A Phase II Study of Intermittent Checkpoint Inhibitor Therapy in Patients With Advanced Urothelial Carcinoma
Phase: PHASE2
Conditions: Urothelial Carcinoma
Sponsor: Case Comprehensive Cancer Center

C A S E 6 8 1 9  
  
  
P a ge 1   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
 
 
 
 
 
 
 
 
 
S T U D Y N U M B E R:  C A S E 6 8 1 9 
 
Cli nical Trials. g o v N C T #:   0 4 3 2 2 6 4 3 
 
Pr ot oc ol Date:               7- 1 7- 2 0 2 0 
 
S T U D Y TI T L E:  A P hase II St u d y of I nter mitte nt C hec k p oi nt I n hi bit or T hera p y i n 
Patie nts wit h A d va nce d Ur ot helial Carci n o ma 
  
  
  
 
  
 
P RI N CI P A L I N V E S TI G A T O R: 
M os he C. Or nstei n, M. D. M. A. 
  
  
  
  
Case C o m pre he nsi ve Ca ncer Ce nter 
Cle vela n d Cli nic  
Ta ussi g Ca n cer Ce nt er  
 
9 5 0 0 E ucli d A ve n ue   
  
  
 
Cle vela n d, O H 4 4 1 9 5 
 
  
  
 
 
  
  
  
  
 
 
C O-I N V E S TI G A T O R S:  
      Ti m ot h y Gilli ga n, M. D. 
  
  
  
  
      S hil pa G u pta, M. D. 
 
S T A TI S TI CI A N:   
 
 
  
  
  
 
 
  
  
 
  
 
  
 
  
  
  
 
   
  
  
 
 
S T U D Y C O O R DI N A T O R: 
  
  
  
  
 
 
  
  
  
 
 
  
  
 
  
 
  
  
 
  

C A S E 6 8 1 9  
  
  
P a ge 2   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
 
S P O N S O R:   
  
  
Case C o m pre he nsi ve Ca ncer Ce nter   
  
  
 
  
  
 
S U P P O R T/ F U N DI N G:   
I nter nal G U f u n d  
 
S U P P LI E D A G E N T: 
 
n o ne  
 
  
  
  
  
 
 
 
 
 
 
 
 
 

C A S E 6 8 1 9  
  
  
P a ge 3   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
Ti tle: A P has e II St u d y of I nter mitte nt C hec k p oi nt I n hi bit or T her a p y I n Patie nts Wit h 
A d va nce d Ur ot helial Car ci n o ma  
 
 
 
 
 
Pri nci p al I n vesti g at or: M os he C. Or nstei n, M. D. M. A. 
 
 
 
 
 
P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E: 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
  
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

C A S E 6 8 1 9  
  
  
P a ge 4   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
S U M M A R Y O F C H A N G E S 
 
 
Pr ot oc ol 
D a te 
Secti o n  
C h a n ge 
2/ 5/ 2 0 2 0 
 
I nitial I R B a p pr o v al 
5/ 2 7/ 2 0 2 0 
C o ver pa ge  
A d de d N C T n u m ber 
  
 
Pr ot oc ol versi o n date 
 
F o oter 
t hr o u g h o ut 
Pr ot oc ol versi o n date  
 
S y n o psis 
Secti o n 3. 0 
Secti o n 4. 0 
C ha n ge d eli gi bilit y t o i n cl u de all p atie nts wit h a d va nce d ur ot helial 
carci n o ma 
w h o ha v e recei ve d c h ec k p oi nt i n hi bit ors f or a 
mi ni m u m of 2 0 wee ks. 
 
Secti o n 6 
Secti o n 9 
A d de d o pti o n of ne w p e m br oliz u ma b d ose ( 4 0 0 m g e v er y 6 w ee ks) 
  
Secti o n 8. 5  
A d de d re p ort o n Me d W atc h F D A F or m 3 5 0 0 A 
  
Secti o n 1 1 
A d de d a c ol u m n i n t he cale n dar f or s c he d ule of visit/tests at t he 6 
wee k mar k f or patie nts w h o are O F F t hera p y  
7/ 1 7/ 2 0  
Secti o n 4. 1 
Re m o ve d t he f oll o wi n g i ncl usi o n criteria: “ 
Meas ura ble 
disease 
as defi ne d b y R E CI S T 1. 1 criteria. ” T he rati o nal e f or t his is t hat 
we are e nr olli n g p atie nts w h o ha v e ha d g o o d res p o nses t o t hera p y 
a n d as s uc h s o me will – b y d efi niti o n, s o me will n o l o n ger h a ve 
meas ura ble disease. 
 

C A S E 6 8 1 9  
  
  
P a ge 5   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
S T U D Y S C H E M A 
 
 
 
 
 
1Patie nts ma y b e treat e d wit h a n y F D A-a p pr o v e d C PI f or cis plati n-i neli gi ble a U C or 
cis plati n resista nt/refr act or y a U C. 
2I n cas es w here a p atie nt is c o nti n ue d o n t hera p y after P D a n d de v el o ps s u bse q ue nt 
d isease pr o gr essi o n, C PI s h o ul d be disc o nti n ue d.  
3Patie nts w h o d o n ot ha ve t u m or b ur de n r e d ucti o n of > 1 0 % after 2 c o nsec uti ve i ma gi n g 
wi ll be re m o ve d fr o m st u d y.  
* Of n ote all i ma gi n g is c o m pare d t o sca ns d o n e pri or t o i nter mitte nt t hera p y i nitiati o n.  

C A S E 6 8 1 9  
  
  
P a ge 6   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
P R O T O C O L S U M M A R Y 
 
Pr ot oc ol N u m ber/ Title  
C A S E 6 8 1 9 A P hase II St u d y of I nter mitte nt C hec k p oi nt 
I n hi bit or T h er a p y I n Patie nts 
Wit h A d va nce d Ur ot helial 
Carci n o ma 
St u d y P has e 
A P hase II st u d y 
Brief Bac k gr o u n d/ Rati o n ale  
 
 
 
I m m u n ot her a p y has r e v ol uti o nize d t he treat me nt of patie nts 
wit h a U C. Fi ve c h ec k p oi nt i n hi bit ors ( C PI) (atez oliz u ma b, 
pe m br oliz u ma b, a vel u ma b, d ur val u ma b, a n d ni v ol u ma b) 
are a p pr o ve d f or rel a pse d/refract or y a U C f oll o wi n g 
plati n u m- base d c he m ot h era p y a n d 2 C PI ( atez oliz u ma b a n d 
pe m br oliz u ma b) are a p pr o ve d f or cis plati n-i neli gi ble 
patie nts. D urati o n of t her a p y re q uir e d t o s ustai n cli nical 
be nefit is u nclear; patie nts are treate d i n defi nitel y u ntil 
i nt olera ble t o xicit y or dis ease pr o gressi o n. 
 
Cli nical trials i n vesti gati n g C PI i n mela n o ma a n d ki d ne y 
ca ncer ha v e s h o w n d ur a ble res p o nses i n patie nts w h o ha ve 
disc o nti n ue d t hera p y f or reas o ns ot her t h a n diseas e 
pr o gressi o n. 1, 2 Si milarl y, i n t he C hec k Mate 2 7 5 trial of 
ni v ol u ma b i n patie nts wit h a U C w h o pr o gr esse d f oll o wi n g 
plati n u m- base d c he m ot h era p y, 6 patie nts h a d s ustai ne d 
res p o nses off t h era p y ( 4 – 1 2 + wee ks).3 Li ke wise, i n t he 
p h ase 1/ 2 trial of d ur v al u ma b i n a U C, a patie nt w h o 
disc o nti n ue d treat me nt, u nrelate d t o pr o gr essi o n, 
mai ntai ne d a res p o ns e off t hera p y f or > 3 2 w ee ks .4 
 
A lt h o u g h 
ge n erall y 
well 
t olerate d, 
t h e 
i n defi nite 
c o nti n uati o n of C PI pr es e nts m ulti ple c halle n ges i ncl u di n g 
c u m ulati ve t o xicities a n d fi na ncial b ur de ns. N o vel d osi n g 
sc he d ules, 
earl y 
disc o nti n uati o n 
c o nsi derati o ns, 
a n d 
bi o mar kers of r es p o nse are nee d e d t o i de ntif y patie nts w h o 
ca n s ustai n disease re gr essi o n w hile off of t her a p y.  
Pri mar y O bj ecti ve   
T o assess t he efficac y of i nter mitte nt C PI t hera p y, defi ne d 
as t he pr o p orti o n of patie nts w h o re mai n off t hera p y f or at 
least 3 6 wee ks 
Sec o n dar y O bj ecti ve(s) 
•  T o deter mi ne t he cli nical o utc o me ( T FI, O R R, P F S, 
O S) i n a d va nce d ur ot heli al car ci n o ma wit h 
i nter mitte nt C PI t hera p y, at 1 2 wee k i nter v als fr o m 
w he n t hera p y is first hel d. 
•  T o assess res p o nse t o re-i nitiati o n of C PI t hera p y. 
E x pl orat or y O bjecti ve(s)  
n/a  
C orrelati ve O bjecti ve(s) 
 
Tiss ue: I n v esti gat e t he ge n o mic a n d i m m u n ol o gic mar ker s 
of res p o nse a n d resista n ce t o t hera p y.  [ See Secti o n 1 0. 2] 

C A S E 6 8 1 9  
  
  
P a ge 7   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
Bl o o d: I n vesti gate t he i m m u n o m o d ulat or y cell ma ke u p 
[s pecificall y, l y m p h oc yte P D- 1 occ u pa n c y, m yel oi d-
deri ve d s u p pr ess or cells ( M D S C), re g ul at or y T cells ( Tre g), 
C D 4 a n d C D 8 T Cells, T C R re pert oire] at t he start of 
treat me nt, d uri n g t he i nter mitte nt p hase a n d off tr eat me nt. [ 
See Secti o n 1 0. 1] 
Sa m ple Size 
2 0 patie nts t hat ha ve e nr olle d i nt o t he i nter mitte nt ar m 
Disease sites/ C o n diti o ns  
A d va nce d ur ot helial carci n o ma 
I nter ve nti o ns 
A p hase II st u d y c o n d uct e d i n vesti gati n g t he us e of 
i nter mitte nt C PI t hera p y i n cis plati n i neli gi ble or treat me nt 
refr act or y p atie nts wit h a U C w h o res p o n d t o t hera p y. 
Patie nts will be treate d wit h C PI t hera p y f or at least 2 0 
wee ks as p er sta n dar d of care ( S O C), at w hic h ti m e t h ose 
wit h a t u m or b ur de n re d u cti o n of 1 0 % or gr eater will 
s us pe n d C PI t her a p y. Patie nts wit h a d oc u me nte d i ncreas e 
i n ≥ 2 0 % t u m or b ur de n ( R E CI S T 1. 1 P D) will re-i nitiate 
C PI. F or t h ose patie nts w h o c o nti n ue t o ha ve r es p o nse, t he y 
will re mai n off t her a p y.  
 
 
 
 
A B B R E VI A TI O N S  
 
 
 
 
C C C C 
Case C o m pre he nsi ve Ca ncer Ce nter 
C R F  
Case Re p ort F or m 
D S T C 
Data Safet y a n d T o xicit y C o m mittee 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
I C F  
I nf or me d C o nse nt F or m 
I R B  
I nstit uti o nal Re vie w B oar d 
P R M C  Pr ot oc ol Re vie w a n d M o nit ori n g C o m mittee  
S O C  
Sta n dar d of Car e 
C C F  
Cle vela n d Cli nic F o u n dati o n 
U H  
U ni versit y H os pitals 
a U C  
A d va nce d ur ot helial carci n o ma 
C PI  
C hec k p oi nt i n hi bit or 
O S  
O verall s ur vi val 
P F S  
Pr o gr essi o n free s ur vi val 
T FI  
Treat me nt Free I nter v al 
O R R  
O verall r es p o nse r ate 

C A S E 6 8 1 9  
  
  
P a ge 8   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
T A B L E O F C O N T E N T S 
 
1. 0   
I N T R O D U C TI O N   
 
1. 1  
Bac k gr o u n d of A d v a nce d Ur ot helial Carci n o ma 
1. 2   
Na me/ descri pti o n 
of I m m u n ot hera pies 
A p pr o ve d i n 
A d va n ce d 
Ur ot helial 
Carci n o ma  
1. 3   
Rati o nale   
 
2. 0  
O B J E C TI V E S 
2. 1  
Pri mar y O bj ecti ve 
 
2. 2   
Sec o n dar y O bj ecti ve(s) 
2. 3  
C orrelati ve O bjecti ve(s) 
 
3. 0  
S T U D Y D E SI G N 
3. 1  
St u d y d esi g n 
3. 2  
N u m ber of S u bjects 
3. 3  
E x pecte d D urati o n of Tr eat me nt a n d S u bject Partici pati o n   
 
 
4. 0   
S U B J E C T S E L E C TI O N 
4. 1  
I n cl usi o n Criteria 
4. 2   
E x cl usi o n Criteria 
4. 3  
I n cl usi o n of W o me n a n d Mi n orities 
 
5. 0  
R E GI S T R A TI O N  
  
 
6. 0   
T R E A T M E N T P L A N 
6. 1  
C hec k p oi nt i n hi bit or Treat me nt Re gi me n O v er vie w  
6. 2  
C hec k p oi nt I n hi bit or I nf usi o n Reacti o ns  
6. 3  
Ge ner al C o nc o mita nt Me dicati o ns a n d S u p p orti ve Care G ui deli nes 
6. 4  
Criteria f or Re m o val fr o m St u d y 
6. 5  
D urati o n of F oll o w- U p 
 
