6. C A Ca ncer J Cli n. 2 0 1 6; 6 6( 1): 7- 3 0.  
S ure d a et al. 2 0 0 5 
S ure da A, C o nsta ns M, Iri o n d o A, et al. Pr o g n ostic fact ors affecti n g l o n g -ter m o utc o me after 
ste m cell tra ns pla ntati o n i n H o d g ki n’s l y m p h o ma a ut o grafte d after a first rela pse. A n n O nc ol. 
2 0 0 5; 1 6( 4): 6 2 5- 3 3. 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 2  of 6 9  
 
1 6.  
A P P E N DI C E S  
 
A p pe n di x A: E C O G Perf or m a nce St at us Criteri a  
 
E C O G Perf or m a nce St at us Sc ale  
 
K ar n ofs k y Perf or m a nce Sc ale  
Gr a de  
Descri pti o ns  
Perce nt  
Descri pti o n  
0 
N or mal acti vit y. F ull y acti ve, a ble t o carr y 
o n all pre -disease perf or ma nc e wit h o ut 
restricti o n. 
 
1 0 0  
N or mal, n o c o m plai nts, n o e vi de nce of 
disease.  
 
9 0  
A ble t o carr y o n n or mal acti vit y; mi n or 
si g ns or s y m pt o ms of disease. 
1 
S y m pt o ms, b ut a m b ulat or y.  R estricte d i n 
p h ysicall y stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure (e. g., li g ht 
h o use w or k, offi ce w or k).  
 
8 0  
N or mal acti vit y wit h eff ort; s o me si g ns or 
s y m pt o ms of disease. 
 
7 0  
Cares f or self, u na ble t o carr y o n n or mal 
acti vit y or t o d o acti ve w or k.  
2 
I n be d < 5 0 % of t he ti me.  A m b ulat or y a n d 
ca pa ble of all self -care, b ut u na ble t o carr y 
o ut a n y w or k acti vities.  U p a n d a b o ut m ore 
t ha n 5 0 % of wa ki n g h o urs. 
 
6 0  
Re q uires occasi o nal assista nce, b ut is a ble 
t o care f or m ost of his/ her nee ds. 
 
5 0  
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care. 
3 
I n be d > 5 0 % of t he ti me.  Ca p a ble of o nl y  
li mite d self-care, c o nfi ne d t o be d or c hair 
m ore t ha n 5 0 % of wa ki n g h o urs.  
 
4 0  
Disa ble d, re q uires s pecial care a n d 
assista nce . 
 
3 0  
Se verel y disa ble d, h os pitalizati o n 
i n dicate d.  Deat h n o i m mi ne nt. 
4 
1 0 0 % be dri d de n.  C o m pletel y disa ble d.  
Ca n n ot carr y o n a n y self -care.  T otall y 
c o nfi ne d t o be d or c hair.  
 
2 0  
Ver y sic k, h os pitalizati o n i n di cate d.  Deat h 
n ot i m mi ne nt.  
 
1 0  
M ori b u n d, fatal pr ocesses pr o gressi n g 
ra pi dl y. 
5 
Dea d  
0 
Dea d  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 3  of 6 9  
 
 
A p pe n di x B: Ne w Y or k He art Ass oci ati o n ( N Y H A) Cl assific ati o n of C ar di ac Dise ase 
T he f oll o wi n g ta ble prese nts t he N Y H A classificati o n of car diac disease.  
Class  
F u ncti o nal Ca pacit y  
O bj ecti ve Assess me nt  
I 
P atie nts wit h car diac disease b ut wit h o ut res ulti n g li mitati o ns of p h ysical 
acti vit y.  Or d i nar y p h ysical acti vit y d oes n ot ca use u n d ue fati g ue, 
pal pitati o n, d ys p nea, or a n gi nal pai n.  
N o o bj ecti ve e vi de nce of 
car di o vasc ular disease.  
II 
P atie nts wit h car diac disease res ulti n g i n sli g ht li mitati o n of p h ysical 
acti vit y.  T he y are c o mf orta bl e at re st.  Or di nar y p h ysical acti vit y res ults i n 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
O bj ecti ve e vi de nce of 
mi ni mal car di o vasc ular 
disease.  
III 
P atie nts wit h car diac disease res ulti n g i n mar ke d li mitati o n of p h ysical 
acti vit y.  T he y are c o mf orta bl e at rest.  Less t ha n or di nar y a cti vit y ca uses 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
O bj ecti ve e vi de nce of 
m o deratel y se vere 
car di o vasc ular disease.  
I V 
P atie nts wit h car diac disease res ulti n g i n i na bilit y t o carr y o n a n y p h ysical 
acti vit y wit h o ut disc o mf ort.  S y m pt o ms of heart fail ure or t he a n gi nal 
s y n dr o me ma y be prese nt e ve n at rest.  If a n y p h ysical acti vit y is u n derta ke n, 
disc o mf ort is i ncrease d.  
O bj ecti ve e vi de nce of 
se vere car di o vasc ular 
disease.  
S o urce:  T he Criteria C o m mitt ee of Ne w Y or k Heart Ass oci ati o n.  N o me nclat ure a n d Crit eria f or Dia g n osis of 
Diseases of t he Heart a n d Great Vessels.  9t h E d. B ost o n, M A:  Little, Br o w n & C o; 1 9 9 4: 2 5 3 -2 5 6.  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 4  of 6 9  
 
