Conditions: Urothelial Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 4
Healthy volunteers: no

Brief summary:
The purpose of this study is to test the safety and effectiveness of immunotherapy (checkpoint inhibitor therapy) in advanced bladder cancer when given intermittently. An unanswered question with the use of CPI (checkpoint inhibitor) is the duration of therapy required for optimal clinical benefit. In the absence of progressive disease or unacceptable toxicities, there are currently no specified criteria for treatment discontinuation. Strategies to reduce toxicity and maximize benefit require investigation. Thus, novel dosing schedules, early discontinuation considerations, and biomarkers of response are needed to identify patients who can sustain disease regression while off of therapy.

Detailed description:
A phase II study design to investigate the use of any CPI on an intermittent dosing schedule. Patients with advanced urothelial carcinoma (aUC) who treatment refractory or cisplatin ineligible will receive CPI of choice as per standard dosing. Patients who have initial \>/=10% tumor burden reduction will discontinue the CPI until they experience a \>/=20% disease progression following 24 weeks +/- 4 weeks of immunotherapy, at which time CPI therapy will be restarted.

All patients who do not meet criteria for the CPI intermittent phase of the study will be treated until unacceptable toxicity or RECIST-defined PD. Patients with RECIST-defined PD may continue CPI therapy at the discretion of the treating MD. These patients will continue with normal imaging every 12 weeks. In cases where a patient is continued on therapy after PD and develops subsequent PD (\> 20% increase in sum of target lesions compared to the initial PD tumor measurements, the patient will come off study).

Patients who meet criteria for the intermittent phase (i.e., have \>/=10% tumor burden reduction) will not receive CPI therapy. Imaging will continue per protocol (every 12 weeks from the initial date they stopped CPI therapy). Patients who have RECIST defined PD on the intermittent phase should reinitiate CPI therapy. Patients who have a subsequent decrease in tumor burden \>/=10% can then restart CPI therapy as per protocol.

Arms:
arm 1: Patients will be treated with CPI therapy for at least 24 weeks (+/- 4 weeks) as per standard of care (SOC), at which time those with a tumor burden reduction of 10% or greater will suspend CPI therapy.

Interventions: intervention 1: Pembrolizumab intervention 2: Atezolizumab intervention 3: Durvalumab intervention 4: Nivolumab intervention 5: Avelumab
Intervention descriptions: intervention 1: Pembrolizumab 200 mg IV over 30 minutes every 3 weeks intervention 2: Atezolizumab 1200 mg IV over 60 minutes every 3 weeks. (if first dose is tolerated, all subsequent infusions may be delivered over 30 minutes) intervention 3: Durvalumab 10 mg/kg IV over 60 minutes every 2 weeks. intervention 4: Nivolumab 480mg IV over 30 minutes every 4 weeks intervention 5: Avelumab 800 mg IV over 60 minutes every 2 weeks

Protocol document:
Prot_SAP_000.pdf: 
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 


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( 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:  


C A S E 6 8 1 9  
  
  
P a ge 2 2   
  
  
Versi o n date: 7- 1 7- 2 0 2 0 
 
•  
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.   
Massar d C, G or d o n M S, S har ma S, et al. Safet y a n d Efficac y of D ur val u ma b 
( M E DI 4 7 3 6), a n A nti- Pr o gr a m me d Cell Deat h Li ga n d- 1 I m m u ne C hec k p oi nt I n hi bit or, 


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Versi o n date: 7- 1 7- 2 0 2 0 
 