7. 0  
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S 
7. 1  
D ose Dela y Criteria  
7. 2  
Criteria t o Res u me Treat me nt 
7. 3  
Disc o nti n uati o n Criteria 
 
8. 0  
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S 
8. 1   
C hec k p oi nt i n hi bit or a d verse e v e nts 
8. 2  
Seri o us A d verse E v e nt Re p ort F or m 
8. 3  
N o n- Seri o us A d vers e E v e nt Re p ort F or m 
8. 4  
A d verse E v e nt E val uati o n  
8. 5  
Re p orti n g Pr oce d ures f or Seri o us A d verse E v e nts a n d O n C ore ®    
8. 6  
Seri o us A d verse E v e nts a n d O n C ore ® 
8. 7  
Data a n d Saf et y M o nit ori n g Pla n 
 

C A S E 6 8 1 9  
  
  
P a ge 9   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
9. 0   
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  
Pe m br oliz u ma b Pr o d uct I nf or mati o n 
9. 2  
Atez oliz u ma b Pr o d uct I nf or mati o n 
9. 3   
D ur val u ma b Pr o d uct I nf or mati o n 
9. 4  
Ni v ol u ma b Pr o d uct I nf or mati o n 
9. 5  
A vel u ma b Pr o d uct I nf or mati o n   
 
1 0. 0 
C O R R E L A TI V E  
1 0. 1  
Bl o o d C orrelati ves  
1 0. 2 
Tiss ue C orrelati ves  
1 0. 3  
A d dress f or Tiss ue a n d Bl o o d S peci me n  
 
1 1 . 0 
S T U D Y P A R A M E T E R S A N D C A L E N D A R 
 
1 2. 0 
M E A S U R E M E N T O F E F F E C T   
 
1 3. 0  
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S 
1 3. 1 
Data Re p orti n g 
1 3. 2 
Re g ulat or y C o nsi der ati o ns  
  
 
1 4. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 4. 1 
Sa m ple Size J ustificati o n 
1 4. 2 
Safet y C o nsi derati o ns 
1 4. 3 
Efficac y 
1 4. 4 
Statistical Pla n 
 
R E F E R E N C E S 
 
  
  
 

C A S E 6 8 1 9  
  
  
P a ge 1 0   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
1. 0   
I N T R O D U C TI O N 
 
1. 1  
Bac k gr o u n d of A d v a nce d Ur ot helial Carci n o ma a n d Sta n dar d T her a pies  
 
Bla d der ca n cer is t he si xt h m ost c o m m o n ca ncer i n t he U S, wit h a n esti mate d 
8 1, 1 9 0 ne w cas es i n 2 0 1 8. 5 W hile t he maj orit y of cases are l ocalize d at i nitial dia g n osis 
ap pr o xi matel y 4 % will prese nt wit h de n ov o  m etastatic disease a n d a n ot her 4 0 % of 
patie nts wit h l ocalize d disease will ulti matel y de v el o p metastasis des pite d efi niti ve 
t hera p y.6 – 8  A d va nce d ur ot helial carci n o ma (a U C) has a 5 year m ortalit y rat e e x cee di n g 
8 5 %. 9, 1 0  
T he  sta n dar d t hera pies f or t he fr o nt-li ne tr eat me nt of a U C ar e cis plati n base d 
c o m bi nati o ns, li ke met h otre x ate, vi n blasti ne, d o x or u bici n, a n d cis plati n ( M V A C) a n d 
ge m cita bi ne wit h cis plati n, w hic h de m o nstrate a n o verall res p o ns e rate u p t o 5 0 %, 
i ncl u di n g a p pr o xi matel y 1 0 % – 1 5 % c o m plete r es p o nses ( C Rs).1 1, 1 2  Al m ost half of 
ur ot helial ca ncer patie nts are u nfit f or cis plati n-c o ntai ni n g c h e m ot hera p y d ue t o i m paire d 
re nal f u n cti o n, p o or perf or ma nce stat us or c o m or bi dit y. Pri or t o i m m u n ot hera p y, t he 
alter nati ve o pti o n f or cis plati n i neli gi ble patie nts was ge mcita bi ne wit h car b o plati n or 
ge m cita bi ne wit h paclita x el. O utc o mes are c o m para ble t o cis plati n base d t h era p y wit h a 
me dia n o verall s ur vi val of 9- 1 3 m o nt hs. 1, 5, 6 1 3, 1 4 Des pite i nitial c he m ose nsiti vit y, patie nts 
are n ot c ure d a n d t h e o utc o me of metastatic ur ot helial ca ncer after t hes e re gi me ns is p o or: 
me dia n ti me t o pr o gressi o n is o nl y 7 m o nt hs a n d me dia n o verall s ur vi val ( O S) is 1 5 
m o nt hs. 9, 1 1 Sec o n d li ne c he m ot hera p y has a li mite d r ole, b ut c hec k p oi nt i n hi bit ors offer 
a n a d diti o nal o pti o n f or p atie nts w h o ha ve pr o gresse d after i nitial s yste mic treat me nt. 
 
1. 2   
I m m u n ot her a p y i n A d va nce d Ur ot helial Carci n o ma  
 
I m m u n ot her a p y has r e v ol uti o nize d t he treat me nt of patie nts wit h a U C. T h ese 
t hera pies r e vers e i n nate i m m u ne i n hi biti o n b y bl o c ki n g pr o gra m me d d eat h 1 ( P D- 1), a n 
i n hi bit or y T-cell rece pt or, as well as tar geti n g t he c o-i n hi bit or y m olec ules pr o gra m me d 
deat h li ga n ds 1 a n d 2 ( P D- L 1 a n d P D- L 2) e x presse d o n t u m or a n d ot her cells. 1, 1 5 T he 
ex pressi o n of P D- 1, P D- L 1, a n d P D- L 2 o n t heir r es pecti ve cells ge ner ates t u m or 
resista nce t o t he e n d o ge n o us i m m u ne res p o nse res ulti n g i n t u m or pr oliferati o n a n d 
gr o wt h. Bl oc ki n g t hese r esista nce mec ha nis ms wit h P D- 1, P D- L 1, a n d P D- L 2 a nti b o dies 
has t he p ote ntial t o e n ha n ce a n d u nleas h t he h ost i m m u ne res p o nse a gai nst t he t u m or. 1 5, 1 6  
Fi ve C PI (atez oliz u ma b, pe m br oliz u ma b, a vel u ma b, d ur val u ma b, a n d ni v ol u ma b) 
are a p pr o ve d f or rel a pse d/refract or y a U C f oll o wi n g plati n u m- bas e d c he m ot hera p y a n d 2 
C PI (atez oliz u ma b a n d pe m br oliz u ma b) are a p pr o ve d f or cis plati n-i neli gi ble patie nts. 
Gi ve n its str o n g p has e III data, pe m br oliz u ma b has bec o me t he defa ult sta n dar d of care.  
 
1. 2. 1 Pe m br oliz u ma b  
  
I n K E Y N O T E- 0 5 2, 3 7 0 patie nts wit h treat me nt naï ve a U C were tr eate d wit h 
pe m br oliz u ma b 2 0 0 m g e ver y 3 w ee ks f or u p t o t w o years. T h e a vera ge a ge was 7 4 years 
ol d, i ncl u di n g 2 9 % of p atie nts ol der t ha n 8 0 years. At a me dia n f oll o w u p of 9. 5 m o nt hs, 
t he O R R was 2 9 %, i ncl u di n g 7 % of p atie nts ac hie vi n g C R.1 7 L o n g ter m f oll o w- u p at 1 1. 5 
m o nt hs, c o nfir me d a n O R R of 2 8. 9 % ( 9 5 % CI 2 4. 3- 3 3. 8) wit h 8. 1 % of pati e nts ac hie vi n g 
a C R. Me dia n d urati o n of res p o nse w as still n ot reac he d a n d me dia n O S was 1 1. 5 m o 

C A S E 6 8 1 9  
  
  
P a ge 1 1   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
( 95 % CI 1 0. 0- 1 3. 3).  I n P D- L 1 p ositi ve t u m ors (c o m bi ne d p ositi ve sc ore ≥ 1 0), O R R was 
4 7. 3 % ( 9 5 % CI 3 7. 7- 5 7. 0) a n d me dia n O S w as 1 8. 5 m o nt hs ( 9 5 % CI 1 2. 2- N E). Ot her 
s u b gr o u ps t hat h a d i m pr o ve d me dia n O S was l y m p h n o de o nl y disease ( N R, 9 5 % CI 2 4. 0- 
5 7. 0), E C O G P S 0/ 1 ( 1 3. 1 m o; 9 5 % CI 1 1. 0- 1 6. 8), a n d E C O G 2 ( 9. 7 m o; 9 5 % CI 5. 7-
1 1. 6). T he m ost c o m m o n a n y gra de treat me nt r elat e d a d vers e e v e nts ( T R A E) wer e 
fati g u e ( 1 8. 1 %) a n d pr uritis ( 1 7. 8 %). I m m u ne rel ate d T R A E occ urre d i n 2 4. 6 % of 
patie nts. 1 5 Base d o n t hese res ults, t he F D A a p pr o ve d pe m br oliz u ma b i n t he fr o nt li ne 
setti n g f or cis plati n i neli gi ble, treat me nt naï ve p atie nts wit h a U C.  
  
I n K E Y N O T E- 0 4 5, patie nts wit h a U C refr act or y t o cis plati n- base d t her a p y were 
ra n d o ml y assi g n e d t o eit her pe m br oliz u ma b ( 2 0 0 m g e v er y 3 w ee ks f or u p t o 2 years) 
vers us i n vesti gat or’s c h oi ce of c h e m ot her a p y (i ncl u di n g paclita x el, d oceta xel, or 
vi nfl u ni ne). At a me dia n f oll o w u p of 2 7. 7 m o nt hs, pe m br oliz u ma b s h o we d i m pr o ve d O S 
( 1 0. 1 vs. 7. 3 m o, H R 0. 7; 9 5 % CI 0. 5 7- 0. 8 5, p < 0. 0 0 0 2), i m pr o ve d O R R ( 2 1 % vs. 1 1 %), 
i m pr o ve d d urati o n of r es p o nse ( N R vs. 4. 4 m o), less gra de ≥3 t o xicit y ( 1 7 % vs. 5 0 %), 
a n d l o n ger ti me t o healt h-relate d q u alit y of lif e det eri orati o n ( 3. 5 vs. 2. 3 m o; H R 
0. 7 2). 1 8, 1 9 T here was n o P F S be nefit. Base d o n t h ese res ults, pe m br oliz u ma b 
m o n ot hera p y is als o a p pr o ve d i n cis plati n refr act or y a U C.   
 
1. 2. 2. Atez oliz u ma b 
I M vi g or 2 1 0 was desi g ne d t o i n vesti gate at ez oliz u ma b i n b ot h t he fr o nt li ne a n d 
sec o n d li ne setti n g.  
I n c o h ort A, 1 1 9 cis plati n i neli gi ble patie nts recei ve d atez oliz u ma b 1 2 0 0 m g 
e ver y 3 w ee ks. At a m e dia n f oll o w u p of 1 7 m o nt hs, O R R was 2 3 %, i ncl u di n g 9 % C R 
a n d me dia n O S was 1 5. 9 m o nt hs. At t he ti me of a nal ysis, me dia n d ur ati o n of res p o nse 
was n ot reac he d yet a n d 1 9 of 2 7 c o nti n ue d t o ha ve res p o nse. 2 0 1 6 % of patie nts 
e x perie nce d gr a de 3 or hi g her T R A E. T h us, atez oliz u ma b is a p pr o ve d f or fr o nt li ne 
t hera p y i n plati n u m-i nt olera nt patie nts. 
I n c o h ort B, 3 1 0 patie nts wit h metastatic ur ot helial carci n o ma p ost- pl ati n u m 
treat me nt s h o we d i m pr o v e d O R R 1 5 % (c o m pare d t o hist orical c o ntr ols O R R 1 0 %; p = 
0. 0 0 5 8) re gar dless of P D- L 1 stat us. Of t he 4 5 r es p o n ders, 8 4 % ha d o n g oi n g res p o nse at a 
me dia n f oll o w u p of 1 1. 7 m o nt hs. Gra de 3 or hi g h er T R A E occ urr e d i n 1 6 % of patie nts 
a n d i m m u ne me diate d A E were 5 % of patie nts; m ost n ota bl y p ne u m o nitis, li ver e nz y me 
a b n or malities, ras h a n d d ys p nea. 2 1 Patie nts w h o c o nti n ue d atez oliz u ma b be y o n d 
p ro gressi o n ha d a l o n ger p ost pr o gr essi o n O S ( 8. 6 m o nt hs) c o m pare d t o t h ose 
tra nsiti o ne d i m me diatel y t o differe nt tr eat me nts ( 6. 8 m o nt hs) a n d t h ose w h o di d n ot ha ve 
f urt her tr eat me nt ( 1. 2 m o nt hs).2 2 Base d o n t hese res ults, F D A gra nte d accel erate d 
a ppr o val f or atez oliz u ma b as a si n gl e a ge nt as sec o n d-li ne treat me nt f or s u bjects wit h 
l ocall y a d va nce d or metastatic ur ot helial car ci n o ma ( m U C).  
Of n ote, base d o n I M Vi g or 2 1 0, a p hase III tri al, I M vi g or 2 1 1, r a n d o mize d 9 3 1 
patie nts, w h o ha d recei ve d plati n u m- base d c he m ot hera p y, t o atez oliz u ma b ( 1 2 0 0 m g I V 
e ver y 3 w ee ks) or t o i n vesti g or’s c h oi ce of s ec o n d li ne c he m ot hera p y ( vi nfl u ni ne, 
paclita x el, or d oceta x el). Atez oliz u ma b ha d si milar me dia n O S ( 1 1. 1 m o nt hs vs. 1 0. 6 
m o nt hs; p = 0. 4 1) a n d O R R ( 2 3 % vs. 2 2 %), b ut less gr a de 3 or hi g h er T R A E ( 2 0 % vs. 
4 3 %). 2 3 Atez oliz u ma b re mai ns a p pr o ve d as s ec o n d li ne t hera p y des pite t hese res ults.  
 
