Phase II Trial of Concurrent Nivolumab in Urothelial Bladder Cancer With Radiation Therapy in Localized/Locally Advanced Disease for Chemotherapy Ineligible Patients [NUTRA]
Phase: PHASE2
Conditions: Stage II Bladder Urothelial Carcinoma AJCC v6 and v7, Stage III Bladder Urothelial Carcinoma AJCC v6 and v7, Stage IV Bladder Urothelial Carcinoma AJCC v7
Sponsor: Barbara Ann Karmanos Cancer Institute

Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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K CI Pr ot oc ol #  2 0 1 6- 1 9 5 
 
P h ase  II T ri al  of C o nc urre nt Ni v ol u m a b i n  Ur o Theli al Bl a d der C a ncer  wit h 
R a di ati o n  T her a p y  i n  L oc alize d/ L oc all y  A d v a nce d 
Dise ase  f or  C he m ot her a p y 
I neli gi ble P atie nts [N U T R A]  
 
Versi o n d ate:     Oct 2 7, 2 0 1 7 , J a n 1 1 , 2 0 1 8, A pr 2 5, 2 0 1 8, J ul y 1 6 2 0 1 8, N o v 3 0 , 2 0 1 8, 
A u g 1 8, 2 0 1 9, Fe b 2 0, 2 0 2 0, J u ne 1 7 2 0 2 0, J ul y 2 9, 2 0 2 0 
I N D # 1 3 4 5 9 9, B M S Pr ot oc ol # C A 2 0 9- 8 9 2 
N C T 0 3 4 2 1 6 5 2  
S p o ns or : 
Kar ma n os Ca n cer I nstit ute  
Dr u g Pr o vi der:  
Brist ol - M yers S q ui b b ( B M S) 
 
Pri nci p al I n vesti g at or:   
Niti n Vais ha m pa ya n , M. D.  
  
  
 
Kar ma n os Ca n cer I nstit ute  
  
  
  
4 1 0 0 J o h n R,  
  
 
Detr oit , MI 4 8 2 0 1 
Tel # 3 1 3- 5 7 6- 9 5 5 0 
E- mail : vais ha m n @ kar m a n os. or g  
 
R a di ati o n O nc ol o g y 
C o -I n vesti g at ors:                  J or da n Maier, M. D.  
Ste p he n Miller , M. D. 
  
  
  
 
Mic hael D o mi nell o , M. D. 
  
  
  
  
 
Me dic al O nc ol o g y  
C o -I n vesti g at ors:                  Elisa bet h Heat h , M. D.     
Kar ma n os Ca n cer I nstit ute  
  
  
  
4 1 0 0 J o h n R, H W 0 4 H O 
  
 
Detr oit, MI 4 8 2 0 1 
Tel  # 3 1 3- 5 7 6- 8 7 1 5 
Fa x # 3 1 3- 5 7 6- 8 7 6 7 
E- mail : heat he @ kar ma n os. or g  
 
J ose p h F o nta na, M. D.  
4 1 0 0 J o h n R 
Detr oit , MI 4 8 2 0 1 
Tel  # 3 1 3- 5 7 6- 3 6 5 9 
E- mail : f o nta naj @ kar m a n os. or g 
 
 

Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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Bi ost atistics:                           La n ce H eil br u n , P h. D.  
Bi ostatistics C ore  
Kar ma n os Ca n cer I nstit ute  
  
  
  
4 1 0 0 J o h n R, M M 0 3BI  
  
 
Detr oit, MI 4 8 2 0 1 
Tel  # 3 1 3- 5 7 6- 8 6 5 2 
E- mail : heil br u n @ kar ma n os. or g  
 
P h ar m a c o d y n a mi cs/ 
C orrel ati v es :  
 
Pra hla d Paraj uli, P h. D. 
Researc h Sci e ntist  
De part me nt of O nc ol o g y 
Wa y ne State U ni v ersit y & Kar ma n os Ca ncer Ce nter  
Elli ma n Cli nical Researc h B uil di n g, # 2 0 2 9 
4 2 1 E. Ca nfiel d St.,  
Detr oit, MI 4 8 2 0 1. 
P h: 3 1 3- 5 7 8- 4 2 6 8 ( Off); 3 1 3- 5 7 7- 0 6 2 9 ( La b) 
Cell 2 4 8 5 0 6 7 1 8 0 
E mail: p paraj uli @ me d. w a y n e.e d u  
 
J ulie B oer n er, P h . D. 
Wa y ne State U ni v ersit y  
Kar ma n os Ca n cer I nstit ute  
H u ds o n- We b ber Ca ncer Researc h C e nter   
C orrelati ve Scie nces La b R m 8 0 8  
4 1 0 0 J o h n R 
Detr oit, M I 4 8 2 0 1 
Tel #  3 1 3- 5 7 6- 8 3 5 1 ( La b) 
E- mail: b oer nerj @ k ar ma n os. or g  
 
Karri Star k , M. S. 
Wa y ne State U ni v ersit y  
Kar ma n os Ca n cer I nstit ute  
H u ds o n- We b ber Ca ncer Researc h C e nter   
C orrelati ve Scie nces La b R m 8 0 8  
4 1 0 0 J o h n R 
Detr oit, M I 4 8 2 0 1 
Tel #  3 1 3- 5 7 6- 8 2 4 8 ( La b) 
E mail:  star k ka @ kar ma n os. or g 
 
D o n g pi n g S hi, M D 
De part me nt of Pat h ol o g y 
Wa y ne State U ni v ersit y  
4 1 0 0 J o h n R 
Detr oit MI 4 8 2 0 1. 

Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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Office P h o ne: 3 1 3- 9 6 6- 4 3 4 3 
e mail: ds hi @ d mc. or g  
 
 
Felicit y Har p er , P h . D. 
H W C R C 4 1 0 0 J o h n R  
Detr oit, MI 4 8 2 0 1 
Tel # 3 1 3- 5 7 6- 8 7 6 3 
E- mail  har perf @ kar ma n os. or g  
 
St u d y C o or di n at or:    
Bre n d a Dic k o w, R N                                          
  
  
  
 
Kar ma n os Ca n cer I nstit ute  
  
  
  
 
  
  
  
 
Cli nical Trials Office     
  
  
 
  
  
  
  
4 1 0 0 J o h n R, M M 0 3 C T 
  
  
  
  
Detr oit, MI 4 8 2 0 1 
  
  
  
  
Tel # 3 1 3- 5 7 6- 9 3 7 2 
  
  
  
  
E-mail: dic k o w b @ kar ma n os. or g  
  
 
 
Gr a nts a n d C o ntr acts:   
Mar y J o O’ L o u g hli n 
  
  
  
 
Kar ma n os Ca n cer I nstit ute   
  
  
  
 
Researc h A d mi nistrati o n   
  
  
  
 
  
  
  
  
4 1 0 0 J o h n R, M M 0 0 R A 
Detr oit, MI 4 8 2 0 1 
Tel # 3 1 3- 5 7 8- 4 4 0 5 
Fa x # 3 1 3- 5 7 8- 4 4 1 9 
E- mail: m ol o u g hl @ wa y n e.e d u  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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P artici p ati n g Sites  
 
R os w ell P ar k C a ncer I nstit ute  
 
Pri nci p al I n vesti g at or: 
Sa b y G e or ge, M . D., F A C P 
  
  
  
  
Ass ociate Pr ofess or of O nc ol o g y a n d Me dici ne 
  
  
  
  
Ge nit o uri nar y O n c ol o g y Di visi o n 
  
  
  
  
El m a n d Carlt o n Streets 
  
  
  
  
B uffal o, N Y 1 4 2 6 3 
  
  
  
 
Tel #  7 1 6- 8 4 5- 3 8 6 3 
  
  
  
 
Fa x # 7 1 6- 8 4 5- 8 0 0 8 
  
  
  
  
E-mail: Sa b y. G e or ge @ R os well Par k. or g  
 
U ni versit y of Ci nci n n ati  
 
 
Pri nci p al I n vesti g at or: 
S h uc hi G ulati, M D M Sc  
Assista nt Pr ofess or of Cli nical Me dici ne  
Di visi o n of He mat ol o g y a n d O nc ol o g y 
U ni versit y of Ci nci n nati Ca ncer I nstit ute  
V o ntz Ce nter f or M olec ular St u dies, R o o m 1 3 1 2 
3 1 2 5, E de n A ve n u e, M L 0 5 6 2 
Ci nci n nati, O H  4 5 2 6 7- 0 5 6 2 
P h o ne N o.: 4 8 4- 9 4 9- 5 8 2 0 
E- mail: g ulatisi @ uc mail. uc.e d u  
 
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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P h ase II Tri al of C o nc urre nt Ni v ol u m a b i n Ur ot heli al Bl a d der C a ncer wit h 
R a di ati o n T her a p y i n L oc alize d / L oc all y A d v a nce d Dise ase f or C he m ot her a p y 
I neli gi ble P atie nts [ N U T R A] 
 
T a ble of C o nte nts 
 
S y n o psis … … … … … … … … … … … … … … … …. 6 
 
1. 0 Bac k gr o u n d a n d Rati o nale … … … … … … … …. 7 
 
2 0 S t u d y Desi g n … … … … … … … … … … … … … 1 2 
 
3. 0 St u d y P o p ulati o n … … … … … … … … … … ….. 1 8 
4. 0 St u d y Assess me nts … … … … … … … … … …. 2 1 
 
5. 0 A d verse E v e nts Re p orti n g … … … … … … … 2 6 
 
6. 0 C orrelati ve St u dies … … … … … … … … … … 3 3 
 
7. 0 Treat me nt Pla n, M o dificati o ns a n d C o nc o mita nt T hera p y … … … … …. 3 6 
 
8. 0 Statistical C o nsi derati o ns … … … … … … … …. 4 3 
 
9. 0 Et hical As pects … … … … … … … … … … … …. 4 7 
 
1 0. 0 St u d y D oc u me ntati o n … … … … … … … … … 4 9 
 
1 1. 0 Refere n ces … … … … … … … … … … … … ….. 5 2 
 
1 2. 0 Data a n d Safet y M o nit ori n g … … … … … … … 5 3 
 
1 3. 0 A p pe n dices … … … … … … … … … … … … ….. 5 5 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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S Y N O P SI S  
P h ase II Tri al of C o nc urre nt Ni v ol u m a b i n Ur ot heli al Bl a d der C a ncer wit h  R a di ati o n 
T her a p y  i n  L oc alize d / L oc all y  A d v a nce d  Dise ase f or  C he m ot her a p y I neli gi ble 
P ati e nts  [ N U T R A]  
 
•  Pri m ar y O bjecti ve:  
T o c o m pare  t he 1 2- m o nt h rate of pr o gressi o n- free  ( P F S)  s ur vi val ac hie ve d wit h t he 
c o m bi nati o n of ni v ol u ma b, a pr o gra m me d deat h ( P D-1) i n hi bit or , a n d ra diati o n t hera p y 
i n  l ocalize d/l ocall y  a d v a nce d  ur ot helial  ca ncer patie nts , w h o  are  i neli gi ble  f or 
c he m ot hera p y, t o a hist orical c o ntr ol refere nce rat e .  
•  Sec o n d ar y O bjecti ves:  
1)  T o assess t he t o xicit y of c o nc urre nt ni v ol u ma b a n d ra diati o n t hera p y i n ur ot helial 
ca ncer.  
2)  T o deter mi ne o verall res p o nse rate ( O R R). 
3)  T o deter mi ne metastasis -free s ur vi val ( M F S). 
4)  T o deter mi ne o verall s ur vi val ( O S). 
5)  T o e val uate t he q u alit y of life a n d bla d der f u ncti o ni n g d uri n g a n d after t he t hera p y . 
6)  T o  e x pl ore  t he  relati o ns hi ps  of  P D -1  e x pressi o n,  P D L -1  e x pressi o n,  a n d  t he 
T h 1/ T h 2 c yt o ki ne rati o t o cli nical o utc o mes (res p o nse, P F S, M F S, a n d O S). 
•  Tre at me nt Pl a n:  
- 
Ni v ol u ma b will be a d mi nistere d at a d ose of 2 4 0 m g I V e ver y 2 wee ks f or a 
ma xi m u m of 1 4 d oses or 6 m o nt hs d urati o n.  
- 
Ra diati o n T hera p y  ( R T)  nee ds t o b e starte d wit hi n  +/ - 3 da ys of ni v ol u m a b 
a d mi nistrati o n.  R T  w o ul d  be  a d mi nistere d  at  a  t otal  d ose  of  6 4  G y  i n  3 2 
fracti o ns o ver a 6- 8 wee k peri o d i n all patie nts.  
•  St u d y Assess me nts:  
Prest u d y  e v al uati o n,  C T/ M RI  sca n,  c yst osc o p y  a n d  bi o ps y,  a n d  arc hi val  tiss ue. 
Cli nical a n d la b e val uati o n o n da y of ni v ol u ma b t hera p y.  Q O L assess me nt at t he 1 5 
ti me p oi nts liste d i n t he hea der of t he St u d y Cal e n dar i n Secti o n 2. 3.    
•  St atistic al Desi g n:  
S a m ple size base d o n a n ass u me d 1 2 m o nt h P F S rate of 5 0 % o n R T al o n e c urre ntl y a n d a 
h y p ot hesize d rate of 7 5 % f or Ni v ol u ma b + R T st u d y patie nts. A t otal of 3 4 patie nts are t o 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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be accr ue d t o get 3 0 e val ua ble f or P F S. E val ua ble f or P F S a n d t o xicit y e v al ua ble ha ve t he 
sa me defi niti o n (i n Secti o n 4. 7). 
1. 0  B A C K G R O U N D A N D R A TI O N A L E  
1. 1 
St u d y O bjecti ves  
T he o bjecti ves of t his st u d y are as f oll o ws: 
•  Pri mar y O bj ecti ve:  
T o  c o m pare  t he 1 2- m o nt h  rate  of pr o gressi o n- free  s ur vi val ( P F S) ac hie ve d  wit h  t he 
c o m bi nati o n of ni v ol u ma b, a pr o gra m me d d eat h ( P D -1) i n hi bit or , a n d ra di ati o n t hera p y i n 
l ocalize d/l ocall y a d va n ce d ur ot helial ca ncer patie nts , w h o are c he m ot hera p y i neli gi ble, t o 
a hist orical c o ntr ol r efere nce 1 2 - m o nt h P F S rate.  
•  Sec o n dar y O bj ecti ves:  
1)  T o assess t he t o xicit y of c o nc urre nt ni v ol u ma b a n d ra diati o n t hera p y i n ur ot helial 
ca ncer.  
2)  T o deter mi ne o verall res p o nse rate ( O R R).  
3)  T o deter mi ne metastasis -free s ur vi val ( M F S). 
4)  T o deter mi ne o verall s ur vi val ( O S). 
5)  T o e val uate t he q u alit y of life a n d bla d der f u ncti o ni n g d uri n g a n d after t he t hera p y . 
6)  T o  e x pl ore  t he  relati o ns hi ps  of  P D -1  e x pressi o n,  P D L -1  e x pressi o n,   a n d t he 
T h 1/ T h 2 c yt o ki ne rati o t o cli nical o utc o mes (res p o nse, P F S, M F S, a n d O S). 
 
1. 2  
B ac k gr o u n d 
T he sta n dar d ma n a ge me nt of l ocalize d ur ot h elial ca ncer of bl a d der c o nsists of ne oa dj u v a nt 
c he m ot hera p y  f oll o we d  b y  r a dical  c ystect o m y  [ 1 ].  If  patie nts  wis h  t o  p urs ue  a  bla d der 
s pari n g pr o ce d ur e t he n r e gi me ns of eit her 5 F U a n d mit o m yci n , or cis plati n c o nc urre ntl y 
wit h ra diati o n  t hera p y ( R T) are  acce pte d t hera p e utic  a p pr oac hes  [ 2].   H o we ver , t hese 
re gi me ns  are  n ot  feasi ble  i n  a  s u bset  of  bla d der  ca ncer  patie nts w h o are  i neli gi ble  f or 
c he m ot hera p y. Bl a d der ca ncer is a disease of t he el derl y a n d t he i nci de n ce i ncreases wit h 
i ncreasi n g a ge. T h e me di a n a ge of i nci de n ce of bla d der ca ncer is 7 3 years a n d 9 of 1 0 cases 
occ ur i n patie nts o ver t h e a ge of 5 5 years.  I n a d diti o n, t he bla d der ca n cer p o p ulati o n has a 
ver y hi g h r ate of ass ociat e d c o m or bi dities s uc h as re nal d ysf u ncti o n, car diac a n d vasc ular 
disease a n d n e ur o pat h y w hic h are fre q u e ntl y deterre nts t o a d mi nisteri n g c h e m ot hera p y.  I n 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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s o me  series  t he  patie nts  w h o  ar e  n ot  ca n di dat es  f or  cis plati n  base d  t hera p y  d u e  t o 
c o m or bi dities ra n ge u p  t o a b o ut 4 0-5 0 % of t he p atie nts prese nti n g wit h l o calize d disease. 
T he  m o r bi dit y  of  bla d der  ca n cer  is  fre q u e ntl y  si g nifica nt,  wit h  he mat uria,  uri nar y 
o bstr ucti o n a n d r e nal d ysf u ncti o n bei n g t he c o m m o n a n d rec urri n g c o m plai nts. Cis plati n 
base d t her a p y c o n c urr e ntl y wit h R T, has d e m o nstrate d res ults c o m para ble t o t he s ur gi cal 
series;  h o we ver, t he  t o xicit y  rates  are  si g nifi ca nt  a n d  a b o ut  4 0 %  of  t he  patie nts  are  n ot 
ca n di dates f or c h e m ot her a p y [ 3, 4 ]. A c o nc urre nt re gi me n of 5 F U a n d mit o m yci n wit h R T 
[ 5] s h o we d i m pr o ve d o utc o mes w he n c o m pare d t o R T al o ne; h o we ver, t he se vere t o xicit y 
rates  of  3 6 %  ar e  a  d efi nite  deterr e nt.  We  ha ve  re p orte d  o n  a  cas e  series  of 1 3  patie nts 
recei vi n g  c o n c urr e nt  ca pecita bi ne  a n d  R T  i n  l ocalize d  bla d der  ca ncer,  i n  w h o m  we 
o bser ve d  reas o na ble  p alliati o n  a n d  res p o ns e  rates  [ 6 ].  1 1  of  1 3  e val ua ble  patie nts 
de m o nstrate d a res p o nse a n d at a me dia n f oll o w u p of 1 0 m o nt hs o nl y 3 ha d rela pse d. T he 
m ost c o m m o n o verall t o xicities were fati g u e ( 4 3 %), diarr h ea ( Gra d e 2, 1 4 % a n d Gra de 3, 
2 9 %), a n d d e h y dr ati o n ( 4 3 %), wit h n o Gra de 4 or 5 t o xicities.  T he t hera p y o pti o ns f o r 
treat me nt of s y m pt o mati c bla d der ca ncer i n patie nts w h o  are i neli gi ble f or c he m ot hera p y  
de m o nstrate  s u b o pti mal  efficac y  a n d  he n ce  t h ere  is  a n  u n met  nee d  t o  i m pr o ve  t he 
t hera pe utic o utc o m es wit hi n t his patie nt p o p ulati o n.  
1. 3  
Ni v ol u m a b a n d R a di ati o n T her a p y ( R T )  
Ni v ol u ma b  is  a  pr o gra m me d  deat h  ( P D)  1  i n hi bit or  t hat  has  de m o nstrate d  safet y  a n d 
efficac y  i n  m ulti ple  h u ma n  mali g na nci es  a n d  is  c urre ntl y  a p pr o ve d  b y  t h e  F D A  f or  t he 
i n dicati o ns of metastatic mela n o ma, l u n g ca ncer, a n d re nal ca ncer. A si n gl e ar m  p hase II 
cli nical  trial  i n  metastatic  a n d  p ost  c he m ot hera p y  ur ot h elial  ca ncer  p o p ulati o n was 
c o m plete d  a n d  res ults  w ere  r ece ntl y  re p orte d . T he  st u d y  s h o we d  a  1 9. 6 %  ( 5 3  of  2 7 0 
patie nts) o ver all res p o ns e rate a n d a 2 5 % res p o ns e rate i n patie nts wit h P D L -1 e x pressi o n 
> 1 %.  S o me  re missi o ns  are  d ur a ble  a n d  f oll o w  u p  is  c o nti n ue d.  T his  data  le d  t o  F D A 
a p pr o val of ni v ol u ma b i n metastatic ur ot helial ca ncer p ost plati n u m base d c he m ot hera p y  
[ 7].  
Precli nical s y ner g y h as bee n n ote d bet w ee n ni v ol u ma b a n d R T i n ur ot helial ca ncer. I n fact 
t he i nfla m mati o n i n d uce d b y t he R T is li kel y t o i ncrease P D-1 e x pressi o n i n t he ca ncer a n d 
will li kel y e n ha n ce efficac y. R T has s h o w n t he f oll o wi n g effec ts i n ur ot helial carci n o ma: 
1)  i ncreas e d  C D 8  cell  f u ncti o n  a n d  i ncreas e d  c yt o ki ne  release , 2)  a bsc o pal  res p o nse  i n 
metastatic sites n ot bei n g treate d  wit hi n t he R T fiel d , 3) t he R T has bee n k n o w n t o release 
t u m or  a nti ge ns  a n d  ca n  c o n vert  t he  t u m or i nt o  a n  i n  sit u  t u m or  vacci ne, a n d  4) 
co m ple me ntar y a n d p ot e ntiall y s y ner gistic effects i n c o m bi nati o n wit h i m m u ne c h ec k p oi nt 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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i n hi bit ors.  I n s u m mar y, ass ociati o n wit h pr oi nfla m mat or y si g nals t hat tri g ger t he i n nate 
i m m u ne  s yst e m  t o  acti vate  t u m or-s pecific  T  cells,  ra diati o n's  effects  o n  t he  t u m or 
micr oe n vir o n me nt  als o  e n ha nce  i nfiltrati o n   of  acti vate d  T  cells  a n d  e na bl e o verc o mi n g 
s o me of t he barriers t o t u m or rejecti o n [8- 1 1]. 
I n t he U S, ni v ol u ma b has bee n a p pr o v e d f or t he treat me nt of patie nts wit h u nresect a ble or 
metastatic mela n o ma a n d disease pr o gressi o n f oll o wi n g i pili m u ma b a n d, if B R A F V 6 0 0 
m utati o n p ositi ve, a B R A F i n hi bit or.  It h as  als o  bee n  a p pr o v e d  f or use i n patie nts wit h 
a d va nce d ( met astatic) s q ua m o us n o n -s mall cell l u n g ca n cer ( N S C L C) wit h pr o gressi o n o n 
or after plati n u m -bas e d c he m ot hera p y.  Ni v ol u m a b was rece ntl y a p pr o ve d f or  metastatic 
ur ot helial ca ncer f or pati e nts wit h disease pr o gressi o n after plati n u m base d c he m ot hera p y.  
Ni v ol u ma b  m o n ot hera p y  h as  bee n  e xte nsi vel y  st u die d  i n  a  n u m ber  of  t u m or  t y p es 
i ncl u di n g n o n-s mall cell l u n g ca ncer, mela n o ma,  re nal ca ncer, a n d h ea d a n d nec k ca ncer  
wit h b o d y wei g ht n or malize d d osi n g ( m g/ k g)  [ 12]. Acr oss t he vari o us t u m or t y pes i n t he 
Brist ol -M yers S q ui b b ( B M S) cli nical pr o gra m, ni v ol u ma b has bee n s h o w n t o be safe a n d 
well  t olerate d  u p  t o  a  d ose  le vel  of  1 0  m g/ k g,  a n d  t he  relati o ns hi p  bet wee n  ni v ol u ma b 
e x p os ure pr o d uce d b y 3 m g/ k g a n d efficac y has bee n f o u n d t o be  u nc h a n ge d at differe nt 
d ose le vels. Ta ke n t o get her, t he P K, safet y, a n d efficac y d ata i n dicate t h at t he safet y a n d 
efficac y pr ofile of 2 4 0 m g ni v ol u ma b will be si milar t o t hat of 3 m g/ k g ni v ol u ma b.  
Ni v ol u ma b has b ee n e val uate d i n a p h ase II ra n d o mize d trial at d ose c o h orts of 0. 3 m g/ k g, 
3 m g/ k g a n d 1 0 m g/ k g [ 13] . N o differe nces were n ote d i n safet y a n d efficac y bet wee n eac h 
of  t hese  d ose  l e vels. B M S  has  teste d  a n d  vali d ate d  a  fl at  d ose  re gi me n  of  2 4 0  m g  I V 
i nf usi o n of ni v ol u ma b e ver y 2 w ee ks w hic h is c urre ntl y a p pr o ve d b y F D A. He nce a flat 
d ose is use d i n t he st u d y re gar dl ess of patie nt wei g ht. 
Ni v ol u ma b p har mac o ki n etics ( P K) a n d e x p os ures of s u bject s i n t hese st u dies ha ve bee n 
c haracterize d  b y  p o p ulati o n  p har mac o ki netic  ( P P K)  a nal ysis  of  d ata  c ollecte d  t hese 
st u dies, t o get her wit h P K data fr o m se v eral p h ase 1, 2, a n d 3 cli nical st u dies of ni v ol u ma b 
m o n ot hera p y i n  s oli d  t u m ors.  P P K a nal yses  ha v e  s h o w n  t hat  t he  P K  of  ni v ol u ma b  are 
li near, wit h d ose pr o p orti o nal e x p os ures o ver a d ose ra n ge of 0. 1 m g/ k g t o 1 0 m g/ k g, a n d 
are si milar acr oss t u m or t y p es. Ni v ol u ma b cleara n ce a n d v ol u me of distri b uti o n were f o u n d 
t o  i ncrease  wit h  i ncreasi n g  b o d y  wei g ht,  b ut  t he  i ncrease  w as  less  t ha n  pr o p orti o nal, 
i n dicati n g t h at a m g/ k g d ose re prese nts a n o v er-a dj ust me nt f or t he effect of b o d y w ei g ht 
o n ni v ol u ma b P K. Gi ve n t he relati o ns hi p bet wee n ni v ol u ma b P K a n d b o d y wei g ht, a flat 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 0  
d ose is e x pecte d t o lea d t o l o wer e x p os ures  i n hea vier patie nts, relati ve t o t he e x p os ures i n 
li g hter patie nts.  
Usi n g  t he  P P K  m o del,  ni v ol u ma b  stea d y -state  tr o u g h,  pea k  a n d  ti me-a vera ge d 
c o nce ntr ati o n  ( C mi nss,  C ma xss,  a n d  Ca v gss,  res pecti vel y)  w ere  pre di cte d  f or  a  flat 
ni v ol u ma b  d ose  of  2 4 0  m g  Q 2 W  a n d  c o m pare d  t o  t h ose  f oll o wi n g  a d mi nistrati o n  of  3 
m g/ k g Q 2 W i n N S C L C s u bjects. A d ose of 2 4 0 m g ni v ol u ma b is i de ntical t o a d ose of 3 
m g/ k g  f or  s u bjects  wei g hi n g  8 0  k g,  w hi c h  is  t h e  a p pr o xi mate  me dia n  b o d y  wei g ht  of 
N S C L C  s u bjects  i n  t he  3  P hase  2  a n d  3  B M S  cli nical  st u dies  of  ni v ol u ma b 
m o n ot hera p y.  T h e ge o metric mea n v al ues of C mi nss, C ma xss, a n d Ca v gss wit h flat d osi n g 
are sli g htl y ( < 1 5 %) hi g her t ha n t hat pr o d u ce d b y a 3 m g/ k g d ose, a n d t h e c o effici e nt of 
variati o n (c v %) i n t hes e meas ures of e x p os ure  are o nl y sli g htl y ( < 1 0 %) greater t h a n t hat 
of 3 m g/ k g d osi n g.  
T h us a flat d ose of 2 4 0 m g e v er y 2 w ee ks is rec o m me n de d f or i n vesti gati o n i n t his st u d y.   
1. 4 
Ris k Be nefit R ati o of Pr o p ose d Re gi me n 
T he pr o p ose d st u d y is s pecificall y a d dressi n g a n u n met ne e d of treati n g bl a d der ca n cer i n 
patie nts w h o ar e n ot ca n di dates f or c he m ot hera p y. T his is a gr o wi n g s u bset of p o p ulati o n 
wit hi n  bla d der  ca ncer  wit h  i ncreasi n g  i nci d e n ce  i n  el d erl y  patie nts  wit h  i m paire d 
perf or ma n ce stat us or re n al f u ncti o n or ass oci ate d c o m or bi dities.  
Als o P D - 1 i n hi biti o n t hera p y has d e m o nstrate d effi cac y i n ur ot helial ca ncer a n d ni v ol u ma b 
was rece ntl y F D A a p pr o ve d f or use i n ur ot helial ca ncer of bla d der. T he b e nefit ris k rati o 
f or  t he  pr o p ose d  st u d y  is  ver y  f a v or a ble  as  ni v ol u ma b  is  well  t olerate d  a n d  has  pr o ve n 
efficac y i n ur ot helial ca n cer. T h ere is a d e q uate cli nical trial data esta blis hi n g t he r ol e of 
ni v ol u ma b i n ur ot helial ca ncer a n d t h e res ults ha ve le d t o F D A a p pr o val f or t his i n dicati o n. 
T here  are  cli nical  trials  c o n d ucte d  i n  l u n g  ca ncer  a n d  mela n o ma  e val uati n g  t he 
c o m bi nati o n of ni v ol u ma b a n d R T wit h pr o misi n g efficac y a n d esta blis he d safet y. 
T he sta n dar d t her a p y f or patie nts w h o ca n n ot t olerate a ra dical c yst ect o m y pr oce d ure f or 
l ocalize d/l ocall y a d va nce d bla d der ca n cer is c o n c urre nt c he m ot hera p y c o nsisti n g of eit her 
cis plati n  a n d  5 F U  or  5 F U  a n d  mit o m yci n  re gi m e n  wit h  R T.  H o we ver  at  least  4 0 %  of 
patie nts wit h bla d der ca n cer are n ot ca n di dat es f or c he m ot hera p y b ut are li kel y t o t olerate 
i m m u ne t hera p y. T his st u d y is pr o p ose d i n t he c he m ot hera p y i neli gi ble patie nt p o p ulati o n 
f or w h o m palliati ve car e is ra diati o n t hera p y al o ne. A d di n g c o n c urre nt ni v ol u ma b is li kel y 
t o ha ve ra di ose nsitizi n g effect a n d e n ha n ce efficac y o utc o mes.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 1  
T he maj orit y of tr eat me nt a n d st u d y pr oce d ures are r o uti ne t hera p y f or treat m e nt of bla d der 
ca ncer. Ni v ol u ma b is bei n g pr o vi d e d b y B M S. T h e ra diati o n t hera p y a n d l a bs are p art of 
r o uti ne care.  Sca ns  f or  sta gi n g  pre  a n d  p ost  t hera p y  are  als o  part  of  r o uti ne  care .  T h e 
bla d der  s ur veilla nce  wit h  c yst osc o p y  a n d  bi o ps y  aft er  t hera p y  c o m pleti o n  are  als o 
c o nsi dere d r o uti ne t hera p y. St u d y r elate d researc h pr oce d ures s uc h as i m m u ne m o nit ori n g 
a n d c orr elati ve st u dies will be c o vere d b y t he st u d y f u n di n g. 
1. 5 
St u d y Sites  
Kar ma n os Ca n cer I nstit ute, Detr oit MI will be t he c o or di nati n g ce nter a n d will be j oi ne d 
b y partici pati n g sites t o o pe n t his trial . T here will be a b o ut 2- 3 ot her s u bsites w here t his 
st u d y will be o pe n. 
1. 6  
Wit h dr a w als 
S u bjects ma y disc o nti n u e st u d y tr eat me nt or wit h dra w t heir c o nse nt t o p artici pate i n t he 
st u d y at a n y ti me wit h o ut prej u dice. T he i n vesti gat or ma y wit h dra w a s u bject fr o m st u d y 
treat me nt or fr o m t he st u d y if, i n his or her cli nical j u d g me nt, it is i n t he best i nterest of t he 
s u bject or if t he s u bject ca n n ot c o m pl y wit h t he pr ot oc ol.  
I n a d diti o n, a n y of t h e f oll o wi n g c o n diti o ns re q uire wit h dra wal of t he s u bj ect fr o m st u d y 
treat me nt: 
•  A n  A E  or  i nter c urr e nt  ill ness  t hat  i n  t he  o pi ni o n  of  t he  i n vesti gat or  w arra nts  t h e 
s u bject’s wit h dra w al fr o m treat me nt 
•  Necessit y f or tr eat me nt wit h ot h er i n vesti gati o nal dr u g or ot her a ntica n cer me dicati o ns 
pr o hi bite d b y pr ot o c ol 
•  Partici pati o n i n a n ot her cli nical st u d y usi n g a n i n v esti gati o nal a ge nt  
•  Re q uest b y re g ulat or y a ge ncies f or ter mi nati o n of treat me nt of a n i n di vi d ual s u bject or 
all s u bjects u n der t his pr ot oc ol 
•  Se x uall y  acti ve  s u bjects  w h o  ref use  t o  use  me dicall y  acce pte d  barrier  met h o ds  of 
c o ntrace pti o n  (e . g., male  c o n d o m,  or  dia p hra g m  wit h  s per mici dal  gel)  d uri n g  t he 
c o urse of t he st u d y a n d f or  3 m o nt hs f oll o wi n g disc o nti n uati o n of st u d y treat me n t. 
•  I n a bilit y t o t olerate ni v ol u ma b 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 2  
•  Ni v ol u ma b treat me nt del a ys great er t ha n 6 w ee ks  
•  Pr o gr essi ve disease ( P D) as deter mi ne d b y t he i n v esti gat or.  
 