i n Patie nts Wit h A d va nce d Ur ot helial Bla d der C a ncer. J Cli n O nc ol Off J A m S oc Cli n 
O nc ol 2 0 1 6; 3 4( 2 6): 3 1 1 9 – 2 5.  
5.   
Ke y Statistics f or Bla d d er Ca ncer [I nter net]. [ cite d 2 0 1 9 J a n 7]; A vaila ble fr o m: 
htt ps:// w w w.ca ncer. or g/ca ncer/ bla d d er- ca n cer/a b o ut/ ke y-statistics. ht ml 
6.   
A n dreass e n B K, Aa g nes B, Gislef oss R, A n dr eass e n M, W a hl q vist R. I n ci d e nce 
a n d S ur vi val of ur ot helial carci n o ma of t he uri nar y bla d d er i n N or w a y 1 9 8 1- 2 0 1 4. B M C 
Ca ncer [I nter n et] 2 0 1 6 [ cite d 2 0 1 9 Fe b 1 5]; 1 6. A vaila ble fr o m: 
htt ps:// w w w. nc bi. nl m. ni h. g o v/ p mc/articl es/ P M C 5 0 6 4 9 0 6/ 
7.   
Mari A, Ca m pi R, Telli ni R, et al. Patter ns a n d pre dict ors of rec urr e nce after o pe n 
ra dical c yst ect o m y f or bl a d der ca ncer: a c o m pre h e nsi ve re vie w of t he liter at ure. W orl d J 
Ur ol 2 0 1 8; 3 6( 2): 1 5 7 – 7 0.  
8.   
Mitra A P, Q ui n n DI, D orff T B, et al. Fact ors i nfl u e nci n g p ost-rec urr e nce s ur vi val 
i n bla d der ca n cer f oll o wi n g r a dical c yst ect o m y. BJ U I nt 2 0 1 2; 1 0 9( 6): 8 4 6 – 5 4.  
9.   
v o n der Maas e H, Se n gel o v L, R o berts J T, et al. L o n g-ter m s ur vi val res ults of a 
ra n d o mize d trial c o m pari n g ge m cita bi ne pl us cis plati n, wit h met h otre x ate, vi n blasti ne, 
d o x or u bici n, pl us cis plati n i n patie nts wit h bla d der ca ncer. J Cli n O nc ol Off J A m S oc 
Cli n O nc ol 2 0 0 5; 2 3( 2 1): 4 6 0 2 – 8.  
1 0.   
Ba bai a n RJ, J o h ns o n D E, Lla mas L, A yala A G. M etastases fr o m tr a nsiti o nal cell 
carci n o ma of uri nar y bla d der. Ur ol o g y 1 9 8 0; 1 6( 2): 1 4 2 – 4.  
1 1.   
v o n der Maas e H, H a nse n S w., R o berts J t., et al. Ge mcita bi ne a n d Cis plati n 
Vers us Met h otre x ate, Vi n blasti ne, D o x or u bici n, a n d Cis plati n i n A d va nce d or Metastatic 
Bla d der Ca ncer: Res ults of a Lar ge, Ra n d o mize d, M ulti nati o nal, M ultice nter, P hase III 
St u d y. J Cli n O nc ol 2 0 0 0; 1 8( 1 7): 3 0 6 8 – 7 7.  
1 2.   
L oe hrer PJ, Ei n h or n L H, Els o n PJ, et al. A ra n d o mize d c o m paris o n of cis plati n 
al o ne or i n c o m bi nati o n wit h met h otre x ate, vi n blasti ne, a n d d o x or u bici n i n patie nts wit h 
metastatic ur ot helial carci n o ma: a c o o per ati ve gr o u p st u d y. J Cli n O nc ol Off J A m S oc 
Cli n O nc ol 1 9 9 2; 1 0( 7): 1 0 6 6 – 7 3.  
1 3.   
De Sa ntis M, Bell m u nt J, Mea d G, et al. Ra n d o mi ze d p hase II/III trial assessi n g 
ge m cita bi ne/car b o plati n a n d met h otre x ate/car b o pl ati n/ vi n blasti ne i n patie nts wit h 
a d va nce d ur ot helial ca ncer w h o are u nfit f or cis plati n- base d c h e m ot hera p y: E O R T C 
st u d y 3 0 9 8 6. J Cli n O nc ol Off J A m S oc Cli n O nc ol 2 0 1 2; 3 0( 2): 1 9 1 – 9.  
1 4.   
Cala br ò F, L or uss o V, R osati G, et al. Ge mcita bi n e a n d paclita x el e ver y 2 wee ks 
i n patie nts wit h pre vi o usl y u ntreate d ur ot h elial car ci n o ma. Ca ncer 2 0 0 9; 1 1 5( 1 2): 2 6 5 2 – 9.  
1 5.   
T o palia n S L, H o di F S, Bra h mer J R, et al. Safet y, Acti vit y, a n d I m m u ne 
C orrelates of A nti – P D- 1 A nti b o d y i n Ca ncer. N E n gl J Me d 2 0 1 2; 3 6 6( 2 6): 2 4 4 3 – 5 4.  
1 6.   
Bra h m er J R, Dra ke C G, W oll ner I, et al. P hase I st u d y of si n gle- a ge nt a nti-
pr o gra m me d deat h- 1 ( M D X- 1 1 0 6) i n r efr act or y s oli d t u m ors: safet y, cli nical acti vit y, 
p har mac o d y n a mics, a n d i m m u n ol o gic c orr elates. J Cli n O nc ol Off J A m S oc Cli n O nc ol 
2 0 1 0; 2 8( 1 9): 3 1 6 7 – 7 5.  
1 7.   
Balar A V, Castella n o D, O’ D o n nell P H, et al. First-li ne pe m br oliz u ma b i n 
cis plati n-i neli gi ble patie nts wit h l ocall y a d va n ce d a n d u nresecta ble or m etastatic 
ur ot helial ca ncer ( K E Y N O T E- 0 5 2): a m ultice ntr e, si n gle- ar m, p hase 2 st u d y. La n cet 
O nc ol 2 0 1 7; 1 8( 1 1): 1 4 8 3 – 9 2.  
1 8.   
Va u g h n DJ, Bell m u nt J, Fra d et Y, et al. H ealt h- R elate d Q ualit y- of- Life A nal ysis 
Fr o m K E Y N O T E- 0 4 5: A P hase III St u d y of Pe m br oliz u ma b Vers us C he m ot hera p y f or 