 

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1. 2 . 3 D ur val u ma b 
D ur val u ma b w as e x pl ore d i n a p hase I/II st u d y, M E DI 4 7 3 6, w hic h l o o ke d at 1 9 1 
patie nts wit h i n o pera ble or metastatic ur ot helial ca ncer w h o ha d pr o gresse d d uri n g or 
after o n e sta n dar d pl ati n u m- base d t her a p y. At a m e dia n f oll o w u p of 5. 7 8 m o nt hs, O R R 
was 1 7. 8 % ( 9 5 % CI 1 2. 7- 2 4. 0), i ncl u di n g 7 p atie nts w h o ac hie ve d C R. T he me dia n ti me 
of res p o nse w as 1. 4 1 m o nt hs a n d me dia n d ura ble res p o nse ha d n ot yet b ee n reac h e d. Of 
n ote, patie nts wit h P D- L 1 e x pressi o n ha d better O R R ( 2 7. 6 % vs. 5. 1 %), me dia n P F S ( 1. 5 
m o, 9 5 % CI 1. 4- 1. 9 m o) a n d me dia n O S ( 1 8. 2 m o, 9 5 % CI 8. 1- N E). A d diti o nall y, 
d ur val u ma b was f o u n d t o be well t olerate d wit h o nl y 6. 8 % of p atie nts e x perie nci n g a 
gr a de 3 or m ore T R A E a n d 2. 1 % of patie nts ha vi n g gr a de 3 or m ore i m m u ne T R A E, 
m ost n ota bl y h e patitis a n d p ne u m o nitis. 4  
 
1 . 2. 4. Ni v ol u ma b  
I n C hec k mate 0 3 2, a n o p e n la bel, m ultice nter p h ase 1/ 2 e x pa nsi o n c o h ort st u d y i n 
patie nts wit h a U C, w h o ha d pr o gress e d after pre vi o us plati n u m base d t hera p y, s h o w e d 
ni v ol u ma b was ass ociate d wit h a s u bsta ntial a n d d ura ble cli nical r es p o nse. At a mi ni m u m 
f oll o w u p of 9 m o nt hs, 1 9 of 7 8 ( 2 4. 4 %) of patie nts ha d a n o bjecti ve r es p o nse, wit h 
1 7. 9 % ac hie vi n g C R. T h e me dia n d urati o n of res p o nse was 9. 4 m o nt hs (I Q R 5. 7- 1 2. 5) 
a n d t he me dia n ti me t o res p o nse was 1. 5 m o nt hs (I Q R 1. 2- 4. 1). I nter esti n gl y, f o ur 
patie nts were a ble t o s ustai n res p o nse after ni v ol u ma b m o n ot hera p y disc o nti n uati o n ( 7-
2 2 + wee ks). 2 4  
I n t he p h ase II C hec k M ate 2 7 5 trial, 2 6 5 pre vi o usl y treate d a U C patie nts w ere 
treate d wit h ni v ol u ma b 3 m g/ k g I V e ver y 2 w ee ks u ntil pr o gressi o n or u n acce pta ble 
t o xicit y. T he O R R was 1 9. 6 %. ( 9 5 % CI 0- 2 4. 9) wit h 2 % of patie nts ac hie vi n g a C R. T he 
me dia n d urati o n of r es p o nse was N R, wit h 7 7 % of patie nts ha vi n g a n o n g oi n g r es p o nse 
a n d t he me dia n O S was 8. 7 4 m o ( 9 5 % CI 6. 0 5 t o N R). 3  
 
1 . 2. 5 A vel u ma b  
A vel u ma b is a n ot her P D- L 1 i n hi bit or t hat has s h o w n be nefit i n t he plati n u m-
refr act or y s pace. I n a p hase 1 b trial, a vel u ma b 1 0 m g/ k g I V e ver y 2 w ee ks. At a me dia n 
f oll o w u p of 1 6. 5 m o nt hs, O R R was 1 8. 2 % ( 9 5 % CI 8. 2 %- 3 2. 7 %) wit h 5 C R. T he me dia n 
d urati o n of res p o ns e was N R ( 9 5 % CI 1 2. 1 wee ks t o N E) a n d r es p o nses wer e o n g oi n g i n 
6 patie nts ( 7 5. 0 %). Of n ote, 7 of 8 of t he r es p o n ders wer e P D- L 1 p ositi ve (I H C ≥ 5 % of 
t u m or cells). T her e was als o a n i m pr o ve me nt i n me dia n P F S ( 1 1. 6 wee ks, 9 5 % CI, 6. 1 t o 
1 7. 4 wee ks), me di a n O S ( 1 3. 7 m o nt hs, 9 5 % CI, 8. 5 m o nt hs t o N R), a n d 1 2- m o nt h O S 
rate ( 5 4. 3 %, 9 5 % CI, 3 7. 9 % t o 6 8. 1 %).2 5 Base d o n a p o ole d a nal ysis of t he t w o 
e x pa nsi o n c o h orts i n t he a b o ve J A V E LI N s oli d t u m or trial, a vel u ma b w as a p pr o ve d f or 
t he treat me nt of plati n u m refr act or y a U C base d o n a p o ole d a nal ysis of t w o e x pa nsi o n 
c o h orts i n t he a b o ve J A V E LI N s oli d t u m or trial. 2 6  
 
1. 3   
Rati o nale  
A n u na ns wer e d q uesti o n wit h t he use of C PI is t he d urati o n of t hera p y re q uire d 
f or o pti mal cli nical be nefit. I n t he a bs e nce of pr o gressi ve diseas e or u nacce pta ble 
t o xicities, t here ar e c urre ntl y n o s pecifi e d criteria f or treat me nt disc o nti n uati o n. Strate gies 
t o re d uce t o xicit y a n d ma xi mize be nefit re q uire i n vesti gati o n. Cli nical trials i n vesti gati n g 
C PI i n mela n o ma a n d ki d ne y ca n cer h a ve s h o w n d ura ble r es p o nses i n patie nts w h o ha ve 

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di sc o nti n ue d t hera p y f or reas o ns ot her t h a n diseas e pr o gressi o n. 1 6, 2 7, 2 8 I n fact, o ur gr o u p 
co n d ucte d a p h ase II trial of i nter mitte nt ni v ol u ma b i n a R C C a n d s h o we d n ot o nl y was it 
feasi ble b ut t hat at 4 8 w ee ks, 4 o ut of 5 patie nts w ere a bl e t o s ustai n res p o nse off 
t hera p y.2 8  
Si milarl y, i n bla d d er ca n cer, i n C hec k m ate 0 3 2, f o ur patie nts wer e a ble t o s ustai n 
res p o nse after ni v ol u ma b m o n ot hera p y disc o nti n uati o n ( 7- 2 2 + w ee ks).2 4 A d diti o nall y, i n 
t he C hec k Mate 2 7 5 trial of ni v ol u ma b i n patie nts wit h a U C w h o pr o gresse d f oll o wi n g 
plati n u m- base d c he m ot h era p y, 9 patie nts h a d s ustai ne d res p o ns es off t hera p y 2 – 1 7 + 
wee ks. 3 Li k e wise, i n M E DI 4 7 3 6, t here was a p atie nt w h o disc o nti n ue d treat me nt, 
u n relate d t o pr o gr essi o n, a n d mai ntai ne d a r es p o ns e f or > 3 2 wee ks.4  
I n ge ner al, m ost patie nts ca n ac hie ve a res p o nse t o a n y of t he 5 a p pr o ve d C PI 
t hera pies wit hi n 2 m o nt hs of treat me nt i nitiati o n (ra n ge 1. 4- 2. 8 5 m o nt hs).3, 4, 1 7, 1 9, 2 1, 2 3 – 2 6  
S p ecificall y wit h pe m br oliz u ma b, i n b ot h cis plati n refr act or y a n d cis plati n i neli gi ble 
patie nts, t he me dia n res p o nse ti me t o res p o nse was 2- 2. 1 m o nt hs a n d t he perce nt a ge of 
patie nts w h o res p o n de d t o pe m br oliz u ma b a n d di d n ot ha ve P D at 1 year was 6 8 % 
( me dia n d urati o n of res p o nse was 1. 6 +- 3 0. 3 + m o nt hs.).1 7, 1 9, 2 9 P hase I dat a i n refract or y 
s oli d t u m ors s h o we d t hat re gar dl ess of d ose, a si n gle I V i nf usi o n of ni v ol u ma b ( 0. 3-
1 0 m g/ k g I V) l ea d t o a ser u m half-life of 1 2- 2 0 da ys wit h a mea n platea u P D- 1 rece pt or 
occ u pa n c y o n peri p heral bl o o d circ ulati n g T cells of 7 2 % (r a n ge 5 9- 8 1 %) f or great er t ha n 
5 7 da ys. 1 6 Si milar fi n di n gs w ere s ee n i n c o h ort A of a st u d y of mela n o ma, R C C, a n d U C, 
w h ere res p o n ders ( R E CI S T C R, P R or S D) ha d s ustai ne d P D- 1 rece pt or o cc u pa n c y 
( > 8 0 % f or u p t o 3 0 0 da y) des pite n o n- detecta ble s er u m ni v ol u ma b le vels.3 0 A re vie w of 
t he p har mac o d y n a mics of all 5 C PI s h o w a flat e x p os ure t o res p o nse relati o ns hi p wit h 
> 7 0 % tar get rece pt or sat urati o n (ra n ge 7 0 %- 9 9 %). 3 1 T his data s u g gests t hat ni v ol u ma b 
ha s a hi g h affi nit y f or P D- 1 a n d t hat s uffici e nt c o n ce ntrati o ns persist t o mai ntai n platea u 
occ u pa n c y e ve n w he n ser u m le vels are n ot d etect a ble.  T hese st u dies s u g gest t hat t h ose 
w h o res p o n d t o c hec k p oi nt i n hi bit or t hera p y d o s o q uic kl y a n d p ot e ntiall y c o ul d ha ve 
d ura ble r es p o nses.  
  
Al o n g wit h p h ysical t o xicit y, fi na n cial t o xicit y is a real c o ncer n f or tr eat m e nts 
wit h a n i n defi nite ti me c o urse. T he a v er a ge c ost of o ne d ose of a n y C PI t h era p y is 
$ 8, 7 9 1. 6 0, wit h a yearl y c ost ra n gi n g fr o m $ 1 6 9, 9 1 1 t o $ 2 0 0, 8 6 5. 3 2 T hese val ues d o n ot 
acc o u nt f or t he c ost of t o xicit y ma na ge me nt t hat ma y i nc ur. I n a n era of h ealt h-care c ost 
c o ntai n me nt a n d d oc u me nte d fi na ncial b ur d e n of ca ncer t her a p y t o patie nts a n d t he 
healt h-care s yste m, it is partic ularl y i m p orta nt t o d e vel o p treat me nt r e gi me ns a n d 
sc he d ules t hat re d u ce c ost.  
T h us, n o vel d osi n g sc h e d ules, earl y disc o nti n uati o n c o nsi derati o ns, a n d 
bi o mar kers of res p o nse are nee d e d t o i de ntif y pati e nts w h o ca n s ustai n disease re gressi o n 
w hile off of t hera p y. Si milar t o t he R C C st u d y w e pre vi o usl y c o n d ucte d, w e h y p ot h esize 
t hat t here is a s u b gr o u p of patie nts wit h a d va nce d ur ot helial car ci n o ma w h o are a bl e t o 
s ustai n res p o nse off of C PI t her a p y.  
 