A p pe n di x C: De a u ville 5 - p oi nt sc ori n g s yste m 
T he De a u ville 5 - p oi nt sc ori n g s yste m is a n i nter n ati o nall y acce pt e d a n d utilize d fi ve- p oi nt 
sc ori n g s yste m f or t he fl u or o de o x y gl uc ose ( F D G) a vi dit y of a H o d g ki n's L y m p h o ma or n o n-
H o d g ki n L y m p h o ma t u m or mass as see n o n F D G P E T : 
•  
Sc ore 1: N o u pta ke a b o v e t he bac k gr o u n d 
•  
Sc ore 2:  U pta ke ≤ me di asti n u m  
•  
Sc ore 3: U pta ke > me diasti n u m b ut ≤ li ver  
•  
Sc ore 4: U pta ke m o derat el y i ncreas e d c o m pare d t o t he li ver at a n y site  
•  
Sc ore 5: U pta ke mar ke dl y i ncr eas e d c o m pare d t o t he li ver at a n y site  
•  
Sc ore X: Ne w ar eas of u pta ke u nli kel y t o b e relat e d t o l y m p h o ma 
 
B arri n gt o n et al. 2 0 1 0 
Barri n gt o n S F, Qia n W , S o mer E J, et al. C o nc or da nce b et wee n f o ur E ur o p ea n ce ntres of P E T 
re p orti n g criteria desi g ne d f or use i n m ultice ntre trials i n H o d g ki n l y m p h o ma. E ur J N ucl Me d 
M ol I ma gi n g . 2 0 1 0( 1 0); 3 7: 1 8 2 4 – 3 3. 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 5  of 6 9  
 
A p pe n di x D: G ui deli nes f or Fe m ale P ati e nt s of C hil dbe ari n g  P ote nti al a n d Fertile  M ale 
P ati e nt s 
 
Acce pt a ble C o nt r ace pti o n Met h o ds:  
W o me n of c hil d beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of b ec o mi n g 
pre g na nt, m ust use hi g hl y effecti ve c o ntrace pti o n d uri n g t he st u d y a n d f or 7 m o nt hs after 
st o p pi n g treat me nt. 
Hi g hl y effecti ve c o ntrace pti o n is defi ne d as eit her: 
Tr ue A bsti ne nce   
W he n t his is i n li ne wit h t he preferre d a n d us ual lifest yl e of t he s u bject. 
Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost-
o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of 
c o ntrace pti o n. 
Steriliz ati o n    
W he n a w o ma n of c hil d b eari n g p ote ntial has h a d s ur gical bilateral 
o o p h orect o m y ( wit h or wit h o ut h yste rect o m y) or t u bal li gati o n at least 
si x wee ks pri or t o st u d y e ntr y.  I n case of o o p h orect o m y al o n e, o nl y 
w he n t he re pr o d ucti ve st at us of t he w o ma n has b ee n c o nfir me d b y 
f oll o w- u p h or m o ne le vel assess me nt. 
M ale P art ner Steriliz ati o n  W he n  t he a p pr o priate p ost- vasect o m y d oc u me ntati o n of t he 
a bse nce of s per m i n t he ejac ulate . 
Use of a c o m bi n ati o n of a n y t w o of t he f oll o wi n g ( o ne fr o m a + o ne fr o m b):  
a)  Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m 
(I U S) or est a blis he d use of oral, i njecte d or i m pla nte d h or m o nal 
met h o ds of c o ntrace pti o n.  
b)  Barrier m et h o ds of c o ntrace pti o n: C o n d o m or Occl usi ve ca p 
( diap hra g m or cer vi cal/ v a ult ca ps) wit h s per mici d al 
f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y. 
Fertile m ale p atie nts , defi ne d as all males p h ysi ol o gicall y ca pa ble of c o n cei vi n g offs pri n g, 
wit h fe male part ners of c hil d beari n g p ot e ntial m ust use c o n d o ms pl us s per mici dal a ge nt d uri n g 
t he st u d y treat me nt peri o d a n d f or 7 m o nt hs after t he last d ose of st u d y dr u g, a n d s h o ul d n ot 
fat her a c hil d d uri n g t his peri o d. 
Male patie nts m ust als o refrai n fr o m d o nati n g s per m  d uri n g t heir p artici pati o n i n t he st u d y a n d 
f or 7 m o nt hs after t he l ast d ose of st u d y dr u g.  
T he f oll o wi n g are acce pt a ble f or ms of b arrier c o ntr ace pti o n:  
•  Lat e x c o n d o m, dia p hra g m or cer vical/ va ult ca p w he n use d wit h s per mici dal 
f oa m/ gel/fil m/crea m/s u p p osit or y 
U n acce pt a ble C o ntr a ce pti o n Met h o ds:  f or w o m e n of c hil d beari n g p ote ntial i ncl u de: 
•  I U D pr o gest er o ne T 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 6  of 6 9  
 
