Clinical trial NCT03421652
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
Start date: 2018-04-24; Completion date: 2023-03-23
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well nivolumab works with radiation therapy in treating patients with urothelial bladder cancer that has spread from its original site of growth to nearby tissues or lymph nodes and are ineligible for chemotherapy. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving nivolumab and radiation therapy may work better in treating patients with urothelial bladder cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the 12-month rate of progression-free survival (PFS) achieved with the combination of nivolumab, a programmed death (PD-1) inhibitor, and radiation therapy in localized/locally advanced urothelial cancer patients, who are chemotherapy ineligible, to a historical control reference 12-month PFS rate.

SECONDARY OBJECTIVES:

I. To assess the toxicity of concurrent nivolumab and radiation therapy in urothelial cancer.

II. To determine overall response rate (ORR). III. To determine metastasis-free survival (MFS). IV. To determine overall survival (OS). V. To evaluate the quality of life and bladder functioning during and after the therapy.

VI. To explore the relationships of PD-1 expression, PDL-1 expression, and the Th1/Th2 cytokine ratio to clinical outcomes (response, PFS, MFS, and OS).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9.

After completion of study treatment, patients are followed up every 3 months for 12 months.

Arms: arm 1: Given IV
Interventions: intervention 1: Nivolumab intervention 2: Radiation
Intervention descriptions: intervention 1: Patients receive nivolumab IV over 30 minutes on day 1. Treatment repeats every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9. intervention 2: Beginning 3 days of course 1, patients undergo radiation therapy over 32-35 on weeks 1, 3, 5, 7 and 9.

Protocol documents:
Prot_SAP_000.pdf: 
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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, 
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I N D # 1 3 4 5 9 9, B M S Pr ot oc ol # C A 2 0 9- 8 9 2 
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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  
  
  
  
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Detr oit , MI 4 8 2 0 1 
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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  
  
  
  
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Detr oit, MI 4 8 2 0 1 
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J ose p h F o nta na, M. D.  
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E- mail : f o nta naj @ kar m a n os. or g 
 
 


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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  
  
  
  
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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. 


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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  
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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     
  
  
 
  
  
  
  
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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   
  
  
  
 
  
  
  
  
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E- mail: m ol o u g hl @ wa y n e.e d u  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 
  
  
  
 
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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  
 
 
 
 


 
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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 


 
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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 


 
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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 


 
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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, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
9  
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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2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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, 
2/ 2 0/ 2 0 2 0 , 6/ 1 7/ 2 0 2 0, 7/ 2 9/ 2 0 0 
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 


 
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 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 
7 3  
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