C A S E 6 8 1 9  
  
  
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Versi o n date: 7- 1 7- 2 0 2 0 
 
Pr e vi o usl y Tr eate d A d v a nce d Ur ot helial Ca n cer. J Cli n O nc ol Off J A m S oc Cli n O nc ol 
2 0 1 8; 3 6( 1 6): 1 5 7 9 – 8 7.  
1 9.   
Bell m u nt J, De Wit R, Va u g h n DJ, et al. T w o- year f oll o w- u p fr o m t he p h ase 3 
K E Y N O T E- 0 4 5 trial of pe m br oliz u ma b ( pe m br o) vs i n vesti gat or’s c h oice ( paclita x el, 
d oceta x el, or vi nfl u ni ne) i n rec urr e nt, a d va n ce d ur ot helial ca ncer ( U C). J Cli n O nc ol 
2 0 1 8; 3 6( 6 _s u p pl): 4 1 0 – 4 1 0.  
2 0.   
Balar A V, G als k y M D, R ose n ber g J E, et al. Atez oliz u ma b as first-li ne treat me nt 
i n cis plati n-i neli gi ble patie nts wit h l ocall y a d v a nce d a n d metastatic ur ot helial carci n o ma: 
a si n gle-ar m, m ultice ntre, p hase 2 trial. La n cet L o n d E n gl 2 0 1 7; 3 8 9( 1 0 0 6 4): 6 7 – 7 6.  
2 1.   
R ose n ber g J E, H off ma n- Ce nsits J, P o wles T, et al. Atez oliz u ma b i n patie nts wit h 
l ocall y a d va nce d a n d met astatic ur ot helial carci n o ma w h o ha ve pr o gresse d f oll o wi n g 
treat me nt wit h plati n u m- base d c he m ot hera p y: a si n gle- ar m, m ultice ntre, p h ase 2 trial. 
T he La ncet 2 0 1 6; 3 8 7( 1 0 0 3 1): 1 9 0 9 – 2 0.  
2 2.   
Necc hi A, J ose p h R W, L ori ot Y, et al. Atez oliz u ma b i n plati n u m-treate d l o call y 
a d va nce d or metastatic ur ot helial car ci n o ma: p ost- pr o gressi o n o utc o mes fr o m t he p hase 
II I M vi g or 2 1 0 st u d y. A n n O nc ol 2 0 1 7; 2 8( 1 2): 3 0 4 4 – 5 0.  
2 3.   
P o wles T, D urá n I, v a n d er Heij de n M S, et al. At ez oliz u ma b vers us c he m ot hera p y 
i n patie nts wit h plati n u m-treate d l o call y a d va n ce d or metastatic ur ot helial carci n o ma 
(I M vi g or 2 1 1): a m ultice ntre, o pe n-la b el, p hase 3 r a n d o mise d c o ntr olle d trial. La n cet 
L o n d E n gl 2 0 1 8; 3 9 1( 1 0 1 2 2): 7 4 8 – 5 7.  
2 4.   
S har ma P, Sief ker- Ra dt k e A, de Bra u d F, et al. Ni v ol u ma b Al o ne a n d Wit h 
I pili m u ma b i n Pre vi o usl y Treate d M etastatic Ur ot helial Carci n o ma: C hec k Mate 0 3 2 