•  Fe male c o n d o m  
•  Nat ural f a mil y pla n ni n g (r h yt h m met h o d) or breastfee di n g  
•  Fertilit y a ware ness  
•  Wit h dra wal  
•  Cer vical s hiel d  
Pre g n a ncies  
T o e ns ure s u bject safet y, eac h pr e g na n c y i n a s u bj ect o n st u d y treat me nt m ust be re p orte d t o 
t he Sara h Ca n n o n D e vel o p me nt I n n o v ati o ns Safet y De p art me nt wit hi n 2 4 h o urs of lear ni n g of 
its occ urre n ce.  T h e pre g na nc y s h o ul d be f oll o we d u p f or 3 m o nt hs after t h e ter mi nati o n of t he 
pre g na nc y t o d eter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details of 
t he birt h, a n d t he pres e nce or a bse n ce of a n y birt h defects, c o n ge nital a b n or malities, or 
mater nal a n d/ or n e w b or n c o m plicati o ns. 
Pre g n a nc y s h o ul d be rec or de d o n a Cli nical St u d y Pre g n a nc y F or m a n d re p orte d b y t h e 
I n v esti gat or t o S ar a h C a n n o n De vel o p me nt  I n n o v ati o ns S afet y De p art me nt .  Pre g na n c y 
f oll o w- u p s h o ul d be rec or de d o n t he sa me f or m a n d s h o ul d i ncl u de a n assess me nt of t he 
p ossi ble relati o ns hi p t o t he st u d y dr u g  of a n y pre g na n c y o utc o me.  A n y S A E e x perie nce d 
d uri n g pr e g na n c y m ust be re p ort e d o n t he S A E Re p ort F or m. 
Pre g n a nc y o utc o mes m ust be c ollecte d f or t he fe male part ners of a n y m ales w h o t o o k st u d y 
treat me nt i n t his st u d y.  C o nse nt t o re p ort i nf or m ati o n re gar di n g t hes e pre g na n c y o utc o mes 
s h o ul d be o btai ne d fr o m t he m ot her. 
W o me n N ot of C hil d be ari n g P ot e nti al are defi ne d as F oll o ws:  
•  W o me n are c o nsi der e d p ost me n o pa usal a n d n ot of c hil d beari n g p ote ntial if t he y h a ve 
ha d 1 2 m o nt hs of nat ural (s p o nta ne o us) a m e n orr h ea wit h a n a p pr o priate cli nical pr ofile 
(e. g., a ge a p pr o pri ate, hist or y of v as o m ot or s y m pt o ms). 
•  W o me n w h o are per ma n e ntl y sterilize d (e. g., t u bal occl usi o n, h ysterect o m y, bilateral 
sal pi n gect o m y, bilateral o o p h orect o m y) . 
•  W o me n w h o are > 4 5 years  of a ge, n ot usi n g h or m o ne-re pl ace m e nt t hera p y a n d w h o 
ha ve e x perie nce d t otal cessati o n of me nses f or at least 1 2 m o nt hs O R w h o ha ve a 
f ollicle sti m ulati n g h or m o ne ( F S H) v al ue > 4 0 mI U/ m L a n d a n estra di ol val ue 
< 4 0 p g/ m L ( 1 4 0  p m ol/ L) . 
•  W o me n w h o are > 4 5 years  of a ge, usi n g h or m o n e-re place me nt t hera p y a n d w h o ha ve 
e x perie nce d t otal cessati o n of me nses f or at least 1 year O R w h o h a ve ha d d oc u me nte d 
e vi de nce of me n o pa us e b ase d o n F S H > 4 0 mI U/ m L a n d estra di ol < 4 0 p g/ m L  pri or t o 
i nitiati o n of h or m o ne-re place me nt t hera p y. 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 7  of 6 9  
 