1. 4  
Bac k gr o u n d a n d rati o nal e of c orrelati ve st u dies 
I m m u n ot her a p y f u ncti o ns t o m o d ulate t he i m m u ne micr oe n vir o n me nt. M yel oi d 
deri ve d s u p pr ess or cells ( M D S C), C D 8 + a n d C D 4 + T cells, re g ul at or y T cells ( Tre gs), T 
cell rece pt or ( T C R) r e pert oire, a m o n g ot h ers are i m p orta nt c o ntri b ut ors b ot h t o t he 

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f uncti o n of a n d r esista nce t o tar gete d t hera p y a n d i m m u n ot hera p y. 3 3- 3 6 F or e x a m ple, i n 
m ela n o ma, patie nts wit h hi g her n u m b ers of circ ul ati n g Tr e g cells a n d Teff cells after C PI 
t hera p y were pr e dicti ve of treat me nt r es p o nses. 3 7, 3 8 C PI t her a p y was als o ass ociate d wit h 
c ha n ges t o t he T C R re p ert oire, w hic h is cr uci al t o T cell f u ncti o ni n g. 3 9 A d diti o nall y, i n 
br east a n d c ol o n ca n cer, M D S C le vels ha ve c orrel ate d wit h treat me nt r es p o nse, disease 
pr o gressi o n, a n d cli nical o utc o mes. 3 4 S pecificall y i n ur ot helial carci n o ma, M D S Cs i n 
pe ri p her al bl o o d ha ve bee n c orr elate d wit h pat h ol o g y a n d res p o nse t o C PI t hera pies.4 0, 4 1 
T he  t u m or micr oe n vir o n me nt as well as t he peri p heral bl o o d ar e d y na mic a n d 
s u bject t o c ha n ge b ase d o n c ha n ges i n t u m or b ur de n a n d t hera p y. T h ere is a lac k of 
pr os pecti ve dat a de m o nstrati n g c orr elati o ns bet wee n c ha n ges i n peri p her al bl o o d a n d 
c ha n ges i n t he t u m or micr oe n vir o n me nt. T he g o al of t his st u d y is t o ge n erat e a 
h y p ot hesis t hat c h a n ges i n t he t y pe a n d be h a vi or of i m m u n o m o d ulat or y cells i n t he 
peri p her al bl o o d will refl ect t u m or b ur de n a n d t hat s uc h c ha n ges will i m pact t u m or 
b ur de n w hile o n C PI t her a p y. T h e pr ese nce of a bi o mar ker ( or c o m p osite bi o mar ker 
sc ore) t o i de ntif y p atie nts li kel y t o be nefit fr o m C PI will hel p pr os pecti vel y select 
patie nts f or t her a p y. Li k e wise, t he de vel o p me nt of bi o mar kers t o deter mi ne w hic h 
patie nts are li kel y t o t oler ate e xte n de d brea ks fr o m t hera p y wit h o ut c o m pr o misi n g 
efficac y, will mi ni mize t o xicit y f or s elect patie nts. 
A n ot her p oi nt of i nterest w o ul d be t o e val uate t h e rate at w hic h t h e P D- 1 rece pt or 
occ u pa n c y o n peri p heral bl o o d circ ulati n g T cells c ha n ges o ver ti me wit h C PI 
s us pe nsi o n. Pre vi o us st u dies ha ve s h o w n P D- 1 r ece pt ors ca n re mai n o cc u pie d f or > 1 0 
m o nt hs des pite n o n- detecta ble le vels i n t he bl o o d. 3 1 T his is p ote ntiall y a r eas o n w h y 
p atie nts ha ve “ d ura ble” r es p o nses a n d sl o w r es ol vi n g t o xicities t o i m m u n ot hera p y e v e n 
after disc o nti n uati o n. U n dersta n di n g t he p har m ac o d y na mics of a nti- P D- 1/ a nti- P D- L 1 
t hera p y o n P D- 1 r ece pt or occ u pa n c y is cr uci al i n de vel o pi n g a d ose s us pe nsi o n sc he d ule.  
Base d o n o ur c urr e nt k n o wle d ge t hes e ar e t he c orrelati ves we are i nterest e d i n a n d will 
p urs ue as l o n g as it is still cli nicall y r ele va nt.  
  
2. 0   
O B J E C TI V E S 
 
2. 1   
Pri mar y O bj ecti ve  
T o assess t he efficac y of i nter mitte nt C PI t her a p y, d efi ne d as t he pr o p orti o n of patie nts 
w h o re mai n off t hera p y f or at least 3 6 wee ks 
 
2. 2  
Sec o n dar y O bj ecti ve(s) 
 
•  T o deter mi ne t he cli nical o utc o me ( T FI, O R R, P F S, O S) i n a d va nce d ur ot h elial 
carci n o ma wit h i nter mitte nt C PI t her a p y.   
•  T o assess res p o nse t o re-i nitiati o n of C PI t hera p y 
 
2. 3  
C orrelati ve O bjecti ve(s) 
 

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•  Tis s ue: I n v esti gat e t he ge n o mic a n d i m m u n ol o gic mar kers of res p o nse a n d resista nce 
t o t hera p y.  
•  Bl o o d: I n vesti gate t he i m m u n o m o d ulat or y cell ma ke u p [s pecificall y, l y m p h oc yt e P D-
1 occ u pa n c y, m yel oi d- deri ve d s u p press or cells ( M D S C), re g ulat or y T cells ( Tre g), 
C D 4 a n d C D 8 T Cells, T C R re pert oire] at t he start of treat me nt, d uri n g t he 
i nter mitte nt p hase a n d off treat me nt 
 
3. 0  
S T U D Y D E SI G N 
 
3. 1   
St u d y d esi g n i ncl u di n g d ose escal ati o n / c o h orts  
 
 
 
 
A p hase II st u d y d esi g n t o i n vesti gate t he us e of a n y C PI o n a n i nter mitte nt d osi n g 
sc he d ule. Patie nts wit h a U C w h o treat me nt refract or y or cis plati n i neli gi bl e will recei v e 
C PI of c h oi ce as p er sta n dar d d osi n g. Patie nts w h o ha ve i nitial ≥ 1 0 % t u m or b ur de n 
1Patie nts ma y b e treat e d wit h a n y F D A-a p pr o v e d C PI f or cis plati n-i neli gi ble a U C or 
cis plati n resista nt/refr act or y a U C. 
2I n cas es w here a p atie nt is c o nti n ue d o n t hera p y after P D a n d de v el o ps s u bse q ue nt 
di sease pr o gr essi o n, C PI s h o ul d be disc o nti n ue d.  
3Patie nts w h o d o n ot ha ve t u m or b ur de n r e d ucti o n of > 1 0 % after 2 c o nsec uti ve 
i ma gi n g will be re m o v e d fr o m st u d y.  
* Of n ote all i ma gi n g is c o m pare d t o sca ns d o n e pri or t o i nter mitte nt t hera p y i nitiati o n.  

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red ucti o n will disc o nti n ue t he C PI u ntil t he y e x perie nce a ≥2 0 % diseas e pr o gr essi o n, at 
w hic h ti me C PI t her a p y will be restarte d.  
T he 1 0 % c ut off was c h ose n o n t he basis of a met a nal ysis i n C PI-treate d m etastatic 
mela n o ma t hat t his c ut p oi nt ma y o pti mall y se p ar ate o ver all s ur vi val i n patie nts ( better 
t ha n t he tra diti o nal R E CI S T P R 3 0 % c ut off) a n d als o fr o m pri or e x perie n ce usi n g t his 
c ut off i n a n i nter mitte nt ni v ol u ma b trial i n ki d ne y ca ncer. 2 8, 4 2 Please ref er t o secti o n 1 4. 0 
fo r statistical c o nsi der ati o n, i ncl u di n g earl y st o p pi n g r ules.  
 
3. 2  
N u m ber of S u bjects 
O ur g oal is t o e nr oll 2 0 C PI- eli gi ble p atie nts o nt o t he i nter mitte nt ar m. 
W e will first 
scree n u p t o 5 0 patie nts f or t his st u d y i n or der t o get o ur tar get sa m ple size. If, t here are 
n ot at least 2 0 p atie nts wit h a t u m or b ur de n re d u cti o n of 1 0 % or gr eater, w e will c o nti n ue 
t o scree n u p t o 2 5 m ore patie nts (t otal of 7 5 patie nts). If w e scree n 7 5 patie nts wit h o ut 
e nr olli n g 2 0 patie nts i nt o t he i nter mitte nt ar m, we will st o p t he trial a n d dee m it n ot 
feasi ble (ref er t o secti o n 1 4. 1 f or sa m ple size j ustificati o n) 
 
3. 3  
E x pecte d D urati o n of Tr eat me nt a n d S u bject Partici pati o n  
Eac h st u d y c ycl e c o nsists of 1 4- 2 8 da ys, de p e n di n g o n  whic h C PI is c h ose n. C PI of 
c h oice will be a d mi nister e d o n da y 1.   
All patie nts w h o d o n ot meet criteria f or t he C PI i nter mitte nt p hase of t he st u d y will be 
treate d u ntil u nacce pta bl e t o xicit y or R E CI S T- defi ne d P D. Patie nts wit h R E CI S T- d efi ne d 
P D ma y c o nti n ue C PI t hera p y at t he discr eti o n of t he treati n g M D. T hes e patie nts will 
c o nti n ue wit h n or mal i ma gi n g e ver y 1 2 wee ks. I n cases w h ere a patie nt is c o nti n ue d o n 
t hera p y after P D a n d d e v el o ps s u bse q ue nt P D ( > 2 0 % i ncrease i n s u m of tar get lesi o ns 
c o m pare d t o t he i nitial P D t u m or meas ure me nts, t he patie nt will c o me off st u d y).  
Patie nts w h o meet criteri a f or t he i nter mitte nt p hase (i.e., ha v e ≥1 0 % t u m or b ur de n 
re d ucti o n) will n ot recei v e C PI t hera p y. I ma gi n g will c o nti n ue per pr ot oc ol (e ver y 1 2 
wee ks fr o m t he i nitial date t he y st o p pe d C PI t hera p y). Patie nts w h o h a ve R E CI S T 
defi ne d P D o n t he i nter mitte nt p hase s h o ul d rei nitiate C PI t hera p y. Patie nts w h o ha ve a 
s u bse q ue nt decreas e i n t u m or b ur de n ≥ 1 0 % ca n t h e n restart C PI t her a p y as per pr ot oc ol. 
(ref er t o sc he m a i n Secti o n 3. 1). 
4. 0  
S U B J E C T S E L E C TI O N 
Eac h of t he criteria i n t he secti o ns t hat f oll o w m ust be met i n or der f or a s u bject t o be 
c o nsi dere d eli gi ble f or t his st u d y. Use t he eli gi bilit y criteria t o c o nfir m a s u bject’s 
eli gi bilit y.  
4. 1  
I n cl usi o n Criteria  
 
Patie nts m ust meet all t he f oll o wi n g criteria t o b e eli gi ble f or st u d y e nr oll me nt.  
•  
Me n a n d w o me n ≥ 1 8 years of a ge.  

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•  
Hist ol o gical c o nfir mati o n of ur ot helial carci n o ma (a n y hist ol o g y)  
•  
A d va nce d or metastatic ur ot helial car ci n o ma.   
•  
Has recei ve d at least 2 0 wee ks o n C PI t hera p y p er sta n dar d of car e ( S O C) f or 
a dv a nce d ur ot helial carci n o ma 
•  
Kar n ofs k y Perf or ma n ce Sc ore ( K P S) ≥7 0 %  (f or m ore i nf or mati o n o n K P S, please 
see: htt p:// w w w. n pcrc. or g/files/ ne ws/ kar n ofs k y p erf or ma n ce s cale. p df ) 
•  
Willi n g a n d a ble t o pr o vi de i nf or me d c o ns e nt.  
•  
La b orat or y criteria f or st u d y e ntr y m ust meet t he f oll o wi n g criteria:  
o  Ser u m creati ni ne ≤ 2 x UL N O R Cr Cl ≥ 3 0 m L/ mi n ( meas ure d or 
calculate d usi n g t he C oc kcr oft- G a ult f or m ula).  
o  H b ≥ 8. 0 g/ d L 
o  A S T a n d A L T ≤ 3. 0 x U L N 
o  Bilir u bi n ≤ 1. 5 x U L N (e x ce pt s u bjects wit h Gil bert S y n dr o me, w h o ca n 
ha ve t otal bilir u bi n < 3. 0 m g/ d L)  
4. 2  
E x cl usi o n Criteria 
T he prese n ce of a n y of t h e f oll o wi n g will e x cl u de a patie nt fr o m st u d y e nr oll me nt:  
•  
Hist or y of s e ver e h y pers e nsiti vit y reacti o n t o a n y m o n ocl o nal a nti b o d y.  
•  
Patie nts are e x cl u de d if t he y h a ve k n o w n HI V/ AI D S.  
•  
Maj or s ur ger y (e g, c yst ect o m y) less t ha n 2 8 da ys pri or t o t he first d ose of st u d y 
dr u g.  
•  
A n y c o n diti o n re q uiri n g s yste mic treat me nt wit h eit her c ortic oster oi ds ( > 1 0 m g 
dai l y pr e d nis o ne e q ui val e nt) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 7 
da ys pri or t o t he first d os e of st u d y dr u g. I n hal e d ster oi ds a n d a dr e nal r e place me nt 
ster oi d d oses > 1 0 m g dail y pre d nis o ne e q ui vale nt are per mitte d i n t he a bse nce of 
acti ve a ut oi m m u ne disease.  
•  
K n o w n me dical c o n diti o n (e g, a c o n diti o n ass oci ate d wit h diarr hea or ac ute 
di v ertic ulitis) t hat, i n t he i n vesti gat or’s o pi ni o n, w o ul d i ncrease t h e ris k ass ociate d 
wit h st u d y partici pati o n or st u d y dr u g a d mi nistrati o n or i nterfer e wit h t he 
i nter pretati o n of safet y r es ults.  
•  
Pre g n a nt w o me n are e x cl u de d fr o m t his st u d y beca use a ni mal st u dies ha ve 
de m o nstrate d t hat P D- 1/ P D- L 1 i n hi bit ors ca n ca use fetal har m w he n a d mi nistere d 
t o pre g n a nt w o me n. Breastfee di n g w o me n are e x cl u de d fr o m t his st u d y beca use 
P D- 1/ P D- L 1 i n hi bit ors ma y b e e x crete d i n h u ma n mil k a n d t he p ote ntial f or 
seri o us a d vers e reacti o ns i n n ursi n g i nfa nts. 4 3    
4. 3 
I n cl usi o n of W o me n a n d Mi n orities  
Me n, w o me n a n d me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial.  
 