T he  reas o n  f or  st u d y  treat me nt  disc o nti n uati o n  will  be  d oc u me nte d.  F or  s u bjects  w h o 
disc o nti n ue or are wit h dr a w n fr o m st u d y treat me nt, e ver y eff ort m ust be ma de t o u n derta ke 
pr ot oc ol- s pecifi e d  f oll o w-u p  pr oce d ures  a n d  e n d - of-treat me nt  assess me nts,  if  p ossi ble, 
u nless c o nse nt f or f oll o w u p i n t he st u d y is als o wit h dra w n. 
If  a  s u bject  fails  t o  ret ur n  f or  t he  pr ot oc ol-defi ne d  visits,  a n  eff ort  m ust  be  ma de  t o 
deter mi ne  t he  reas o n.  If  t he  s u bject  ca n n ot  be  reac h e d  b y  tele p h o n e,  a  re gistere d  letter 
s h o ul d be se nt t o t he s u bject ( or t he s u bject’s le gal g uar dia n) re q uesti n g c o ntact wit h t he 
cli nic. 
If a s u bject is disc o nti n ue d fr o m st u d y treat me nt beca use of a n A E c o nsi dere d t o be relate d 
t o st u d y treat me nt a n d t h e e v e nt is o n g oi n g 3 0 d a ys after t he last d ose of st u d y treat me nt, 
t he e ve nt m ust be f oll o w e d u ntil res ol uti o n or deter mi nati o n b y t he i n v esti gat or t h at t he 
e ve nt has bec o me sta ble or irre versi ble.  
If a s u bject wit h dra ws c o nse nt t o partici pate i n t he st u d y, t he reas o n f or wit h dra wal will be 
d oc u me nte d, n o st u d y pr oce d ures or assess me nts will be perf or me d, a n d n o f urt her st u d y 
data will be c ollecte d f or t his s u bject,  ot her t ha n t he deter mi nati o n of s ur vi val stat us fr o m 
p u blic rec or ds s u c h as g o ver n me nt vital statistics or o bit uaries.  
2. 0  S T U D Y D E SI G N  
2. 1  
 Ni v ol u m a b a d mi nistr ati o n 
Ni v ol u ma b will be a d mi nistere d at a flat d ose of 2 4 0 m g I V i nf usi o n o ver 3 0 mi n utes +/ - 
1 0  mi n utes  e ver y  2  w ee ks  f or  a  ma xi m u m  of  1 4  d oses  or  6  m o nt hs  d urati o n. N o 
pre me dicati o ns  are  re q uire d.  If  i nf usi o n  reacti o n  occ urs,  t he n  pre m e dicati o ns  s h o ul d  be 
a d de d  wit h  a nti hista mi ne,  n o nster oi dal  a nti -i nfla m mat or y  dr u gs  a n d/ or  ster oi ds.  Ster oi d 
t hera p y s h o ul d be a v oi de d if p ossi ble as pre me dicati o n. T he i nf usi o n s h o ul d be gi ve n o ver 
6 0- 9 0 mi n utes  +/ - 1 0 mi n utes if i nf usi o n reacti o n o cc urs.  
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 3  
2. 2   
        
R a di ati o n T her a p y 
Ra diati o n T hera p y ( R T) nee ds t o be starte d wit hi n +/ - 3 da ys of ni v ol u ma b a d mi nistrati o n. 
Eit her t her a p y ca n be starte d first. R T w o ul d be a d mi nistere d at a t otal d ose of 6 4 G y i n 3 2 
fracti o ns o ver a 6- 8-wee k peri o d i n all patie nts. T h e R T ca n b e d o ne at a n y i nstit uti o n as it 
is  Sta n dar d  of  Care  a n d  n ot  c o vere d  b y  t he  st u d y.  T he d etails  of  ra diati o n  t hera p y  as 
re q uire d p er pr ot oc ol will be se nt t o t he treati n g ra diati o n o nc ol o gist. 
SI M U L A TI O N  
•  Patie nt  s h o ul d  be  i nstr ucte d  t o  v oi d  pri or  t o  si m ulati o n  f or  P T V 4 0  t o  4 6  G y  
ra diati o n c o urse.   Re-si m ulati o n wit h f ull bla d d er p er missi ble f or  P T V 6 4  G y    if 
bla d der  lesi o ns  ca n  be  vis ualize d  a n d  a de q uatel y  treate d  wit h  dail y  I G R T C T 
si m ulati o n  will  be  perf or me d  i n  t he  s u pi ne  p ositi o n  wit h  cra dle  i m m o bilizati o n 
rec o m me n de d.    Use  of  c o ntrast  is  at  t he  discreti o n  of  t he  treati n g  ra diati o n 
o nc ol o gist.   
T E C H NI C A L F A C T O R S  
•  Ra di ot hera p y will be deli vere d via li near accelerat or wit h a mi ni m u m e ner g y of 6 
M V.  
•  Treat me nt will be deli vere d usi n g eit her a t hree di me nsi o nal c o nf or mal a p pr oac h 
(t y picall y 3-4 fiel d) or i nte nsit y m o d ulate d ra di ot hera p y (I M R T) pe r i nstit uti o nal 
prefere nce.  I nte nsit y m o d ulate d ra di ot hera p y is o nl y p er missi ble if p erf or me d wit h 
dail y C B C T or M V C T.  
T R E A T M E N T P L A N NI N G  
•  Caref ul  deli neati o n  of  gr oss  tar get  v ol u me  ( G T V B L A D D E R )  s h o ul d  be  perf or me d 
utilizi n g a vaila ble i ma gi n g a n d bla d d er m a p pi n g t o e nc o m pass all k n o w n areas of 
gr oss disease.  F or patie nts wit h ra di o gra p hicall y or pat h ol o gicall y i n v ol ve d pel vic 
l y m p h n o des, a s e par ate n o dal G T V ( G T VN O D E ) s h o ul d be defi ne d. 
•  T he cli nical tar get v ol u mes ( C T V) will be deli neate d as f oll o ws:  
o  C T V P RI M A R Y = G T V B L A D D E R  
o  C T V B L A D D E R :    T he  e ntire  bla d der,  i ncl u di n g  all  gr oss  i ntra vesic ular  a n d 
e xtra vesic ular diseas e  
o  C T V N O D E  = G T V N O D E  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 4  
o  C T V P E L VI S :  I n cl usi o n of areas of p ot e ntial micr osc o pic s prea d, i ncl u di n g 
e xter nal iliac, i nter nal iliac, peri vesical, pre sacral a n d o bt urat or n o d es, as 
well  as , t he  pr ostate  i n  male  patie nts,  is  at  t he  discreti o n  of  t he  treati n g 
p h ysicia n.    I n  t he  case  of  n o de  p ositi ve  disease,  t he  pel vic  l y m p h  n o des 
s h o ul d be i ncl u de d i n t he i nitial treat me nt fiel d. 
 
•  T he pla n ni n g t ar get v ol u me ( P T V) e x pa nsi o ns are t o be perf or m e d as f oll o ws: 
o  P T V B L A D D E R :  1. 5 c m e x pa nsi o n ar o u n d t he bla d d er C T V 
o  P T V N O D E :  0. 5 t o 1 c m e x pa nsi o n ar o u n d ra di o gra p hicall y or p at h ol o gi call y 
p ositi ve l y m p h n o d e G T V 
o  P T V P E L VI S :  0. 5 t o 1 c m e x pa nsi o n ar o u n d t he electi ve n o dal C T V as defi ne d 
a b o ve 
o  P T V 4 0 t o 4 6  G y  is a B o olea n of P T VP E L VI S   +  P T V N O D E  +  P T V B L A D D E R  +  
P T V 6 4 G y  .   
o  P T V 5 4 t o 6 0 G y is a B o olea n of P T V N O D E  +  P T V  6 4 G y 
o  A dj ust me nt  of  t he  P T V  t o  meet  d ose  c o nstrai nts  is  all o wa ble  at  t he 
discreti o n of t he treati n g ra diati o n o nc ol o gist.  If t he tre at me nt c o urse is t o 
be delivere d  i n m ore t h a n o ne p h ase, it is necess ary t o ge ner ate se p ar ate 
pl a n ni n g t ar get v ol u mes (e. g. P T V B L A D D E R , P T VN O D E , etc) utilizi n g t he P T V 
ex p a nsi o ns as deli ne ate d a b ove.   
•  
T he t otal P T V 6 4 G y d os e deli vere d will be 6 4 G y i n 2 G y per fracti o n.   
o  
6 4 G y R x t o c o ver at least 9 8 % of P T V 6 4 G y   
o 
Mi ni m u m d ose wit hi n P T V 6 4 G y – 9 5 % of pres cri be d d ose a n d f or a v ol u me t hat 
is 0. 0 3 cc   
o 
Ma xi m u m d ose wit hi n t he P T V 6 4 G y – 1 1 0 % of prescri be d d ose a n d f or a v ol u me 
t hat is 0. 0 3 cc 
• 
t he  i nitial  p hase  of  t her a p y  will  c o nsist  of  a  d ose  of  4 0  t o  4 6  G y  deli v ere d  t o 
P T V P E L VI S, P T V N O D E, a n d P T V B L A D D E R.   
• 
T he i nitial c o urse of t hera p y s h o ul d be deli vere d wit h a n e m pt y bla d d er a n d t he 
b o ost s h o ul d be deli vere d wit h a partial/f ull bla d der. 
•  
Ra diati o n t hera p y ma y b e deli vere d i n u p t o t hree p hases: 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 5  
o 
Treat me nt t o t he pel vic l y m p h n o d es is rec o m me n de d; t he i nitial p has e of  t hera p y 
will  c o nsist  of  a  d ose  of  4 0  t o  4 6  G y  d eli vere d  t o  P T V P E L VI S,  P T V N O D E,  a n d 
P T V B L A D D E R.  T h e i nitial c o urse of t hera p y s h o ul d be deli vere d wit h a n e m pt y bla d d er 
o  
T he i nitial p hase of t her a p y will c o nsist of a d ose of P T V 4 0 t o 4 6 G y    
•  
4 0- 4 6 G y R x t o c o ver at least 9 8 % of P T V 4 0 t o 4 6 G y   
• 
Mi ni m u m d ose wit hi n P T V 4 0 t o 4 6 G y  – 9 5 % of prescri be d d os e a n d f or a v ol u me 
t hat is 0. 0 3 cc  
• 
Ma xi m u m d ose wit hi n t he P T V 4 0 t o 4 6 G y  – 1 1 0 % of prescri be d d ose a n d f or a 
v ol u me t hat is 0. 0 3 cc 
o 
F or p atie nts  wit h p ositi ve n o dal disease, a s ec o n d p hase of treat me nt will c o nsist of 
a d ose of 5 4 G y t o 6 0 G y deli vere d t o P T V 5 4 t o 6 0 G y ( B o olea n of P T V N O D E a n d P T V 6 4 
G y.)  
o 
T he fi nal p has e of tr eat m e nt will c o nsist of a t otal d ose of 6 4 G y d eli vere d t o P T V 6 4 
G y.    I n  cas es  w her e  t he  bla d der  G T V  is  rea dil y  discer ni ble  a n d  d ail y  I G R T  wit h  C B 
i ma gi n g is utilize d, a partial bla d der b o ost ( P T V 6 4 G y) f or t he fi nal 5 treat me nts ( 1 0 G y) 
is per missi ble at t he discr eti o n of t he treati n g ra diati o n o nc ol o gist.  
•  T h e t ot al P T V 6 4 G y  d eli v er e d will b e 6 4 G y i n 2 G y p er fr acti o n.   
o  6 4 G y R x t o c o v er at l e ast 9 8 % of P T V 6 4 G y   
o  Mi ni m u m d o s e wit hi n P T V 6 4 G y – 9 5 % of pr e s cri b e d d o s e a n d f or a v ol u m e t h at i s 
0. 0 3 c c   
o  M a xi m u m d o s e wit hi n t h e  P T V 6 4 G y – 1 1 0 % of pr e s cri b e d d o s e a n d f or a v ol u m e 
t h at i s 0. 0 3 c c 
 
•  Ra diati o n t hera p y ma y b e deli vere d i n u p t o t hree p hases: 
o  T h e i niti al c o urs e of t h er a p y s h o ul d b e d eli v er e d wit h a n e m pt y 
bl a d d er  
o  T he i nitial p hase of t hera p y will c o nsist of a d ose of P T V 4 0 t o 4 6  G y    
 
•  4 0 -4 6 G y R x t o c o v er at l e ast 9 8 % of P T V 4 0 t o 4 6  G y   
•  
Mi ni m u m d o s e wit hi n P T V 4 0 t o 4 6  G y  – 9 5 % of pr e s cri b e d d o s e a n d f or a 
v ol u m e t h at i s 0. 0 3 c c  
•  
M a xi m u m d o s e wit hi n t h e P T V 4 0 t o 4 6  G y  – 1 1 0 % of pr e s cri b e d d o s e a n d 
f or a v ol u m e t h at i s 0. 0 3 c c 
 
o  F or patie nts wit h p ositi ve n o dal diseas e, a s ec o n d p hase of treat me nt will 
c o nsist of a d ose of 5 4 G y t o 6 0 G y d eli vere d t o P T V 5 4 t o 6 0 G y  ( B o olea n of 
P T V N O D E  a n d P T V6 4 G y .) 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 6  
o  T he fi nal p hase of treat m e nt will c o nsist of a t otal d ose of 6 4 G y d eli vere d 
t o  P T V6 4  G y .   I n  cases  w here  t he  bl a d der  G T V  is  rea dil y  discer ni ble  a n d 
dail y I G R T wit h C B i ma gi n g is utilize d, a partial bla d der b o ost ( P T V 6 4 G y)  
f or  t he  fi nal  5  treat me nts  ( 1 0  G y)  is  per missi ble  at  t he  discreti o n  of  t he 
treati n g ra di ati o n o nc ol o gist.  I n t his case, t h e  patie nt  ma y  u n der g o  a    re-
si m ulati o n  wit h  a  f ull  bla d der  at  t he  discreti o n  of  t he  treati n g  ra diati o n 
o nc ol o gist. 
C RI TI C A L S T R U C T U R E S  
•  Bla d der,  rect u m  a n d  fe m oral  hea ds  s h o ul d  be  defi ne d  as  or ga ns  at  ris k  ( O A R).  
Rect u m  s h o ul d  be  defi n e d  fr o m  t he  a n orect al  ri n g  ca u d all y  t o  t he  rect osi g m oi d 
j u ncti o n cra niall y.  T he f oll o wi n g d ose c o nstrai nts s h o ul d be met: 
o  Rect u m V 3 0 < 5 0 % 
o  Rect u m V 5 5 < 1 0 % 
o  Fe m oral h ea ds Ma xi m u m d ose li mit < 4 5 G y per R T O G 0 9 2 6 
o  S mall b o wel a n d si g m oi d. V 3 0 < 3 0 %, ma xi m u m d ose li mit 5 0 G y. 
2. 3  
      
St u d y C ale n d ar  
Prest u d y la bs , p h ysical e x a m a n d E K G s h o ul d be d o ne wit hi n 2 8 da ys of d a y 1. Da y 1 
la bs ca n be d o n e wit hi n 3 da ys of da y 1. A wi n d o w of +/- 3 da ys is per mitte d f or t he d a ys 
of ni v ol u ma b t hera p y. 
T esti n g  
Pre  
st u d y 
W k 1  W k 3  W k 5  W k 7  W k  9  W k  1 1  W k 1 3  W ks  
1 5, 1 7,
1 9, 2 1,
2 3, 2 5 
6 , 9 
a n d 
1 2 
mt hs 4 
H a n d P  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
V S, Wt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P S  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
T o x  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
La bs 1  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
T S H, free 
T 3/ T 4  
X  
 
 
 
X  
 
 
X  
 
X  
E C G 2 
X  
 
 
 
 
 
 
 
 
 
C yst osc o p y 7 
X  
 
 
 
 
 
 
X  
 
X  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 7  
Bi o ps y 7 
X  
 
 
 
 
 
 
X  
 
X  
C T/ M RI 3 of 
a b d o me n/ 
pel vis  
X  
 
 
 
 
 
 
X  
 
X  
C X R/  
c hest C T 3 
 
X 
 
 
 
 
 
 
 
 
 
Ni v ol u ma b  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
Visits d uri n g  R T 5 
 
X  
X  
X  
X  
X  
 
 
 
 
P F S/ O S 6 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bi o mar kers 3 
X  
 
 
 
X  
 
 
X  
 
X  
Q O L 
q uesti o n n aires
3 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1.  La bs  i ncl u de:  C B C  diff,  platelets,  Electr ol yt es,  B U N,  creati ni ne,  gl uc ose,  Al b u mi n, 
al kali ne p h os p hatase, t ot al bilir u bi n, calci u m, t otal pr otei n, S G O T, S G P T.  Pre g n a nc y test 
f or w o me n of c hil d beari n g p ote ntial wit hi n 7 da ys of st u d y e nr oll me nt a n d e ver y 6 wee ks 
t hereafter.   
2. E C G at scree ni n g a n d re peat if cli nicall y i n dicate d.  
3. I C F,  Bas eli ne bi o mar kers,  Q O L  q uesti o naires  a n d  a ll  t u m or  e val uati o n/ meas ure me nt 
sca ns m ust be wit hi n 4 2 d a ys pri or t o treat me nt. C T/ M RI of a b d o me n a n d pel vis is re q uire d 
f or pretr eat me nt a n d s u bs e q ue nt t u m or assess me nts. C X R/ C T c hest is re q uire d at scree ni n g 
o nl y t o e val u ate f or m etastases.  Bi o mar k ers s h o ul d be c ollecte d at ti me of P D.  
4.  6,  9  a n d  1 2  m o nt h  visits  will  be  fr o m start  of  t hera p y.  A  wi n d o w  of  +/-  2 8 da ys  is 
per mitte d f or t hese visits.  
5. R T  will  be  d o ne c o nti n u o usl y  dail y  M o n da y  t o  Fri da y  (e x ce pt  f or  wee ke n ds  a n d 
h oli da ys) f or a t otal of 3 2 -3 5 fracti o ns  fr o m wee k 1 t o wee k 8. T he ti me peri o d of 8 wee ks 
is a ma xi m u m d urati o n as t he r a diati o n fracti o ns ca n get dela ye d d ue t o h oli da ys, mac hi ne 
d o w nti me,  patie nt  ca ncellati o n  d ue  t o  tra ns p ortati o n  etc.  D uri n g  R T  patie nts  s h o ul d  be 
e val uate d f or t o xicit y at a mi ni m u m e ver y ot her w ee k.  Ni v ol u ma b s h o ul d be starte d +/- 3 
da ys of first da y of R T.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 8  
6.  After 1 2 m o nt hs t he patie nts will be f oll o we d f or P F S a n d O S e v er y 3 m o nt hs f or a 
ma xi m u m of 5 years.  
7. Scree ni n g c yst osc o p y a n d bi o ps y ca n be perf or me d wit hi n 6 m o nt hs of  da y 1 .  O n st u d y 
c yst osc o p y will be d o ne at wee k 1 3 a n d at m o nt hs 6, 9 a n d 1 2 +/ - 2 8 da ys . Bi o psies will 
be  re q uir e d  at  wee k  1 3,  m o nt h  6  a n d  m o nt h  1 2  +/ -  2 8 da ys . M o nt h  9  bi o psies  d o ne  if 
cli nicall y i n dicat e d.  
T he 6, 9 a n d 1 2 m o nt h ti me p oi nts f or c yst osc o p y a n d bi o ps y (if nee de d) are t o be f oll o we d 
f or patie nts wit h n o e/ o mali g na n c y i n t he blad der a n d n o e/ o metastas es.  
F or p atie nts re q uiri n g i ntr a -vesical t her a p y f or resi d ual/ ne w T 1 or CI S i n bla d der, treat me nt 
will pr ocee d as p er sta n dar d of care a n d n o s pecifie d ti me p oi nts will be f oll o we d. H o we v er,  
res ults of c yst osc o p y a n d bi o ps y s h o ul d c o nti n ue t o be c ollecte d. 
 