A p pe n di x E: Sc he d ule of Assess me nts  f or p atie nts recei vi n g st u d y dr u g 
A S S E S S M E N T S  
B aseli ne a  
 
S T U D Y T R E A T M E N T ( Cycles re pe ate d every 2 wee ks ) 
D a y 1 of e ver y 
c ycle ( ±2 d a ys as 
l o n g as i nter v al 
bet w ee n d oses is 
1 2 -1 6 d a ys ) 
Res p o nse assesse d at 6 
m o nt hs  a n d 1 ye ar p ost -
A S C T  
E n d of Tre at me nt j 
F oll o w -U p k  
Tests a n d O bserv ati o ns  
I nf or me d c o nse nta 
X  
 
 
 
 
Me dical hist or y  
X b 
 
 
 
 
P h ysical e xa m c  
X b 
X  
 
X  
 
Vital Si g ns d 
X b 
X  
 
X  
 
E C O G P S  
X b 
X  
 
X  
 
1 2 -lea d E C G 
X b 
 
 
 
 
A d verse e ve nt e val uati o n  
 
X  
 
X  
X j 
C o nc o mita nt me dicati o n re vie w  
X b 
X  
 
X  
 
St u dy Tre at m e nt  
Ni v ol u ma b  
 
X  
 
 
 
L a b or at ory O bserv ati o ns m  
C B C, 3 -part differe ntial, a n d 
platelets  
X b 
X  
 
X  
 
C M P e 
X b 
X  
 
X  
 
P T/ P T T/I N R f  
X b 
 
 
 
 
Ser u m or Uri ne Pre g na nc y 
T est g 
X b 
 
 
X g 
 
Researc h bl o o d sa m ple h 
 
X ( C 1 D 1 , C 2 D 1, 
a n d C 3 D 1  o nl y)  
 
X  
X  
St a gi n g  
 
 
 
 
 
P E T -C T  sca n 
X b 
 
X i 
 
 
B o ne marr o w bi o ps y l 
X  
 
X  
 
 
S ur vi val  
 
 
 
 
X  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 8  of 6 9  
 
A p pe n di x E: Sc he d ule of Assess me nts (c o nti n ue d)    
 