 

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5. 0 
R E GI S T R A TI O N  
All s u bjects w h o ha ve bee n c o nse nte d are t o b e re giste re d i n t he O n C ore ® Data base. F or 
t h ose s u bjects w h o ar e c o nse nte d, b ut n ot e nr olle d, t he reas o n f or e x cl usi o n m ust be 
rec or d e d.  
All s u bjects will be re gistere d t h o u g h Cle vela n d Cli nic Lea d St u d y C o or di n at or a n d will 
be pr o vi de d a st u d y n u m ber b y c o ntacti n g t he st u d y c o or di nat or. I n t he e v e nt t hat t he 
Lea d St u d y C o or di nat or ca n n ot be r eac h e d, t he D ata base M a na ger ma y be c o ntacte d t o 
re gister a p atie nt. C o ntact i nf or mati o n f or t hese i n di vi d uals is liste d bel o w.  
Title 
N a m e 
P h o ne 
E m ail 
Le a d St u d y 
C o or di n at or 
 
 
 
D at a b ase 
M a n a ger 
 
 
 
 
6. 0   
T R E A T M E N T P L A N 
 
6. 1  
C hec k p oi nt I n hi bit or Tr eat me nt Re gi me n O v er vie w 
Treat me nt will be a d mi nistere d o n a n o ut patie nt b asis a n d a d mi nistere d as t he f oll o wi n g: 
•  Pe m br oliz u ma b 2 0 0 m g I V o ver 3 0 mi n utes e ver y 3 wee ks 
•  Pe m br oliz u ma b 4 0 0 m g I V o ver 3 0 mi n utes e ver y 6 wee ks ( D ecisi o n o n 
pe m br oliz u ma b d ose will be base d o n pr o vi d er dis creti o n). 
•  Atez oliz u ma b 1 2 0 0 m g I V o ver 6 0 mi n utes e ver y 3 wee ks. (if first d ose is 
t olerate d, all s u bse q ue nt i nf usi o ns ma y b e deli ver e d o ver 3 0 mi n utes) 
•  D ur val u ma b 1 0 m g/ k g I V o ver 6 0 mi n utes e ver y 2 wee ks.  
•  Ni v ol u ma b 4 8 0 m g I V o v er 3 0 mi n utes e ver y 4 wee ks 
•  A vel u ma b 8 0 0 m g I V o v er 6 0 mi n utes e ver y 2 wee ks 
* Please ref er t o Secti o n 9. 0 f or f urt her p har m ace utical details. 
 
6. 2  
C hec k p oi nt I n hi bit or Reacti o ns: f oll o w I nstit uti o n al g ui deli nes. I n t he a bse nce of 
a n y s u c h g ui deli nes, or p er pr o vi der dis creti o n, a p pl y t he f oll o wi n g:  
F or Gr a de 1 s y m pt o ms: Mil d reacti o n; itc hi n g, r as h, hi ves, fe ver, ri g ors): St o p t he 
i nf usi o n, n otif y pr o vi der a n d st u d y n urs e. I nitiate n or mal sali ne i nf usi o n at 5 0 0 ml/ hr, 
titrate u p t o mai ntai n s yst olic B P > 1 0 0. A d mi nister di p he n h y dra mi ne 5 0 m g I V. 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 yl actic pre- me di cati 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 paracet a m ol 3 2 5 t o 1 0 0 0 m g 
(acet a mi n o p he n) at least 3 0 mi n utes bef ore a d diti o nal C PI a d mi nistrati o ns.  
F or Gr a de 2 s y m pt o ms: M o derate r eacti o n s uc h as S O B, c hest ti g ht ness, b ac k pai n, 
w hic h re q uir es 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 F oll o w a b o v e f or Gra d e 1 a n d a d d o x y g e n at 2 L via nas al ca n n ul a a n d titrate t o 

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ke e p O 2 sat ur ati o n > 9 2 % a n d gi ve h y dr o c ortis o ne 1 0 0 m g I V P o nce; r e 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. If s y m pt o ms pr o gr ess, d o n ot re- d ose 
me dicati o ns alrea d y gi ve n, m o ve o n t o treat me nt f or se ver e / Gra d e 3 reacti o ns. 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 nal 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 after 3 0 mi n utes, t he r ate ma y be 
i ncreas e d t o 1 0 0 % of t he ori gi nal i nf usi o n r ate.  
M o nit or s u bject cl osel y. If s y m pt o ms r ec ur, t he n n o f urt her C PI will be gi ve n. 
Di p he n h y dra mi ne 5 0 m g I V a n d r e mai n at be dsi d e 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 d e d o n t he 
electr o nic case re p ort f or m (e C R F). T he f oll o wi n g pr o p h ylactic pr e- me dicati o ns are 
rec o m me n de d f or f ut ur e 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 (aceta 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 C PI a d mi nistrati o ns. If necessar y, c ortic oster oi ds (r ec o m me n de d d ose: 
u p t o 2 5 m g of I V h y dr oc ortis o ne or e q ui vale nt) m a y b e use d.  
F or Gr a de 3 or Gra d e 4 s y m pt o ms: ( Se vere reacti o n, a na p h yla xis, br o nc h os pas m, stri d or, 
w heezi n g, r es pirat or y distress, a n gi oe de ma, s yst olic B P < 8 0 m m H g, or L O C. 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 bri ef i nterr u pti o n 
of i nf usi o n] rec urr e 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, r e nal i m pair me nt, p ul m o nar y i nfiltrates]). Gra de 
4: (life t hreate ni n g; pr ess or or ve ntilat or y s u p p ort i n dicate d): I m me diatel y disc o nti n ue 
i nf usi o n of ni v ol u ma b. F oll o w g ui deli nes f or Gra des 1 a n d 2 a n d a d d t he f oll o wi n g: 
Acti vate e mer ge nc y res p o nse tea m as a p pr o priate. A d mi nister me dicati o ns fr o m Gra d e 1 
a n d 2 reacti o n g ui d eli nes if n ot yet gi ve n a n d a d d 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. 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. C PI will be per ma ne ntl y disc o nti n ue d.  
I n t he cas e of late- occ urri n g h y perse nsiti vit y s y m pt o ms (e g, a p peara nce of a l ocalize d or 
ge n eralize d pr uritis wit hi n 1 wee k after tr eat me nt), s y m pt o matic treat me nt ma y b e gi ve n 
(e g, oral a nti hista mi ne, or c ortic oster oi ds).  
6. 3  
Ge ner al C o nc o mita nt Me dicati o ns a n d S u p p orti ve Care G ui deli nes 
T he f oll o wi n g m e dicati o ns are pr o hi bite d d uri n g t he st u d y:  
•  
A n y c o nc urre nt a nti ne o pl astic t hera p y (i e, c he m ot hera p y, h or m o n al t hera p y, 
im m u n ot hera p y, e xte nsi ve ra diati o n t her a p y, or sta n dar d or i n vesti gati o nal a ge nts 
f or treat me nt of ca n cer).  
Palliati ve (li mite d-fiel d) ra diati o n t hera p y is per mitte d, if all of t he f oll o wi n g criteria are 
met:  
•  T he lesi o n bei n g c o nsi dere d f or p alliati ve ra diati o n is n ot a tar get lesi o n.  

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6. 4   
Criteria f or Re m o val fr o m St u d y 
Patie nts will be treate d p er pr ot oc ol u ntil:  
1.  R E CI S T- P D (treati n g M D ma y c o nti n ue C PI). St u d y PI m ust be i nf or me d via 
e mail ( or Site C o m m u nicati o n F or m”) t h at s u bject is c o nti n ui n g base d o n cli nical 
be nefit. T hese p atie nts will c o nti n ue per n or mal i ma gi n g sc h e d ule ( e ver y 1 2 
wee ks).     
2.  Patie nts o n C PI tr eat me nt w h o de vel o p a R E CI S T- P D ( P D 1) ca n c o nti n ue C PI 
treat me nt if t her e is cli nical be nefit. If o n s u bse q u e nt i ma gi n g t he y c o nti n ue t o 
ha ve R E CI S T- P D ( P D 2), t he y will be r e m o ve d fr o m trial.  
3.  U nacce pta ble t o xicit y (see Secti o n 7. 3)  
4.  Wit h dra wal of c o nse nt  
5.  Ge ner al or s pecific c h a n ges i n t he p atie nts’ c o n diti o n t hat re n der t he p atie nt 
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or.  
6.  A n y p atie nt w h o o n c o ns ec uti ve i ma gi n g (i.e., f or 2 4 wee ks) h as S D w hile o n 
t hera p y a n d d o es n ot ac hi e ve > 1 0 % t u m or b ur de n re d ucti o n will be re m o v e d 
fr o m t he trial.  
6. 5  
D urati o n of F oll o w U p 
Patie nts will c o nti n ue t o be f oll o we d f or at least 3 0 da ys after t h e last d ose of trial dr u g or 
u ntil ne w a nti-ca ncer tr eat me nt is i nitiate d, w hic he ver is earlier.  
7. 0   
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S 
Pa tie nts will be m o nit ore d cl osel y f or t o xicit y a n d d ose dela ys will be i m ple me nte d 
w here cli nicall y n ecessar y as p er t he A S C O g ui deli ne: Ma na ge me nt of I m m u ne- Relate d 
A d verse E v e nts i n Patie nts Treate d wit h I m m u ne C hec k p oi nt I n hi bit ors. ( F or m ore 
i nf or mati o n, please see: htt ps://asc o p u bs. or g/ d oi/f ull/ 1 0. 1 2 0 0/J C O. 2 0 1 7. 7 7. 6 3 8 5 ) N o 
d ose m o dificati o ns are p er mitte d.) 
7. 1 D ose Dela y Criteria  
C PI a d mi nistrati o n s h o ul d be wit h hel d f or t he f oll o wi n g:  
1.  A n y gra de 3 dr u g-r elate d A E   
2.  A n y dr u g-r elate d A E re q uiri n g t he i nitiati o n of pr e d nis o ne > 1 0 m g per d a y ( or 
e q ui vale nt ster oi d d ose).  
3.  A n y A E, la b orat or y a b n or malit y, or i nter c urr e nt ill ness w hic h, i n t he j u d g m e nt of 
t he i n vesti gat or, warra nts dela yi n g t h e d ose of st u d y me dicati o n.  
7. 2 Criteria t o Res u me Treat me nt  
S u bjects ma y r es u me treat me nt w he n t he f oll o wi n g criteria are met  

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1.  S u bjects ma y r es u me treat me nt w he n a n y dr u g-relate d la b orat or y or cli nicall y A E 
re vert t o gr a de 1 or l ess.   
2.  A n y A E t hat i n t he j u d g me nt of t he i n vesti gat or has s ufficie ntl y res ol v e d.  
3.  Pre d nis o ne < 1 0 m g per d a y ( or e q ui v ale nt ster oi d d ose).  
7. 3 Disc o nti n uati o n Criteria  
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:  
1.  A n y gra de 4 dr u g-r elate d A E warra nts per m a ne nt disc o nti n uati o n, u nless it is a 
re versi ble e n d ocri n o p at h y.  
2.  A n y a d vers e e ve nt, la b or at or y a b n or malit y, or i nterc urr e 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 C PI d osi n g  
8. 0  
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S 
8. 1 A d verse E v e nt Defi niti o n 
A n A d verse E ve nt ( A E) is defi ne d as a n y ne w u nt o war d me dical occ 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 necess aril y h a ve a 
ca usal r elati o ns hi p wit h t his treat me nt. A n A E ca n t heref or e be a n y u nfa v or a ble a n d 
u ni nte n de d si g n (s u c h as 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 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 ne d b y a p h ysi cia 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 reas 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 here is n ot a reas o n a ble ca usal r elati 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.  
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 usal 
relati o ns hi p.  
A d verse e ve 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 r e p orti n g bi as, 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 n ce of o n e or m or e A Es.)  
8. 2 Seri o us A d verse E v e nts Defi niti o n 
A Seri o us A d verse E ve 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:  

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•  
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 
th e ti me of t he e ve nt; it d oes n ot refer t o a n e v e nt w hic h h y p ot h eticall y mi g ht 
ha ve ca use d deat h if it were m or e se vere)  
•  
re q uires i n patie nt h os pitalizati o n or ca uses pr ol o n gati o n of e xisti n g 
h o s 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 
im me diatel y life-t hreat e ni n g or r es ult i n deat h or h os pitalizati o n b ut, base d u p o n 
a p pr o priate m e dical a n d scie ntific j u d g m e nt, ma y je o par dize t he s u bject or ma y 
re q uire i nter v e nti o n [ e g, me dical, s ur gical] t o pre v e nt o ne of t he ot her seri o us 
o utc o mes liste d i n t he defi 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 m er 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 ys crasias 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 nic) 
vi a t he st u d y dr u g is a n S A E.  
•  
Alt h o u g h pr e g na nc y, o v er d ose, a n d ca ncer are n ot al wa ys seri o us b y r e g ulat or y 
de fi niti o n, t hese e ve nts m ust be ha n dle d as S A Es.  
8. 3 N o n- Seri o us A d vers e E ve nts Defi niti o n  
•  
A n o n-seri o us a d v erse e v e nt is a n A E n ot classifie d as seri o us.  
8 . 4 A d verse E v e nt E val uati o n  
T he c ollecti o n of Gra de ≥2 A E a n d S 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 n-seri o us a d v erse e v e nts ( n ot o nl y t h os e dee me d t o b e treat me nt-relate 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 3 0 
da ys f oll o wi n g t he l ast d ose of st u d y tr eat me nt or u ntil ne xt treat me nt is i nitiate d, 
w hic he ver c o mes first.  
Baseli ne p h ysical a n d la b orat or y Gr a de ≥2 A Es s h o ul d be f oll o we d t o res ol uti o n or 
stabilizati 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 n-seri 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 priat e.  
A la b orat or y test a b n or m alit y c o nsi dere d cli nicall y r ele va nt ( e. g., ca usi n g t he s u bject t o 
wit h dra w fr o m t he st u d y, re q uiri n g treat me nt or ca usi n g a p p are nt cli nical ma nifestati o ns, 
res ult i n a dela y or d os e m o dificati o n of st u d y tr eat me nt, or j u d ge d rel e va nt b y t he 
i n vesti gat or), s h o ul d b e r e p orte d as a n a d verse e v e nt.  