3. 0  S T U D Y P O P U L A TI O N  
3. 1   
  I ncl usi o n Criteri a 
1)  L ocalize d ur ot helial ca ncer of bla d der wit h  pres e n ce of tra nsiti o nal cell carci n o ma 
( T C C) c o m p o ne nt. Mi x e d hist ol o gies are all o we d. 
2)  Cli nical or pat h ol o gic sta ge T 2 – T 4 disease  i ncl u di n g T 4a a n d 4 b  if feasi ble t o treat 
wit h ra diati o n t hera p y.  
3)  L oc ore gi o nal  l y m p h  n o de  metastases  are  per mitte d  b ut  patie nts  wit h  dista nt 
metastases ar e i neli gi ble.  I ma gi n g t o e val uat e f or dista nt metastases s h o ul d c o nsist 
of a mi ni m u m of C T/ M RI of a b d o me n/ pel vis  or C T ur o gra m a n d a C X R or C T 
c hest. Patie nts f or w hic h t here is cli nical s us pici o n or s y m pt o ms of b o ne metastasis 
s h o ul d ha ve a b o ne sca n c o m plete d t o r ule o ut m etastatic disease pri or t o e nr oll me nt 
o n st u d y. 
4)  A greea ble t o c o nsi der ra diati o n t hera p y ( R T) f or t h e ur ot helial ca ncer: p atie nts ha ve 
t o be e val uate d b y a ra di ati o n o nc ol o gist a n d dee me d t o be ca n di dat es f or R T. 
5)  T he patie nts m ust n ot be ca n di dates f or c he m ot h era p y  d ue t o at least o ne of t he 
f oll o wi n g r eas o ns: 
a. Perf or ma nce stat us of 2  
b.  Creati ni ne  cle ara nce <  6 0  ml/ mi n  as  calc ulate d  b y  t he  C oc kcr oft -G a ult 
f or m ula. 
c. Car diac  disease  s u c h  as  N Y H A  Class  III  or  I V  heart  fail ure  or  car diac 
isc he mia wit hi n t he last 1 2 m o nt hs, gra d e 2 or greater n e ur o pat h y, or ot h er 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
1 9  
c o m or bi dities  base d  o n  w hic h  patie nt  is  n ot  c o nsi dere d  a  ca n di date  f or 
c he m ot hera p y.  
6)  A de q uate li ver f u n cti o n  wit h al kali ne p h os p hatas e, A S T a n d A L T < 3 x u p per li mit 
of n or mal a n d bilir u bi n < 1. 5 x U L N  
7)  A de q uate B o n e marr o w f u ncti o n defi ne d as a bs ol ute ne utr o p hil c o u nt  > 1 5 0 0/ m m3 
a n d he m o gl o bi n > 9 g/ d L  a n d platelets > 1 0 0 K / m m3. 
8)  P S of 0 - 2 b y Z u br o d s c or e 
9)  Lif e e x pecta nc y of 1 2 m o nt hs 
1 0)  A ge > 1 8 years of a ge 
1 1)  Willi n g ness t o si g n i nf or me d c o nse nt 
1 2)  Patie nts ca n n ot ha ve acti ve a ut oi m m u ne disease or i m m u n os u p pressi ve  c o n diti o ns. 
1 3)  Ser u m creati ni ne < 1. 5 X i nstit uti o nal U L N or creati ni ne cleara nce > 4 0 ml/ mi n as 
calc ulate d b y t he C o c kcr oft -Ga ult f or m ula . 
1 4)  I n  f e males  wit h  c hil d beari n g  p ote ntial,  or  me n  wit h  part ners  of  c hil d  beari n g 
p ote ntial, w illi n g ness t o use a de q uate c o ntrace pti o n d uri n g t he treat me nt peri o d a n d 
for a mi ni m u m d urati o n of 5 m o nt hs after last d os e of ni v ol u ma b. 
1 5)  Ma xi mal t u m or resecti o n has bee n perf or m e d  as feasi ble. 
3. 2  
 E xcl usi o n Criteri a  
A s u bject w h o meets a n y of t he f oll o wi n g criteri a is i neli gi ble f or t he st u d y:  
1)  T he  s u bject  has  recei v e d  c yt ot o xic c he m ot hera p y  (i ncl u di n g  i n v esti gati o nal 
c yt ot o xic  c he m ot hera p y)  or  bi ol o gic  a ge nts  (e . g., cyt o ki nes  or  a nti b o dies) f or 
ur ot helial ca n cer wit hi n 4  wee ks, or i ntra vesical B C G wit hi n 6  wee ks of t he first 
d ose of st u d y tr eat me nt. 
2)  Pri or treat me nt wit h a n y P D- 1 or P D L - 1 i n hi bit or 
3)  T he s u bject has r ecei ve d t hera pe utic ra diati o n: 
a. t o t he bla d der/ pr ostate/rect u m pel vis  
b.  t o a n y ot her site(s) wit hi n 2 8 da ys of t he first d os e of st u d y treat me nt 
4)  O bstr ucti ve re n al fail ure t hat is n ot relie ve d wit h ste nts or ne p hr ost o m y t u b e/s. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 0  
5)  T he  s u bject  has  recei ve d  a n y  ot her  t y pe  of  i n vesti gati o nal  a ge nt  wit hi n  2 8  da ys 
bef ore t h e first d ose of st u d y treat me nt.  
6)  Ster oi d d oses gr eater t ha n a n e q ui vale nt of pre d nis o ne 1 0 m g d ail y  
7)  U nc o ntr olle d he mat uri a 
8)  T he  s u bject  has  u nc o ntr olle d, si g nifica nt  i nterc urre nt  or  rece nt  ill ness  i ncl u di n g, 
b ut n ot li mite d t o, t he f oll o wi n g c o n diti o ns: 
a. Car di o vasc ular dis or d ers s uc h as u nc o ntr olle d arr h yt h mias or u n c o ntr olle d 
c o n gesti ve heart fail ur e.  
b.  Gastr oi ntesti nal dis or ders partic ularl y t h ose ass ociate d wit h a hi g h ris k of 
perf or ati o n or fist ula f or mati o n i ncl u di n g: 
i. A n y of t he f oll o wi n g at t he ti me of scree ni n g  
1.  acti ve pe ptic ulcer diseas e,  
2.  acti ve i nfla m mat or y  b o wel  disease  (i ncl u di n g ulcerati ve 
c olitis  a n d  Cr o h n’s  dis ease) ,  di vertic ulitis,  c h olec ystitis, 
s y m pt o matic c h ola n gitis or a p pe n dicitis 
ii. A n y of t h e f oll o wi n g wit hi n 6 m o nt hs bef ore t he first d ose of st u d y 
treat me nt: 
1.   hist or y of a b d o mi nal fist ula  
2.  B o wel perf orati o n  
9)  T he s u bject has a pre vi o usl y i d e ntifie d aller g y or h y pers e nsiti vit y t o c o m p o ne nts 
of t h e st u d y tr eat me nt f or m ulati o n.  
1 0)  T he s u bject is u na ble or u n willi n g t o a bi de b y t he st u d y pr ot oc ol or c o o p erate f ull y 
wit h t he i n vesti gat or or d esi g nee.  
1 1)  Prese nce of a n ot her i n vasi ve mali g na n c y , w hic h re q uire d s yste mic t hera p y wit hi n 
1 2  m o nt hs  of  pr ot oc ol  e nr oll me nt,  e x ce pt f or  resecte d  s ki n  ca ncers  or  pr ostate 
ca ncer t hat is i n re missi o n.  
1 2)  Pre g n a nt or n ursi n g w o m e n 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 1  
1 3)  Patie nt is a ca n di date f or ra dical c ystect o m y as a p ote ntiall y c urati ve o pti o n.  T he 
patie nt ma y n ot be a ca n di date f or ra dical c ystect o m y d u e t o a n y of t he f oll o wi n g 
reas o ns: c o m or bi dities, p atie nt prefere n ce, or p h ysicia n discreti o n. 
1 4)  Patie nts  wit h  i n herite d  s y n dr o mes  ass ociate d  wit h  h y pers e nsiti vit y  t o  i o nizi n g 
ra diati o n (e. g., At a xia-Tela n giectasia, Nij me ge n Brea ka ge S y n dr o me ) 
 
4. 0  S T U D Y A S S E S S M E N T S  
4. 1 Pre -Tre at me nt Peri o d  
D uri n g t he Pre -Treat me nt Peri o d, s u bjects are c o nse nte d a n d q u alifie d (scree ne d) f or t h e 
st u d y.  I nf or m e d  c o nse nt  m ust  be  o btai ne d  bef ore  i nitiati o n  of  a n y  cli nical  scree ni n g 
pr oce d ur e t hat is perf or m e d s olel y f or t he p ur p os e of det er mi ni n g eli gi bilit y f or t his st u d y. 
E val uati o ns perf or me d as part of r o uti ne care bef ore i nf or me d c o ns e nt ca n be c o nsi dere d 
as scr ee ni n g e v al uati o ns if d o ne wit hi n t he d efi ne d scree ni n g peri o d, a n d if per mitte d b y 
t he  site’s  i nstit uti o nal  re vie w  b oar d  (I R B)/  et hi cs  c o m mittee  ( E C)  p olicies.  I nf or m e d 
c o nse nt ma y be o btai ne d wit hi n 4 2 da ys pri or t o first d ose of st u d y treat me nt. At i nf or me d 
c o nse nt, s u bjects will be assi g ne d a s u bject i de ntifier at ti me of re gistrati o n .  
F or  eac h  s u bject,  t he  Pre -Treat me nt  Pe ri o d  e n ds  u p o n  recei pt  of  t he  first  d ose  of  st u d y 
treat me nt or fi nal d eter mi nati o n t hat t he s u bject is i neli gi ble f or t h e st u d y. 
4. 2  
St u d y Tre at me nt Peri o d   
Pre g n a nc y  T est: I n  W o me n  of  c hil d  Beari n g  P ote ntial  (W O C B P ) pri or  t o  d osi n g 
ni v ol u ma b.  A  ser u m  or  uri ne  pre g n a nc y  testi n g  is  re q uire d  wit hi n 7  da ys  of  st u d y 
e nr oll me nt,  t he n  e ver y  6  wee ks.  [ m ore  fre q ue ntl y  if  re q uire d  b y  l ocal  sta n dar d].  After 
disc o nti n uati o n fr o m ni v ol u ma b t hese s h o ul d b e re peat e d at a p pr o xi matel y 3 0 da ys a n d 
a p pr o xi matel y 7 0 da ys [ or m ore fr e q ue ntl y if re q uire d b y l ocal sta n d ar d]. 
La b orat or y testi n g pri or t o eac h d ose: Wit hi n 7 2 hrs pri or t o re -d osi n g t o i ncl u de C B C w/ 
differe ntial, L F Ts ( A L T, A S T, t otal bilir u bi n, al kali ne p h os p hatase), B U N or s er u m urea 
le vel,  creati ni ne,  Ca,  Na,  K,  Cl,  Gl uc ose,  T S H  ( wit h  Free  T 4  a n d  Free  T 3).  T h yr oi d 
f u ncti o n  testi n g  s h o ul d  be  d o ne  at  wee ks  7  a n d  1 3,  a n d  t he n  6  a n d  1 2  m o nt hs  p ost 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 2  
e nr oll me nt. If t he s u bject is u na ble t o ha ve a st u d y assess me nt ta ke n wit hi n t he defi ne d 
ti me wi n d o w d ue t o a n e ve nt o utsi de of his or h er c o ntr ol (e. g., cli nic cl os ure, pers o nal 
e mer ge n c y, i ncle me nt w eat her, v acati o n), t he ass ess me nt s h o ul d be perf or me d as cl ose as 
p ossi ble t o t he re q uire d s c he d ule.  
S u bjects s h o ul d be i nstr u cte d t o i n f or m t he i n v esti gat or of a n y A Es. S u bjects e x perie nci n g 
dizzi ness,  slee pi ness,  or  ot her  s y m pt o ms  t hat  c o ul d  i nfl ue nce  alert ness  or  c o or di nati o n 
s h o ul d be a d vise d n ot t o dri ve or o per ate ot her hea v y m ac hi ner y. 
S u bjects  ma y  r ecei ve  st u d y  treat me nt  u ntil  t he earlier  of  P D  or  u nacce pta ble  t o xicit y. 
Re g ular  t u m or  assess me nts i ncl u di n g  c yst osc o pi es  a n d  bi o psies s h o ul d  be  perf or me d 
acc or di n g t o t he pr ot oc ol g ui deli nes if patie nt disc o nti n ues st u d y t h era p y d ue t o t o xicities 
a n d if feasi ble per t heir me dical stat us.  
T he Treat me nt Peri o d e n ds w he n a s u bject recei ves his or her last d os e of st u d y treat me nt; 
t he s u bject t he n e nters t he P ost-Treat me nt Peri o d . 
4. 3  
P ost -Tre at me nt Peri o d  
S u bjects will be f oll o we d per pr ot oc ol g ui deli nes. If patie nts ha ve resi d ual or pr o gres si ve 
disease  n ote d  d uri n g  e val uati o n  i n  t he  first  1 2  m o nt hs,  re q uiri n g  ot her  t hera p e utic 
m o dalities,  t he n  t he y  will  e nter  f oll o w  u p  p hase.    A d diti o nal  f oll o w -u p  will  occ ur  f or 
s u bjects wit h A Es relate d t o st u d y treat me nt t hat are o n g oi n g at e ver y visit, a n d f or s u bjects 
wit h S A Es relate d t o st u d y treat me nt t hat occ ur aft er t he ti me of t his visit.  
4. 4  
L a b or at or y Assess me nts  
L ocal la b orat ories will perf or m all la b orat or y tests. Bl o o d sa m ples f or sta n dar d he mat ol o g y 
a n d  ser u m  c he mistr y will be d o ne usi n g sta n dar d pr oce d ures. S ur veilla nce c yst osc o pies 
a n d bi o psies as i n dicate d are rec o m me n de d e ver y 3 m o nt hs d uri n g t he first 1 2 m o nt hs after 
starti n g st u d y t her a p y. 
A c yst osc o p y a n d bi o ps y s h o ul d be perf or me d  at a n y ti me pri or t o st u d y e ntr y, 1 3 w ee ks , 
6 m o nt hs, a n d 1 2 m o nt hs after start of st u d y treat me nt. At 9 m o nt hs c yst osc o p y nee ds t o 
be d o ne a n d bi o psies are d o ne if cli nicall y i n dicat e d  a n d se n d arc hi val sli d es if a vaila ble . 
T hese  ass ess me nts  ar e  c o nsi dere d  sta n d ar d  of  care  a n d  ma y be  dela ye d  +/ -2 8  da ys  per 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 3  
i ns ura nce  re q uir e me nts. Arc hi val  sli des fr o m  pre-t hera p y bi o ps y  a n d  fr o m  wee k  1 3,  6 
m o nt hs, a n d 1 2 m o nt hs nee d t o be se nt t o: 
J ulie B oer n er, P h. D.  
Kar ma n os Ca n cer I nstit ute  
4 1 0 0 J o h n R, Detr oit MI 4 8 2 0 1 
C orrelati ve Scie nces La b R m 8 0 8  
Tel # 3 1 3- 5 7 6- 8 3 5 1 
E- mail: b oer nerj @ k ar ma n os. or g  
Karri Star k, M. S.  
Kar ma n os Ca n cer I nstit ute  
4 1 0 0 J o h n R, Detr oit MI 4 8 2 0 1 
C orrelati ve Scie nces La b R m 8 0 8  
Tel # 3 1 3- 5 7 6- 8 2 4 8 
E mail:  star k ka @ kar ma n os. or g 
 
4. 5 
T u m or Assess me nt  
Res p o nse criteri a:  
F or meas ur a ble disease i n t he bla d der a n d/ or l y m p h n o de/s , R E CI S T criteri a 1. 1 will be use d 
[ 1 4].  
T H E R E CI S T 1. 1 C RI T E RI A WI T H U NI DI M E N SI O N A L M E A S U R E M E N T A R E 
T O B E U S E D F O R M E A S U R A B L E DI S E A S E  R E S P O N S E E V A L U A TI O N  
 Met h o ds of Assess me nt  
T he  sa me  met h o d  of  assess me nt  a n d  t he  sa m e  tec h ni q u e  s h o ul d  be  use d  t o 
c haracterize eac h i de ntifi e d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w - u p. 
C T  is  t he  best  c urre ntl y  a vaila ble  a n d  re pr o d u ci ble  met h o d  t o  meas ure  lesi o ns 
selecte d f or res p o nse ass ess me nt. M RI is als o acce pta ble i n certai n sit uati o ns (e. g., 
f or  b o d y  s ca ns  b ut  n ot  f or  l u n g). Lesi o ns  o n  a  c hest  X -ra y  m a y  be  c o nsi dere d 
meas ura ble  lesi o ns  if  t h e y  ar e  cl earl y  d efi ne d  a n d  s urr o u n de d  b y  aerate d l u n g. 
H o we ver, C T is prefera bl e. 
 B aseli ne Dise ase Assess me nt  
All baseli ne e val uati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o t he be gi n ni n g 
of treat me nt a n d n e ver m ore t ha n 4 2 da ys b ef ore t he be gi n ni n g of t he treat me nt. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 4  
Meas ura ble lesi o ns m ust be acc uratel y meas ure d i n at least o n e di me nsi o n (l o n gest 
dia meter i n t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:  
•  1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m; w he n 
C T sca ns ha ve slice t hic k ness > 5 m m, t he mi ni m u m size s h o ul d be t wice 
t he slice t hic k ness). 
•  Mali g na nt  l y m p h  n o des:  T o  be  c o nsi dere d  pat h ol o gicall y  e nlar ge d  a n d  
meas ura ble, a l y m p h n o d e m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y 
C T sca n ( C T sca n slice t hic k ness is rec o m me n de d t o be n o greater t ha n 5 
m m). At  baseli ne a n d i n f oll o w -u p, o nl y t he s h ort a xis will be meas ure d a n d 
f oll o we d. 
N o n -me as ur a ble lesi o ns  
N o n -meas ur a ble  lesi o ns  are  all  ot her  lesi o ns,  i ncl u di n g  s mall  lesi o ns  (l o n gest 
dia meter < 1 0 m m or pat h ol o gical l y m p h n o d es wit h 1 0 t o < 1 5 m m s h ort a xis), as 
well as tr ul y n o n- meas ur a ble lesi o ns.  
T ar get Lesi o ns  
•  All m e as ur a bl e l esi o ns u p t o a m a xi m u m of t w o l esi o ns p er or g a n a n d 
fi v e l esi o ns i n t ot al, r e pr es e nt ati v e of all i n v ol v e d or g a ns, s h o ul d b e 
i d e ntifi e d as t ar g et l esi o ns a n d r ec or d e d a n d m e as ur e d at b as eli n e. 
•  Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he 
l o n gest dia met er) a n d be re prese ntati ve of all i n v ol ve d or ga ns, as well as 
t heir s uita bilit y f or r e pr o d uci ble re peate d meas ure me nts. 
•  All meas ure me nts s h o ul d be rec or de d i n metric n otati o n usi n g cali pers if 
cli nicall y assesse d. A s u m of t he di a meters (l o n gest f or n o n -n o dal l esi o ns, 
s h ort a xis f or n o dal lesi o ns) f or all tar get lesi o ns. 
N o n -t ar get Lesi o ns 
All  lesi o ns  ( or  sites  of  disease)  n ot  i de ntifie d  as  tar get  lesi o ns, 
i ncl u di n g 
pat h ol o gical l y m p h n o des a n d all n o n -meas ura ble lesi o ns, s h o ul d be i d e ntifie d as 
n o n- tar get lesi o ns a n d be rec or de d at bas eli ne. Meas ure m e nts of t hese lesi o ns are 
n ot  re q uire d  a n d  t h e y  s h o ul d  be  f oll o we d  as  ‘ prese nt’,  ‘a bse nt’  or  i n  rare  cases, 
‘ u ne q ui v ocal pr o gressi o n’. 
E v al u ati o n of t ar get lesi o ns 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 5  
C o m plete Res p o nse ( C R): 
Disa p pear a nce of all tar get lesi o ns. A n y pat h ol o gi cal l y m p h n o des ( w het her tar get 
or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
Partial Res p o nse ( P R):  
At least a 3 0 % decreas e i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere n ce 
t he baseli ne s u m of dia m eters. 
Pr o gr essi ve Diseas e ( P D):  
At least a 2 0 % i ncreas e i n t he s u m of dia m eters of t ar get lesi o ns, ta ki n g as refere n ce 
t he s mallest s u m o n st u d y (t his ma y incl u d e t he b aseli ne s u m). T he s u m m ust als o 
de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m.  
Sta ble Disease ( S D):  
Neit her s ufficie nt s hri n k a ge t o q ualif y f or P R n or s ufficie nt i ncrease t o q u alif y f or 
P D.  
4. 6     
Res p o nse E v al u a ble P atie nts 
All patie nts re gistere d o n t he pr ot oc ol a n d c o m pleti n g a mi ni m u m of o ne d ose of ni v ol u ma b  
t hera p y f oll o wed b y cli n ical or r a di ol o gic assess m e nt of disease stat us.  
 
4. 7     
T o xicit y- E v al u a ble p atie nts 
All  patie nts  re gistere d  o n  t he  pr ot oc ol  a n d  starti n g  t hera p y  wit h   ni v ol u ma b will  be 
c o nsi dere d t o xicit y e v al ua ble.  
 
4. 8  
      Met ast asis -Free S ur vi v al ( M F S)   
T he ti me fr o m start of t h era p y t o t he a p p eara nce of metastases or ca ncer rel ate d deat h. 
 4. 9  
      Pr o g ressi o n -Free S ur vi v al ( P F S)  
P F S  will  be  meas ure d  fr o m  treat me nt  start dat e  t o  date  of  first  d oc u me nte d  disease 
rela pse/pr o gressi o n, or d eat h fr o m  ur ot helial  ca n cer  w hic h e ver  o cc urs  first.     If patie nts 
ha ve  r esi d ual    i n vasi ve  disease  n ote d  at  c yst osc o p y  a n d  bi o ps y p ost  t hera p y  t he y  are 
dee me d  t o  ha ve  disease  pr o gr essi o n  at  t he  ti me  of  t he  pr oce d ure.     After  treat me nt  is 
disc o nti n ue d /c o m plete d, patie nts  will  be  f oll o we d  e ver y  3  m o nt hs  f or  pr o gressi o n  a n d 
s ur vi val f or a ma xi m u m of 5 years. 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 6  
 
 4. 1 0        O ver all S ur vi v al ( O S)  
O S will be meas ure d fr o m treat me nt start date t o deat h or last f oll o w u p.   After treat me nt 
is disc o nti n ue d f or a n y r eas o n, p atie nts will be f oll o we d e ver y 3 m o nt hs f or pr o gressi o n 
a n d s ur vi val f or a ma xi m u m of 5 years. 
5. 0   A D V E R S E E V E N T R E P O R TI N G  
5. 1  
A d verse E ve nts a n d L a b or at or y A b n or m alities 
T o xicit y  will  b e  gr a de d  per  C T C A E  versi o n 4 . 03 .  A n  A E  is  a n y  u nt o war d  me di cal 
occ urr e nce i n a patie nt or cli nical i n vesti gati o n s u bject w h o has b ee n e nr olle d i n a cli nical 
st u d y a n d w h o ma y ha ve bee n gi v e n a n i n vesti gati o nal pr o d uct, re gar dl ess of w het her or 
n ot  t he  e ve nt  is  assesse d  as  relate d  t o  t he  st u d y  treat me nt.  A n  A E  ca n  t h eref ore  be  a n y 
u nfa v ora bl e a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or 
disease  te m p orall y  ass ociate d  wit h  t he  use  of  a n  i n vest i gati o nal  pr o d uct,  re gar dless  of 
w het her or n ot t he e ve nt is assesse d as relate d t o t he i n vesti gati o nal pr o d uct. Pre -e xisti n g 
me dical  c o n diti o ns  t hat  w orse n  d uri n g  a  st u d y  s h o ul d  be  rec or d e d  as  A Es.  A b n or mal 
la b orat or y val ues, electr ocar di o gr a m ( E C G) fi n di n gs, or vital si g ns are t o be rec or d e d as 
A Es if t he y  re q uire cli nical i nter ve nti o n or res ults i n c ha n ges i n st u d y t hera p y. All u nt o war d 
e ve nts t hat are t h o u g ht t o be pr o b a bl y/ d efi nitel y treat me nt rel ate d s h o ul d be f oll o we d u ntil 
res ol uti o n e ve n after st u d y tr eat me nt has bee n disc o nti n ue d. T his re q uire me nt i ncl u des A Es 
fr o m u nsc he d ule d as well as sc he d ule d visits. 
As s o o n as a n i n vesti gat or bec o mes a ware of a n A E t hat meets t he defi niti o n of ‘seri o us,’ 
t his s h o ul d be d oc u me nte d t o t he e xte nt t hat i nf or mati on is a vaila ble.  
•  T his  re p ort  m ust  be  s u b mitte d  b y  t he  st u d y  site  t o  Kar ma n os  Ca ncer  I nstit ute  a n d 
Brist ol -M yers S q ui b b wit hi n 2 4  h o urs via a Me d watc h f or m , e ve n if it is n ot felt t o be 
dr u g relate d.  
•  E mail: vais ha m n @ kar ma n os. or g  or dic k o w b @ kar ma n os. or g  
•  T he i n vesti gat or a gr ees t o pr o vi de s u p ple m e ntar y i nf or mati o n re q ueste d b y t h e PI or 
des i g nee. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 7  
•  Pre g n a nc y, alt h o u g h n ot itself a n S A E, s h o ul d als o be re p orte d o n a Me d watc h f or m 
a n d  be  f oll o we d  u p  t o  deter mi ne  o utc o me,  i n cl u di n g  s p o nta ne o us  or  v ol u ntar y 
ter mi nati o n,  details  of  birt h,  a n d  t he  prese nce  or  a bse nce  of  a n y  birt h  defects  or 
c o n ge nit al a b n or malities.  
5. 2 
L oc al I R B re p orti n g   
Re p orti n g is als o re q uire d per t he l ocal I R B re p orti n g pr oce d ures f or eac h site. 
5. 3 
A d verse e v e nt re p orti n g t o B M S   
•  All treat me nt  relate d or  u nrelate d  Seri o us  A d verse  E ve nts  ( S A Es)  t hat  occ ur 
f oll o wi n g t he s u bject’s writte n c o nse nt t o partici pate i n t he st u d y t hr o u g h 1 0 0 da ys 
of disc o nti n uati o n of d osi n g m ust be re p ort e d t o  Kar ma n os Ca ncer  I nstit ute a n d 
B M S W orl d wi de Safet y.  
•  F or s u bjects c o nse nte d a n d ne ver treate d wit h st u d y dr u g, S A Es s h o ul d be c ollecte d 
f or 3 0 da ys fr o m t he date of c o nse nt. 
•  If t he B M S safet y a d dr ess is n ot i ncl u de d i n t he pr ot oc ol d oc u me nt (e. g. m ultice nter 
st u dies w here e ve nts are r e p orte d ce ntrall y), t he pr oce d ure f or s afet y re p orti ng m ust 
be  re vi e we d/a p pr o ve d  b y  t he  B M S  Pr ot oc ol  Ma na ger.    Pr oce d ures  f or  s uc h 
re p orti n g m ust be re vie w e d a n d a p pr o v e d b y B M S pri or t o st u d y acti vati o n. 
•  T he Me d w atc h/ B M S f or m s h o ul d be us e d t o re p ort S A Es.  If t he B M S f or m ca n n ot 
be use d, a n ot her acce pta ble  f or m (i.e. CI O M S or Me d watc h) m ust be re vie we d a n d 
a p pr o ve d b y B M S.  T he B M S pr ot oc ol I D n u m ber m ust be i ncl u d e d o n w hate ver 
f or m is s u b mitte d b y t he S p o ns or/I n vesti gat or. 
•  F oll o wi n g  t he  s u bj ect’s  writte n  c o nse nt  t o  partici pate  i n  t he  st u d y,  all  S A Es, 
w het her relat e d or n ot r el ate d t o st u d y dr u g, are c ollecte d, i ncl u di n g t h ose t h o u g ht 
t o be ass ociate d wit h pr ot oc ol-s pecifie d pr oce d ures. T he i n vesti gat or s h o ul d re p ort 
a n y S A E occ urri n g after t hese ti me peri o ds t hat is belie ve d t o be relate d t o st u d y 
dr u g or pr ot o c ol- s pecifi e d pr oce d ure. F or dr u gs wit h p ote ntial f or dela ye d S A Es 
(e. g.,  d ela ye d  e x creti o n  of  t he  p are nt  or  acti ve  meta b olites),  a  l o n ger  f oll o w- u p 
peri o d ma y be w arr a nte d t o all o w c ollecti o n of t h ese S A Es, la b orat or y tests, a n d 
ot her assess me nts.  
•  F o r  st u dies  wit h  l o n g-t er m  f oll o w-u p  peri o ds  i n  w hic h  safet y  d ata  are  bei n g 
re p orte d, i ncl u d e t he ti mi n g of S A E c ollecti o n  
•  I n acc or d a nce wit h l ocal re g ulati o ns, B M S will n otif y i n v esti gat ors of all re p orte d 
S A Es  t hat  are  s us pecte d  (relate d  t o  t he  i n vesti gat i o nal  pr o d uct)  a n d  u ne x pecte d 
(i.e., n ot pre vi o usl y d escri be d i n t he  I B).  I n  t he  E ur o pea n U ni o n ( E U), a n e ve nt 
meeti n g t hese criteri a is t er me d a S us pect e d, U n e x pecte d Seri o us A d verse R eacti o n 
( S U S A R).  I n vesti gat or  n otificati o n  of  t hes e  e v e nts  will  be  i n  the  f or m  of  a n 
e x pe dite d safet y re p ort ( E S R).  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 8  
o  Ot her i m p orta nt fi n di n gs w hic h ma y be re p orte d b y t h e as a n E S R i ncl u de: 
i ncreas e d  fre q u e nc y  of  a  cli nicall y  si g nifica nt  e x pecte d  S A E,  a n  S A E 
c o nsi dere d ass o ciate d wit h st u d y pr oce d ures t hat c o ul d m o dif y t he c o n d uct 
of t he st u d y, lac k of efficac y t hat p os es si g nifi ca nt hazar d t o st u d y s u bjects, 
cli nicall y si g nifica nt safet y fi n di n g fr o m a n o ncli nical (e g, a ni mal) st u d y, 
i m p orta nt  safet y  rec o m me n dati o ns  fr o m  a  st u d y  data  m o nit ori n g 
c o m mittee, or s p o ns or decisi o n t o e n d or te m p oraril y halt a cli nical st u d y 
f or saf et y reas o ns. 
o  U p o n recei vi n g a n E S R fr o m B M S, t he i n vesti gat or m ust re vie w a n d retai n 
t he E S R wit h t he I B. W here re q uire d b y l o cal re g ulati o ns or w he n t here is 
a  ce ntr al  I R B/I E C  f or  t he  st u d y,  t he  s p o ns or  will  s u b mit  t he  E S R  t o  t he 
a p pr o priate I R B/I E C. T h e i n vesti gat or a n d I R B/I E C will deter mi ne if t he 
i nf or me d  c o nse nt  r e q uires  re visi o n.  T he  i n vesti gat or  s h o ul d  als o  c o m pl y 
wit h t he I R B/I E C pr oce d ures f or re p orti n g a n y ot h er safet y i nf or mati o n.  
o  I n  a d diti o n,  s us pecte d  seri o us  a d vers e  reacti o ns  ( w het her  e x pecte d  or 
u ne x pecte d)  s hall  be  re p orte d  b y  B M S  t o  t he  rel e va nt  c o m pete nt  h ealt h 
a ut h orities i n all c o ncer n e d c o u ntries acc or di n g t o l ocal re g ulati o ns (eit her 
as e x pe dite d a n d/ or i n a g gre gate re p orts). 
5. 4  
  
S eri o us A d verse E ve nt C ollecti o n a n d Re p orti n g  
F oll o wi n g  t h e  s u bject’s  writte n  c o nse nt  t o  p artici pate  i n  t he  st u d y,  all  S A Es,  w het her 
relate d  or  n ot  r elate d  t o  st u d y  dr u g,  m ust  be  c ollecte d,  i ncl u di n g  t h ose  t h o u g ht  t o  be 
ass ociate d  wit h  pr ot oc ol -s pecifie d  pr oce d ures.  All  S A Es  m ust  be  c ollect e d  t hat  occ ur 
wit hi n 1 0 0 da ys of disc o nti n uati o n of d osi n g.  
All S A Es m ust be c ollecte d t hat occ ur d uri n g t h e scree ni n g peri o d.  If a p plica ble, S A Es 
m ust be c ollecte d t hat r elate t o a n y pr ot oc ol -s p ecifie d  pr oce d ure  (e. g., a  f oll o w-u p s ki n 
bi o ps y).  T he i n vesti gat or s h o ul d re p ort a n y S A E t hat occ urs after t hes e ti me peri o ds t hat 
is belie ve d t o be rel ate d t o st u d y dr u g or pr ot oc ol-s pecifie d pr o ce d ure.  
S A Es, w het her relat e d or n ot relate d t o st u d y dr u g, a n d pre g na n cies m ust b e re p orte d t o 
Kar ma n os  C a ncer  I nstit ute  a n d  B M S  wit hi n  2 4  h o urs.  S A Es  m ust  b e  rec or d e d  o n  
Me d watc h f or m; pre g na n cies als o o n a Me d watc h f or m . 
S A E E m ail A d dress:  W orl d wi de. Safet y @ B M S.c o m 
S A E F acsi mile N u m ber:  6 0 9- 8 1 8- 3 8 0 4 
If  o nl y  li mite d  i nf or mati o n  is  i nitiall y  a v aila ble,  f oll o w-u p  re p orts  are  re q uire d.  ( N ote: 
F oll o w- u p S A E re p orts s h o ul d i ncl u de t he sa me i n vesti gat or t er m(s) i nitiall y re p orte d.)  
If  a n  o n g oi n g  S A E  c h a n ges  i n  its  i nte nsit y  or  relati o ns hi p  t o  st u d y  dr u g  or  if  ne w 
i nf or mati o n bec o mes a vaila ble, a f oll o w-u p S A E re p ort s h o ul d be se nt wit hi n 2 4 h o urs t o 
t he  B M S  ( or  d esi g n ee)  usi n g  t he  sa m e  pr oce d ure  use d  f or  tra ns mitti n g  t he  i nitial  S A E 
re p ort.  
All S A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
2 9  
T he S p o ns or/I n vesti gat or will e ns ure t ha t all S A Es i n t he cli nical data base are re p orte d t o 
B M S a n d a n y a p plica ble healt h a ut h orit y d uri n g t he c o n d uct of t he st u d y i ncl u di n g peri o dic 
rec o nciliati o n.  
 