a 
I nf or me d c o nse nt m ust be o btai ne d ≤2 8 da ys pri or t o t he i nitiati o n of treat me nt. 
b 
T he baseli ne p h ysical e xa mi nati o n, me dical hist or y, E C O G P S, c o m plete bl o o d c o u nts ( C B C) wit h differe ntial a n d platelets, c o m pre he nsi ve meta b olic 
pr ofile ( C M P),  a n d P T/ P T T/I N R s h o ul d be d o ne ≤7  da ys pri or t o i nitiati o n of treat me nt.  H o we ver, if t hese i nitial e xa mi nati o ns are o btai ne d wit hi n 
7 2  h o urs of C ycle 1 Da y 1 t he y d o n ot ha ve t o be re peate d.  A pre g na nc y test m ust be perf or me d wit hi n 7 2 h o urs of C ycle 1 Da y 1.   P E T sca ns s h o ul d 
be perf or me d ≤6 wee ks pri or t o i nitiati o n of treat me nt.  E C G a n d researc h sa m ples s h o ul d be perf or me d ≤2 8 da ys pri or t o i nitiati o n of st u d y treat me nt. 
c 
P h ysical e xa mi nati o n will i ncl u de meas ure me nts of hei g ht ( pretreat me nt visit o nl y), wei g ht, a n d vital si g n s. 
d 
Vital si g ns will i ncl u de resti n g heart rate, bl o o d press ure, res pirat or y rate, a n d te m perat ure.  
e 
C M P will i ncl u de meas ure me nts of gl uc ose, B U N, creati ni ne, s o di u m, p otassi u m, c hl ori de, calci u m, C O 2, A L P , A S T ( S G O T), A L T ( S G P T), t otal 
bilir u bi n, t otal  pr otei n, a n d al b u mi n.  
f 
If P T/ P T T/I N R are n or mal at baseli ne t he y d o n ot nee d t o be re peate d.  P atie nts re q uiri n g t he i nitiati o n of a n a nti-c oa g ul ati o n t hera p y d uri n g st u d y 
treat me nt s h o ul d ha ve c oa g ulati o n tests perf or me d acc or di n g t o sta n dar d practice gui deli nes.  
g 
Ser u m or uri ne pre g na nc y tests are t o be c o n d ucte d i n w o me n of c hil d beari n g p ote ntial.  
h 
A researc h bl o o d sa m ple will be ta ke n at, pre -d ose o n C ycle 1 Da y 1, C ycle 2 Da y 1, C ycle 3 Da y 1 , E O T  (6 m o nt hs),  a n d 1 year after t he first d ose of 
ni v ol u ma b . 
i 
P atie nts s h o ul d ha ve P E T -C T sca ns d o ne per i nstit uti o n sta n dar d of care.  P E T -C T sca ns are re q uire d p ost -A S C T pri or t o i nitiati o n of t hera p y, 6 m o nt hs 
p ost -A S C T , a n d 1 year p ost -A S C T.   P atie nts disc o nti n ui n g t hera p y earl y recei vi n g > 6 c ycl es wit h meas ura ble disease at baseli ne are rec o m me n de d t o 
ha ve a n E O T P E T -C T.  P atie nts  e n di n g treat me nt earl y nee d t o ha ve a P E T -C T sca n  at 1 year  p ost -A S C T  u nless patie nt pr o gresses or starts a ne w 
t hera p y. 
j 
E O T e val uati o ns m ust be c o m plete d wit hi n 3 0 da ys after  t he last d ose of st u d y treat me nt.  P atie nts m ust be f oll o we d f or A Es f or 1 0 0  cale n dar da ys aft er 
t he last d ose of ni v ol u ma b . 
k 
P atie nts will be f oll o we d e ver y m o nt h ( ± 1 wee k ) f or 3 m o nt hs a n d t he n e ver y 3 m o nt hs t hereafter fr o m t he date of last d ose of niv ol u ma b f or u p t o 
2 years.  A p h o ne call ma y be use d t o assess s ur vi val  a n d t o rec or d i nitiati o n of a n alter nati ve f or m of treat me nt f or l y m p h o ma after res p o nse assess me nt 
at 1 year p ost-A S C T . 
 l 
B o ne marr o w bi o ps y is re q ueste d at baseli ne  o nl y i n patie nts  wit h pri or b o ne marr o w i n v ol ve me nt .  At s u bse q ue nt sta gi n g visits, patie nts wit h pri or 
b o ne marr o w i n v ol ve me nt, if i n C R, s h o ul d als o ha ve b o ne marr o w bi o ps y perf or me d  t o d oc u me nt res p o nse . 
m 
La b orat or y sa m ples fr o m c o ntr ol patie nts will be c ollecte d as d escri be d i n Secti o n 5. 4. 2 . 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 5 9  of 6 9  
 