Ni v ol u ma b 1 m g/ k g Pl us I pili m u ma b 3 m g/ k g E x pa nsi o n C o h ort Res ults. J Cli n O nc ol 
Off J A m S oc Cli n O nc ol 2 0 1 9; 3 7( 1 9): 1 6 0 8 – 1 6.  
2 5.   
A p ol o A B, I nfa nte J R, Bal ma n o u kia n A, et al. A v el u ma b, a n A nti- Pr o gra m me d 
Deat h- Li ga n d 1 A nti b o d y, I n Patie nts Wit h Refract or y M etastatic Ur ot helial Carci n o ma: 
Res ults Fr o m a M ultice nter, P hase I b St u d y. J Cli n O nc ol Off J A m S oc Cli n O nc ol 
2 0 1 7; 3 5( 1 9): 2 1 1 7 – 2 4.  
2 6.   
Patel M R, Ellert o n J, I nf a nte J R, et al. A vel u ma b i n metastatic ur ot helial 
carci n o ma after plati n u m fail ure (J A V E LI N S oli d T u m or): p o ole d res ults fr o m t w o 
e x pa nsi o n c o h orts of a n o pe n-la bel, p has e 1 trial. La n cet O n c ol 2 0 1 8; 1 9( 1): 5 1 – 6 4.  
2 7.   
Mc Der m ott D F, Ri ni B, M otzer RJ, et al. Meeti n g Li br ar y | Tr eat me nt-free 
s ur vi val ( T F S) after disc o nti n uati o n of first-li ne ni v ol u ma b ( NI V O) pl us i pili m u ma b (I PI) 
or s u niti ni b ( S U N) i n i nte nti o n-t o-treat (I T T) a n d I M D C f a v or a ble-ris k pati e nts ( pts) wit h 
a d va nce d re n al cell carci n o ma (a R C C) fr o m C hec k Mate 2 1 4. [I nter net]. A S C O Meet. 
Li br. [ cite d 2 0 1 9 Fe b 2 1]; A vaila ble fr o m: 
htt ps:// meeti n gli brar y.asc o. or g/r ec or d/ 1 6 9 4 8 3/a bstract 
2 8.   
Or nstei n M C, W o o d L S, H o b bs B P, et al. A p has e II trial of i nter mitte nt 
ni v ol u ma b i n patie nts wit h metastatic re nal cell car ci n o ma ( m R C C) w h o ha ve recei ve d 
pri or a nti-a n gi o ge nic t h er a p y. J I m m u n ot her Ca ncer 2 0 1 9; 7( 1): 1 2 7.  
2 9.   
Bell m u nt J, de Wit R, Va u g h n DJ, et al. Pe m br oliz u ma b as Sec o n d- Li ne T h era p y 
f or A d va n ce d Ur ot helial Carci n o ma. N E n gl J Me d 2 0 1 7; 3 7 6( 1 1): 1 0 1 5 – 2 6.  
3 0.   
Ta n g B, Y a n X, S he n g X, et al. Safet y a n d cli nical acti vit y wit h a n a nti- P D- 1 
a nti b o d y J S 0 0 1 i n a d va nce d mela n o ma or ur ol o gi c ca n cer p atie nts. J He mat ol O nc olJ 
He mat ol O nc ol 2 0 1 9; 1 2( 1): 7.  