F or  st u dies  c o n d ucte d  u n der  a n  I n vesti g at or  I N D  i n  t he  U S  i ncl u de  t he  f oll o wi n g 
ti meli nes or text:  
F or st u dies c o n d ucte d u n der a n I n v esti gat or I N D i n t he U S, a n y e v e nt t hat is b ot h seri o us 
u ne x pecte d  a n d relat e d  m ust be re p orte d t o t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) as 
s o o n as p ossi ble a n d n o l ater t ha n 7 da ys (f or a deat h or life -t hreate ni n g e ve nt) or 1 5 da ys 
(f or all ot her S A Es) after t he i n vesti gat or’s or i nstit uti o n’s i nitial recei pt of t he i nf or mati o n. 
B M S will be pr o vi de d wit h a si m ulta ne o us c o p y of all a d vers e e ve nts file d wit h t he F D A.  
S A Es  s h o ul d  be  re p ort e d  o n  Me d Watc h  F or m  3 5 0 0 A,  w hic h  ca n  b e  accesse d  at: 
htt p:// w w w.access dat a.f d a. g o v/scri pts/ me d watc h/.  
Me d Watc h S A E f or ms s h o ul d be se nt t o t he F D A at: 
M E D W A T C H  
5 6 0 0 Fis hers La n e 
R oc k ville, M D 2 0 8 5 2- 9 7 8 7 
Fa x: 1 - 8 0 0-F D A - 0 1 7 8 ( 1- 8 0 0- 3 3 2- 0 1 7 8) 
htt p:// w w w.access dat a.f d a. g o v/scri pts/ me d watc h/  
 
All S A Es s h o ul d si m ulta ne o usl y b e fa x e d or e- maile d t o B M S at:  
Gl o bal P har mac o vi gila nce & E pi de mi ol o g y 
Brist ol - M yers S q ui b b C o m pa n y 
Fa x N u m ber: 6 0 9- 8 1 8- 3 8 0 4 
E mail: W orl d wi de.safet y @ b ms.c o m  
 
•  A n S A E r e p ort s h o ul d b e c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its 
seri o us ness.  
•  F or  st u dies  wit h  l o n g -t er m  f oll o w-u p  peri o ds  i n  w hic h  safet y  d ata  are  bei n g 
re p orte d, i ncl u d e t he ti mi n g of S A E c ollecti o n i n t he pr ot oc ol. 
•  If t he i n vesti gat or b elie ves t hat a n S A E is n ot relate d t o st u d y dr u g, b ut is p ot e ntiall y 
relate d t o t he c o n diti o ns of t he st u d y (s uc h as wit h dra wal of pre vi o us t hera p y or a 
c o m plicati o n  of  a  st u d y  pr oce d ure),  t he  relati o ns hi p  s h o ul d  be  s pecifie d  i n  t he 
narrati ve s ecti o n of t he S A E Re p ort F or m. 
•  If  o nl y  li mite d  i nf or m ati o n  is  i nitiall y  a v aila ble,  f oll o w-u p  re p orts  are  re q uire d. 
( N ote: F oll o w-u p S A E re p orts s h o ul d i ncl u de t he sa me i n vesti gat or ter m(s) i nitiall y 
re p orte d.) 
•  If a n o n g oi n g S A E c h a n ges i n its i nte nsit y or relati o ns hi p t o st u d y dr u g or if ne w 
i nf or mati o n bec o mes a v aila ble, a f oll o w-u p S A E re p ort s h o ul d be se nt wit hi n 2 4 
h o urs t o B M S usi n g t he s a me pr o ce d ure us e d f or tr a ns mitti n g t he i nitial S A E re p ort. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 0  
All S A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n.  All S A Es s h o ul d be 
f oll o we d t o res ol uti o n or sta bilizati o n. 
5. 5  
 
Defi niti o ns  
S E RI O U S A D V E R S E E V E N T S  
A S eri o us A dverse Eve nt ( S A E)  is a n y u nt o war d me dical occ urre n ce t hat at a n y d ose:  
•  res ults i n deat h 
•  is life-t hreate ni n g ( d efi ne d as a n e ve nt i n w hic h t h e s u bject was at ris k of d eat h at 
t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve 
ca use d deat h if it wer e m ore se vere)  
•  re q uires i n p atie nt h os pitalizati o n or ca uses pr ol o n gati o n of e xisti n g h os pitalizati o n 
(see N O T E  bel o w) 
•  res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y 
•  is a c o n ge nital a n o mal y/ birt h defect  
•  is  a n  i m p orta nt  me dical  e ve nt  ( defi ne d  as  a  me dical  e ve nt(s)  t hat  ma y  n ot  be 
i m me diatel y life-t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut, base d u p o n 
a p pr o priate  me dical  a n d  scie ntific  j u d g me nt,  ma y  j e o par dize  t he  s u bject  or  ma y 
re q uire  i nter ve nti o n  [ e. g.,  me dical,  s ur gical]  t o pre ve nt  o n e  of  t he  ot her  seri o us 
o utc o mes liste d i n t he d efi niti o n a b o ve.) E x a m ples of s uc h e ve nts i ncl u de, b ut are 
n ot li mite d t o, 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 f or aller gic 
br o nc h os pas m;  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.)  
•  P ote ntial dr u g i n d uce d li ver i nj ur y ( DI LI) is als o c o nsi dere d a n i m p orta nt me dical 
e ve nt.  
•  S us pecte d tra ns missi o n of a n i nfecti o us a ge nt (e . g., pat h o ge nic or n o n pat h o ge ni c) 
via t he st u d y dr u g is a n S A E.  
•  Alt h o u g h  pre g n a nc y,  o v er d ose,  a n d  ca ncer  are  n ot  al wa ys  seri o us  b y  re g ulat or y 
defi niti o n, t hese e ve nts m ust be ha n dle d as S A Es. 
T he f oll o wi n g h os pitalizati o ns are n ot c o nsi dere d S A Es i n t his cli nical trial::  
− a visit t o t he e mer ge n c y r o o m or ot her h os pital de part me nt < 2 4 h o urs,  t hat d oes 
n ot  res ult  i n  a d missi o n  ( u nless  c o nsi dere d  a n  i m p orta nt  me dical  or  life -
t hreate ni n g e v e nt) 
− electi ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt 
− a d missi o ns as per pr ot oc ol f or a pla n ne d m e dical/s ur gical pr oce d ure 
− r o uti ne healt h assess m e nt re q uiri n g a d missi o n f or baseli ne/tre n di n g of h ealt h 
stat us (e. g., r o uti ne c ol o n osc o p y) 
− Me dical/s ur gical a d missi o n ot her t ha n t o re m e d y ill healt h a n d pla n n e d pri or t o 
e ntr y i nt o t he st u d y. A p pr o priate d oc u m e ntati o n is re q uire d i n t hese cas es 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 1  
− A d missi o n e nc o u nter e d f or a n ot her life circ u msta nce t hat carries n o beari n g o n 
healt h stat us a n d re q uir es n o me dical/s ur gical i nter ve nti o n (e g, lac k of h o usi n g, 
ec o n o mic i na de q u ac y, care gi ver res pite, fa mil y circ u msta nces, a d mi nistrati ve 
reas o n). 
P ote ntial Dr u g I n d u ce d Li ver I n j ur y ( DI LI) 
W here ver   p ossi ble, ti m ely co nfir mati o n   of i nitial li ver-relate d  la b orat or y a b n or malities  
s h o ul d occ u r pri or t o t he re p orti n g of a  p ote ntial DI LI e v e nt.  All occ urre n ces of p ote ntial 
DI LIs, meeti n g t he d efi n e d criteri a, m ust be re p o rte d as S A Es 
P ote ntial dr u g i n d uce d li ver i nj ur y is defi ne d as: 
1)  A L T or A S T ele v ati o n > 3 ti mes u p per li mit of n or mal ( U L N)  
A N D  
2)  T otal  bilir u bi n  > 2  ti mes U L N,  wit h o ut i nitial fi n di n gs of c h olestasis  (ele vate d 
ser u m al kali ne p h os p h atase) 
A N D  
3)  N o  ot her i m me diatel y a p pare nt  p ossi ble ca us es of A S T/ A L T  ele vati o n a n d  
h y per bilir u bi ne mia, i ncl u di n g, b u t n ot li mit ed t o, viral h e p atitis , pr e-e xisti ng 
c hr o nic o r ac ut e li ver dis eas e , or t h e a d mi nistrati o n of ot her dr u g(s) k n o w n t o 
be he pat ot o xic. 
 
A D V E R S E E V E N T S  
A n A d verse E v e nt ( A E) is defi ne d as a n y n e w u nt o war d m e dical o cc urre n ce or w orse ni n g 
of  a  pree xisti n g  me dical  c o n diti o n  i n  a  cli nical  i n vesti gati o n  s u bject  a d mi nistere d  a n 
i n vesti gati o nal ( me dici nal) pr o d uct a n d t hat d oes n ot necessaril y ha v e a ca us al relati o ns hi p 
wi t h t his treat me nt. A n A E ca n t her ef ore be a n y u nfa v ora bl e a n d u ni nte n de d si g n (s uc h as 
a n a b n or m al la b or at or y fi n di n g), s y m pt o m, or disease t e m p orall y ass o ciat e d wit h t he use 
of i n vesti gati o nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he i n vesti gati o nal pr o d uct.  
T he ca us al relati o ns hi p t o st u d y dr u g is deter mi n e d b y a p h ysicia n a n d s h o ul d be use d t o 
assess all a d verse e v e nts ( A E). T he cas ual relati o ns hi p ca n be o ne of t he f oll o wi n g:  
Relate d: T here is a r eas o na ble ca us al relati o ns hi p bet wee n st u d y dr u g  a d mi nistrati o n a n d 
t he A E. 
N ot  relate d:  T her e  is  n ot  a  r eas o n a ble  ca usal  relati o ns hi p  bet w ee n  st u d y  dr u g 
a d mi nistrati o n a n d t he A E.  
T he  ter m  "reas o na ble  ca usal  relati o ns hi p"  mea ns  t here  is  e vi de n ce  t o  s u g gest  a  ca us al 
relati o ns hi p.  
A d verse e v e nts ca n be  s p o nta ne o usl y re p orte d or elicite d d uri n g o pe n-e n d e d q uesti o ni n g, 
e x a mi nati o n, or e val uati o n of a s u bject. (I n or der t o pre ve nt re p orti n g bias, s u bjects s h o ul d 
n ot be q uesti o ne d re gar di n g t he s p ecific o cc urre nce of o ne or m ore A Es.) 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 2  
N O N S E RI O U S A D V E R S E E V E N T  
•  N o nseri o us A d verse E v e nts are t o be pr o vi de d t o B M S i n a g gre gate via i nt eri m or 
fi nal st u d y re p orts as s pecifie d i n t he a gree me nt or, if a re g ulat or y re q uire me nt [e. g. 
I N D U S trial] as part of a n a n n ual re p orti n g re q uire me nt.  
•  N o nseri o us  A E  i nf or mati o n  s h o ul d  als o  be  c ollecte d  fr o m  t he  start  of  a  place b o 
lea d-i n peri o d or ot her o bser vati o nal p eri o d i nte n de d t o esta blis h a bas eli ne stat us 
f or t he s u bjects.  
A  n o nseri o us a dverse eve nt  is a n A E n ot classifie d as seri o us.  
N o nseri o us A d verse E v e nt C ollecti o n a n d Re p orti n g  
T he c ollecti o n of n o nseri o us A E i nf or mati o n s h o ul d be gi n at i nitiati o n of st u d y dr u g. All 
n o nseri o us  a d vers e  e v e nts  ( n ot  o nl y  t h ose  dee me d  t o  be  treat me nt -rel ate d)  s h o ul d  be 
c ollecte d  c o nti n u o usl y  d uri n g  t he  treat me nt  peri o d  a n d  f or  a  mi ni m u m  of  1 0 0  da ys 
f oll o wi n g t he last d ose of st u d y treat me nt.  
N o nseri o us A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n, or re p orte d as S A Es if 
t he y b ec o me s eri o us. F oll o w-u p is als o re q uire d f or n o nseri o us A Es t hat ca use i nterr u pti o n 
or  disc o nti n uati o n  of  st u d y  dr u g  a n d  f or  t h ose  prese nt  at  t he  e n d  of  st u d y  treat me nt  as 
a p pr o priate.  
L a b or at or y Test A b n or m alities 
All  la b orat or y  t est  res ults  ca pt ure d  as  part  of  t he  st u d y  s h o ul d  be  rec or de d  f oll o wi n g 
i nstit uti o nal  pr oce d ures.  Test  r es ults  t hat  c o nstit ute  S A Es  s h o ul d  be  d oc u me nte d  a n d 
re p orte d as s uc h. 
T he f oll o wi n g la b orat or y a b n or malities s h o ul d be d oc u me nte d a n d re p orte d a p pr o priatel y:  
a n y la b or at or y test res ult t hat is cli nicall y si g nifica nt or meets t he d efi niti o n of a n S A E  
a n y la b orat or y a b n or malit y t hat re q uire d t he s u bject t o ha ve st u d y dr u g disc o nti n ue d or 
i nterr u pte d 
a n y  la b or at or y  a b n or malit y  t hat  re q uire d  t he  s u bject  t o  recei ve  s pecifi c  c orrecti ve 
t hera p y.  
 
Pre g n a nc y  
If, f oll o wi n g i nitiati o n of t he i n vesti gati o nal pr o d uct, it is s u bse q ue ntl y disc o vere d t hat a 
st u d y s u bject is pr e g na nt or ma y ha ve bee n pre g na nt at t he ti me of i n vesti gati o nal pr o d uct 
e x p os ure,  i ncl u di n g  d uri n g  at  least  6  h alfli ves  after  pr o d u ct  a d mi nistrati o n,  t he 
i n vesti gati o nal  pr o d uct  will  be  per ma ne ntl y  disc o nti n ue d  i n  a n  a p pr o priate  ma n ner  (e g, 
d ose ta peri n g if necessar y f or s u bject safet y).  
T he i n vesti gat or m ust i m me diatel y n otif y W orl d wi de Safet y @ B M S of t his e ve nt via t he 
Pre g n a nc y S ur veilla n ce F or m i n acc or da n ce wit h S A E re p orti n g pr oce d ures.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 3  
F oll o w- u p  i nf or mati o n  re gar di n g  t he  c o urse  of  t he  pre g na nc y,  i ncl u di n g  peri natal  a n d 
ne o natal o utc o me a n d,  w here  a p plica ble, offs pri n g i nf or m ati o n m ust  be re p orte d o n t he 
Pre g n a nc y S ur veilla n ce F or m [ pr o vi de d u p o n re q uest fr o m B M S] 
A n y  pre g n a nc y  t hat  occ urs  i n  a  fe male  part ner  of  a  male  st u d y  partici pa nt  s h o ul d  be 
re p orte d  t o  B M S.  I nf or mati o n  o n  t his  pre g na n c y  will  be  c ollecte d  o n  t he  Pre g na nc y 
S ur veilla nce F or m.  
O ver d ose  
A n  o ver d ose  is  defi ne d  as  t he  acci de ntal  or  i nte nti o nal  a d mi nistrati o n  of  a n y  d ose  of  a 
pr o d uct  t hat  is  c o nsi der e d  b ot h  e x cessi ve  a n d  me dicall y  i m p ort a nt.  All  occ urre nces  of 
o ver d ose m ust be r e p orte d as a n S A E. 
Ot her S af et y C o nsi der ati o ns  
A n y  si g nifica nt  w ors e ni n g  n ote d  d uri n g  i nteri m  or  fi n al  p h ysi cal  e x a mi nati o ns, 
electr ocar di o gr a ms,  x -ra ys,  a n d  a n y  ot her  p ote ntial  safet y  assess me nts,  w het her  or  n ot 
t hese pr oce d ures are r e q uire d b y t he pr ot oc ol, s h o ul d als o be rec or d e d as a n o nseri o us or 
seri o us A E, as a p pr o priat e, a n d re p orte d acc or di n gl y. 
 
6. 0     C O R R E L A TI V E S T U DI E S  ( A P P E N DI X G) 
 
6. 1   
 
T u m or Bi o ps y S a m ples  
 
•  T u m or bi o ps y  sa m ples  will  be  c ollecte d  pre -t hera p y,  at  wee k  1 3,  6  m o nt hs, 9 
m o nt hs (if cli nicall y i n dicate d) ,1 2 m o nt h s a n d at ti me of pr o gressi o n. 1 0 u nstai ne d 
sli des or t u m or bl oc k is re q uire d. 
C o nt act i nf or m ati o n f or  tiss ue pic k u p  a n d s hi p pi n g: 
 
J ulie B oer n er, P h. D.  
Kar ma n os Ca n cer I nstit ute 
4 1 0 0 J o h n R, Detr oit MI 4 8 2 0 1 
C orrelati ve Scie nces La b R m 8 0 8  
Tel #  3 1 3- 5 7 6- 8 3 5 1 
E- mail : b oer nerj @ k ar ma n os. or g  
Karri Star k, M. S.  
Kar ma n os Ca n cer I nstit ute  
4 1 0 0 J o h n R, Detr oit MI 4 8 2 0 1 
C orrelati ve Scie nces La b R m 8 0 8  
Tel # 3 1 3- 5 7 6- 8 2 4 8 
E mail:  star k ka @ kar ma n os. or g 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 4  
Please se n d e mail wit h re q uisiti o n f or m at ti me of s u b missi o n t o  
b oer nerj @ k ar ma n os. or g 
a n d 
dic k o w b @ kar ma n os. or g  
 
6. 2  
 
T u m or Tiss ue S peci me ns  ( A p pe n di x G) 
T u m or tiss ue s peci me ns i n t he f or m of a paraffi n e m be d de d  bl oc k or a mi ni m u m of 1 0 
u nstai ne d  sli des, wit h a si n gle s ecti o n o n p ositi vel y c har ge d slides will be s u b mitte d f or 
P D -1 a n d P D -L 1 i m m u n o hist oc he mistr y (I H C) assess me nt. T hese bi o ps y s a m ples s h o ul d 
be  e x cisi o nal,  i ncisi o nal,  p u nc h  or  c ore  n ee dle.  Fi ne  n ee dle  as pirates  or  ot her  c yt ol o g y 
s peci me ns are i ns ufficie nt f or d o w nstrea m bi o mar ker a n al ys es. P D -1 a n d P D -L 1 stai ne d 
tiss ue secti o ns will be assesse d b y a p at h ol o gist a n d sc ore d as p ositi ve o n a 1 + t o 3 + scal e 
if me m bra ne stai ni n g is o bser ve d.  
 
T hese t u m or sa m ples, m a y als o b e assesse d f or t he e x pressi o n of ot her i m m u ne or relate d 
ge n es, R N As a n d/ or pr ot ei ns, as well as, t he prese nce of i m m u ne cell p o p ulati o ns usi n g a 
variet y  of  met h o d ol o gi es  i ncl usi ve  of,  b ut  n ot  li mite d  t o  i m m u n o hist oc he mistr y  (I H C), 
q R T- P C R,  ge netic  m utati o n  detecti o n  a n d  fl u oresce nt  i n -sit u  h y bri dizati o n  ( FI S H). 
Vari o us m olec ular mar kers wit h p ote ntial pre dic ti ve val ue are c urre ntl y u n der i n vesti gati o n 
a n d  ma y  be  assesse d  i n  t his  st u d y.  T hese  t u m or  tiss ue  bi o mar kers  i ncl u d e,  b ut  are  n ot 
li mite d t o P D-1, P D -L 2, t u m or i nfiltrati n g l y m p h oc yt es ( TI Ls) or s u b p o p ulati o ns of TI Ls 
a n d a T h 1 i m m u ne m R N A e x pressi o n si g nat ure. I n a d diti o n, ot her met h o ds of meas uri n g 
t u m or P D-L 1 e x pressi o n ma y als o be assesse d. M utati o n l oa d will be e x pl ore d o n t u m or 
tiss ue. Tiss ue  ma y  be  assesse d  f or  r esi d ual  t u m or  cells  a n d  f or  mar k ers  e x pecte d  t o 
acc o m pa n y t u m or s hri n k a ge i n t his st u d y,  i ncl u di n g, b ut n ot li mite d t o TI Ls a n d s u bsets 
t hereof.  
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 5  
6. 3  
 
I m m u ne res p o nse m o nit ori n g [A p pe n di x G]  
Peri p heral bl o o d ( 3 0 ml) will be dra w n pre -treat me nt, a n d at f oll o wi n g ti me-p oi nts ( wee k 7 a n d 1 3,   
6  m o nt hs , a n d  1 2  m o nt hs)  after  i nitiati o n  of i m m u n ot hera p y.  T he  plas ma  a n d  P B M C  will  be 
is olate d f oll o wi n g a sta n dar d pr ot oc ol ( S O P attac he d). I n or der t o mai ntai n c o nsiste nt q ualit y, all 
cli nical sites will is olate plas ma a n d P B M C f oll o wi n g t he e xact sa me pr ot oc ol a n d cr y o -s hi p t he 
sa m ples t o K CI f or f urt her a nal ysis. See a p pe n di x G f or details re gar di n g sa m ple c ollecti o n a n d 
s hi p pi n g. T he sa m ples s h o ul d be se nt  t o Dr. Paraj uli, c o ntact i nf or mati o n gi ve n bel o w. 
 
P r a hl a d P ar aj uli, P h. D.  
Elli ma n Cli nical Researc h B uil di n g, # 2 0 2 9 
4 2 1 E. Ca nfiel d St.,  
Detr oit, MI 4 8 2 0 1.  
Cell 2 4 8 5 0 6 7 1 8 0 ( preferre d) 
P h: 3 1 3- 5 7 8- 4 2 6 8 ( Off); 3 1 3- 5 7 7- 0 6 2 9 ( La b) 
E mail: p paraj uli @ me d. wa y ne.e d u  
 
 
T he c orrelati ve st u dies will f oc us o n a n y p he n ot y pic or f u ncti o nal c ha n ges wit h re gar ds t o t he T 
cell  hel p,  c yt ot o xicit y  or  re g ulat or y  c haracteristics  as  well  as  B  cell  a nti b o d y  pr ofile  f oll o wi n g 
i m m u n ot hera p y c o m pare d t o t he pre-treat me nt sa m ples. T he plas ma will be a nal yze d f or le vels of 
t we nt y-fi ve differe nt c yt o ki nes, c he m o ki nes an d gr o wt h fact ors i ncl u di n g, I F N -γ, T N F-α , M C P- 1, 
G M -C S F, I L -1, I L -2, I L -6, I L -8 a n d I L -1 0, usi n g a m ulti ple x c yt o ki ne arra y. A m ulti -para metric 
fl o w  c yt o metr y  will  be  perf or me d  f or  p he n ot y pic  c haracterizati o n  of  i m m u n e  cell  s u bsets, 
i ntracell ular c yt o ki ne stai ni n g i n s pecific s u bsets as well as t o a nal yze c yt ot o xic T cell acti vati o n. 
T u m or a nti ge n- s pecific i m m u ne cell f u ncti o nal pr ofili n g will be perf or me d via E LI S P O T a nal ysis 
of  sti m ulate d  a n d  n o n -sti m ulate d  T  a n d  B  cells.  W hile  T  cells  will  be  a nal yze d  for  I F N -γ  a n d 
Gra nz y me B secreti o n, B cells will be assa ye d f or a nti ge n -s pecific I g G a n d I g M pr o d ucti o n.  
 