C A S E 6 8 1 9  
  
  
P a ge 2 3   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
T he i n vesti gat or or s u b-i n vesti gat or (treati n g p h ysicia n if a p plica ble) will pr o vi de t he 
f oll o wi n g f or all a d verse e ve nts ( b ot h seri o us a n d n o n-seri o us):  
•  
E ve nt ter m (as p er C T C A E)  
•  
Descri pti o n of t he e v e nt  
•  
Date of o nset a n d res ol uti o n  
•  
E x pecte d ness of t he t o xicit y  
•  
Gra de of t o xicit y  
•  
Attri b uti o n of relate d ness t o t he i n vesti gati o nal a ge nt- (t his m ust be assi g n e d b y 
a n in vesti gat or, s u b-i n vesti gat or, or tr eati n g p h ysicia n)  
•  
Acti o n ta ke n as a res ult of t he e ve nt, i ncl u di n g b ut n ot li mite d t o; n o c ha n ges, 
d os e i nterr u pte d, r e d uce d, disc o nti n ue d, etc. or acti o n ta ke n wit h re gar d t o t he 
e ve nt, i.e. n o acti o n, recei ve d c o n me d or ot her i nter ve nti o n, etc.  
•  
O utc o me of e v e nt  
Des cri pti o ns a n d gr a di n g sc ales  f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( C T C A E) versi o n 5. 0 will be utilize d f or A E re p orti n g. (f or m ore 
i nf or mati o n, please see 
htt ps://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m #ctc 5 0 )  
A n e x pect e d a d verse e v e nt  is a n e ve nt pr e vi o usl y k n o w n or a ntici pate d t o res ult fr o m 
partici pati o n i n t he resear c h st u d y or a n y u n derl yi n g diseas e, dis or der, or c o n diti o n of t he 
s u bject. T he e v e nt is us uall y liste d i n t he I n vesti gat or Br o c h ur e, c o nse nt f or m or researc h 
pr ot oc ol.  
A n u ne x pecte d a d verse e ve nt  is a n a d v erse e ve nt n ot pre vi o usl y k n o w n or a ntici pate d t o 
res ult fr o m t he res ear c h st u d y or a n y u n derl yi n g disease, dis or der, or c o n diti o n of t he 
s u bject.  
Attri b uti o n  is t he relati o ns hi p bet wee n a n a d vers e e ve nt or s eri o us a d vers e e ve nt a n d t h e 
st u d y dr u g. Attri b uti o n will be assi g ne d as f oll o ws:  
o  Defi nite – T he A E is clearl y r elate d t o t he st u d y dr u g.  
o  Pr o ba ble – T he A E is li k el y r elate d t o t he st u d y dr u g.  
o  P ossi ble – T he A E ma y b e relate d t o t he st u d y dr u g.  
o  U nli kel y – T he A E is d o u btf ull y rel ate d t o t he st u d y dr u g.  
o  U nrelate d – T h e A E is cl earl y N O T relate d t o t he st u d y dr u g.  
Pr o t oc ol m ust s pecif y if attri b uti o n is re q uire d f or i n di vi d ual c o m p o ne nts of t he treat me nt 
re gi me n or t he tr eat me nt re gi me n as a w h ole.  
8. 5 Re p orti n g Pr oce d ures f or Seri o us A d verse E ve nts a n d O n C ore ®    
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, 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 

C A S E 6 8 1 9  
  
  
P a ge 2 4   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
ass ociate d wit h pr ot oc ol-s pecifie d pr o ce d ur es. All S A Es m ust be c ollecte d t hat occ ur 
wit hi n 3 0 da ys of disc o nti n uati o n of d osi n g or u ntil ne xt treat me nt is i nitiate d 
All S A Es m ust be c ollecte d t hat occ ur d uri n g t he s cree ni n g p eri o d. If a p plica ble, S A Es 
m ust be c ollecte d t hat rel ate 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). All S A Es s h o ul d be m o nit ore d u ntil t he y are r es ol ve d or are clearl y det er mi ne d 
t o be d ue t o a s u bject’s st a ble or c hr o nic c o n diti o n or i nterc urre nt ill ness(es).  T he 
i n vesti gat or s h o ul d r e p ort a n y S A E t hat occ urs aft er 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 oc ol-s pecifie d pr o ce d ure.  
S A Es will be rec or d e d o n t he F D A F or m 3 5 0 0 A ( Me d W atc h) acc or di n g t o t he re p orti n g 
g ui deli nes i n secti o n 8. 5. 
8. 6  
Seri o us A d verse E v e nts a n d O n C ore ® 
All S A Es will be e ntere d i nt o O n C ore.   
 
8. 7   
Re p orti n g Pr oce d ures f or Seri o us A d verse E v e nts a n d O n C ore ®    
It is t he res p o nsi bilit y of eac h site PI t o e ns ure t hat A L L S A Es occ urri n g o n t his trial 
(i nter nal or e xter nal) are re p orte d t o t he Case C o m pre he nsi ve Ca ncer Ce nter’s Data a n d 
Safet y T o xicit y C o m mittee. T his s u b missi o n is si m ulta ne o us wit h t heir s u b missi o n t o t he 
s p o ns or a n d/ or ot her r e g ulat or y b o dies.  
 
T he s p o ns or-i n vesti gat or is res p o nsi ble f or s u b mitti n g a n a n n u al r e p ort t o t he D S T C as 
per C C C C Data a n d Safet y M o nit ori n g Pla n. 
  
8. 8  
Data a n d Saf et y M o nit ori n g Pla n  
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer Ce nter Data 
a n d Safet y M o nit ori n g Pl a n i n acc or da nce wit h N CI g ui deli nes.  
 
9. 0  
P H A R M A C E U TI C A L I N F O R M A TI O N  
9. 1  Pe m br oliz u ma b Pr o d uct I nf or mati o n 
 
Please ref er t o F D A pac k a ge i nsert f or f urt her details. 
(htt ps:// w w w.access d ata.f da. g o v/ dr u gsatf d a _ d ocs/la bel/ 2 0 1 6/ 1 2 5 5 1 4s 0 1 2l bl. p df ) 
Pr o d uct 
descri pti o n a n d 
d osa ge f or m 
P ote nc y  
Pri mar y Pac ka gi n g 
( v ol u me)/ La bel 
t y pe 
A p peara nce  
St ora ge 
c o n diti o n ( per 
la bel) 
Pe m br oliz u ma b 
S ol uti o n f or 
I nj ecti o n 
1 0 0 m g/ Vial 
( 2 5 m g/ m L) 
 
4 m L t y pe 1 fli nt 
glass vials 
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 
St ores at 2 t o 
8 de grees 
Celsi us ( 3 6 t o 
4 6 de grees 
Fa hre n heit) 
a n d pr otecte d 
fr o m li g ht a n d 
freezi n g. 

C A S E 6 8 1 9  
  
  
P a ge 2 5   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
Pe m br oliz u ma b will be gi ve n e ver y t hr ee w ee ks at a d ose of 2 0 0 m g t o be a d mi nistere d 
as a 3 0 mi n ute I V i nf usi o n. Pe m br oliz u ma b ca n als o be gi v e n e ver y si x wee ks at a d ose 
of 4 0 0 m g t o be a d mi nistere d as a 3 0 mi n ute I V i nf usi o n. Decisi o n o n pe m br oliz u ma b 
d ose will be base d o n pr o vi der discreti o n. 
S u bjects ma y be d os e d e ver y 2 1 da ys ( or 4 2 da ys f or 4 0 0 m g d os e) +/- 3 da ys fr o m t he 
pre vi o us d ose of dr u g. T here are n o pr e me dicati o ns rec o m me n de d f or pe m br oliz u ma b o n 
t he first c ycle. S u bjects s h o ul d be car ef ull y m o nit ore d f or i nf usi o n r eacti o ns d uri n g 
pe m br oliz 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 Secti o n 6. 1.  
9. 2 Atez oliz u ma b Pr o d uct i nf or mati o n  
Pr o d uct 
d escri pti o n a n d 
d osa ge f or m 
P ote nc y  
Pri mar y Pac ka gi n g 
( v ol u me)/ La bel 
t y pe 
A p peara nce  
St ora ge 
c o n diti o n ( per 
la bel) 
Atez oliz u ma b 
S ol uti o n f or 
i njecti o n  
1 2 0 0 m g/ Vial 
( 6 0 m g/ m L) 
2 0 m L t y pe 1 fli nt 
glass vials 
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 
St ores at 2 t o 
8 de grees 
Celsi us ( 3 6 t o 
4 6 de grees 
Fa hre n heit) 
a n d pr otecte d 
fr o m li g ht a n d 
freezi n g. 
Please ref er t o F D A pac k a ge i nsert f or f urt her details. 
(htt ps:// w w w.access d ata.f da. g o v/ dr u gsatf d a _ d ocs/la bel/ 2 0 1 8/ 7 6 1 0 3 4s 0 1 0l bl. p df )  
Atez oliz u ma b will be gi ve n e ver y t hree wee ks at a d ose of 1 2 0 0 m g t o b e a d mi nistere d as 
a 6 0 mi n ute I V i nf usi o n. If t he first i nf usi o n is t olerate d, all s u bse q ue nt i nf usi o ns ma y be 
deli vere d o ver 3 0 mi n utes.  
S u bjects ma y be d os e d e ver y 2 1 da ys +/- 3 da ys fr o m t he pre vi o us d ose of dr u g. T h ere 
are n o pr e me dicati o ns rec o m me n de d f or atez oliz u ma b o n t he first c ycle. S u bjects s h o ul d 
be car ef ull y m o nit ore d f or i nf usi o n reacti o ns d uri n g at ez oliz 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 Pr ot oc ol 
Secti o n 6. 1. 
9. 3 D ur val u ma b Pr o d uct I nf or mati o n  
Pr o d uct 
de scri pti o n a n d 
d osa ge f or m 
P ote nc y  
Pri mar y Pac ka gi n g 
( v ol u me)/ La bel 
t y pe 
A p peara nce  
St ora ge 
c o n diti o n ( per 
la bel) 
D ur val u ma b 
S ol uti o n f or 
I nj ecti o n 
5 0 0 m g/ vial ( 5 0 
m g/ m L) 
1 2 0 m g/ vial ( 5 0 
m g/ m L)  
1 0 m L t y pe 1 fli nt 
glass vials 
2. 4 m L t y pe 1 fli nt 
glass vials  
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 
St ores at 2 t o 8 
de grees 
Celsi us ( 3 6 t o 
4 6 de grees 
Fa hre n heit) 
a n d pr otecte d 

C A S E 6 8 1 9  
  
  
P a ge 2 6   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
fr o m li g ht a n d 
freezi n g. 
4 h o urs at 
r o o m 
te m perat ure 
u p t o 2 5 
de gree Celsi us 
( 7 7 de gree 
Fa hre n heit) 
Please  ref er t o F D A pac ka ge i nsert f or f urt her det ails. 
(htt ps:// w w w.access d ata.f da. g o v/ dr u gsatf d a d ocs/la bel/ 2 0 1 7/ 7 6 1 0 6 9s 0 0 0l bl. p df ) 
 
D ur val u ma b will be gi ve n e ver y 2 w ee ks at a d ose of 1 0 m g/ k g t o be a d mi nistere d as a 6 0 
mi n ute I V i nf usi o n.  
S u bjects ma y be d os e d e ver y 1 4 da ys +/- 2 da ys fr o m t he pre vi o us d ose of dr u g. T h ere 
are n o pr e me dicati o ns rec o m me n de d f or d ur val u ma b o n t he first c ycle.  S u bjects s h o ul d 
be car ef ull y m o nit ore d f or i nf usi o n reacti o ns d uri n g d ur v al 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 Pr ot oc ol 
Secti o n 6. 1.  
9. 4 Ni v ol u ma b Pr o d uct I nf or mati o n 
Pr o d uct 
des cri pti o n a n d 
d osa ge f or m 
P ote nc y  
Pri mar y Pac ka gi n g 
( v ol u me)/ La bel 
t y pe 
A p peara nce  
St ora ge 
c o n diti o n ( per 
la bel) 
Ni v ol u ma b 
S ol uti o n f or 
I nj ecti o n  
1 0 0 m g/ Vial ( 1 0 
m g/ m L) 
4 0 m g/ vial ( 1 0 
m g/ m L) 
2 4 0 m g/ vial ( 1 0 
m g/ m L) 
1 0 m L t y pe 1 fli nt 
glass vials 
4 m L t y pe 1 fli nt 
glass vials 
2 4 m L t y pe 1 fli nt 
glass vials  
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 
St ores at 2 t o 
8 de grees 
Celsi us ( 3 6 t o 
4 6 de grees 
Fa hre n heit) 
a n d pr otecte d 
fr o m li g ht a n d 
freezi n g.  
Please ref er t o F D A pac k a ge i nsert f or f urt her details. 
(htt ps:// w w w.access d ata.f da. g o v/ dr u gsatf d a d ocs/la bel/ 2 0 1 8/ 1 2 5 5 5 4s 0 5 8l bl. p df ) 
Ni v ol u ma b will be gi ve n e ver y f o ur wee ks at a d os e of 4 8 0 m g t o be a d mi nistere d as a 3 0 
mi n ute I V i nf usi o n.  
S u bjects ma y be d os e d e ver y 2 8 da ys +/- 3 da ys fr o m t he pre vi o us d ose of dr u g. T h ere 
are n o pr e me dicati o ns rec o m me n de d f or ni v ol u m a b o n t he first c ycl e. 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 Pr ot oc ol Secti o n 6. 1.  
9. 5 A vel u ma b Pr o d uct I nf or mati o n 