A p pe n di x F: Rec o m me n d ati o ns f or I niti al E v al u ati o n, St a gi n g, a n d Res p o nse Assess me nt of H o d g ki n a n d N o n - H o d g ki n 
L y m p h o m a: T he L u g a n o Cl assific ati o n  
T hese criteria are bas e d u p o n t he criteria fr o m t he Rec o m me n dati o ns f or I nitial E val uati o n, Sta gi n g, a n d Res p o nse Assess me nt of 
H o d g ki n a n d N o n- H o d g ki n  L y m p h o ma: T he L u ga n o Classificati o n (C hes o n et al. 2 0 1 4 ) 
Re vise d Criteria f or Res p o nse Assess me nt  
Res p o nse a n d Site  
P E T -C T – B ase d Res p o nse  
C T -B ase d Res p o nse  
C o m plete  
L y m p h n o des a n d 
e xtral y m p hatic sites  
C o m plete meta b olic res p o nse  
Sc ore 1, 2, or 3 * wit h or wit h o ut a resi d ual mass o n 5 P S †  
It is rec o g nize d t hat i n W al de yer’s ri n g or e xtra n o dal sites wit h hi g h p h ysi ol o gic 
u pta ke or wit h acti vati o n wit hi n s plee n or marr o w (e . g., wit h c he m ot hera p y or 
m yel oi d c ol o n y -sti m ulati n g fa ct ors), u pta ke ma y be greater t ha n n or mal 
me diasti n u m a n d/ or li ver. I n t his circ u msta nce, c o m plete meta b olic res p o nse 
ma y be i nfe rre d if u pta ke at sit es of i nitial i n v ol ve me nt is n o greater t ha n 
s urr o u n di n g n or mal tiss ue e ve n if t he tiss ue has hi g h p h ysi ol o gic 
C o m plete ra di ol o gic res p o nse (all of t he f oll o wi n g)  
T ar get n o des/ n o dal masses m ust re gress t o ≤1. 5 c m i n 
L Di  
N o e xtral y m p hat ic sites of dis ease 
N o n meas ure d lesi o n  
Or ga n e nlar ge me nt  
Ne w lesi o ns  
B o ne marr o w  
N ot a p plica ble  
N ot a p plica ble  
N o ne  
N o e vi de nce of F D G -a vi d dise ase i n marr o w 
A bse nt  
Re gress t o n or mal  
N o ne  
N or mal b y m or p h ol o g y; if i n deter mi nate, I H C ne gati ve  
P artial  
L y m p h  n o des a n d 
e xtral y m p hatic sites  
P artial me tab olic res p o nse 
Sc ore 4 or 5 † wit h re d uce d u pta ke c o m pare d wit h baseli ne a n d resi d ual 
mass(es) of a n y size  
At i nteri m, t hese fi n di n gs s u g gest res p o n di n g disease  
At e n d of treat me nt, t hese fi n di n gs i n dicate resi d ua l disease 
P artial re missi o n (all of t he f oll o wi n g)  
≥5 0 %  decrease i n S P D of u p t o 6 tar get meas ura ble 
n o des a n d e xtra n o dal sites  
W he n a lesi o n is t o o s mall t o meas ure o n C T, assi g n 
5 m m × 5 m m as t he defa ult val ue  
W he n n o l o n ger visi ble, 0 x 0 m m  
F or a n o de  > 5 m m × 5 m m, b ut s maller t ha n n or mal, 
use act ual meas ure me nt f or calc ulati o n  
N o n meas ure d lesi o ns  
Or ga n e nlar ge me nt  
N ot a p plica ble  
N ot a p plica ble  
A bse nt/ n or mal, re gresse d, b ut n o i ncrease  
S plee n m ust ha ve re gresse d b y > 5 0 % i n le n gt h be y o n d 
n or mal  
Ne w le si o ns 
B o ne marr o w  
N o ne  
Resi d ual u pta ke hi g her t ha n u pta ke i n n or mal marr o w b ut re d uce d c o m pare d 
wit h baseli ne ( diff use u pta ke c o m pati ble wit h reacti ve c ha n ges fr o m 
c he m ot hera p y all o we d).  If t here are persiste nt f ocal c ha n ges i n t he marr o w i n 
t he c o nte xt of a n o dal res p o nse, c o nsi derati o n s h o ul d be gi ve n t o f urt her 
e val uati o n wit h M RI or bi o ps y or a n i nter val sca n  
N o ne  
N ot a p plica ble  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 0  of 6 9  
 
Re vise d Criteria f or Res p o nse Assess me nt  
Res p o nse a n d Site  
P E T -C T – B ase d Res p o nse  
C T -B ase d Res p o nse  
N o res p o nse or sta ble 
disease  
T ar get n o des/ n o dal 
masses, e xtra n o dal 
lesi o ns 
N o meta b olic res p o nse  
Sc ore 4 or 5 wit h n o si g ni fica nt c ha n ge i n F D G u pta ke fr o m baseli ne at i nteri m 
or e n d of treat me nt  
Sta ble disease  
˂  5 0 % decrease fr o m baseli ne i n S P D of u p t o 6 
d o mi na nt, meas ura ble n o des a n d e xtra n o dal sites; n o 
criteria f or pr o gressi ve disease are met  
N o n meas ure d lesi o ns  
Or ga n e nlar ge me nt  
Ne w lesi o ns  
B o ne marr o w  
N ot a p plica ble  
N ot a p plica ble  
N o ne  
N o c ha n ge fr o m bas eli ne  
N o i ncrease c o nsiste nt wit h pr o gressi o n  
N o i ncrease c o nsiste nt wit h pr o gressi o n  
N o ne  
N ot a p plica ble  
Pr o gressi ve disease  
I n di vi d ual tar get 
n o des/ n o dal masses  
E xtra n o dal lesi o ns  
Pr o gressi ve meta b olic disease  
Sc ore 4 or 5 wit h a n i ncrease i n i nte nsit y of u pta ke fr o m bas eli ne a n d/ or  
Ne w F D G -a vi d f oci c o nsiste nt wit h l y m p h o ma at i nteri m or e n d -of -treat me nt 
assess me nt  
Pr o gressi ve disease re q uires at least o ne  of t he 
f oll o wi n g: 
P P D pr o gressi o n:  
 