6. 4  
 
Q u alit y of Lif e ( Q O L) Q uesti o n n aires  [ A p pe n di x F] 
T he Q O L q u esti o n naire will be a d mi nistere d at t he 1 5 ti me p oi nts liste d i n t he hea der of 
t he  St u d y  C ale n dar  i n  S ecti o n  2. 3.     T he  F A CI T  s y m pt o m  i n de x  sc ore  f or  ca n cer  a n d 
s pecific b la d d er  s y m pt o m  i n de x q uesti o n naires will  be  c o m plete d  at  a  ma xi m u m  of 1 5 
ti me p oi nts starti n g  wit h  pre-t her a p y,  t he  da ys  of  ni v ol u ma b  t hera p y,  a n d  t he n  6  a n d  1 2 
m o nt h ti me p oi nts   T he  c ha n ge  i n  sc ore  i n dices  will  be  a n al yze d  b y  re peate d  meas ures 
a nal ysis a n d m o deli n g a n d will be re p orte d.  
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 6  
 
7. 0 T R E A T M E N T P L A N, M O DI FI C A TI O N S A N D C O N C O MI T A N T T H E R A P Y  
7. 1   
Pr o d uct I nf or m ati o n T a ble   
Please als o see Dr u g I nf or mati o n A p pe n di x  C 
T he st u d y me di cati o n ( Ni v ol u ma b) will be s hi p pe d t o eac h site b y B M S. 
* Ni v ol u ma b ma y b e la bele d as B M S- 9 3 6 5 5 8- 0 1 S ol uti o n f or I njecti o n 
 
If st ore d i n a glass fr o nt refri gerat or, vials s h o ul d be st ore d i n t he cart o n. Rec o m me n de d 
safet y meas ures f or pre p arati o n a n d ha n dli n g of ni v ol u ma b i ncl u de la b orat or y c o ats a n d 
gl o ves. 
F or  a d diti o nal  details  o n  pre pare d  dr u g  st ora ge  a n d  use  ti me  of  ni v ol u ma b  u n der  r o o m 
te m perat ur e/li g ht  a n d  r efri ger ati o n,  please  refer  t o  t he  B M S-9 3 6 5 5 8  ( ni v ol u ma b) 
I n v esti gat or Br oc h ur e secti o n f or “ Rec o m me n d e d St ora ge a n d Use C o n diti o ns”  
7. 2  
H a n dli n g a n d Dis pe nsi n g  
T he  i n vesti gat or  s h o ul d  e ns ure  t hat  t he  st u d y  dr u g  is  st ore d  i n  acc or da nce  wit h  t he 
e n vir o n me ntal c o n diti o ns (te m perat ur e, li g ht, a n d h u mi dit y) as per pr o d uct i nf or mati o n a n d 
t he  I n v esti gat or  Br o c h ure  a n d  per  l ocal  re g ulati o ns. It  is  t he  res p o nsi bilit y  of  t he 
i n vesti gat or t o e ns ure t hat i n vesti gati o nal pr o d uct is o nl y dis pe nse d t o st u d y s u bjects. T h e 
Pr o d uct Descri pti o n:  Ni v ol u m a b ( Ot her n a mes = M D X-1 1 0 6, O N O -4 5 3 8, a nti -P D -1 ) 
Pr o d uct 
Descri pti o n 
a n d D os a ge 
F or m  
P ot e nc y  
Pri m ar y 
P ac k a gi n g 
( V ol u me)/ 
L a bel 
T y pe  
Sec o n d ar y 
P ac k a gi n g 
( Qt y) 
/ L a bel 
T y pe  
A p pe ar a nce  
St or a ge 
C o n diti o ns  
( per l a bel) 
Ni v ol u ma b 
( B M S-
9 3 6 5 5 8- 0 1) * 
I njecti o n 
dr u g pr o d uct 
is a sterile, 
n o n-
p yr o ge nic, 
si n gle- us e, 
is ot o nic 
a q ue o us 
s ol uti o n 
f or m ulate d at 
1 0 m g/ m L   
1 0 0 
m g/ Vial 
( 1 0 
m g/ m L).  
Cart o n of 5 
or 1 0 vials 
1 0 -cc T y p e 1 
fli nt glass 
vials 
st o p pere d 
wit h b ut yl 
st o p pers a n d 
seale d wit h 
al u mi n u m 
seals. 
Clear t o 
o palesce nt, 
c ol orless t o pale 
yell o w li q ui d.  
Ma y c o ntai n 
particles  
B M S -9 3 6 5 5 8 -0 1 
I njecti o n m ust be 
st ore d at 2 t o 8 
de grees C ( 3 6 t o 
4 6 de grees F) a n d 
pr otecte d fr o m 
li g ht a n d  freezi n g  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 7  
i n vesti gati o nal  pr o d uct  m ust  be  dis pe nse d  o nl y  fr o m  offi cial  st u dy  sites  b y  a ut h orize d 
pers o n nel acc or di n g t o l ocal re g ulati o ns. If c o ncer ns re gar di n g t he q ualit y or a p peara nce 
of  t he  st u d y  dr u g  arise,  t he  st u d y  dr u g  s h o ul d  n ot  be  dis pe nse d  a n d  c o ntact  B M S 
i m me diatel y. 
Please ref er t o t he c urr e nt versi o n of t he I n vesti g at or Br o c h ure a n d/ or s hi p me nt refere nce 
s heets f or a d diti o nal i nf or mati o n o n st ora ge, ha n dli n g, dis pe nsi n g, a n d i nf usi o n 
i nf or mati o n f or ni v ol u ma b. 
 
Destr ucti o n   
 
S p o ns or/I n vesti gat or dr u g destr u cti o n is all o we d pr o vi de d t he f oll o wi n g mi ni mal sta n dar ds 
are met:  
 
•  O n -site dis p osal practices m ust n ot e x p ose h u ma ns t o ris ks fr o m t he dr u g. 
o  O n -site dis p osal practices a n d pr oce d ures are i n a gree me nt wit h a p plica ble 
la ws a n d re g ulati o ns, i ncl u di n g a n y s p ecial re q uire me nts f or c o ntr olle d or 
hazar d o us s u bsta nces. 
•  Wri tte n pr oce d ures f or o n-site dis p osal are a vaila ble a n d f oll o we d. T he pr oce d ures 
m ust be file d wit h t he S p o ns or S O Ps a n d a c o p y pr o vi de d t o B M S u p o n re q uest. 
•  Rec or ds are mai ntai ne d t hat all o w f or tracea bilit y of eac h c o ntai n er, i ncl u di n g t he 
date dis p ose d of, q ua ntit y dis p ose d, a n d i de ntificati o n of t he pers o n dis p osi n g t he 
c o ntai ners.  T he  met h o d  of  dis p osal,  ie,  i nci nerat or,  lice nse d  sa nitar y  l a n dfill,  or 
lice nse d waste dis p osal v e n d or m ust be d oc u me nt e d. 
•  Acc o u nta bilit y  a n d  dis p osal  rec or ds  are  c o m plete,  u p -t o-date,  a n d  a vaila ble  f or 
B M S t o re vie w t hr o u g h o ut t he cli nical trial peri o d as per t he st u d y a gree m e nt.  
•  If c o n diti o ns f or destr u cti o n ca n n ot be met, please c o ntact B M S.  
•  It is t he S p o ns or I n v esti gat or’s res p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y 
c o ntai ners,  pr o vi de d  t hat  pr oce d ures  f or  pr o p er  dis p osal  ha ve  bee n  esta blis he d 
acc or di n g  t o  a p plica ble  fe deral,  state,  l ocal,  a n d  i nstit uti o nal  g ui deli nes  a n d 
pr oce d ur es, a n d pr o vi d e d t hat a p pr o priate rec or ds of dis p osal are k e pt. 
 
7. 3  
D ose c alc ul ati o ns a n d a d mi nistr ati o n  
Ni v ol u ma b will be gi ve n e ver y t w o wee ks at a d ose of 2 4 0  m g t o be a d mi nistere d as a n 
a p pr o xi matel y 3 0- 6 0 mi n ute  +/ - 1 0 mi n I V i nf usi o n. 
Ni v ol u ma b I njecti o n, 1 0 0 m g ( 1 0 m g/ m L)   Ni v ol u ma b i njecti o n is t o be a d mi nistere d as 
a n  I V  i nf usi o n  t hr o u g h  a  0. 2-micr o n  t o  1. 2 -micr o n  p ore  size,  l o w -pr otei n  bi n di n g 
p ol yet hers ulf o ne  me m br a ne  i n -li ne  filter  at  t he  pr ot oc ol-s pecifi e d  d oses.  It  is  n ot  t o  be 
a d mi nistere d  as  a n  I V  p us h  or  b ol us  i njecti o n.  Ni v ol u ma b  i njecti o n  ca n  be  i nf use d 
u n dil ute d  ( 1 0  m g/ m L)  or  dil ute d  wit h  0. 9 %  S o di u m  C hl ori de  I njecti o n,  U S P  or  5 % 
De xtr ose I njecti o n, U S P t o pr otei n c o nce ntrati o ns as l o w as . 3 5 m g/ m L. Care m ust be ta ke n 
t o ass ure sterilit y of t he pre par e d s ol uti o n as t he pr o d uct d oes n ot c o ntai n a n y a nti micr o bi al 
preser v ati ve or bacteri ost atic a ge nt.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 8  
S u bjects ma y be d os e d n o less t ha n 1 2 da ys fr o m t he pre vi o us d os e of dr u g. T h ere are n o 
pre me dicati o ns r ec o m me n de d f or ni v ol u ma b. 
S u bjects  s h o ul d  be  caref ull y  m o nit ore d  f or  i nf usi o n  reacti o ns  d uri n g  ni v ol u ma b 
a d mi nistrati o n.  If  a n  ac ute  i nf usi o n  reacti o n  is  n ote d,  s u bjects  s h o ul d  be  ma na ge d 
acc or di n g t o A p p e n di x C. 
D oses of ni v ol u ma b ma y be i nterr u pte d, dela ye d, or disc o nti n ue d de pe n di n g o n h o w w ell 
t he s u bject t olerates t he treat me nt. 
 
7. 4  
  
D ose M o dific ati o ns 
D ose re d u cti o ns or d ose escalati o ns ar e n ot per mitte d.  
 
7. 5  
 
D ose Del a y C riteri a  
Beca use of t he p ote ntial f or cli nicall y mea ni n gf ul ni v ol u ma b -relate d A Es re q uiri n g earl y 
rec o g niti o n  a n d  pr o m pt  i nter ve nti o n,  ma na ge me nt  al g orit h ms  ha ve  b ee n  de vel o pe d  f or 
s us pecte d  A Es  of  select e d  cate g ories.  [see  c urre nt  I n v esti gat or  Br oc h ure  a n d  A p pe n di x 
D f or citati o n e x a m ples] 
D ose del a y criteria a p pl y f or all t her a p y relate d a d verse e ve nts (re gar dless of w h et her or 
n ot t he e ve nt is attri b ute d t o ni v ol u ma b).  
Ni v ol u m a b a d mi nistr ati o n s h o ul d be del a ye d f or t he f oll o wi n g:  
A n y Gra d e ≥ 2 n o n-s ki n, dr u g-relat e d A E, wit h t he f oll o wi n g e x ce pti o ns: 
•  Gra de 2 dr u g -rel ate d f ati g ue or l a b orat or y a b n or m alities d o n ot re q uire a treat me nt 
dela y  
•  A n y Gra d e 3 s ki n, dr u g- r elate d A E 
A n y  Gra d e  3  dr u g -r elat e d  lab or at or y  a b n or malit y,  wit h  t he  f oll o wi n g  e x ce pti o ns  f or 
l y m p h o pe nia, le u k o p e nia, A S T, A L T, t otal bilir u bi n, or as y m pt o matic a m yl ase or li pase: 
•  Gra de 3 l y m p h o pe nia or le u k o pe nia d oes n ot re q uire d ose dela y. 
•  If a s u bject has a baseli ne A S T, A L T, or t otal bilir u bi n t hat is wit hi n n or mal li mits, 
dela y d osi n g f or dr u g-rel ate d Gra d e ≥ 2 t o xicit y. 
•  If a s u bject has baseli ne A S T, A L T, or t otal bilir u bi n wit hi n t he Gra de 1 t o xicit y 
ra n ge, del a y d osi n g f or dr u g-relat e d Gra de ≥ 3 t o xicit y. 
•  A n y Gra de ≥ 3 dr u g -rel ate d a myl ase or li pas e a b n or malit y t hat is n ot ass ociate d 
wit h  s y m pt o ms  or  cli nical  ma nifestati o ns  of  pa n creatitis  d oes  n ot  re q uire  d ose 
dela y. T he I n vesti gat or s h o ul d be c o ns ulte d f or s uc h Gra de ≥  3 a m ylas e or li pase 
a b n or malities.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
3 9  
A n y  A E,  la b or at or y  a b n or malit y,  or  i nterc urre nt  ill ness  w hic h,  i n  t he  j u d g me nt  of  t h e 
i n vesti gat or, w arr a nts del a yi n g t he d os e of st u d y me dicati o n. 
S u bjects w h o r e q uire d el a y of ni v ol u ma b s h o ul d b e re -e v al uate d as  cli nicall y i n dicate d a n d 
res u me ni v ol u ma b d osi n g w h e n re-treat me nt criteria are met.  
 
7. 6  
 
Criteri a t o Res u me T re at me nt  
S u bjects ma y res u m e treat me nt wit h st u d y dr u g w he n t he dr u g -relate d  A E(s) res ol ve t o 
Gra de  ≤1 or baseli ne v al ue, wit h t he f oll o wi n g e x ce pti o ns: 
•  S u bjects ma y r es u me treat me nt i n t he prese n ce of Gra de 2 fati g ue  
•  S u bjects w h o ha v e n ot e x perie nce d a Gra de 3 dr u g -relate d s ki n A E ma y res u me 
treat me nt i n t he pres e nce of Gra d e 2 s ki n t o xicit y  
•  S u bjects wit h baseli ne Gr a de 1 A S T/ A L T or t otal bilir u bi n w h o re q uire d ose dela ys 
f or reas o ns ot her t ha n a 2-gra de s hift i n A S T/ A L T or t otal bilir u bi n ma y res u me 
treat me nt i n t he pres e nce of Gra d e 2 A S T/ A L T O R t otal bilir u bi n 
•  S u bjects  wit h  c o m bi ne d  Gra de  2  A S T/ A L T A N D  t otal  bilir u bi n  val ues  meeti n g 
disc o nti n uati o n para meters s h o ul d ha ve treat me nt per ma ne ntl y disc o nti n ue d 
•  Dr u g -relate d p ul m o nar y t o xicit y, diarr hea, or c olitis, m ust ha ve res ol ve d t o b aseli ne 
bef ore  tr eat me nt  is  res u me d. S u bjects  wit h  persiste nt  Gr a de  1  p ne u m o nitis  after 
c o m pleti o n of a ster oi d t a per over at le ast 1 m o nt h m ay be eli gi ble f or retre at me nt 
if i nvesti g at or all o ws, b ut s h o ul d be disc usse d wit h t he PI. 
•  Dr u g -r elate d  e n d ocri n o pat hies  a de q u atel y  c o ntr olle d  wit h  o nl y  p h ysi ol o gic 
h or m o ne re place me nt m a y res u me treat me nt if i nvesti g at or all o ws, b ut s h o ul d be 
st ate d i n t he pr ot oc ol cle arly. 
 
If t he criteria t o r es u me treat me nt are met, t he s u bject s h o ul d restart treat m e nt at t he ne xt 
sc he d ule d ti me p oi nt per pr ot oc ol.  
If  treat me nt  is  dela ye d  or  i nterr u pte d  f or  >  6  w ee ks,  t he  s u bj ect  m ust  b e  per m a ne ntl y 
disc o nti n ue d fr o m st u d y t hera p y, e x ce pt as s pecifi e d i n disc o nti n uati o n secti o n.  
 
7. 7  
  
M a n a ge me nt Al g orit h ms 
G ui deli nes  f or  t he  ma na ge m e nt  of  i m m u ne  relate d  e ve nts  ca n  be  f o u n d  i n  t he  c urre nt 
I n v esti gat or Br oc h ur e A N D i n t he a p pr o ve d U S PI i n t he U S. I n v esti gat ors s h o ul d deci de 
t he a p pr o priat e s o urce of A E ma na ge me nt f or eac h pr ot oc ol. 
I m m u n o-o n c ol o g y  (I -O)  a ge nts  ar e  ass ociate d  wit h  A Es  t hat  ca n  differ  i n  se verit y  a n d 
d urati o n  t ha n  A Es  ca use d  b y  ot her  t hera pe utic  classes.  Ni v ol u ma b  is  c o nsi dere d  a n 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 0  
i m m u n o-o nc ol o g y  a ge nt  i n  t his  pr ot oc ol.  Earl y  rec o g niti o n  a n d  ma n a ge me nt  of  A Es 
ass ociate d  wit h  i m m u n o -o nc ol o g y  a ge nts  ma y  miti gate  se v ere  t o xicit y.  Ma n a ge me nt 
al g orit h ms  h a ve  bee n  d e vel o pe d  t o  assist  i n vesti gat ors  i n  ass essi n g  a n d  ma na gi n g  t h e 
f oll o wi n g gr o u ps of A Es: 
Gastr oi ntesti nal, Re nal, P ul m o nar y, He patic, E n d o cri n o pat hies, S ki n, Ne ur ol o gical. 
F or  s u bjects  e x pecte d  t o  re q uire  m ore  t ha n  4  wee ks  of  c ortic oster oi ds  or  ot her 
i m m u n os u p pressa nts  t o  ma na ge  a n  A E,  c o nsi der  rec o m me n dati o ns  pr o vi de d  i n  t he 
al g orit h ms. T hes e al g orit h ms are f o u n d i n t he Ni v ol u ma b I B [a n d i n A p pe n di x G ] of t his 
pr ot oc ol. T he g ui da n ce pr o vi de d i n t hese al g orit h ms s h o ul d n ot re place t he I n v esti gat or’s 
me dical j u d g m e nt b ut s h o ul d c o m ple me nt it. 
 
7. 8  
 
Disc o nti n u ati o n Criteri a  
Treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d f or t he f oll o wi n g: 
•  Gra de 4 n e utr o pe nia l asti n g > 7 d a ys  
•  A n y Gr a de 2 dr u g -relate d u veitis or e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d 
t o t o pical t hera p y a n d d o es n ot i m pr o ve t o Gra de 1 se verit y wit hi n t he re-treat me nt 
peri o d O R re q uir es s yst e mic treat me nt  
•  A n y  Gra d e  3  n o n -s ki n, dr u g -relate d  a d vers e  e ve nt  lasti n g  >  7  d a ys,  wit h  t he 
f oll o wi n g  e x ce pti o ns  f or  dr u g-relate d  l a b orat or y  a b n or malities,  u veitis, 
p ne u m o nitis, br o nc h os pas m, h y p erse nsiti vit y reacti o ns, a n d i nf usi o n reacti o ns, a n d 
e n d ocri n o pat hies: 
o  Gra de 3 dr u g -rel ate d u v eitis, p ne u m o nitis, br o nc h os pas m, h y p erse nsiti vit y 
reacti o n, or i nf usi o n r eacti o n of a n y d urati o n re q uires disc o nti n uati o n 
o  Gra de  3  dr u g -r elate d  e n d ocri n o pat hies  a de q u atel y  c o ntr olle d  wit h  o nl y 
p h ysi ol o gic h or m o ne r e place me nt d o n ot re q uire disc o nti n uati o n 
o  Gra de  3  dr u g -relate d  la b orat or y  a b n or malities  d o  n ot  re q uire  treat me nt 
disc o nti n uati o n e x ce pt t h ose n ote d bel o w 
•  Gra de  3  dr u g -r elate d  t hr o m b oc yt o pe ni a  >  7  da ys  or  ass ociate d  wit h 
blee di n g re q uir es disc o nti n uati o n 
•  A n y dr u g -relate d li ver f u ncti o n test ( L F T) a b n or malit y t hat m eets t he 
f oll o wi n g criteria r e q uire disc o nti n uati o n:  
• 
A S T or A L T > 8 x U L N   
 
•  
T otal bilir u bi n > 5 x U L N 
•  
C o nc urre nt A S T or A L T > 3 x U L N a n d t otal bilir u bi n > 2 x U L N 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 1  
•  A S T or A L T > 3 x U L N wit h t he a p peara n ce of fati g ue, n a usea, v o miti n g, ri g ht 
u p per q ua dr a nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) s h o ul d 
lea d t o treat me nt disc o nti n uati o n. 
•  A n y Gra d e 4 dr u g -rel ate d a d vers e e v e nt or la b orat or y a b n or malit y, e x ce pt f or t he 
f oll o wi n g e v e nts w hic h d o n ot re q uire disc o nti n uati o n: 
•  Is olat e d Gr a de 4 a m ylase or li pase a b n or malities t h at are n ot ass o ciate d wit h 
s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis a n d decrease t o < Gra de 
4 wit hi n 1 wee k of o nset.  
•  Is olat e d  Gra d e  4  electr ol yte  i m bala n ces/a b n or malities  t hat  are  n ot 
ass ociate d  
wit h  
cli nical  
se q uelae  
a n d  
are  
c orrecte d  
wit h 
s u p ple me ntati o n/a p pr o priate ma na ge me nt wit hi n 7 2 h o urs of t heir o nset 
•  Gra de 4 l y m p h o pe nia or le uc o pe nia 
•  Gra de  4  dr u g -r elate d  e n d ocri n o pat h y  a d v erse  e ve nts,  s uc h  as  a dre n al 
i ns ufficie nc y,  A C T H  deficie nc y, h y per - or  h y p ot h yr oi dis m,  or  gl uc os e 
i nt olera nce,  w hic h  r es ol ve  or  are  a d e q uatel y  c o ntr olle d  wit h  p h ysi ol o gic 
h or m o ne  re place me nt  (c ortic oster oi ds,  t h yr oi d  h or m o nes)  or  gl uc os e -
c o ntr olli n g  a ge nts,  res p ecti vel y,  ma y  n ot  re q uire  disc o nti n uati o n  after 
disc uss i o n wit h a n d a p pr o val fr o m t he I n v esti gat or [as all o we d b y pr ot oc ol] 
•  
A n y d osi n g i nterr u pti o n lasti n g > 6 wee ks wit h t he f oll o wi n g e x ce pti o ns: 
•  D osi n g  del a ys  or  i nterr u pti o ns  t o  all o w  f or  pr ol o n ge d  ster oi d  ta pers  t o 
ma na ge  dr u g -r elate d  a d verse  e ve nts  are  allo we d.  Pri or  t o  re -i nitiati n g 
treat me nt  i n  a  s u bject  wit h  a  d osi n g  i nterr u pti o n  lasti n g  >  6  w ee ks,  t h e 
I n v esti gat or m ust be c o ns ulte d. T u m or assess me nts s h o ul d c o nti n ue as per 
pr ot oc ol e ve n if d osi n g is i nterr u pte d or del a ye d 
•  D osi n g i nterr u pti o ns or dela ys lasti n g > 6 wee ks t hat occ ur f or n o n - dr u g-
relate d r eas o ns ma y be all o we d if a p pr o ve d b y t he I n v esti gat or. Pri or t o re-
i nitiati n g treat me nt i n a s u bject wit h a d osi n g i nterr u pti o n lasti n g > 6 wee ks, 
t he I n vesti gat or m ust be c o ns ulte d. T u m or assess me nts s h o ul d c o nti n ue as 
per pr ot oc ol e v e n if d osi n g is i nterr u pte d 
•  
A n y a d verse e v e nt, la b or at or y a b n or m alit y, or i nterc urre nt ill ness w hic h, i n t he 
j u d g me nt of t he I n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he s u bject wit h 
c o nti n ue d ni v ol u ma b d osi n g 
7. 9  
 
Tre at me nt of Ni v ol u m a b Rel ate d I nf usi o n Re acti o ns  
Si nce ni v ol u ma b c o ntai ns o nl y h u ma n i m m u n o gl o b uli n pr otei n se q ue nces, it is u nli kel y t o 
be  i m m u n o ge nic  a n d  i n d uce  i nf usi o n  or  h y perse nsiti vit y  reacti o ns.  H o we ver,  if  s u c h  a 
reacti o n wer e t o occ ur, it mi g ht ma nifest wit h fe ver, c hills, ri g ors, hea dac he, ras h, pr uritis, 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 2  
art hral gias,  h y p o - or  h y perte nsi o n,  br o nc h os pas m,  or  ot her  s y m pt o ms  of    aller gic -li ke 
reacti o ns.  
All Gra de 3 or 4 i nf usi o n reacti o ns s h o ul d be re p orte d as a n S A E if criteri a are met. I nf usi o n 
reacti o ns s h o ul d be gr a de d acc or di n g t o N CI C T C A E 4. 0 g ui d eli nes.  
Treat me nt  rec o m me n dati o ns  are  pr o vi de d  b el o w  a n d  ma y  be  m o difie d  base d  o n  l ocal 
treat me nt sta n dar ds a n d g ui deli nes as a p pr o pri ate: 
F or Gr a de 1 s y m pt o ms:  ( Mil d reacti o n; i nf usi o n i nterr u ptio n n ot i n dicate d; i nter ve nti o n 
n ot i n dicate d) 
Re mai n  at  be dsi de  a n d  m o nit or  s u bject  u ntil  rec o ver y  fr o m  s y m pt o ms.  T he  f oll o wi n g 
pr o p h ylactic pre me dicati o ns are rec o m me n de d f or f ut ure i nf usi o ns: di p he n h y dra mi ne 5 0 
m g ( or e q ui val e nt) a n d/ or paraceta m ol 3 2 5 t o 1 0 0 0 m g (acet a mi n o p he n) at l east 3 0 mi n utes 
bef ore a d diti o nal ni v ol u ma b a d mi nistrati o ns. 
F or Gr a de 2 s y m pt o ms : ( M o der ate r eacti o n re q uires t hera p y or i nf usi o n i nterr u pti o n b ut 
res p o n ds  pr o m ptl y  t o  s y m pt o matic  treat me nt  [e g,  a nti hista mi nes,  n o n-ster oi dal a nti-
i nfla m mat or y  dr u gs,  n ar c otics,  c ortic oster oi ds,  br o nc h o dilat ors,  I V  fl ui ds];  pr o p h ylactic 
me dicati o ns i n dicate d f or 2 4 h o urs). 
St o p t he ni v ol u ma b i nf usi o n, be gi n a n I V i nf usi o n of n or m al sali ne, a n d treat t he s u bject 
wit h  di p he n h y dra mi ne  5 0  m g  I V  ( or  e q ui vale nt)  a n d/ or  paraceta m ol  3 2 5  t o  1 0 0 0  m g 
(acet a mi n o p he n);  re mai n  at  be dsi de  a n d  m o nit or  s u bject  u ntil  res ol uti o n  of  s y m pt o ms. 
C ortic oster oi d or br o nc h o dilat or t hera p y ma y als o be a d mi nistere d as a p pr o priate. If t he 
i nf usi o n is i nterr u pte d, t he n restart t he i nf usi o n at 5 0 % of t he ori gi n al i nf usi o n rate w he n 
s y m pt o ms  res ol ve;  if  n o  f urt her  c o m plicati o ns  e ns ue  aft er  3 0  mi n utes,  t he  rate  ma y  be 
i ncreas e d t o 1 0 0 % of t he ori gi nal i nf usi o n rate. M o nit or s u bject cl osel y. If s y m pt o ms rec ur 
t he n n o f urt her ni v olu ma b will be a d mi nistere d at t hat visit. A d mi nister di p he n h y dra mi ne 
5 0 m g I V, a n d re mai n at be dsi de a n d m o nit or t he s u bject u ntil res ol uti o n of s y m pt o ms. T he 
a m o u nt of st u d y dr u g i nf use d m ust be rec or de d o n t he electr o ni c cas e re p ort f or m (e C R F). 
T he  f oll o wi n g  pr o p h yl actic  pr e me dicati o ns  are  rec o m me n de d  f or  f ut ure  i nf usi o ns: 
di p he n h y dra mi ne  5 0  m g  ( or  e q ui vale nt)  a n d/ or  paraceta m ol  3 2 5  t o  1 0 0 0  m g 
(acet a mi n o p he n) s h o ul d be a d mi nistere d at least 3 0 mi n utes bef ore a d diti o nal ni v ol u ma b 
a d mi nistrati o ns.  If  n ecess ar y,  c ortic oster oi ds  (rec o m me n de d  d ose:  u p  t o  2 5  m g  of  I V 
h y dr o c ortis o ne or e q ui vale nt) ma y b e use d. 
F or Gr a de 3 or Gr a de 4 s y m pt o ms:  ( Se v ere reacti o n, Gra de 3: pr ol o n ge d [ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic me dicati o n a n d/ or brief i nterr u pti o n of i nf usi o n]; rec urre nce of 
s y m pt o ms  f oll o wi n g  i nitial  i m pr o ve me nt;  h os pitalizati o n  i n dicate d  f or  ot her  cli nical 
se q uelae [ e g, re n al i m pair me nt, p ul m o nar y i nfiltrates]). Gra de 4: (life t hreat e ni n g; press or 
or ve ntilat or y s u p p ort i n dicate d).  
I m me diat el y  disc o nti n ue i nf usi o n of ni v ol u ma b. Be gi n a n I V i nf usi o n of n or mal sali ne, 
a n d treat t he s u bject as f oll o ws. Rec o m me n d br o nc h o dilat ors, e pi ne p hri ne 0. 2 t o 1 m g of a 
1: 1, 0 0 0 s ol uti o n f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 m g of a 1: 1 0, 0 0 0 s ol uti o n 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 3  
i njecte d sl o wl y  f or  I V  a d mi nistrati o n,  a n d/ or  di p he n h y dra mi ne  5 0  m g  I V  wit h 
met h yl pre d nis ol o ne 1 0 0 m g I V ( or e q ui vale nt), as nee d e d. S u bject s h o ul d be m o nit ore d 
u ntil t he i n vesti gat or is c o mf orta ble t hat t he s y m pt o ms will n ot rec ur. Ni v ol u ma b will be 
per ma ne ntl y disc o nti n ue d. I n vesti gat ors s h o ul d f oll o w t heir i nstit uti o nal g ui deli nes f or t he 
treat me nt  of  a na p h yla xis.  Re mai n  at  be dsi de  a n d  m o nit or  s u bject  u ntil  rec o ver y  fr o m 
s y m pt o ms.  
I n t he cas e of late-occ urri n g h y p erse nsiti vit y s y m pt o ms (e g, a p peara nce of a l ocal ize d or 
ge n eralize d pr uritis wit hi n 1 wee k after treat me nt), s y m pt o matic treat me nt ma y be gi ve n 
(e g, oral a nti hista mi ne, or c ortic oster oi ds). 
 