C A S E 6 8 1 9  
  
  
P a ge 2 7   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
Pr o d uct 
d escri pti o n a n d 
d osa ge f or m 
P ote nc y  
Pri mar y Pac ka gi n g 
( v ol u me)/ La bel 
t y pe 
A p peara nce  
St ora ge 
c o n diti o n ( per 
la bel) 
A vel u ma b 
S ol uti o n f or 
I nj ecti o n 
2 0 0 m g/ Vial ( 2 0 
m g/ m L) 
1 0 m L t y pe 1 fli nt 
glass vials 
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 
St ores at 2 t o 
8 de grees 
Celsi us ( 3 6 t o 
4 6 de grees 
Fa hre n heit) 
a n d pr otecte d 
fr o m li g ht a n d 
freezi n g. 
Please ref er t o F D A pac k a ge i nsert f or f urt her details. 
(htt ps:// w w w.access d ata.f da. g o v/ dr u gsatf d a _ d ocs/la bel/ 2 0 1 9/ 7 6 1 0 4 9s 0 0 6l bl. p df ) 
 
A vel u ma b will be gi ve n e ver y 2 w ee ks at a d ose of 8 0 0 m g t o be a d mi nistere d as a 6 0 
mi n ute I V i nf usi o n.  
S u bjects ma y be d os e d e ver y 1 4 da ys +/- 2 da ys fr o m t he pre vi o us d ose of dr u g. Patie nts 
will nee d t o be pre me di cate d wit h aceta mi n o p he n a n d a n a nti hista mi ne f or t he first 4 
i nf usi o ns a n d s u bse q ue ntl y as nee de d. S u bjects s h o ul d be car ef ull y m o nit ore d f or 
i nf usi o n reacti o ns d uri n g a vel 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 Pr ot oc ol Secti o n 6. 1.  
1 0. 0 
C O R R E L A TI V E S T U DI E S 
Please ref er e nce Secti o n 1. 4 f or Bac k gr o u n d a n d Rati o nale f or C orr elati ve St u dies 
1 0. 1 Bl o o d C orrelati ves 
At t he ti me of i ma gi n g p atie nts will als o u n der g o bl o o d dra ws f or i m m u n o m o d ulat or y 
cells. W h ole bl o o d ( 2 1 0 ml S o di u m He pari n vac utai ner t u bes) will be c ollecte d f or all 
ti me p oi nts b y a me m ber of t he resear c h tea m a n d deli vere d t o t he la b of Dr. Marcel a 
Díaz- M o nter o ( Cle vela n d Cli nic Ler n er Researc h I nstit ute) f or pr ocessi n g. Le v els of 
c yt o ki nes ass ociate d wit h t he s u p pressi ve f u n cti o n of M D S Cs a n d Tre gs (I L- 1 B, I L- 1 0, 
I L- 6, T G F- bet a) a n d/ or ass ociate d wit h a nti-t u m or acti vit y of T cells (I F N- ga m ma, T N F-
al p ha) will be meas ure d b y E LI S A i n t he plas m a a n d c orr elate d wit h le v els of M D S C 
s u bt y pes ( P M N( gra n ul oc ytic) ( C D 3 3 + C D 1 5 + C D 1 4- H L A D R-), i m mat ur e 
( C D 3 3 + C D 1 5- C D 1 4- H L A D R-) a n d m o n oc ytic ( C D 3 3 + C D 1 4 + C D 1 5- H L A D R-)) a n d 
Tre gs ( C D 4 + C D 2 5 + F O X P 3 +) b y fl o w c yt o metr y. Plas ma will als o be fr o ze n a n d st ore d 
f or f ut ure a nal yses.  
1 0. 2 Tiss ue C orrelati ves 
Bi o psies ar e rec o m me n d e d at s pecifi c ti me p oi nts t o i n vesti gate t he ge n o mic a n d 
i m m u n ol o gic mar kers t hat are ass ociate d wit h r es p o nse or resista n ce t o t hera p y. 
Re gar di n g bi o ps y ti mi n g, a bi o ps y is r ec o m me n de d at a n y ti me d uri n g c ycl e 1 (f or P R 
a n d S D patie nts) a n d wit hi n 3 wee ks of a n y ot h er ti me peri o d at w hic h a P D or P R is 

C A S E 6 8 1 9  
  
  
P a ge 2 8   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
ac hie ve d i n a n y patie nt ( u nless n ot feasi ble or u ns afe per i n vesti gat or discr eti o n). Fr es h 
bi o p s y s peci me ns will be se nt t o t he La b of Dr. M arcel a Diaz f or n ucl eic aci d is olati o n 
f or ge ne e x pressi o n a nal ys es.  I n t he e v e nt t hat ar c hi val tiss ue is o nl y a vail a ble n ucleic 
aci d will be is olate d fr o m f or mali n fi x e d tiss ue. A mi ni m u m of 3 u nstai ne d sli des, u p t o 6 
m o nt hs pri or t o e nr oll me nt are all o we d. Sa m ples will be se nt t o t he la b of Dr. C Marcela 
Diaz- M o nter o wit hi n 3 0 da ys of e nr oll me nt. N ucl eic aci d will be st or e d i n a desi g n ate d 
freezer at - 8 0°C. 
1 0. 3 A d dress f or tiss ue a n d bl o o d s peci me n 
Ler ner R esearc h 
2 1 1 1 E. 9 6 t h St. 
 
Cl evela n d, O H 4 4 1 0 6 
Atte nti o n: 
  
 
Please pr o vi de a d v a nce n otice b y calli n g t he la b at 
or e m aili n g  
 
 

C A S E 6 8 1 9  
  
  
P a ge 2 9   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
1 1 . 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
 
S cree ni n g 
(≤ 4 w ee ks 
pri or t o 
d osi n g) 
 
C ycle 
1 
D a y 1 
( +/- 3 
d a ys) 1
* 
C ycle 2 + D 1 
( +/- 2 or 3 
d a ys) f or 
p atie nts o n 
t her a p y a n d 
f or p atie nts 
re- st arti n g 
t her a p y2 * 
P a tie nts 
O F F 
t her a p y: 
e ver y 6 
w ee ks 
( +/- 3 
d a ys) 1 3 
P atie nts 
O F F 
t her a p y: 
E ver y 1 2 
w ee ks 
( +/- 3 
d a ys) 1 3 
E n d of 
Tr e at me
nt ( +/- 3 
d a ys)  1 4 
P o st 
St u d y 
f oll o w 
u p( +/- 3 
d a ys)  1 5 
I nf or me d 
C o nse nt 
X  
 
 
  
  
  
 
E C O G P S, 
Wei g ht 
(scree ni n g 
o nl y), Vit al 
Si g ns 
X  
X  
X 
X  
X    
X  
 
Hist or y/ P h ysic
al 3 
X 
X  
X 
X  
X  
X  
 
A d verse E ve nts  
  
X  
X 
X  
X  
X  
X  
He m at ol o g y 4  
X  
X  
X 
X  
X  
X  
 
C he mistr y 5  
X  
X  
X 
X  
X  
X  
 
T S H, T 4, T 3
6  
X  
  
X 
  
X  
  
 
A ut oi m m u ne 
l a bs7 
X 
 
 
  
  
  
 
C orrel ati ve 
St u dies 8 
X 
  
X  
  
X  
  
 
C PI 
  
X  
X 
  
  
  
 
T u m or 
I m a gi n g 9 
X 
  
X 
  
X 
As 
cli nic all y 
i n dic ate
d 
As 
cli nic all y 
i n dic ate d 
B r ai n C T or 
M RI
1 0 
As  
cli nic all y 
i n dic ate d 
  
As cli nic all y 
i n dic ate d 
  
X  
As 
cli nic all y 
i n dic ate
d 
As 
cli nic all y 
i n dic ate d 
B o ne Sc a n
1 1 
As 
cli nic all y 
i n dic ate d 
  
As cli nic all y 
i n dic ate d 
  
X  
As 
cli nic all y 
i n dic ate
d 
As 
cli nic all y 
i n dic ate d 
Bi o ps y 1 2  
X 
* O ne C ycle is 1 4- 2 8 da ys. Visit wi n d o w +/- 3 da ys f or Atez oliz u ma b, Ni v ol u ma b, a n d 
Pe m br oliz u ma b. Visit wi n d o w is +/- 2 da ys f or A vel u ma b a n d D ur v al u ma b. 
 
1. C ycle 1 Da y 1 He mat ol o g y, c he mistr y, a ut oi m m u ne la bs, a n d p h ysical e xa m nee d n ot be 
repeate d if d o ne wit hi n 1 4 da ys 
2. Hist or y, p h ysical, A Es, He mat ol o g y, C he mistr y t o be d o ne D 1 ( +/- 3 da ys) of e ver y c ycle 
3. Baseli ne e xa m s h o ul d be c o m pre he nsi ve. S u bse q ue nt p h ysical e xa ms ca n be tar gete d e xa ms. 

C A S E 6 8 1 9  
  
  
P a ge 3 0   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
4. He m at ol o g y : C B C wit h differe ntial, he m o gl o bi n, he mat ocrit, platelets 
5. Bl o o d c he mistr y:  s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, creati ni ne, al b u mi n, t otal 
al b u mi n, bicar b o nate, A S T, A L T, gl uc ose, L D H ( baseli ne o nl y) 
6. T S H, T 4, T 3 : Scree ni n g, a n d o n all i ma gi n g da ys, t he n as cli nicall y i n dicate d. 
7. A ut oi m m u ne l a bs A N A b y I F A scree n, A nti- E N A, A nti- D N A D S, R he u mat oi d fact or, C C P 
a nti b o d y, E S R, C R P. T hese o nl y nee d t o be dra w n if n ot dra w n pri or t o i nitial treat me nt wit h C PI 
t hera p y. 
8. C orrel ati ve st u dies:  C orrelati ve st u dies will be dra w n wit h bl o o d dra ws at bi o ps y, scree ni n g 
a n d pri or t o eac h i ma gi n g. 
9. T u m or i m a gi n g:  C T of t he c hest, a b d o me n, a n d pel vis ( wit h c o ntrast, if p ossi ble) t o be 
perf or me d t o assess disease stat us at scree ni n g, a n d e ver y 1 2 wee ks fr o m C ycle 1 Da y 1. T u m or 
i ma gi n g s h o ul d als o be d o ne w he ne ver disease pr o gressi o n is s us pecte d a n d as cli nicall y 
i n dicate d. 
1 0. Br ai n i m a gi n g Brai n C T or M RI sca n t o be perf or me d as cli nicall y i n dicate d. 
1 1. B o ne i m a gi n g: B o ne sca n t o be perf or me d if cli nicall y i n dicate d. 
1 2.  Bi o ps y is rec o m me n de d at a n y ti me d uri n g c ycle 1 (f or P R a n d S D patie nts) a n d wit hi n 3 
wee ks of a n y ot her ti me peri o d at w hic h a P D or P R is ac hie ve d i n a n y patie nt ( u nless n ot feasi ble 
or u nsafe per i n vesti gat or discreti o n. Arc hi val tiss ue u p t o 6 m o nt hs pri or t o e nr oll me nt is 
acce pta ble i n lie u of a c ycle 1 bi o ps y 
1 3. O F F tre at me nt Patie nts will be see n e ver y 1 2 wee ks. T he 6- wee k i nteri m visit bet wee n sca ns 
will be d o ne if cli nicall y i n dicate d. La bs d uri n g t he 6- wee k i nteri m visit s h o ul d be as cli nicall y 
i n dicate d. 
1 4. E n d of tre at me nt:  E n d of treat me nt visit is defi ne d as t he visit d uri n g w hic h t he patie nt will 
be re m o ve d fr o m t he st u d y (e ve n if n ot recei vi n g dr u g at t hat visit. 
1 5. P ost - st u d y f oll o w u p Patie nts will c o nti n ue t o be f oll o we d f or at least 3 0 da ys after t he last 
d ose of C PI t hera p y or u ntil ne w a nti-ca ncer treat me nt is i nitiate d, w hic he ver c o mes first. P h o ne 
f oll o w- u p is s ufficie nt. 
 