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Versi o n date: 7- 1 7- 2 0 2 0 
 
3 1 .   
S he n g J, Sri vasta va S, Sa n g ha vi K, et al. Cli nical P har mac ol o g y C o nsi derati o ns 
f or t he De v el o p me nt of I m m u ne C hec k p oi nt I n hi bit ors. J Cli n P har mac ol 2 0 1 7; 5 7 S u p pl 
1 0: S 2 6 – 4 2.  
3 2.   
Ste ne hje m D D, Tra n D, N kr u ma h M A, G u pta S. P D 1/ P D L 1 i n hi bit ors f or t he 
treat me nt of a d v a nce d ur ot helial bla d der ca ncer. O nc o Tar gets T her 2 0 1 8; 1 1: 5 9 7 3 – 8 9.  
3 3.   
A ki ya m a Y, N o n o m ur a C, K o n d o u R, et al. I m m u n ol o gical eff ects of t he a nti-
pr o gra m me d deat h- 1 a nti b o d y o n h u ma n p eri p her al bl o o d m o n o n uclear cells. I nt J O nc ol 
2 0 1 6; 4 9( 3): 1 0 9 9 – 1 0 7.  
3 4.   
Diaz- M o nter o C M, Fi n k e J, M o nter o AJ. M yel oi d deri ve d s u p pr ess or cells i n 
ca ncer: t her a pe utic, pr e dicti ve, a n d pr o g n ostic i m plicati o ns. Se mi n O nc ol 
2 0 1 4; 4 1( 2): 1 7 4 – 8 4.  
3 5.   
Fi n ke J, K o J, Ri ni B, Ra y m a n P, Ir ela n d J, C o he n P. M D S C as a mec ha nis m of 
t u m or esca pe fr o m s u niti ni b me diate d a nti-a n gi o ge nic t hera p y. I nt I m m u n o p har mac ol 
2 0 1 1; 1 1( 7): 8 5 6 – 6 1.  
3 6.   
M o nter o AJ, Diaz- M o nter o C M, K yri a k o p o ul os C E, Br o nte V, Ma n dr uzzat o S. 
M yel oi d- d eri ve d s u p pr ess or cells i n ca ncer p atie nts: a cli nical pers pecti ve. J I m m u n ot her 
Ha gerst o w n M d 1 9 9 7 2 0 1 2; 3 5( 2): 1 0 7 – 1 5.  
3 7.   
T w y ma n- Sai nt Vict or C, Rec h AJ, Mait y A, et al. Ra diati o n a n d d ual c hec k p oi nt 
bl oc ka de acti vate n o n-re d u n da nt i m m u ne mec ha nis ms i n ca ncer. N at ure 
2 0 1 5; 5 2 0( 7 5 4 7): 3 7 3 – 7.  
3 8.   
W a n g W, La u R, Y u D, Z h u W, K or ma n A, W e b er J. P D 1 bl oc ka de re v erses t he 
s u p pressi o n of mela n o ma a nti ge n-s pecifi c C T L b y C D 4 + C D 2 5( Hi) r e g ulat or y T cells. 
I nt I m m u n ol 2 0 0 9; 2 1( 9): 1 0 6 5 – 7 7.  
3 9.   
R o bert L, Ts oi J, W a n g X, et al. C T L A 4 bl oc ka d e br oa de ns t h e peri p heral T-cell 
rece pt or re p ert oire. Cli n Ca ncer Res Off J A m Ass oc Ca ncer R es 2 0 1 4; 2 0( 9): 2 4 2 4 – 3 2.  
4 0.   
Or nstei n M C, Diaz- M o nter o C M, Ra y m a n P, et al. M yel oi d- d eri ve d s u p pr ess ors 
cells ( M D S C) c orr elate wit h cli nic o pat h ol o gic f act ors a n d pat h ol o gic c o m plete res p o nse 
( p C R) i n patie nts wit h ur ot helial carci n o ma ( U C) u n der g oi n g c ystect o m y. Ur ol O nc ol 
Se mi n Ori g I n v esti g 2 0 1 8; 3 6( 9): 4 0 5 – 1 2.  
4 1.   
Tze n g A, Diaz- M o nter o C M, Ra y ma n P A, et al. I m m u n ol o gical C orrel ates of 
Res p o nse t o I m m u ne C h ec k p oi nt I n hi bit ors i n Metastatic Ur ot helial Carci n o ma. Tar get 
O nc ol 2 0 1 8; 1 3( 5): 5 9 9 – 6 0 9.  
4 2.   
W a n g M, C he n C, J e mielita T, et al. Are t u m or size c ha n ges pre dicti ve of s ur vi val 
f or c hec k p oi nt bl oc ka de base d i m m u n ot hera p y i n metastatic mela n o ma? J I m m u n ot her 
Ca ncer 2 0 1 9; 7( 1): 3 9.  
4 3.   
J o h ns o n D B, S ulli va n RJ, Me nzies A M. I m m u ne c hec k p oi nt i n hi bit ors i n 
c halle n gi n g p o p ulati o ns. Ca ncer 2 0 1 7; 1 2 3( 1 1): 1 9 0 4 – 1 1.   
4 4.   
R E CI S T 1. 1 | R E CI S T [I nter net]. [ cite d 2 0 1 9 J ul 3 0]; A vaila ble fr o m: 
htt ps://recist.e ortc. or g/recist- 1- 1- 2/ 
4 5.   
Fra d et Y, Bell m u nt J, Va u g h n DJ, et al. Ra n d o mize d p hase III K E Y N O T E- 0 4 5 
trial of pe m br oliz u ma b vers us paclita x el, d oceta x el, or vi nfl u ni ne i n rec urr e nt a d va nce d 
ur ot helial ca ncer: r es ults of  >  2 years of f oll o w- u p. A n n O nc ol Off J E ur S oc Me d O nc o l 
2 0 1 9;  
 