7. 1 0   
C o nc o mit a nt T her a p y  
Per mitte d T her a p y  
S u bjects  are  per mitte d  t o  use  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 mic  a bs or pti o n).  P h ysi ol o gic  re place me nt  d oses  of 
s yste mic c ortic oster oi ds are p er mitte d, e v e n if > 1 0 m g/ da y pre d nis o n e e q ui vale nts. A brief 
c o urse of c ortic oster oi ds f or pr o p h yl a xis (e g, c o n trast 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, dela ye d -t y pe h y perse nsiti vit y reacti o n ca use d b y c o ntact aller ge n) is 
per mitte d.  
 
8. 0       S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1  
 
O bjecti ves  
Pri mar y O bj ecti ve:  
T o c o m pare t he 1 2-m o nt h rate of  pr o gressi o n-free s ur vi val ( P F S) ac hie ve d wit h t he 
c o m bi nati o n of ni v ol u ma b, a pr o gra m me d deat h ( P D -1) i n hi bit or , a n d ra diati o n t hera p y 
i n  l ocalize d/l ocall y  a d v a nce d  ur ot helial  ca ncer patie nts,  w h o  are  i neli gi ble  f or 
c he m ot hera p y,  t o a hist orical c o ntr ol refere nce 1 2- m o nt h P F S rate.  
Sec o n dar y O bj ecti ves:  
1)  T o  assess  t he  t o xicit y  of  c o nc urre nt  ni v ol u ma b  a n d  ra diati o n  t hera p y  i n 
ur ot helial ca ncer.  
2)  T o deter mi ne o verall res p o nse rate ( O R R).  
3)  T o deter mi ne metastasis -free s ur vi val ( M F S). 
4)  T o deter mi ne o verall s ur vi val ( O S). 
5)  T o e val uate t he q u alit y of life ( Q OL) a n d bla d der f u ncti o ni n g d uri n g a n d after  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 4  
t he t hera p y.  
6)  T o  e x pl ore  t he  relati o ns hi p s of  P D -1  e x pressi o n, P D L -1  e x pressi o n , a n d t he 
T h 1/ T h 2 c yt o ki ne rati o t o cli nical o utc o mes (res p o nse, P F S, M F S, a n d O S). 
 
8. 2  
 
E n d p oi nts  
8. 2. 1  T he pri mar y e n d p oi nt ( P F S) is defi ne d i n Secti o n 4. 9. 
8. 2. 2  T he sec o n d ar y e n d p oi nts are defi ne d i n t he f oll o wi n g pr ot oc ol secti o ns: 
 T o xicit y assess me nt is d efi ne d i n Secti o n 5, a n d t o xicit y-e v al ua ble p atie nts are  
  
defi ne d i n Secti o n 4. 7. 
Res p o nse is defi ne d i n Secti o n 4. 5, a n d res p o ns e- e val ua ble p atie nts are  
  
defi ne d i n Secti o n 4. 6. 
M F S a n d O S are d efi ne d i n Secti o ns 4. 8 a n d 4. 1 0, re s pecti vel y. 
Q o L a n d bla d der f u ncti o ni n g q uesti o n naires ( F A C T- BI a n d BI SI) are s pecifie d i n  
Secti o n 7. 3 a n d s h o w n i n A p pe n di x E.  
P D L - 1 (a n d ot her bi o mar kers) are liste d i n Secti o n 7. 2, a n d will be assesse d b y  
I H C ( or ot her assa y met h o ds). 
 
8. 3  
 
Desi g n  
   T his is a 1 -ar m 1-sta ge s ur vi val t y p e desi g n f o c use d o n t he pri mar y e n d p oi nt of t he 1 2-
m o nt h P F S rate.   T he st u d y desi g n ass u m pti o ns are: 
1)  A p o p ulati o n r efere nce v al ue of 5 0 % 1 2 -m o nt h P F S rate fr o m sta n d ar d of care  wit h 
R T al o ne (fr o m S u p ple m e ntar y A p pe n di x Fi g ure 1(a) i n ref ere nce [ 4] ); 
2)  A h y p ot hesize d 7 5 % 1 2- m o nt h P F S rate f or patie nts treate d wit h Ni v ol u ma b + R T; 
3)  E x p o ne ntiall y distri b ute d P F S ti mes;  
4)  Accr u al ti me of 2 4 m o nt hs; 
5)  A n a d diti o nal f oll o w- u p ti me of 1 2 m o nt hs f or all patie nts; 
6)  Si g nifica nce le vel  al p ha = 0. 0 2 5 ( 1-si de d, d u e t o t he directi o nal h y p ot hesis); 
7)  P o wer = 0. 9 5 ( hi g h d ue t o t he u n met nee d f or i m pr o ve d t hera p y o pti o ns f or st u d y 
eli gi ble patie nts).  
 U n der t hese 7 ass u m pti o ns, t he st u d y will re q uire N = 3 0  e val u a ble patie nts , as calc ulat e d 
usi n g t he “ O ne Ar m S ur vi val” pr o gra m o n t he w w w.cra b. or g  we bsite .   E v al ua ble f or 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 5  
P F S a n d t o xicit y e v al ua ble (see Secti o n 4. 7) ha ve t he sa me defi niti o n :  re gistere d a n d 
ha vi n g starte d Ni v ol u ma b t hera p y.   All o wi n g f or u p t o 1 0 % of e nr olle d patie nts w h o 
ma y b ec o me i ne v al ua ble, u p t o 3 4 patie nts ma y nee d t o be e nr olle d. 
 
8. 4  
  
A n al ysis  
 
8. 4. 1  F or t he P ri mar y O bjecti ve, t he ce ns ore d P F S distri b uti o n will be s u m marize d wit h 
t he Ka pla n-M eier ( K -M) s ur vi v ors hi p esti mate.   A gra p h of t he K -M c ur v e f or P F S will 
be  ge ner ate d  al o n g  wit h  t he  Hall -Well ner  9 5 %  c o nfi de nce  ba n d,  a n d  a  dis pla y  of  t he 
n u m ber of p atie nts at r is k at se veral ti me p oi nts, bel o w t he X -a xis.   S u m mar y statistics 
( 1 2-m o nt h P F S rate, me dia n P F S, etc.) will be calc ulate d fr o m t he K -M life ta ble, eac h o n e 
wit h its res pecti ve 9 5 % c o nfi de nce i nter v al ( CI).   T o test w het her t he p oi nt esti mate of t he 
1 2- m o nt h P F S rate is st atisticall y si g nifica ntl y greater t ha n t he ass u me d hist orical refere nce 
val ue  of  0. 5 0,  t he  p oi nt  esti mate  will  be  c o m pare d  t o  t he  u p per  critical  val ue  of  0. 6 4 
o btai ne d fr o m t he “ O ne Ar m S ur vi val” pr o gra m me nti o ne d i n Secti o n 8. 3. 
 
8. 4. 2     F or  Sec o n dar y  O bjecti ve  ( 1)  t o xicit y  rates  will  be  esti mate d  a m o n g  t he  t o xicit y 
e val ua ble patie nts ( defi n e d i n Secti o n 4. 7).   Fre q ue nc y distri b uti o ns of eac h t o xicit y t y pe 
b y se verit y gr a de will be ge n erat e d.   F or a gi ve n gra de(s), t he p oi nt esti ma te of t he t o xicit y 
rate will be c o m p ute d, al o n g wit h its 9 5 % ( Wils o n t y pe) CI.    
 
8. 4. 3      F or  Sec o n dar y  O bjecti ve  ( 2),  t he  O R R  will  be  esti mate d  a m o n g  t he  res p o nse 
e val ua ble  patie nts  ( d efi ne d  i n  Secti o n  4. 6),  a n d  a m o n g  all  p atie nts.     Fre q ue nc y 
distri b uti o ns of best res p o nse will be ge n erate d f or eac h of t h ose sets of patie nts.   T he 
p oi nt esti mate of t he O R R will be c o m p ute d, al o n g wit h its 9 5 % ( Wils o n t y p e) CI.    
 
8. 4. 4   F or Sec o n dar y O bjecti ves ( 3) a n d ( 4), s u m mar y statistics of M F S a n d O S will be 
calc ulate d  fr o m  t heir  res pecti ve  K -M  life  ta bles  i n  t he  si milar  fas hi o n  as  descri be d  i n 
Secti o n 8. 4. 1 f or O S.   K- M gra p hs of t he ce ns ore d M F S a n d O S distri b uti o ns will als o be 
ge n erat e d.  
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 6  
8. 4. 5   F or Sec o n dar y O bjecti ve ( 5),  t he Q O L data will be use d t o test t he f oll o wi n g h y p ot heses: 
1.     De m o gra p hics  a n d  cli nical  varia bl es  (a ge,  s e x,  race/et h nicit y)  will  be  rel ate d  t o 
le n gt h of ti me o n trial (i. e., da ys or w ee ks); 
2.     De m o gra p hic a n d cli nical varia bles (ca ncer sta ge, perf or m a nce stat us, n u m ber of 
c o m or bi dities) will be relate d t o:  (a) a v era ge le v els of Q O L;  a n d ( b) v ari a bilit y i n 
Q O L o ver t he c o urse of t he trial.  
We will use a li near mi xe d -effects m o del t o test t he ass ociati o n bet wee n b aseli ne patie nt 
fact ors ( de m o gra p hic a n d cli nical meas ures) an d Q O L.   T he m o del will ha ve a ra n d o m 
i nterce pt, sl o pe, a n d lea di n g c oefficie nt f or t he m eas ure m e nt of Q O L acr oss all 1 5 ti me 
p oi nts i de ntifie d i n t he St u d y Cale n d ar, Secti o n 2. 3.   T he patie nt fact ors will be use d as 
pre dict ors of Q O L wit h baseli ne Q O L a s a c o variate.   T he ass ociati o n will be i n vesti gat e d 
base d o n t he statistical testi n g f or eac h of t he sl o pe a n d i nterce pt fi x e d -effects usi n g a Wal d 
test.   As  t he  meas ur e m e nts  o n  eac h  i n di vi d ual  w o ul d  be  c orrelat e d,  t he  first -or d er 
a ut ore gr essi ve  A R( 1)  r esi d ual  will  be  use d  f or  t he  resi d u al  varia nce -c o v aria n ce 
str uct ure.    We will als o i n vesti gate ot her varia nce -c o varia n ce resi d ual str uct ures t o f urt her 
i m pr o ve  t he  m o del  fitti n g.   T he  fi nal  m o del  will  be  selecte d  bas e d  o n  t he  A kai ke 
i nf or mati o n criteri on ( AI C).  
 
8. 4. 6   F or Sec o n d ar y O bj ecti ve ( 6), t he tiss ue mar k ers (e. g., P D-1, P D L -1, TI Ls) a n d ser u m 
mar ker T h 1/ T h 2 c yt o ki ne rati o first will be s u m marize d descri pti vel y.   T he cate g ori cal 
mar kers P D -1 a n d P D L -1 will be s u m marize d via fre q ue n c y distri b uti o ns ( o ver t heir I H C 
e x pressi o n cate g ories of 0, 1 +, 2 +, a n d 3 +).   T he c o nti n u o us  mar kers (e. g., TI Ls, T h 1/ T h 2 
c yt o ki ne  r ati o,  etc.)  will  be  s u m marize d  wit h  sta n dar d  descri pti ve  statistics.      T hese 
descri pti ve a n al yses of t he tiss ue a n d pl as ma bi o mar kers will be perf or me d f or eac h ti me 
p oi nt at w hic h t he eac h mar ker is deter mi ne d. 
   Res p o nse ( C R/ P R vs n ot) will be m o dele d as a f u ncti o n of a dic h ot o mize d versi o n of 
prest u d y P D -1 a n d P D L -1 e x pressi o n (se parat el y) usi n g e x act l o gistic re gressi o n.   Si milar 
lo gistic m o del a nal ys es of t h ose tiss ue mar kers deter mi ne d at ot her ti me p oi nts  pri or t o 
res p o nse deter mi nati o n will als o be perf or me d.   Si milar m o deli n g will be perf or m e d f or 
t he c o nti n u o us ( u n gr o u pe d) mar kers (e. g., TI Ls fr o m tiss ue, a n d t he T h 1/ T h 2 c yt o ki ne rati o 
).   T he statistical g o al  of t hese  e x pl orat or y  a nal ys es is t o o btai n t h e p oi nt a n d 9 5 % CI 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 7  
esti mates of t he o d ds rati o ( O R), a n d t o si m pl y d eter mi ne t he directi o n a n d a p pr o xi mate 
ma g nit u de of t h ese ass o ciati o ns f or use i n pla n ni n g a s u bs e q ue nt st u d y.  
   Ce ns ore d P F S will be m o dele d as a f u ncti o n of a dic h ot o mize d versi o n of prest u d y P D -
1  a n d  P D L -1  e x pressi o n  (se par atel y)  usi n g  C o x  pr o p orti o nal  hazar ds  ( P H)  re gressi o n.    
Ti me - de pe n d e nt C o x m o del a nal yses of t h ose tiss ue mar kers deter mi ne d at all ti me p oi nts  
will als o be perf or me d.   A si milar C o x m o deli n g strate g y will be use d f or t he c o nti n u o us 
( u n gr o u pe d) mar kers ( e. g., TI Ls fr o m tiss ue, a n d t he T h 1/ T h 2 c yt o ki ne ratio fr o m ser u m).   
F or all C o x m o dels, t he P H ass u m pti o n will be e x a mi ne d gra p hicall y b y i ns pecti o n of l o g(-
l o g) s ur vi v al pl ots, a n d of E pa nec h ni k o v ker nel -s m o ot he d hazar d f u ncti o ns.   N o n -P H f or 
a gi ve n mar ker v aria ble will be i nc or p orate d i nt o t he C o x m o de l b y i ncl u di n g a ( l n( P F S) 
* mar ker ) i nter acti o n ter m i n t he C o x m o del.   T he statistical g oal of t h ese e x pl orat or y 
a nal ys es is t o o btai n t he p oi nt a n d 9 5 % CI esti mates of t he hazar d rati o ( H R), a n d t o si m pl y 
deter mi ne  t he  directi o n  a n d  a p pr o xi mate  ma g nit u de  of  t hese  ass ociati o ns  f or  use  i n 
pla n ni n g a s u bs e q ue nt st u d y.    
8. 5  
  
E x pecte d accr u al r ate, accr u al d ur ati o n, a n d t ot al st u d y d ur ati o n 
   T he  e x pecte d  accr u al  rate  is  3 -4  p atie nts/ year/i nstit uti o n.      It  is  e x pecte d  t hat 2-
3 i nstit uti o ns will partici pate i n t his st u d y, yiel di n g a c o m bi ne d e x pecte d accr ual rate of 1 2 
– 1 5 patie nts / year.   At t hat rate, 3 4 patie nts (t o yiel d 3 0 e val ua ble  f or P F S) w o ul d be accr ue d 
i n – 3 0 - 3 6 m o nt hs, a ti m e i nter v al w hic h c o ntai ns t he 2 4 -m o nt h ass u me d accr ual d urati o n 
i n t he st u d y desi g n. 
   All o wi n g f or t h e re q uir e d 1 2 m o nt hs of a d diti o nal f oll o w -u p ti me, t he pri mar y e n d p oi nt 
s h o ul d be o btai ne d f or all patie nts i n – 3 2 - 4 6 m o nt hs (i.e., 2. 7 – 3. 8 years).  
   All o wi n g f or  4 m or e  m o nt hs  t o  deter mi ne  all  c orrelati ves  o n  t h e  last  fe w  patie nts 
e nr olle d, t hat w o ul d ta ke 3 6 – 5 0 m o nt hs (i.e., 3. 0 – 4. 2 years).  
   Fi nall y, si n ce f oll o w -u p f or P F S a n d O S will occ ur f or a ma xi m u m of 5 years (as per 
Secti o ns 2. 3, 4. 9 a n d 4. 1 0), t he n t he t otal st u d y d urati o n is a ma xi m u m of 6 0 m o nt hs ( i.e., 
5. 0 years).  
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 8  
9. 0     E T HI C A L A S P E C T S  
9. 1  
  L oc al Re g ul ati o ns 
T he  st u d y  m ust  f ull y  a d here  t o  t h e  pri nci ples  o utli ne d  i n  “ G ui deli ne  f or  G o o d  Cli nical 
Practice”  ( G C P)  I C H  E 6  Tri partite  G ui deli ne  (J a n uar y  1 9 9 7).  T h e  i n vesti gat or /s will 
e ns ure t hat t h e c o n d u ct of t he st u d y c o m plies wit h t he basic pri nci ples of G C P as o utli ne d 
i n  t he  c urre nt  versi o n  of  2 1 C o de  of  Fe deral  Re g ulati o ns,  s u b part  D,  Part  3 1 2, 
“ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors ” Part  5 0, “ Pr otecti o n of H u ma n S u bjects” 
a n d Part  5 6, “I nstit uti o nal Re vie w B oar ds.” 
9. 2  
 I nf or me d C o nse nt 
It is t he res p o nsi bilit y of t he i n vesti gat or, or  a pers o n desi g nate d b y t he i n vesti gat or, t o 
o btai n writte n i nf or me d c o nse nt fr o m eac h s u bject partici pati n g i n t his st u d y after a d e q uate 
e x pla nati o n of t he ai ms, met h o ds, a ntici pate d be n efits, a n d p ote ntial hazar ds of t he st u d y. 
I n  t he  case  w her e  t he  s u bject  is  u na ble  t o  rea d,  a n  i m partial  wit ness  s h o ul d  be  pres e nt 
d uri n g t he e ntire i nf or m e d c o nse nt disc ussi o n. After t he  s u bject has orall y  c o nse nte d t o 
partici pati o n i n t he trial, t he wit ness’s si g n at ure o n t he f or m will attest t hat t he i nf or mati o n 
i n t he c o nse nt f or m was acc ur atel y e x plai ne d a n d u n derst o o d. 
D oc u me ntati o n of i nf or m e d s u bject c o nse nt m ust b e c o m plete d a p pr o priatel y. If ne w s afet y 
i nf or mati o n res ults i n si g nifica nt c ha n ges i n t he ris k/ be nefit assess me nt, t he c o nse nt f or m 
s h o ul d  be  re vie w e d  a n d  u p date d  as  n ecess ar y.  All  s u bjects  (i ncl u di n g  t h ose  w h o  ha v e 
alrea d y c o m plet e d st u d y t hera p y) s h o ul d be i nf or me d of t he ne w i nf or mati o n, s h o ul d be 
gi ve n a c o p y of t he re vis e d f or m, a n d s h o ul d gi ve t heir c o nse nt t o c o nti n ue i n t he st u d y. 
9. 3  
  C o n diti o ns f or M o dif yi n g t he P r ot oc ol  
Pr ot oc ol m o dificati o ns ma y be m a de a n d will be pre pare d, re vie w e d, a n d a p pr o ve d b y t h e 
pri nci pal i n vesti gat or or r e prese nt ati ves of t he i n vesti gat or. 
All pr ot oc ol m o dificati o ns m ust be s u b mitte d t o t he I R B/ E C f or i nf or mati o n a n d a p pr o v al 
i n  acc or da n ce  wit h  l ocal  re q uire me nts  a n d  t o  re g ulat or y  a ge ncies  if  re q uire d.  A p pr o val 
m ust be o btai ne d bef or e a n y c ha n ges ca n b e i m ple me nte d, e x ce pt f or c h a n ges necess ar y t o 
eli mi nate a n i m me diate  hazar d t o st u d y s u bjects or t h ose t hat i n v ol ve o nl y l o gistical or 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
4 9  
a d mi nistrati ve  as pects  of  t he  trial  (e g,  c ha n ge  i n  data  m o nit or  or  c ha n ge  of  t ele p h o n e 
n u m ber). 
9. 4  
 C o n diti o ns f or T er mi n ati n g t he S t u d y 
Kar ma n os  Ca n cer  I nstit ute reser ves  t he  ri g ht  t o  ter mi nate  t he  st u d y,  a n d  i n vesti gat ors 
reser v e t he ri g ht t o ter mi nate t heir partici pati o n i n t he st u d y, at a n y ti me. S h o ul d t his be 
necessar y, t he i n vesti gat or will arra n ge t he pr oce d ures o n a n i n di vi d ual st u d y b asis aft er 
re vie w a n d c o ns ultati o n. I n ter mi nati n g t he st u d y, a de q uate c o nsi derati o n will be gi ve n t o 
t he pr otecti o n of t he s u bj ects’ i nterests. 
1 0. 0 S T U D Y D O C U M E N T A TI O N  
Acc ur ate  a n d  c o m plete  st u d y  rec or ds  will  be  mai ntai ne d  a n d  ma d e  a vaila ble  t o 
re pres e ntati ves of t he c o or di nati n g site as n ecess ar y f or re vie w a n d d ata e xtracti o n. 
1 0. 1  
  P ati e nt Re gist r ati o n a n d D at a C ollecti o n   
 
All patie nts s hall be re gistere d wit h t he Kar ma n os Ca ncer I nstit ute  Cli nical Trials Office 
at ( 3 1 3) 5 7 6 -9 3 7 2 ( Bre n da Dic k o w) or  Ki m berl ee D o bs o n 3 1 3 - 5 7 6- 9 8 3 7 or Sara h R us k  
3 1 3- 5 7 6- 9 7 7 1.   
 
At  t he  ti me  of  re gistrati o n,  a  pre -st u d y  f or m  a n d  all  i nf or mati o n  re q uire d  t o  verif y 
eli gi bilit y s hall b e ne cess ar y o n eac h patie nt pri or t o treat me nt. T his f or m s h o ul d be fa x e d 
t o  3 1 3- 5 7 6-8 9 7 4  a n d  eli gi bilit y  verificati o n  will  be  se nt  wit hi n  4 8  h o urs.  Data  will  be 
c ollecte d  a n d  mai ntai ne d  o n  st u d y  s p ecific  electr o nic  case  re p ort  f or ms  i n  t he  O nc ore 
Researc h  E nt er prise s yste m at Kar ma n os Ca ncer  I nstit ute. Trai ni n g a n d s u p p ort will be 
pr o vi de d f or all staff e nteri n g d ata. Dat a e ntr y m ust occ ur wit hi n 2 wee ks of visits al o n g 
wit h s u b missi o n of a p plica ble s o ur ce d oc u m e ntati o n.  
 
 
1 0. 2    
I n vesti g at or’s Files a n d Re q ui re d D oc u me nts  
T he i n vesti gat or m ust mai ntai n a de q uat e a n d acc urate rec or ds t o e n a ble t he c o n d uct of t he 
st u d y  t o  be  f ull y  d oc u me nte d  a n d  t h e  st u d y  d ata  t o  be  s u bse q ue ntl y  verifie d.  T h ese 
d oc u me nts  s h o ul d  be  classifie d  i nt o  t w o  se parate  cate g ories  as  f oll o w s:  ( 1) t he 
i n vesti gat or’s st u d y file, a n d ( 2) s u bjects’ cli nical s o urce d oc u m e nts. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 0  
T he i n vesti gat or’s st u d y  file will c o ntai n t he pr ot oc ol  a n d  pr ot oc ol a me n d me nts, C R Fs, 
q uer y f or ms, I R B/ E C a n d g o ver n me ntal a p pr o v als wit h c orres p o n de n ce, sa m ple i nf or me d 
co nse nt, dr u g r ec or ds, staff c urric ul u m vitae a n d a ut h orizati o n f or ms, a n d ot her a p pr o priate 
d oc u me nts a n d c orres p o n de nce. 
S u bjects’  cli nical  s o ur ce  d oc u me nts  i ncl u d e  t he  s u bjects’  h os pital/  cli nic  rec or ds; 
p h ysicia ns’  a n d  n urses’  n otes;  t he  a p p oi nt me nt  b o o k;  ori gi nal  la b orat or y,  E C G, sca ns, 
X- ra y,  p at h ol o g y  a n d  s pecial  assess me nt  re p orts;  si g ne d  i nf or me d  c o nse nt  f or ms; 
c o ns ulta nt letters; a n d s u bject scree ni n g a n d e nr oll me nt l o gs.  
T he i n vesti gat or m ust kee p t hese d oc u me nts o n file f or at least 2  years afte r t he st u d y has 
bee n  ter mi nate d. After  t hat  peri o d,  t he  d oc u me nts  ma y  be  destr o ye d  s u bject  t o  l ocal 
re g ulati o ns. If t he i n vesti gat or w a nts t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve 
t he m t o a n ot her l ocati o n, Kar ma n os Ca n cer I nstit ute m ust be n oti fie d i n a d va nce. 
W he n  s o urce  d oc u me nts  are  r e q uire d  f or  t he  c o nti n ue d  care  of  t he  s u bject,  a p pr o priate 
c o pies s h o ul d be ma de f or st ori n g o utsi de of t he st u d y site. 
1 0. 3     
S o urce D oc u me nts a n d B ac k gr o u n d D at a  
U p o n re q uest, t he i n vesti gat or will s u p pl y its  lice nsees a n d c olla b orat ors wit h a n y re q uire d 
bac k gr o u n d  data  fr o m  t he  st u d y  d oc u me ntati o n  or  cli nic  rec or ds.  T his  is  partic ularl y 
i m p orta nt w he n C R Fs ar e ille gi ble or w h e n err ors i n data tra nscri pti o n are s us pecte d. I n 
case of s pecial pr o ble ms or g o ver n me ntal q ueries or re q uests f or a u dit i ns pecti o ns, it is als o 
necessar y  t o  ha ve  access  t o  t he  c o m plete  st u d y  rec or ds,  pr o vi de d  t hat  s u bject 
c o nfi de ntialit y is pr otecte d.  
1 0. 4    
C ase Re p ort F or ms ( C R F) 
F or  e nr olle d  s u bjects,  o nl y  d ata  fr o m  t he  pr oce d ures  a n d  assess me nts  s pecifie d  i n  t his 
pr ot oc ol a n d re q uir e d b y t he C R Fs s h o ul d be s u b mitte d o n t he a p pr o priat e C R F. A d diti o nal 
pr oce d ur es a n d assess me nts ma y be perf or me d as part of t he i n v esti gat or’s i nstit uti o n or 
me dical practice sta n dar d of car e a n d ma y n ot b e re q uire d f or C R F e ntr y.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 1  
F or eac h s u bject e nr olle d, t he C R F ( p a per or electr o nic) m ust be c o m plete d a n d si g n e d b y 
t he PI or a ut h orize d dele gat e fr o m t he st u d y staff. 
All pa per f or ms s h o ul d be t y p e d or fille d o ut usi n g i n deli ble i n k a n d m ust be le gi ble. Err ors 
s h o ul d be cr osse d o ut b ut n ot o bliterate d, t he c orrecti o n i nserte d, a n d t he c ha n ge i nitiale d 
a n d date d b y t he i n vesti gat or or his or her a ut h orize d dele gat e.  
T he  i n vesti gat or s h o ul d e ns ure t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness of t he 
data re p orte d i n t he C R F a n d i n all re q uire d re p orts. T he C R Fs will be c o m plete d a n d st ore d 
electr o nicall y wit hi n t he O nc ore Res earc h E nter prise s yste m at K ar ma n os C a ncer I nstit ute.  
1 0. 5     
C o nfi de nti alit y of T ri al D oc u me nts a n d S u bjec t Rec or ds  
T he i n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y will be mai ntai ne d  a n d t hat t heir 
i de ntities are pr otecte d fr o m u na ut h orize d parties. O n C R Fs or ot her d o c u me nts s u b mitte d 
t o K CI or desi g nees, s u bj ects s h o ul d be i de ntifie d b y i d e ntificati o n c o d es a n d n ot b y t heir 
na mes. T he i n vesti gat or s h o ul d kee p a s u bject e nr oll me nt l o g s h o wi n g c o d es, na mes, a n d 
a d dresses.  T he  i n vesti gat or  s h o ul d  mai ntai n  d oc u me nts  n ot  f or  s u b missi o n  t o K CI or 
desi g nees (e g,  s u bjects’ writte n c o nse nt f or ms) i n strict c o nfi de nce. 
All t u m or sca ns, res ear c h sa m ples, p h ot o gra p hs, a n d res ults fr o m e x a mi nati o ns, tests, a n d 
pr oce d ur es ma y be s e nt t o K CI a n d its part ners or desi g nees f or re vie w. 
1 0. 6  
 