A n i n di vi d ual n o de/lesi o n m ust be a b n or mal wit h:  
L Di > 1. 5 c m a n d  
I ncrease b y ≥5 0 % fr o m P P D na dir a n d  
A n i ncrease i n L Di or S Di fr o m na dir  
0. 5 c m f or lesi o ns ≤2 c m  
1. 0 c m f or lesi o ns > 2 c m  
I n t he setti n g of s ple n o me gal y, t he s ple nic le n gt h m ust 
i ncrease b y > 5 0 % of t he e xte nt of its pri or i ncrease 
be y o n d baseli ne (e . g., a 1 5-c m s plee n m ust i ncrease t o 
> 1 6 c m). If n o pri or s ple n o me gal y, m ust i ncrease b y at 
least 2 c m fr o m baseli ne 
Ne w or rec urre nt s ple n o me gal y  
N o n meas ure d lesi o ns  
N o ne  
Ne w or clear pr o gressi o n of pr e -e xisti n g n o n meas ure d 
lesi o ns 
Ne w lesi o ns  
Ne w F D G -avi d f oci c o nsiste nt wit h l y m p h o ma rat her t ha n a n ot her eti ol o g y 
(e. g., i nfecti o n, i nfla m mati o n).  If u ncertai n re gar di n g eti ol o g y of ne w lesi o ns, 
bi o ps y or i nter val sca n ma y be c o nsi dere d  
Re gr o wt h of pre vi o usl y res ol ve d lesi o ns A ne w n o de 
> 1. 5 c m i n a n y a xi s 
A ne w e xtra n o dal site ˂ 1. 0 c m i n a n y a xis; if > 1. 0 c m 
i n a n y a xis, its prese nce m ust be u ne q ui v ocal a n d m ust 
be attri b uta ble t o l y m p h o ma  
Assessa ble disease of a n y size u ne q ui v ocall y 
attri b uta ble t o l y m p h o ma  
B o ne marr o w  
Ne w or rec urre nt F D G -a vi d f oci 
Ne w  or rec urre nt i n v ol ve me nt  