 
 
1 2. 0  
M E A S U R E M E N T O F E F F E C T  
Patie nts m ust ha ve meas ura ble diseas e at scr ee ni n g a n d  will be e val uat e d f or res p o nse o n 
t he basis of R E CI S T criteria versi o n 1. 1.4 4 T u m or meas ure me nts usi n g p h ysical 
e x a mi nati o n, s piral C T sca n a n d/ or M RI or ot her a p pr o priate t ec h ni q ues d ee me d s uita ble 
b y t he i n vesti gat or will be perf or me d at scree ni n g wit hi n 2 8 da ys of p atie nt re gistrati o n 
a n d re peate d per st u d y cale n dar ( Secti o n 1 1. 0) Sca ns ca n be d o n e m ore fre q ue ntl y per 
M D discreti o n; t hese sca ns will be s u b mitte d o n a n u nsc he d ule d diseas e assess me nt. 
1 3. 0 
D A T A R E P O R TI N G / R E G U L A T O R Y C O N SI D E R A TI O N S  
1 3. 1 Data Re p orti n g 
T he F ort e ™ E D C a n d O n C ore ® data bas es will be utilize d, as re q uire d b y t he Case 
C o m pre he nsi ve Ca ncer Ce nter a n d Cle vela n d Cli nic, t o pr o vi de data c ollecti o n f or b ot h 
accr u al e ntr y a n d trial dat a ma na ge m e nt. F orte ™ E D C a n d O n C ore ® are Cli nical Trials 
Ma na ge me nt S yste ms h o use d o n sec ur e ser v ers. A ccess t o data t hr o u g h F orte ™ E D C a n d 
O n C ore ® is restricte d b y user acc o u nts a n d assi g n e d r oles. O nce l o g ge d i nt o t he F orte ™ 

C A S E 6 8 1 9  
  
  
P a ge 3 1   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
E D C  or O n C ore ® s yste m wit h a user I D a n d pass w or d, F ort e ™ E D C a n d O n C ore ® 
defi ne r oles f or eac h user w hic h li mits access t o a p pr o priate dat a. User i nf or mati o n a n d 
pass w or d ca n be o btai ne d b y c o nt acti n g t he O n C ore ® A d mi nistrat or at O n C ore-
re gistrati o n @cas e.e d u f or O n C ore ® access, a n d ta ussi g o nc or e @ccf. or g f or F orte ™ E D C 
access. 
 
F orte ™ E D C is desi g ne d wit h t he ca pa bilit y f or st u d y set u p, acti vati o n, trac ki n g, 
re p orti n g, data m o nit ori n g a n d re vie w, a n d eli gi bilit y verifi cati o n.  W he n pr o perl y 
utilize d, F orte ™ E D C is 2 1 C F R 1 1 c o m plia nt.  T his st u d y will utilize electr o nic Case 
Re p ort F or m c o m pleti o n i n t he F orte ™ E D C dat a base. A cale n dar of e v e nts a n d re q uire d 
f or ms are a vaila ble i n F orte ™ E D C. 
1 3. 2 Re g ulat or y C o nsi derati o ns  
T he st u d y will be c o n d ucte d i n c o m plia nce wit h I C H g ui deli nes a n d wit h all a p plica ble 
fe der al (i ncl u di n g 2 1 C F R parts 5 6 & 5 0), state or l ocal la ws.  
1 3. 2. 1 Writte n I nf or m e d c o nse nt  
Pr o visi o n of writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y st u d y-r elate d 
pr oce d ur es. T he Pri nci pal I n vesti gat or will e ns ure t hat t he s u bject is gi ve n f ull a n d 
a de q uate oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris ks a n d 
be nefits of t he st u d y as w ell as t he s u bject’s fi na n cial res p o nsi bilit y. S u bjects m ust als o 
be n otifie d t hat t he y ar e free t o disc o nti n ue fr o m t he st u d y at a n y ti me. T he s u bject 
s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d be all o we d ti me t o c o nsi der t he 
i nf or mati o n pr o vi de d.  
T he ori gi nal, si g n e d writt e n I nf or me d C o ns e nt F or m m ust be ke pt wit h t he Researc h 
C hart i n c o nf or ma n ce wit h t he i nstit uti o n’s sta n dar d o perati n g pr o ce d ur es. A c o p y of t he 
si g ne d writte n I nf or me d C o nse nt F or m m ust be gi ve n t o t he s u bject. A d diti o nall y, 
d oc u me ntati o n of t he c o nse nti n g pr o cess s h o ul d b e l ocate d i n t he r esearc h c hart.  
1 3. 2. 2 S u bject Data Pr otecti o n  
I n acc or da n ce wit h t he H ealt h I nf or mati o n P orta bilit y a n d Acc o u nta bilit y A ct ( HI P A A), a 
s u bject m ust si g n a n a ut h orizati o n t o release me di cal i nf or mati o n t o t he s p o ns or a n d/ or 
all o w t he s p o ns or, a r e g ulat or y a ut h orit y, or I nstit uti o nal Re vie w B oar d access t o 
s u bject’s me dical i nf or m ati o n t hat i ncl u des all h os pital rec or ds r ele va nt t o t he st u d y, 
i ncl u di n g s u bjects’ me di cal hist or y  
1 3. 2. 3 Rete nti o n of rec or ds 
T he Pri nci pal I n vesti gat or of t he Case C o m pre h e nsi ve Ca ncer Ce nt er s u per vises t he 
rete nti o n of all d oc u me nt ati o n of a d vers e e ve nts, r ec or ds of st u d y dr u g recei pt a n d 
dis pe nsati o n, a n d all I R B c orres p o n d e nce f or as l o n g as n ee de d t o c o m pl y wit h l ocal, 

C A S E 6 8 1 9  
  
  
P a ge 3 2   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
na ti o nal a n d i nter nati o nal re g ulati o ns. N o rec or ds will be destr o ye d u ntil t he Pri nci pal 
I n v esti gat or c o nfir ms d estr ucti o n is per mitte d.  
1 3. 2. 4 A u dits a n d i ns pecti o ns 
A ut h orize d re pres e ntati ves of t he s p o ns or, a re g ul at or y a ut h orit y, a n I n d e p e n de nt Et hics 
C o m mittee (I E C) or a n I nstit uti o nal Re vie w B oar d (I R B) m a y visit t he site t o perf or m 
a u dits or i ns pecti o ns, i ncl u di n g s o urce data v erificati o n. T he p ur p ose of a n a u dit or 
i ns pecti o n is t o s yst e maticall y a n d i n de pe n d e ntl y e x a mi ne all st u d y-rel ate d acti vities a n d 
d oc u me nts t o deter mi ne w het her t hes e acti vities were c o n d ucte d, a n d data were rec or de d, 
a nal yze d, a n d acc ur atel y re p orte d acc or di n g t o t he pr ot oc ol, G o o d Cli nical Practice 
( G C P), g ui deli nes of t he I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H), a n d a n y 
a p plica ble r e g ulat or y r e q uire me nts. F or m ulti-ce nter st u dies, partici pati n g sites m ust 
i nf or m t he s p o ns or-i n vesti gat or of p e n di n g a u dits.  
1 4. 0 S T A TI S TI C A L C O N SI D E R A TI O N S  
1 4. 1 Sa m ple Size J ustificati o n 
I n t his p has e II st u d y, we will e nr oll at least 5 0 patie nts wit h a d va nce d ur ot helial 
carci n o ma w h o ar e refract or y t o first li ne t her a p y or w h o ar e cis plati n i neli gi ble. Patie nts 
will be treate d wit h C PI t hera p y f or at least 2 0 w ee ks as per sta n d ar d of car e ( S O C), at 
w hic h ti me t h ose wit h a t u m or b ur de n r e d ucti o n of 1 0 % or gr eater will s us pe n d C PI 
t hera p y. If t h e n u m ber of patie nts wit h t u m or b ur de n re d ucti o n of ≥1 0 % aft er 2 0 wee ks is 
less t ha n 2 0 patie nts, we will c o nti n ue e nr oll me nt u p t o a ma xi m u m of 7 5 patie nts u ntil 
t he tar get sa m ple size of 2 0 c o m plete or partial res p o n ders has bee n reac h e d. If we are 
n ot a ble t o e nr oll 2 0 patie nts t o t he i nter mitte nt ar m, after e nr olli n g 7 5 pati e nts, t he n we 
will dee m t he trial n ot feasi ble. 
1 4. 2 Safet y c o nsi der ati o ns:  
T he pri mar y safet y e n d p oi nt 
is pr o gr essi o n at 2 4 wee ks 
p ost C PI s us p e nsi o n Bas e d o n 
Ke y n ote 0 4 5, we e x pect 
a p pr o xi matel y 4 0 % of 
patie nts i n t his gr o u p t o 
pr o gress wit hi n o ne year, 4 5  
w e w o ul d c o nsi der a 
pr o gressi o n rat e of 6 0 % or 
m ore wit hi n t he first 2 4 
wee ks of C PI s us pe nsi o n t o 
be u nacce pta ble. A hi g h er 
t ha n e x pecte d rate of ra pi d pr o gressi o n w o ul d i n dicate C PI s us pe nsi o n is n ot safe i n t his 
patie nt p o p ulati o n. Acc or di n gl y, we h a ve i nc or p or ate d c o nti n u o us safet y m o nit ori n g 
st o p pi n g r ules i nt o o ur desi g n t o e ns ur e patie nt saf et y ( Ta ble 1). S pecificall y, w e will st o p 
T a ble 1: Ba yesia n safet y m o nit ori n g st o p pi n g r ules. E. g. if 
we  o bser ve d 4 or m ore P D b y wee k 2 4 o ut of t he first 6 
patie nts, t he trial will st o p earl y. 
T otal n u m ber of patie nts  
N u m ber of patie nts wit h P D at 
2 4 wee ks 
6  
4- 6 
7 – 8  
5- 8 
9 – 1 0  
6- 1 0 
1 1 – 1 2  
7- 1 2 
1 3 – 1 4  
8- 1 4 
1 5 – 1 7 
9- 1 7 
1 8- 1 9  
1 0- 1 9 

C A S E 6 8 1 9  
  
  
P a ge 3 3   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
t he trial earl y a n d declare C PI s us pe nsi o n u nsaf e if t here is str o n g e vi de n ce t hat C PI 
s us pe nsi o n res ults i n hi g her t ha n e x pecte d rates of pr o gressi o n at 2 4 w ee ks. W e will use 
Ba yesi a n saf et y m o nit ori n g a n d st o p t he tri al earl y if Pr o b( P D 2 4 w k > 0. 4 | d ata) > 0. 8 5. 
W e use a beta ( 0. 4, 0. 6) pri or f or t he tr u e rat e of pr o gressi o n at 2 4 wee ks, w hic h 
c orres p o n ds t o a pri or e x pecte d pr o gressi o n rate of 0. 4. Ta ble 1 s h o ws t he c orres p o n di n g 
st o p pi n g b o u n daries.  If a patie nt pr o gresse d or die d of disease, or l ost t o f oll o w- u p 
bef ore 1 2 wee ks, t h e n t he patie nt will be c o nsi der e d fail ure. T a ble 2 s u m m arizes t he 
o perati n g c haracteristics. 
T a ble 2. S u m mar y of o perati n g c haracteristics base d o n 1 0, 0 0 0 si m ulati o ns usi n g m o nit ori n g 
ru les s pecifie d i n ta ble 1. If t he tr ue P D rate at 2 4 wee ks is 6 0 %, t he earl y st o p pi n g pr o ba bilit y 
is 0. 8 8. 
Sce nari o  
Tr ue P D rate at 2 4 
wee ks 
Pr( Earl y 
St o p p pi n g) 
A vera ge 
Sa m ple Size 
A vera ge N u m ber of P D 
O bser ve d b y Wee k 2 4 
1  
0. 3 
0. 1 2  
1 8. 6  
5. 6 
2  
0. 4 
0. 3 4  
1 6. 3  
6. 5 
3  
0. 5 
0. 6 5  
1 2. 9  
6. 5 
4  
0. 6 
0. 8 8  
9. 7 
5. 8 
1 4. 3 Efficac y: 
O ur pri mar y efficac y e n d p oi nt is s ustai ni n g a res p o nse at 3 6 wee ks f oll o wi n g C PI 
s us pe nsi o n, a n d o ur pri m ar y o bjecti ve is t o esti mate t he pr o p orti o n of patie nts a ble t o 
s ustai n a res p o nse. W e will esti mate t his pr o p orti o n a n d c o nstr uct a n e x act bi n o mial 9 5 % 
CI. Wit h 2 0 patie nts, t he half- wi dt h of t he 9 5 % CI w o n’t e x cee d 0. 2 3. 
1 4. 4 A nal ysis Pla n 
S u m mar y statistics of t o xicit y a n d s uccess stat us will be pr o vi de d i n fre q ue n cies a n d 
perce nt a ges. T o xicit y a n d s uccess r ates will be esti mate d al o n g wit h 9 5 % CIs. L o gistic 
re gressi o n m o del will be use d t o e x pl ore effects of patie nt a n d t u m or c haracteristics o n 
t o xicit y or s uccess stat us. S ur vi val e n d p oi nts will be esti mate d b y Ka pla n- Meier met h o d 
a n d c o m par e d b y l o g ra n k test. C o x pr o p orti o nal hazar d m o del will be use d t o ass ociate 
cli nical fact ors a n d bi o mar kers wit h s ur vi val e n d p oi nts. Ot her statistical a nal yses will be 
carri e d o ut as a p pr o priate.  
1 5. 0 R E F E R E N C E S 
1.   
Bra h m er J R, T y k o di S S, C h o w L Q M, et al. Safet y a n d acti vit y of a nti- P D- L 1 
a nti b o d y i n patie nts wit h a d va nce d ca n cer. N E n gl J Me d 2 0 1 2; 3 6 6( 2 6): 2 4 5 5 – 6 5.  
2.   
M otzer RJ, Ri ni BI, Mc D er m ott D F, et al. Ni v ol u ma b f or Metastatic Re n al Cell 
Carci n o ma: Res ults of a Ra n d o mize d P hase II Tri al. J Cli n O nc ol 2 0 1 5; 3 3( 1 3): 1 4 3 0 – 7.  
3.   
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 Mate 2 7 5): a m ultice ntre, si n gle-ar m, p hase 2 
trial. La ncet O n c ol 2 0 1 7; 1 8( 3): 3 1 2 – 2 2.  
4.   
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