P u blic ati o n of D at a  
T he Pri nci pal I n v esti gat or ( Pr ot oc ol C hair) h ol ds t he pri mar y res p o nsi bilit y f or p u blicati o n 
of t he st u d y r es ults; pr o vi de d t hat t he PI will pr o vi de a n y s uc h p u blicati o n t o Brist ol M yers 
S q ui b b I nc. f or r e vie w pri or t o s u b missi o n a n d als o c o m pl y wit h  a n y p r o visi o ns re gar di n g 
p u blicati o n. T he r es ults will be ma de p u blic wit hi n 2 4  m o nt hs of t he e n d of data c ollecti o n. 
H o we ver, if a re p ort is pl a n ne d t o be p u blis he d i n a peer -re vie we d j o ur nal, t he n t hat i nitial 
releas e ma y be a n a bstract t hat meets the re q uire me nts of t he I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors. I n a n y e ve nt, a f ull re p ort of t he o utc o mes s h o ul d be ma de p u blic 
n o later t ha n t hree ( 3) years after t he e n d of data c ollecti o n. A ut h ors hi p f or a bstracts a n d 
ma n uscri pts  res ulti n g  fr o m  t his  st u d y  will  be  deter mi ne d  acc or di n g  t o  g ui deli nes 
esta blis he d b y t h e I nter n ati o nal C o m mi ttee of Me dical J o ur nal E dit ors. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 2  
 
1 1. 0  R E F E R E N C E S  
1) Gr oss ma n,  H B,  R o nal d  B.  Natale,  Cat heri ne  M.  Ta n ge n,  P. H.,  V. O.  S pei g hts,  D. O., 
Nic h olas J. V o gelza n g, D o nal d L. Tr u m p, Ral p h W. de Vere W hite, Mic h ael F. Sar os d y, 
Da vi d P. W o o d, Jr., Dere k Ra g h a va n, a n d E. Da vi d Cra wf or d. Ne oa dj u v a nt C he m ot hera p y 
pl us  C yst ect o m y  C o m pare d  wit h  C ystect o m y  Al o ne  f or  L o call y  A d v a nce d  Bla d der 
Ca ncer. N E n gl J Me d 2 0 0 3; 3 4 9: 8 5 9- 8 6 6 
2) Ma k R H, H u nt D, S hi ple y W U, Efstat hi o u J A, Tester WJ, Ha ga n M P, Ka uf ma n D S, 
He ne y N M, Ziet ma n A L. L o n g -ter m o utc o mes i n patie nts wit h m uscle-i n vasi ve bla d der 
ca ncer after selecti ve bla d der - pr eser vi n g c o m bi ne d-m o dalit y t hera p y: a p o ole d a nal ysis of 
Ra di ati o n T hera p y O nc ol o g y Gr o u p pr ot oc ols 8 8 0 2, 8 9 0 3, 9 5 0 6, 9 7 0 6, 9 9 0 6, a n d 0 2 3 3.J 
Cli n O nc ol. 2 0 1 4 Dec 1; 3 2( 3 4): 3 8 0 1- 9. 
3) Gals k y  M D,  H a h n  N M,  R ose n ber g  J,  et  al.  Treat me nt  of  patie nts  wit h  metastatic 
ur ot helial ca ncer “ u nfit” f or cis plati n -base d c he m ot hera p y. J Cli n O nc ol. 2 0 1 1; 1 0; 2 9: 2 4 3 2 -
2 4 3 8. 
4 )  Gals k y  M D,  Ha h n  N M,  R ose n ber g  J,  et  al.  A  c o nse ns us  defi niti o n  of  patie nts  wit h 
metastatic  ur ot helial  car ci n o ma  w h o  are  u nfit  f or  cis plati n -base d  c h e m ot hera p y.  La n cet 
O nc ol. 2 0 1 1; 1 2: 2 1 1- 2 1 4. 
5 ) J a mes N D 1, H uss ai n S A, Hall E, J e n ki ns P, Tre mlett J, Ra wli n gs C, Cr u n d well M, Sizer 
B, Sree ni vas a n T, He n dr o n C, Le wis R, Waters  R, H u d dart R A; B C 2 0 0 1  I n vesti gat ors. 
Ra di ot hera p y wit h or wit h o ut c he m ot hera p y i n m uscle -i n vasi ve bla d der ca ncer. N E n gl J 
Me d. 2 0 1 2 A pr 1 9; 3 6 6( 1 6): 1 4 7 7- 8 8.  
6 ) Patel B, F or ma n J, F o nta na J, Frazier A, P o ntes E, Vais ha m pa ya n U. A si n gle i nstit uti o n 
e x perie nce  wit h  c o n c urr e nt  ca pecita bi ne  a n d  ra diati o n  t hera p y  i n  wea k  a n d/ or  el derl y 
patie nts wit h ur ot helial ca ncer.I nt J Ra diat O nc ol Bi ol P h ys. 2 0 0 5 A u g 1; 6 2( 5): 1 3 3 2- 8.  
7 )  S har ma  P,  Retz  M,  Sief ker-Ra dt ke  A,  et  al.  Ni v ol u ma b  i n  metastatic  ur ot helial 
carci n o ma  after  plati n u m  t hera p y  ( C hec k M ate  2 7 5):  a  m ultice ntre,  si n gle -ar m,  p h ase  2 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 3  
trial.  La ncet  O nc ol.  P u blis he d  o nli ne  J a n uar y  2 5,  2 0 1 7.  d oi:  1 0. 1 0 1 6/ S 1 47 0-
2 0 4 5( 1 7) 3 0 0 6 5- 7. 
8 )  De maria  S,  G ol de n  E B,  F or me nti  S C.  R ole  of  L ocal  R a diati o n  T h era p y  i n  Ca n cer 
I m m u n ot her a p y.J A M A O nc ol. 2 0 1 5 Dec; 1( 9): 1 3 2 5- 3 2.  
9 ) Pil o nes K A, Va n p o uille-B o x C, De maria S C o m bi nati o n of ra di ot hera p y a n d i m m u ne 
c hec k p oi nt i n hi bit ors. Se mi n Ra diat O nc ol. 2 0 1 5 J a n; 2 5( 1): 2 8- 3 3.  
1 0 )  Der er  A,  Fre y  B,  Fi et ka u  R,  Gai pl  U S.  I m m u ne-m o d ulati n g  pr o p erties  of  i o nizi n g 
ra diati o n: rati o nale f or t he treat me nt of ca ncer b y c o m bi nati o n ra di ot hera p y a n d i m m u ne 
c hec k p oi nt i n hi bit ors. Ca ncer I m m u n ol I m m u n ot her. 2 0 1 6 J ul; 6 5( 7): 7 7 9- 8 6.  
1 1 )  F or m e nti  S C,  De maria  S.  C o m bi ni n g  ra di ot hera p y  a n d  ca n cer  i m m u n ot hera p y:  a 
para di g m s hift. J Natl Ca ncer I nst. 2 0 1 3 Fe b 2 0; 1 0 5( 4): 2 5 6- 6 5.  
1 2 ) O P DI V O [ pac k a ge i nsert]. Pri ncet o n, NJ: Brist ol- M yers S q ui b b C o m pa n y; 2 0 1 7. 
1 3 ) M otzer  RJ,  Ri ni  BI,  Mc Der m ott  D F,  et  al.  Ni v ol u ma b  f or  Met astatic  Re nal  Cell 
Carci n o ma:  Res ults  of  a  Ra n d o mize d  P hase  II  Trial.  J  Cli n  O nc ol.  2 0 1 5  Ma y 
1; 3 3( 1 3): 1 4 3 0- 7. 
1 4 ) Eise n ha u er E A, T h er asse P, B o gaerts J, Sc h w artz L H, Sar ge nt D, F or d R, Da n ce y J, 
Ar b uc k S, G w yt h er S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pl a n R, Lac o m be 
D, Ver weij J. Ne w r es p o nse e v al uati o n criteria i n s oli d t u m o urs: re vise d R E CI S T g ui deli n e 
( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9 J a n; 4 5( 2): 2 2 8- 4 7.  
 
 
 
 
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 4  
 
1 2. 0    D A T A A N D S A F E T Y M O NI T O RI N G  
Sc he d ule d meeti n gs/ telec o nfer e nces will be hel d m o nt hl y or m ore fre q ue ntl y de pe n di n g 
o n t he acti vit y of t h e pr ot oc ol.  T hes e meeti n gs will i ncl u de t he pr ot oc ol i n vesti gat ors a n d 
data ma na gers i n v ol ve d wit h t he c o n d uct of t he pr ot oc ol. T he Data a n d Safet y M o nit ori n g 
C o m mittee at t he c o or di nati n g site ( K ar ma n os C a ncer I nstit ute) will ha ve o versi g ht of all 
patie nts e nr olle d o n t he trial at all partici pati n g sites.  
 
D uri n g t h ese meeti n gs t h e i n vesti gat ors will disc uss matters relate d t o:  
 
•  
Safet y o f pr ot oc ol partici pa nts ( A d vers e E ve nt re p orti n g) 
•   
Vali dit y a n d i nte grit y of t he data 
•  
E nr oll me nt rate rel ati ve t o e x pectati o n of tar get accr ual, c h aracteristics of  
 
partici pa nts  
•   
Rete nti o n of partici pa nts, a d here n ce t o t he pr ot oc ol ( p ote ntial or real 
pr ot oc ol vi olati o ns) 
•  
Data c o m plete n ess o n case re p ort f or ms a n d c o m plete s o urce 
d oc u me ntati o n 
 
C o m plete d Data a n d Safet y M o nit ori n g Re p orts of t hese re g ular i n vesti gat or meeti n gs 
will be ke pt o n file i n t he office of t he Cli nical Trials C ore (see f or m i n  a p p e n di x E). T he 
data ma na ger assi g ne d t o t he cli nical trial  at eac h site will be res p o nsi ble f or c o m pleti n g 
t he  re p ort  f or m.    T he  c o m plete d  re p orts  will  be  re vie we d  a n d  si g ne d  off  b y  t he site 
Pri nci pal I n vesti gat or ( PI) or b y o n e of t he C o -i n vesti gat ors i n t he a bse nce of t he PI.  T he 
si g ne d off f or ms will t he n be f or war d e d t o t he st u d y c o or di n at or at Kar m a n os C a ncer 
I nstit ute (c o or di nati n g sit e), f or re vie w of c o m plete ness a n d pr ocessi n g wit h t he Data a n d 
Safet y M o nit ori n g C o m mittee.  
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 5  
T he  Kar ma n os  Ca ncer  I nstit ute, Data a n d Safet y M o nit ori n g C o m mittee will meet o n a 
re g ular  basis  t o  re vie w  t he  pri or  Seri o us  A d verse  E ve nt  f or ms  a n d  Data  a n d  Safet y 
M o nit ori n g st u d y s p ecifi c re p orts t hat ha v e bee n file d. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 6  
A P P E N DI X  A  
Z u br o d/ E C O G / K ar n ofs k y Perf or m a nce St at us Criteri a  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 7  
E C O G P erf or m a nce St at us 
Sc ale  
 
K ar n ofs k y Perf or m a nce Sc ale  
Descri pti o ns  
Perce nt  
Descri pti o n  
N or mal acti vit y. F ull y acti ve, 
a ble t o carr y o n all pre disease 
perf or ma nce wit h o ut restricti o n. 
1 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.  
S y m pt o ms, b ut a m b ulat or y. 
Restricte d i n p h ysicall y 
stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut 
w or k of a li g ht or se de ntar y 
nat ure (e g, li g ht h o use w or k, 
office w or k).  
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.  
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. 
I n be d > 5 0 % of t he ti me. 
Ca pa ble of o nl y li mite d self- care, 
c o nfi ne d t o be d or c hair m ore 
t ha n 5 0 % of wa ki n g h o urs. 
4 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 ot i m mi ne nt. 
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 dicate 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.  
Dea d  
0 
Dea d  
E C O G = Easter n C o o perati ve O nc ol o g y Gr o u p. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 8  
 
A P P E N DI X B  
S A M P L E O F D R U G O R D E R I N G A N D P H A R M A C Y R E F E R E N C E M A T E RI A L 
Ni v ol u m a b ( B M S- 9 3 6 5 5 8) P h ar m ac y R efere nce M ateri al 
•  Ni v ol u ma b has a c o nce ntrati o n of 1 0 m g/ m L a n d is pr o vi de d i n a 1 0 m L vial.  Te n or 
fi ve vials are pr o vi de d i n a cart o n. 
 
I niti al Or ders  
•  F oll o wi n g  s u b missi o n  a n d  a p pr ov al  of  t he  re q uire d  re g ul at ory  d o c u me nts,  a n d  a n 
exec ute d st u dy a gree me nt, a s u p ply of niv ol u m a b m ay be or dere d by c o m pleti n g a Dr u g 
Re q uest F or m pr ovi de d b y B M S f or t his s pecific tri al. T he first re q uest m ay t ake pl ace 
u p o n scree ni n g of t h e first p atie nt  
•  T he i niti al or der s h o ul d be li mite d t o 2 0 vi als. All o w 5 b usi ness d ays f or s hi p me nt of 
dr u g fr o m B M S recei pt of t he Dr u g Re q u est F or m. Dr u g is pr ot oc ol s pecific, b ut n ot 
p atie nt  s pecific.  All  dr u g  pr o d uct  will  be  s hi p pe d  by  c o urier  i n  a  te m per at ure-
c o ntr olle d  c o nt ai ner.  It  is  p ossi ble  t h at  sites  m ay  h ave  m ore  t h a n  o ne  niv ol u m a b 
cli nic al  st u dy  o n g oi n g  at  t he  s a me  ti me.  It  is  i m per ative  t h at  o nly  dr u g  pr o d uct 
desi g n ate d f or t his pr ot oc ol n u m ber be use d f or t his st u dy.  
•  P h ar m acy  s u p plies  n ot  pr ovi de d  by  B M S:    E m pty  I V  b a gs/ c o nt ai ners, a p pr ove d 
dil ue nts,  I n-li ne filters a n d i nf usi o n t u bi n g 
Re - S u p ply 
•  Dr u g re -s u p ply re q uest f or m s h o ul d be s u b mitte d electr o nic ally 5 b usi ness d ays bef ore 
t he ex pecte d delivery d at e.  Deliveries will be m a d e T ues d ay t hr o u g h Fri d ay. 
•  W h e n assessi n g n ee d f or res u p ply, i nstit uti o ns s h o ul d kee p i n mi n d t he n u m ber of vi als 
use d  per  tre at me nt  d ose,  a n d  t h at  s hi p me nts  m ay  t ake u pt o 1 4  b usi ness  d ays  fr o m 
recei pt of re q uest. Dr u g is n ot p atie nt-s pecific. Be s ure t o c heck wit h y o ur p h ar m acy 
re g ar di n g existi n g i nvesti g ati o n al st ock t o ass ure o pti m al use of dr u g o n h a n d. 
Dr u g E xc ursi o ns  
•  Dr u g  exc ursi o ns s h o ul d be re p orte d i m me di atel y t o B M S o n t he f or m pr ovi de d wit h 
t he st u dy-s pecific dr u g or der f or m 
Ple ase r ef er t o t he m ost rece nt versi o n of t he I nvesti g at or Br oc h ure f or a d diti o n al 
i nf or m ati o n. 
St or a ge C o n diti o ns & H a n dli n g: 
•  St ore at 2 - 8° C ( 3 6- 4 6° F), pr otect fr o m li g ht, freezi n g, a n d s h a ki n g. 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
5 9  
•  If a n y t e m perat ure  e x c ursi o ns are  e nc o u ntere d d uri n g st ora ge, pl ease  re p ort t hese t o 
B M S f or assess me nt via t he Te m perat ure E x c ursi o n Res p o nse F or m.    
•  As  wit h  all  i njecta ble  dr u gs,  car e  s h o ul d  be  ta ke n  w he n  ha n dli n g  a n d  pre pari n g 
ni v ol u ma b. W he ne ver p ossi ble, ni v ol u ma b s h o ul d be pre pare d i n a la mi nar fl o w h o o d 
or saf et y ca bi net usi n g st a n dar d preca uti o ns f or t he safe ha n dli n g of i ntra v e n o us a ge nts 
a p pl yi n g as e ptic tec h ni q u e.  
•  Partiall y use d vi als s h o ul d be dis p ose d at t he site f oll o wi n g pr oce d ures f or t he dis p osal 
of a ntica ncer dr u gs.  
 
After  fi nal  dr u g  rec o nciliati o n,  u n use d  ni v ol u ma b  vials  s h o ul d  be  dis p ose d  at  t he  site 
f oll o wi n g pr oce d ur es f or t he dis p osal of a ntica ncer dr u gs. F or f urt her i nf or mati o n, please 
eit her disc uss wit h y o ur B M S C S R & O pr ot oc ol ma na ger or refer t o y o ur site I P D estr ucti o n 
p olicies a n d pr oce d ures  
 
Use Ti me/ St a bilit y:  
 
T he a d mi nistrati o n of B M S - 9 3 6 5 5 8-0 1 i njecti o n pre pare d f or d osi n g ni v ol u ma b i nf usi o n 
m ust be c o m plete d wit hi n 2 4 h o urs of pre parati o n. If n ot use d i m me diatel y, t he i nf usi o n 
s ol uti o n ma y be st or e d u p t o 2 0 h o urs i n a refri gerat or at u n der refri gerati o n c o n diti o ns ( 2°-
°- 8° C (, 3 6°- 4 6° F) a n d use d wit hi n 4 f or u p t o 2 4 h o urs, a n d a ma xi m u m of 8 h o urs of t he 
t otal 2 4 h o urs ca n be at r o o m te m perat ure ( 2 0°-2 5° C, 6 8° -7 7° F) a n d u n der r o o m li g ht. T he 
ma xi m u m 4 -h o ur peri o d u n der r o o m te m perat ure a n d r o o m li g ht c o n diti o ns f or u n dil ute d 
a n d dil ute d s ol uti o ns of B M S - 9 3 6 5 5 8-0 1 i njecti o n i n t he I V b a g s h o ul d b e i ncl usi ve of  t he 
pr o d uct a d mi nistrati o n peri o d. 
 
Pre p ar ati o n a n d A d mi nistr ati o n: 
1.  Vis uall y i ns pect t he dr u g pr o d uct s ol uti o n f or p artic ulate matter a n d disc ol orati o n pri or 
t o  a d mi nistrati o n.   Discar d  if  s ol uti o n  is  cl o u d y,  if  t here  is  pr o n o u nce d  disc ol orati o n 
(s ol uti o n ma y ha ve a pal e-yell o w c ol or), or if t here is f orei g n p artic u late matter ot her 
t ha n a fe w tra nsl uce nt-t o- w hite, a m or p h o us particles. 
N ote:  Mix by ge ntly  i nverti n g sever al ti mes.  D o n ot  s h ake. 
2.  Ase pticall y  wit h dr a w  t he  re q uire d  v ol u me  of  ni v ol u ma b  s ol uti o n  i nt o  a  s yri n ge,  a n d 
dis pe nse i nt o a n I V. ba g.  If m ulti ple vials are nee d e d f or a s u bject, it is i m p orta nt t o use 
a se parat e sterile s yri n ge a n d nee dle f or eac h vial t o pre ve nt pr o ble ms s uc h as  d ulli n g of 
nee dle ti p, st o p per c ori n g, re peate d fricti o n of pl u n ger a gai nst s yri n ge b arrel w all  D o 
n ot  a d mi nister st u d y dr u g as a n I V p us h or b ol us i njecti o n 
3.  A d d t he a p pr o priate v ol u me of 0. 9 % S o di u m C hl ori de I njecti o n s ol uti o n or 5 % De xtr ose 
I njecti o n  s ol uti o n. It  is  acce pt a ble  t o  a d d  ni v ol u m a b  s ol uti o n  fr o m  t he  vi als  i nt o  a n 
a p pr o pri ate pre-fille d b a g of dil ue nt.  
N ote:  Niv ol u m a b i nf usi o n c o nce ntr ati o n m ust be at or a b ove  t he mi ni m u m all o w a ble 
c o nce ntr ati o n of 0. 3 5 m g/ m L [I B V 1 3 A d de n d u m Secti o n 3. 2. 2] 
N ote:  It  is  n ot  r ec o m m e n de d  t h at  s o-c alle d  “c h a n nel ”  or  t u be  syste ms  are  use d  t o 
tr a ns p ort pre p are d i nf usi o ns of niv ol u m a b. 
4.  Attac h t he I V b a g c o ntai ni n g t he ni v ol u ma b s ol uti o n t o t he i nf usi o n set a n d filter.  

 
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6 0  
5.  At t he e n d of t he i nf usi o n peri o d, fl us h t he li ne wit h a s ufficie nt q ua ntit y of a p pr o ve d 
dil ue nts.  
A P P E N DI X C   
I m p ort a nt  S afet y  I nf or m ati o n  f or  Ni v ol u m a b [ F or  t he  m ost  u p d ate d 
i nf or m ati o n  refer  t o  t he  p ac k a ge  i nsert  of  O p di v o/ Ni v ol u m a b] 
htt ps:// p ac k a gei nserts. b ms.c o m/ pi/ pi _ o p di v o. p df  
 
Ge ner al G ui deli nes  
• 
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.  T he  g ui da nce 
a p plies t o all i m m u n o - o nc ol o g y (I-O) a ge nts a n d re gi me ns.  
• 
W here a p plica ble t he A p pr o ve d  La bel s h o ul d b e use d  f or  g ui da n ce ar o u n d d ose 
m o dificati o ns a n d disc o nti n uati o n 
• 
A  ge n eral  pri nci ple  is  t hat  differe ntial  dia g n oses  s h o ul d  be  dili ge ntl y  e val uate d 
acc or di n g t o sta n d ar 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 pri atel y tr eat e 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 d verse 
e ve nts.  T he  oral  e q ui v ale nt  of  t h e  rec o m me n de d  I V  d oses  ma 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 wer  bi oa v aila bilit y  of  oral 
c ortic osteroi 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 val e 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 peci alist, es peciall y pri or t o a n i n vasi ve 
dia g n ostic or t h era p e utic pr oce d ur e, is rec o m me n d e d. 
• 
T he  fre q u e nc y  a n d se v erit y  of  t he  relate d  a d verse  e ve nts  c o v ere d  b y  t h ese 
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 
I n v esti gat ors  s h o ul d  r efer  t o  t he  m ost  c urre nt  versi o n  of  t he  I B  or  A p pr o ve d  La b el  f or 
c urre nt r ec o m me n d ati o ns f or ma na ge me nt of a s p ecific A d verse E ve nt of i nterest.  
I nf or mati o n  m ust  be  i n cl u de d  i n  t he  pr ot oc ol  f or  A E  ma n a ge me nt,  m o dificati o ns  a n d 
disc o nti n uati o n. T he f or mat s h o ul d be t hat w hic h is acce pta ble per i nstit uti o nal practices 
or pr oce d ures:  
I m p ort a nt Safet y I nf or matio n 
 
I m m u ne-Me diate d P ne u m o nitis  
Ni v ol u ma b ca n  ca us e  i m m u ne -me diate d  p ne u m o nitis.  Fatal  cases  h a ve  bee n  re p orte d. 
M o nit or patie nts f or si g ns wit h ra di o gra p hic i ma gi n g a n d f or s y m pt o ms of p ne u m o nitis. 
A d mi nister  c ortic oster oi ds  f or  Gra de  2  or  m ore  se vere  p ne u m o nitis.  Per ma ne ntl y 
disc o nti n ue f or Gra de 3 or 4 a n d wit h h ol d u ntil res ol uti o n f or Gra de 2. I n patie nts recei vi n g 
Ni v ol u ma b m o n ot hera p y,  fatal  cases  of  i m m u ne -me diate d  p ne u m o nitis  ha ve  occ urre d. 
I m m u ne- me diate d p n e u m o nitis occ urre d i n 3. 1 % ( 6 1/ 1 9 9 4) of patie nts. 
 
I m m u ne-Me diate d C olitis  
Ni v ol u ma b ca n ca use i m m u ne -me diate d c olitis. M o nit or patie nts f or si g ns a n d s y m pt o ms 
of c olitis. A d mi nister c ortic oster oi ds f or Gra de 2 ( of m ore t ha n 5 da ys d urati o n), 3, or 4 
c olitis. Wit h h ol d m o n ot hera p y f or Gr a de 2 or 3 a n d per ma ne ntl y disc o nti n ue f or Gra de 4 
o r rec urrent c olitis u p o n re -i nitiati o n of Ni v ol u ma b. I n patie nts recei vi n g m o n  Ni v ol u ma b 
ot hera p y, i m m u ne -me diate d c olitis occ urre d i n 2. 9 % ( 5 8/ 1 9 9 4) of patie nts.  I n patie nts w h o 
recei v e d O P DI V O as a si n gle a ge nt, i m m u ne- me diate d c olitis occ urre d i n 2. 9 % ( 5 8/ 1 9 9 4) 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
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6 1  
of  patie nts;  t he  me dia n  ti me  t o  o nset  was  5. 3  m o nt hs  (ra n ge:  2  da ys  t o  2 0. 9  m o nt hs). 
I m m u ne-me diate d  c olitis  le d  t o  per m a ne nt  disc o nti n uati o n  of i n    ni v ol u ma b  0. 7 %  a n d 
wit h h ol di n g of O P DI V O i n 1 % of patie nts. A p pr o xi matel y  9 1 % of  patie nts wit h c ol itis 
recei v e d hi g h-d os e c ortic oster oi ds ( at least 4 0 m g pre d nis o ne e q ui vale nts per da y) f or a 
me dia n d urati o n of 2 3 da ys (ra n ge: 1 d a y t o 9. 3 m o nt hs). F o ur patie nts re q uire d a d diti o n 
of  i nfli xi ma b  t o  hi g h -d ose  c ortic oster oi ds.  C o m plete  res ol uti o n  occ urre d  i n  7 4 %  of 
patie nts.  A p pr o xi matel y  1 6 %  of  patie nts  ha d  rec urre nce  of  c olitis  after  re -i nitiati o n  of 
ni v ol u ma b. 
 
I m m u ne-Me diate d H e patitis  
Ni v ol u ma b ca n ca us e i m m u ne -me diate d h e patitis. M o nit or patie nts f or a b n or mal li ver tests 
pri or t o a n d peri o dicall y d uri n g treat me nt. A d mi nister c ortic ost er oi ds f or Gra de 2 or greater 
tra nsa mi nase ele vati o ns. Wit h h ol d f or Gra de 2 a n d per ma ne ntl y disc o nti n ue f or Gra d e 3 
or 4 i m m u ne- me diate d h e patitis.  
I n p atie nts w h o recei ve d ni v ol u ma b as a si n gle a ge nt, i m m u ne-me diate d he p atitis 
occ urr e d i n 1. 8 % ( 3 5/ 1 9 9 4) of patie nts; t he me dia n ti me t o o nset was 3. 3 m o nt hs (ra n ge: 
6 da ys t o 9 m o nt hs). I m m u ne- me diate d he p atitis le d t o per ma ne nt disc o nti n uati o n of 
ni v ol u ma b i n 0. 7 % a n d wit h h ol di n g of O P DI V O i n 1 % of patie nts. All patie nts wit h 
he patitis recei ve d hi g h - d ose c ortic oster oi ds (at least 4 0 m g pre d nis o ne e q ui vale nts) f or a 
me dia n d urati o n of 2 3 da ys (ra n ge: 1 d a y t o 2 m o nt hs). T w o patie nts re q uire d t he 
a d diti o n of m yc o p h e n olic aci d t o hi g h- d ose c ortic oster oi ds. C o m plete res ol uti o n occ urre d 
i n 7 4 % of patie nts. A p pr o xi matel y 2 9 % of patie nts ha d rec urre n ce of h e patitis after re-
i nitiati o n of ni v ol u ma b. 
 