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 1  of 6 9  
 
A b bre viati o ns: 5 P S, 5 -p oi nt sc ale; C T, c o m p ute d t o m o gra p h y; F D G, fl u or o de o x y gl uc ose; I H C, i m m u n o hist oc he mistr y; L Di, l o n gest tra ns verse dia met er of  a 
lesi o n; M RI, ma g netic res o na nce i ma gi n g; P E T, p ositr o n e missi o n t o m o gra p h y; P P D, cr oss pr o d uct of t he L Di a n d per pe n dic ular dia meter; S Di, s h ortest a xis 
per pe n dic ular  t o t he L Di; S P D, s u m of t he pr o d uct of t he per pe n dic ular dia meters f or m ulti ple lesi o ns. 
* A sc ore of 3 i n ma n y patie nts i n dicates a g o o d pr o g n osis wit h sta n dar d treat me nt, es peciall y if at t he ti me of a n i nteri m s ca n.   H o we ver, i n trials i n v ol vi n g P E T 
w here de -escalati o n is i n vesti gate d, it ma y be prefera ble t o c o nsi der a sc ore of 3 as i na de q uate res p o nse (t o a v oi d u n dertreat me nt).   Meas ure d d o mi na nt lesi o ns: 
U p t o si x o f t he lar gest d o mi na nt n o des, n o dal masses, a n d e xtra n o dal lesi o ns selecte d t o be clearl y meas ura ble i n t w o di a meters.  N o des s h o ul d prefera bl y be 
fr o m dis parate re gi o ns of t he b o d y a n d s h o ul d i ncl u de, w here a p plica ble, me diasti nal a n d retr o perit o neal areas.  N o n -n o dal lesi o ns i ncl u de t h ose i n s oli d or ga ns 
(e. g., li ver, s plee n, ki d ne ys, l u n gs), GI i n v ol ve me nt, c uta ne o us lesi o ns, or t h ose n ote d o n pal pati o n.  N o n meas ure d lesi o ns: A n y disease n ot selecte d as meas ure d, 
d o mi na nt disease a n d tr ul y ass essa ble disease s h o ul d be c o nsi dere d n ot meas ure d.  T hese sites i ncl u de a n y n o des, n o dal masses, a n d e xtra n o dal sites n ot selecte d 
as d o mi na nt or meas ura ble or t hat d o n ot meet t he re q uire me nts f or meas ura bilit y b ut are still c o nsi dere d a b n or mal, as well a s tr ul y assessa ble disease, w hic h is 
a n y site of s us pecte d disease t hat w o ul d be diffic ult t o f oll o w q ua ntitati vel y wit h meas ure me nt, i ncl u di n g ple ural eff usi o ns,  ascites, b o ne lesi o ns, le pt o me ni n geal 
disease, a b d o mi nal masses, a n d ot her lesi o ns t hat ca n n ot be c o nfir me d a n d f oll o we d b y i ma gi n g.   I n W al de yer’s ri n g or i n e xtra n o dal sites (e. g., GI tract, li ver, 
b o ne marr o w), F D G u pta ke ma y be greater t ha n i n t he me diasti n u m wit h c o m plete meta b olic res p o nse, b ut s h o ul d be n o hi g her t ha n s urr o u n di n g n or mal 
p h ysi ol o gic u p ta ke (e. g., wit h marr o w acti vati o n as a res ult of c he m ot hera p y or m yel oi d gr o wt h fact ors). 
† P E T 5 P S: 1, n o u pta ke a b o ve bac k gr o u n d; 2, u pta ke ≤ me di asti n u m; 3, u pta ke > me diasti n u m b ut ≤ li ver; 4, u pta ke m o deratel y >  li ver; 5, u pta ke mar ke dl y 
hi g her t ha n l i ver a n d/ or ne w l esi o ns; X, ne w areas of u pta ke u nli kel y t o be relate d t o l y m p h o ma. 
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 2  of 6 9  
 
A p pe n di x G:  M a n a ge me nt Al g orit h ms f or I m m u n o- O nc ol o g y A ge nts 
T hese ge n eral g ui deli nes c o nstit ute g ui da nce t o t he I n vesti gat or a n d m a y b e s up ple me nte d b y 
disc ussi o ns wit h t he Me dical M o nit or re prese nti n g t he S p o ns or.  T he g ui da nce a p plies t o all 
i m m u n o- o nc ol o g y a ge nts a n d re gi me ns. 
A ge ner al pri nci ple is t hat differe ntial dia g n os es s h o ul d be dili ge ntl y e val u ate d acc or di n g t o 
sta n dar d me dical practice.  N o n -i nfla m mat or y eti ol o gies s h o ul d be c o nsi dere d a n d a p pr o priatel y 
treate d. 
C ortic oster oi ds are a pri mar y t h era p y f or i m m u n o - o nc ol o g y dr u g-relate d A Es .  T he oral 
e q ui vale nt of t he r ec o m me n de d I V d oses m a y be c o nsi dere d f or a m b ulat or y p atie nts wit h l o w-
gr a de t o xicit y.  T he l o w er bi oa vaila bilit y of oral c ortic oster oi ds s h o ul d be ta ke n i nt o acc o u nt 
w he n  s witc hi n g t o t he e q ui vale nt d ose of oral c ortic oster oi ds. 
C o ns ultati o n wit h a me dical or s ur gical s pecialist, es peciall y pri or t o a n i n v asi ve  dia g n ostic or 
t hera pe utic pr oce d ure, is rec o m me n de d. 
T he fre q u e nc y a n d se verit y of t he relate d A Es  c o v ere d b y t hes e  al g orit h ms will de pe n d o n t he 
i m m u n o- o nc ol o g y a ge nt or re gi me n bei n g use d.


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 3  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 4  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 5  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 6  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 7  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 8  of 6 9  
 


 
C O N FI D E N TI A L  
S T U D Y D R U G :  NI V O L U M A B  
    
 
S A R A H C A N N O N D E V E L O P M E N T I N N O V A TI O N S  S T U D Y N U M B E R :   
  
 
B M T  2 4  
FI N A L P R O T O C O L D A T E :  0 7  F E B  2 0 2 0   
  
  
VE R SI O N 7 
P a ge 6 9  of 6 9