I m m u ne- Me diate d E n d o cri n o pat hies 
Ni v ol u ma b 
ca n  ca us e  i m m u ne -me diate d  h y p o p h ysitis,  i m m u ne -me diate d  a dre n al 
i ns ufficie nc y,  a ut oi m m u ne t h yr oi d  dis or ders,  a n d  T y p e  1  dia b etes  mellit us.  M o nit or 
patie nts  f or  si g ns  a n d  s y m pt o ms  of  h y p o p h ysitis,  si g ns  a n d  s y m pt o ms  of  a dre nal 
i ns ufficie nc y,  t h yr oi d  f u ncti o n  pri or  t o  a n d  peri o dicall y  d uri n g  treat me nt,  a n d 
h y per gl yce mia.  A d mi nister  h or m o ne  re plac e me nt  as  cli nicall y  i n dicate d  a n d 
c ortic oster oi ds  f or  Gra d e  2  or  greater  h y p o p h ysitis.  Wit h h ol d  f or  Gra de  2  or  3  a n d 
per ma ne ntl y disc o nti n ue f or Gr a de 4 h y p o p h ysitis. A d mi nister c ortic oster oi ds f or Gra de 3 
or 4 a dre nal i ns ufficie n c y. Wit h h ol d f or Gra de 2 a n d per ma ne ntl y disc o nti n ue f or Gra d e 3 
or 4 a dre n al i ns ufficie nc y. A d mi nister h or m o ne -re place m e nt t hera p y f or h y p ot h yr oi dis m. 
I nitiate m e dical ma n a ge me nt f or c o ntr ol of h y pert h yr oi dis m. Wit h h ol d  f or Gra d e  3  a n d 
per ma ne ntl y disc o nti n ue f or Gr a de 4 h y per gl yc e mia. 
•I n patie nts r ecei vi n g Ni v ol u ma b m o n ot hera p y, h y p o p h ysitis occ urre d i n 0. 6 % ( 1 2/ 1 9 9 4) 
of patie nts. I n patie nts r ecei vi n g ni v ol u ma b m o n ot hera p y, a dre nal i ns uffici e nc y occ urre d 
i n  1 %  ( 2 0/ 1 9 9 4)  of  patie nts.  I n  patie nts  recei vi n g Ni v ol u ma b  m o n ot hera p y, 
h y p ot h yr oi dis m or t h yr oi ditis res ulti n g i n h y p ot h yr oi dis m occ urre d i n 9 % ( 1 7 1/ 1 9 9 4) of 
patie nts.  H y p ert h yr oi dis m  occ urr e d  i n  2. 7 %  ( 5 4/ 1 9 9 4)  of  patie nts  recei vi n g Ni v ol u ma b 
m o n ot hera p y.  I n patie nts recei vi n g Ni v ol u ma b m o n ot hera p y, dia bet es occ urre d i n 0. 9 % 
( 1 7/ 1 9 9 4) of patie nts. 
 
I m m u ne- Me diate d N e p hritis a n d Re nal D ysf u n cti o n 

 
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6 2  
Ni v ol u ma b ca n  ca use  i m m u ne -me diate d  n e p hritis.  M o nit or  patie nts  f or  ele vate d  s er u m 
creati ni ne pri or t o a n d peri o dicall y d uri n g treat me nt. A d mi nister c ortic oster oi ds f or Gra d es 
2- 4 i ncrease d ser u m cr eati ni ne. Wit h h ol d  Ni v ol u ma b  f or Gra de 2 or 3 a n d per ma ne ntl y 
disc o nti n ue  f or  Gr a de  4  i ncreas e d  ser u m  creati ni ne.  I n  patie nts  recei vi n g Ni v ol u ma b 
m o n ot hera p y,  i m m u ne -me diate d  ne p hritis  a n d  re nal  d ysf u ncti o n  occ urre d  i n  1. 2 % 
( 2 3/ 1 9 9 4) of patie nts. 
 
I m m u ne- Me diate d S ki n A d verse Reacti o ns 
Ni v ol u ma b ca n ca use i m m u ne -me diate d ras h, i ncl u di n g Ste ve ns -J o h ns o n s y n dr o me ( SJ S) 
a n d  t o xic  e pi der mal  necr ol ysis  ( T E N),  s o me  cases  wit h  fatal  o utc o me.  A d mi nister 
c ortic oster oi ds f or Gra de 3 or 4 ras h. Wit h h ol d f or Gra de 3 a n d p er ma n e ntl y disc o nti n ue 
f or Gra d e 4 ras h. F or s y m pt o ms or si g ns of SJ S or T E N, wit h h ol d Ni v ol u ma b an d refer t he 
patie nt  f or  s p ecialize d  care  f or  assess me nt  a n d  treat me nt;  if  c o nfir me d,  per ma n e ntl y 
disc o nti n ue.  I n  p atie nts  recei vi n g   Ni v ol u ma b m o n ot hera p y,  i m m u ne -me diate d  ras h 
occ urr e d i n 9 % ( 1 7 1/ 1 9 9 4) of patie nts. 
 
I m m u ne-Me diate d E n ce p halitis  
Ni v ol u ma b 
ca n  ca use  i m m u ne -me diate d  e n ce p halitis.  E val uati o n  of  patie nts  wit h 
ne ur ol o gi c s y m pt o ms ma y i ncl u de, b ut n ot be li mite d t o, c o ns ultati o n wit h a ne ur ol o gist, 
brai n  M RI,  a n d  l u m bar  p u nct ure.  Wit h h ol d Ni v ol u ma b i n  patie nts  wit h  ne w- o nset 
m o derate t o se vere ne ur ol o gic si g ns or s y m pt o ms a n d e v al uate t o r ule o ut ot her ca uses. If 
ot her  eti ol o gies  are  r ule d  o ut,  a d mi nister  c ortic oster oi ds  a n d  p er ma n e ntl y  disc o nt i n ue  
Ni v ol u ma b 
f or  i m m u ne-me diate d  e n ce p h alitis.  I n  patie nts  recei vi n g 
Ni v ol u ma b 
m o n ot hera p y, e nce p halitis occ urre d i n 0. 2 % ( 3/ 1 9 9 4) of patie nts. Fatal li m bic e nce p halitis 
occ urr e d i n o ne patie nt after 7. 2 m o nt hs of e x p os ure des pite disc o nti n uati o n of  Ni v ol u ma b 
a n d a d mi nistrati o n of c ortic oster oi ds. 
 
Ot her I m m u ne -M e diate d A d verse Reacti o ns  
Ni v ol u ma b ca n ca use ot her cli nicall y si g nifica nt a n d p ote ntiall y  fatal i m m u ne -me diate d 
a d verse r eacti o ns. I m m u ne -me diate d a d v erse reacti o ns ma y o cc ur after dis c o nti n uati o n of 
t hera p y.  F or  a n y  s us p ecte d  i m m u ne-me diate d  a d verse  reacti o ns,  e x cl u de  ot her  ca uses. 
Base d  o n  t he  se v erit y  of  t he  a d vers e  reacti o n,  per ma ne ntl y  disc o nti n ue  or  wit h h ol d  
ni v ol u ma b ,  a d mi nister  hi g h-d ose  c ortic oster oi ds,  a n d  if  a p pr o priate,  i nitiate  h or m o ne -
re place me nt t hera p y. U p o n i m pr o ve me nt t o Gra d e 1 or less, i nitiate c ortic oster oi d ta per 
a n d  c o nti n ue  t o  t a per  o ver  at  l east  1  m o nt h.  C o nsi der  restarti n g  aft er  c o m pleti o n  of 
c ortic oster oi d ta per base d o n t he se verit y of t he e ve nt . Acr oss cli nic al trials of O P DI V O 
a d mi nistere d as a si n gle a ge nt or i n c o m bi nati o n wit h i pili m u ma b, t he f oll o wi n g cli nicall y 
si g nifica nt  i m m u ne-me diate d  a d vers e  reacti o ns,  s o me  wit h  fatal  o utc o me,  occ urre d  i n 
< 1. 0 %  of  p atie nts  w h o  recei ve d   ni v ol u ma b:  m y ocar ditis,  r ha b d om y ol ysis,  m y ositis, 
u veitis, iritis, pa ncreatitis, facial a n d a b d u ce ns n er ve paresis, de m yeli nati o n, p ol y m yal gia 
r he u matica, a ut oi m m u ne ne ur o pat h y, G uillai n-Barré s y n dr o me, h y p o pit uitaris m, s yste mic 
i nfla m mat or y res p o nse s y n dr o me, gastritis, d u o de nitis, sarc oi d osis, histi oc ytic necr otizi n g 
l y m p ha de nitis  ( Ki k u c hi  l y m p ha de nitis),  m ot or  d ysf u n cti o n,  vasc ulitis,  a plastic  a ne mia, 
pericar ditis,  a n d  m yast he nic  s y n dr o me.  If  u veitis  occ urs  i n  c o m bi nati o n  wit h  ot her 
i m m u ne-me diate d  a d verse  reacti o ns,  c o nsi der  a  V o gt -K o ya na gi -Hara da -li ke  s y n dr o me, 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 3  
w hic h has bee n o bser ve d i n patie nts w h o recei ve d ni v ol u ma b a n d ma y re q uire treat me nt 
wit h s yste mic ster oi ds t o re d uce t h e ris k of per ma n e nt visi o n l oss.  
 
I nf usi o n Reacti o ns 
I n patie nts w h o recei ve d ni v ol u ma b as a 6 0- mi n ute i ntra ve n o us i nf usi o n, i nf usi o n-relate d 
reacti o ns occ urr e d i n 6. 4 % ( 1 2 7/ 1 9 9 4) of patie nts. I n a trial assessi n g t he p h ar mac o ki netics 
a n d safet y of a m ore ra pi d i nf usi o n, i n w hic h patie nts recei ve d ni v ol u ma b as a 6 0 -mi n ute 
i ntra ve n o us  i nf usi o n  or  a  3 0-mi n ute  i ntra ve n o us  i nf usi o n,  i nf usi o n-relate d  reacti o ns 
occ urr e d i n 2. 2 % ( 8/ 3 6 8) a n d 2. 7 % ( 1 0/ 3 6 9) of patie nts, res pecti vel y. A d diti o nall y, 0. 5 % 
( 2/ 3 6 8) a n d 1. 4 % ( 5/ 3 6 9) of patie nts, res pecti vel y, e x perie nce d a d vers e reacti o ns wit hi n 
4 8 h o urs of i nf usi o n t hat le d t o d ose dela y, per ma ne nt disc o nti n uati o n or wit h h ol di n g of 
ni v ol u ma b.  
 
E m br y o -Fetal T o xicit y  
• Base d o n its mec ha nis m of acti o n, O P DI V O ca n ca use fetal h ar m w he n a d mi nistere d t o a 
pre g na nt w o ma n. A d vise pre g na nt w o me n of t he p ote ntial ris k t o a fet us. A d vise fe males 
of re pr o d ucti ve p ot e ntial t o use effecti ve c o ntra ce pti o n d uri n g treat me nt wit h a  Ni v ol u ma b 
c o ntai ni n g r e gi me n a n d f or at least 5 m o nt hs after t he last d ose of Ni v ol u ma b. 
 
Lactati o n  
•It  is  n ot  k n o w n  w het her  O P DI V O  is  pres e nt  i n  h u ma n  mil k.  Because  ma n y  dr u gs, 
i ncl u di n g a nti b o dies, ar e e x crete d i n h u ma n mil k a n d beca use of t he p ote ntial f or seri o us 
a d verse reacti o ns i n n ursi n g i nfa nts fr o m Ni v ol u ma b - c o ntai ni n g re gi me n, a d vise w o me n 
t o disc o nti n ue breastfee di n g d uri n g treat me nt. 
 
Seri o us A d verse Reacti o ns  
•I n  C hec k m ate  0 1 7  a n d  0 5 7,  seri o us  a d verse  reacti o ns  occ urre d  i n  4 6 %  of  patie nts 
recei vi n g Ni v ol u ma b ( n = 4 1 8). T he m ost fre q ue nt seri o us a d verse reacti o ns re p orte d i n at 
least 2 % of patie nts recei vi n g Ni v ol u ma b were p n e u m o nia, p ul m o nar y e m b olis m, d ys p nea, 
p yr e xia, ple ural eff usi o n, p ne u m o nitis, a n d res pirat or y fail ure. 
 
C o m m o n A d verse Reacti o ns 
•I n  C hec k m ate  0 1 7  a n d  0 5 7,  t he  m ost  c o m m o n  a d verse  reacti o ns  ( ≥2 0 %)  i n  patie nts 
recei vi n g Ni v ol u ma b ( n = 4 1 8)  were  f ati g u e,  m usc ul os keletal  pai n,  c o u g h,  d ys p nea,  a n d 
decrease d a p petite.  
         
 
A P P E N DI X D M A N A G E M E N T A L G O RI T H M S  
D ose  M o dific ati o ns  f or Ni v ol u m a b / O p di v o  ( P ac k a ge  I nsert  Brist ol-M yers  S q ui b b ) 
Rec o m me n dati o ns  f or  O P DI V O  m o dificati o ns  are  pr o vi de d  i n  Ta ble  bel o w.  T here  are  n o 
rec o m me n de d  d ose m odificati o ns  f or  h y p ot h yr oi dis m  or  h y pert h yr oi dis m.  I nterr u pt  or  sl o w 
t he rate of i nf usi o n i n patie nts wit h mil d or m o derate i nf usi o n reacti o ns. Disc o nti n ue O P DI V O 
i n patie nts wit h se vere or life-t hreate ni n g i nf usi o n reacti o ns.  

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 4  
Rec o m me n de d 
D ose 
M o dific ati o ns 
f or Ni v ol u ma b  
A d verse Re acti o n  
Se verit y *  
D ose M o dific ati o n  
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 p ne u m o nitis  
Wit h h ol d d ose
 (a) 
Gra de 3 or 4 p ne u m o nitis  
P er ma ne ntl y disc o nti n ue  
He patitis  
As partate a mi n otra nsferase ( A S T)/ or ala ni ne 
a mi n otra nsferase ( A L T) m ore t ha n 3 a n d u p t o 5 
ti mes t he u p per li mit of n or mal or t otal bilir u bi n 
m ore t ha n 1. 5 a n d u p t o 3 ti mes t he u p per li mit of 
n or mal  
Wit h h ol d d ose  (a) 
A S T or A L T m ore t ha n 5 ti mes t he u p per li mit of 
n or mal or t otal bilir u bi n m ore t ha n 3 ti mes t he u p per 
li mit of n or mal  
P er ma ne ntl y disc o nti n ue  
H y p o p h ysitis  
Gra de 2 or 3 h y p o p h ysitis  
Wit h h ol d d ose  (a ) 
Gra de 4 h y p o p h ysitis  
P er ma ne ntl y disc o nti n ue  
A dre nal 
I ns ufficie nc y  
Gra de 2 a dre nal i ns ufficie nc y  
Wit h h ol d d ose  (a)  
Gra de 3 or 4 a dre nal i ns ufficie nc y  
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 ue  
Ne p hritis a n d Re nal 
D ysf u ncti o n  
Ser u m creati ni ne m ore t ha n 1. 5 a n d u p t o 6 ti mes t he 
u p per li mit of n or mal  
Wit h h ol d d ose  (a ) 
Ser u m creati ni ne m ore t ha n 6 ti mes t he u p per li mit 
of n or mal  
P er ma ne ntl y disc o nti n ue  
S ki n  
Gra de 3 ras h or s us pecte d Ste ve ns -J o h ns o n 
s y n dr o me ( SJ S) or t o xic e pi der mal necr ol ysis ( T E N)  Wit h h ol d d ose  (a)  
Gra de 4 ras h or c o nfir me d SJ S or T E N  
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 n g 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 p er Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts. Versi o n 4. 0 ( N CI C T C A E v 4). a Res u me treat me nt w he n a d verse 
reacti o n i m pr o ves t o Gra de 0 or 1.  
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 5  
 
 
 
 
 
 
 
 
 
A P P E N DI X E   
B ar b ar a A n n K ar m a n os C a ncer I nstit ute  D at a a n d S afet y M o nit ori n g Re p ort 
P R O T O C O L #:  
 
 
R E P O R T D A T E:  
     
                                                                                       
P R O T O C O L TI T L E  
 
A T T E N D A N C E  
 
 
 
 
 
 
P R O T O C O L A C TI VI T Y SI N C E L A S T R E P O R T  
Accr ual G oal:  
Eli gi ble:  
 
T otal n u m ber of A E’s t o date:  
 
Accr ual t o Date:  
 I neli gi ble:  
( pr o vi de reas o n):  
Accr ual Si nce  
Last M o nt hl y Re p ort:    
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 6  
  S P E CI FI C A L L Y F O R P H A S E I T RI A L &/ O R D O S E E S C A L A TI N G T RI A L S:  
D O S E L E V E L  
A C C R U A L   
 
 
 
 
R E C O R D A L L G R A D E 3, 4, A N D 5 A D V E R S E E V E N T S ( A E).  G R O U P B Y C A T E G O R Y O F A E.  R E C O R D T H E D A T E 
O F T H E O C C U R R E N C E, A T T RI B U TI O N A N D I F R E P O R T A B L E T O T H E I R B.     S H A D E T H E R O W S O F T H E A E’ S 
T H A T H A V E O C C U R R E D F O R T HI S R E P O R T.  A T T A C H T H E HI C U P R E P O R T F O R M F O R T H E S E R E P O R T A B L E 
E V E N T S T H A T O C C U R R E D  O N T HI S R E P O R T.  
Pt. I D #  
Cate g or y a n d  t y pe of a d verse reacti o n  
 
Date of 
Occ urre nce  
Gra de 1 
Attri b uti o n 2 
Re p orta ble t o I R B 
( Y/ N) 
Yes wit h date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Gra de: 1 -Mil d, 2 -M o derate, 3 - Se vere, 4 -Life -t hreate ni n g, or 5- Deat h.  
2. Attri b uti o n: 1 -u nrelate d, 2 - u nli kel y, 3 - p ossi bl y, 4 - pr o ba bl y, or 5 - defi nitel y   
 
O F F T R E A T M E N T  Pr o vi de re as o n [ pr o gressi o n, de at h, t o xicit y, c o m plete d t her a p y, etc].  
 
 
P R O T O C O L VI O L A TI O N S  De vi ati o ns fr o m pr ot oc ol tre at me nt, m o nit ori n g, or st u d y c ale n d ar.  
  
 
P R O T O C O L A M E N D M E N T S  I ncl u de d ate s u b mitte d t o re g ul at or y b o dies a n d d ate a p pr o ve d. 
 
 
O T H E R C O M M E N T S  
 
 
I n vesti g at or Si g n at ure: 
 
D at a M a n a ger 
Si g n at ure:  
 
 
A P P E N DI X F 
F A C T -I T a n d BI SI Q uesti o n naires 
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are 
i m p orta nt. Ple ase ci rcl e or m ar k o ne n u m be r per li ne t o i n dic ate y o ur 
res p o nse as it a p plies t o t he p ast 7 d a ys.  
 
 
 
 
 
N ot at 
all  
A little 
bit  
S o me -
w h at  
Q uite  
a bit  
Ver y 
m uc h  
 
 
 
 
 
 
 
G P 4  
I h a ve 
pai n
 .....................................................................  
0 
1 
2 
3 
4 
G P 1  
I h a ve a l ac k of 
 
  
0 
1 
2 
3 
4 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 7  
C 2  
I a m l osi n g 
wei g ht
 .....................................................................  
0 
1 
2 
3 
4 
G P 2  
I h a ve 
 
  
0 
1 
2 
3 
4 
G P 6  
I feel 
 
  
0 
1 
2 
3 
4 
G E 6  
I w orr y t hat m y c o n diti o n will get 
 
  
0 
1 
2 
3 
4 
B L 1  
I h a ve tr o u ble c o ntr olli n g m y 
uri ne
 
  
0 
1 
2 
3 
4 
 
 
 
 
P H Y SI C A L W E L L - B EI N G 
 
N ot 
at all 
A little 
bit  
S o me -
w h at  
Q uite
a bit  
Ver y 
m uc h  
 
G P 1  
I h a ve a l ac k of 
e ner g y
 .......................................................................................... 
0 
1 
2 
3 
4 
G P 2  
I h a ve 
na usea
 .......................................................................................... 
0 
1 
2 
3 
4 
G P 3  
Beca use of m y p h ysical c o n diti o n, I ha ve tr o u ble 
meeti n g t he n ee ds of m y 
fa mil y
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
G P 4  
I h a ve 
pai n
 .......................................................................................... 
0 
1 
2 
3 
4 
G P 5  
I a m b ot here d b y si de eff ects of 
treat me nt
 .......................................................................................... 
0 
1 
2 
3 
4 
G P 6  
I feel 
ill
 .......................................................................................... 
0 
1 
2 
3 
4 
G P 7  
I a m f orce d t o s pe n d ti me i n 
be d
 
 
0 
1 
2 
3 
4 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 8  
 
 
 
 
S O CI A L/ F A MI L Y W E L L -B EI N G  
 
N ot 
at all 
A little 
bit  
S o me -
w h at  
Q uite
a bit  
Ver y 
m uc h  
 
G S 1  
I feel cl ose t o m y 
frie n ds
 .......................................................................................... 
0 
1 
2 
3 
4 
G S 2  
I get e m oti o nal s u p p ort fr o m m y 
fa mil y
 .......................................................................................... 
0 
1 
2 
3 
4 
G S 3  
I get s u p p ort fr o m m y 
frie n ds
 .......................................................................................... 
0 
1 
2 
3 
4 
G S 4  
M y f a mil y has acce pte d m y 
ill ness
 .......................................................................................... 
0 
1 
2 
3 
4 
G S 5  
I a m satisfie d wit h fa mil y c o m m u nicati o n a b o ut m y 
ill ness
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
G S 6  
I feel cl ose t o m y p art ner ( or t he pers o n w h o is m y mai n 
s u p p ort)
 .......................................................................................... 
 
0 
 
1 
 
2 
 
3 
 
4 
Q 1  
Re g ar dless of y o ur c urre nt level of sex u al activity, ple ase 
a ns wer t he f oll o wi n g q uesti o n. If y o u prefer n ot t o a ns wer it, 
ple ase m ark t his b ox           a n d g o t o t he next secti o n.  
 
 
 
 
 
G S 7  
I a m satisfie d wit h m y s e x 
life
 
  
0 
1 
2 
3 
4 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
6 9  
 
Ple ase circle or m ar k o ne n u m ber per li ne t o i n dic ate y o ur res p o nse as it 
a p plies t o t he p ast 7 d a ys. 
 
 
 
E M O TI O N A L W E L L -B EI N G  
N ot 
at all 
A little 
bit  
S o me -
w h at  
Q uite
a bit  
Ver y 
m uc h  
 
G E 1  
I feel 
sa d
 .......................................................................................... 
0 
1 
2 
3 
4 
G E 2  
I a m satisfie d wit h h o w I a m c o pi n g wit h m y 
ill ness
 .......................................................................................... 
0 
1 
2 
3 
4 
G E 3  
I a m l osi n g h o pe i n t he fi g ht a gai nst m y 
ill ness
 .......................................................................................... 
0 
1 
2 
3 
4 
G E 4  
I feel 
ner v o us
 .......................................................................................... 
0 
1 
2 
3 
4 
G E 5  
I w orr y a b o ut 
d yi n g
 .......................................................................................... 
0 
1 
2 
3 
4 
G E 6  
I w orr y t hat m y c o n diti o n will get 
 
 
0 
1 
2 
3 
4 
 
 
 
 
F U N C TI O N A L W E L L -B EI N G  
 
N ot 
at all 
A little 
bit  
S o me -
w h at  
Q uite
a bit  
Ver y 
m uc h  
 
G F 1  
I a m a ble t o w or k (i ncl u d e w or k at 
h o me)
 .......................................................................................... 
0 
1 
2 
3 
4 
G F 2  
M y w or k (i ncl u de w or k at h o me) is 
f ulfilli n g
 .......................................................................................... 
0 
1 
2 
3 
4 
G F 3  
I a m a ble t o e nj o y 
life
 .......................................................................................... 
0 
1 
2 
3 
4 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
7 0  
G F 4  
I h a ve acce pte d m y 
ill ness
 .......................................................................................... 
0 
1 
2 
3 
4 
G F 5  
I a m slee pi n g 
well
 .......................................................................................... 
0 
1 
2 
3 
4 
G F 6  
I a m e nj o yi n g t h e t hi n gs I us u all y d o f or 
f u n
 .......................................................................................... 
0 
1 
2 
3 
4 
G F 7  
I a m c o nte nt wit h t he q ualit y of m y life ri g ht 
 
 
0 
1 
2 
3 
4 
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
7 1  
 
Bl a d der S y m pt o m I n de x Q uesti o n n aire 
 
Ple ase circle or m ar k o ne n u m ber per li ne t o i n dic ate y o ur res p o nse as it 
a p plies t o t he p ast 7 d a ys. 
 
 
 
A D DI TI O N A L C O N C E R N S  
N ot  
at all 
A little 
bit  
S o me -
w h at  
Q uite
a bit  
Ver y 
m uc h  
 
B L 1  
I h a ve tr o u ble c o ntr olli n g m y 
uri ne
 ..........................................................................................  
0 
1 
2 
3 
4 
C 2  
I a m l osi n g 
wei g ht
 ..........................................................................................  
0 
1 
2 
3 
4 
C 3  
I h a ve c o ntr ol of m y 
b o wels
 ..........................................................................................  
0 
1 
2 
3 
4 
B L 2  
I uri nate m ore fre q u e ntl y t ha n 
us ual
 ..........................................................................................  
0 
1 
2 
3 
4 
C 5  
I h a ve diarr hea 
( diarr h oea)
 ..........................................................................................  
0 
1 
2 
3 
4 
C 6  
I h a ve a g o o d 
a p petite
 ..........................................................................................  
0 
1 
2 
3 
4 
C 7  
I li ke t he a p peara n ce of m y 
 
  
0 
1 
2 
3 
4 
B L 3  
It b ur ns w he n I 
uri nate
 ..........................................................................................  
0 
1 
2 
3 
4 
B L 4  
I a m i ntereste d i n 
se x
 ..........................................................................................  
0 
1 
2 
3 
4 
B L 5  
( F or me n o nl y)  I a m a bl e t o ha ve a n d m ai ntai n a n 
erecti o n
 
  
0 
1 
2 
3 
4 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
7 2  
Q 2  
D o y o u h a ve a n ost o m y a p plia nce? 
N o _ _ _ Yes _ _ _  If yes, a ns wer t he f oll o wi n g t w o ite ms: 
 
↓ 
 
 
 
 
 
C 8  
I a m e m barrasse d b y m y ost o m y 
a p plia nce
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
C 9  
Cari n g f or m y ost o m y a p plia nce is 
diffic ult
 ..........................................................................................  
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Pr ot oc ol versi o n date     Oct 2 7, 2 0 1 7, 1/ 1 1/ 2 0 1 8, 4/ 2 5/ 2 0 1 8, 7/ 1 6/ 2 0 1 8, 1 1/ 3 0/ 2 0 1 8, 8/ 1 8/ 2 0 1 9, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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A P P E N DI X  G 
Please ref er t o La b M a n u al f or S peci me n c ollecti o n, Pr ocessi n g a n d S hi p pi n g i nstr ucti o ns 
if a p plica ble. 
Please n otif y Dr . Par aj uli w he n se n di n g sa m ples.  C o ntact i nf o: 
Pra hla d Paraj uli, P h. D. 
Wa y ne State U ni v ersit y & Kar ma n os Ca ncer I nstit ute  
La n d e Researc h  B uil di n g, # 4 6 0 
5 5 0 E. Ca nfiel d  
Detr oit, MI 4 8 2 0 1 
Tel #  3 1 3- 5 7 7- 6 3 7 7 ( Office); 3 1 3- 5 7 7-0 6 2 9 ( La b)  
E- mail: p paraj uli @ me d. wa y ne.e d u