ICF_001.pdf: 


 
C A S E 6 8 1 9   
C o nse nt versi o n date  2 6 F E B 2 0 2 0  
2 
 
T h us, we t hi n k t hat t here are patie nts t hat res p o n d t o t hera p y w h o d o n ot nee d t o be o n t he dr u g 
i n defi nitel y. We t hi n k t hat it is safe t o st o p t hera p y wit h cl ose m o nit ori n g. We h o pe t hat we ca n 
fi g ure o ut t he best treat me nt sc he d ule t o hel p mi ni mize si de effects a n d hel p wit h q ualit y of life. 
T his st u d y will all o w t he researc hers t o k n o w w het her t his differe nt a p pr oac h is t he sa me , better,  
or w orse t ha n c o nti n ue d c hec k p oi nt i n hi bit or t hera p y. T o be better, t he st u d y w o ul d s h o w si milar 
res p o nse rates c o m pare d t o t he us ual a p pr oac h. T here is n o i n vesti gati o nal dr u g i n t his st u d y.  
 
O ne or m ore of t he I n vesti gat ors c o n d ucti n g t his st u d y ser ve as c o ns ulta nts f or t he c o m pa n y t hat 
ma kes pr o d ucts use d i n t his st u d y.  T hese fi na ncial i nterests are wit hi n per missi ble li mits 
esta blis he d b y t he l ocal i nstit uti o nal C o nflict of I nterest P olic y.   If y o u ha ve a n y q uesti o ns 
re gar di n g c o nflicts of i nterest, please as k y o u st u d y d oct or or call t he Cle vela n d Cli nic 
I nstit uti o nal Re vie w B oar d at ( 2 1 6) 4 4 4-2 9 2 4 or U ni versit y H os pitals I nstit uti o nal Re vie w B oar d 
at ( 2 1 6) 8 4 4- 1 5 2 9.  [ Select a p pr o priate I R B(s)]  
 
H o w l o n g will t he rese arc h l ast a n d w h at will I nee d t o d o ?  
Y o u  will  be  i ncl u de d  i n  t his  trial  o nl y  if  y o u  ha ve  ha d  a  g o o d  res p o nse  t o  y o ur  c urre nt 
i m m u n ot hera p y treat me nt. If y o ur ca ncer has decrease d b y at least 3 0 % t he n treat me nt will be 
hel d. If y o u are i ncl u de d i n t he trial wit h “sta ble disease” (t u m or di d n ot s hri n k b y at least 3 0 % b ut 
di d n ot gr o w b y m ore t ha n 2 0 %), y o u will c o nti n ue o n y o ur c urre nt i m m u n ot hera p y  treat me nt as 
y o u ha ve bee n. If  y o ur treat me nt has bee n o n h ol d a n d  t he ca ncer gr o ws y o u will restart t he sa me 
i m m u n ot hera p y treat me nt y o u were getti n g pri or t o y o ur treat me nt bei n g hel d. 
After y o u fi nis h t he st u d y, y o ur d oct or will c o nti n ue t o watc h y o u f or si de effects a n d f oll o w 
y o ur c o n diti o n f or 3 0 da ys l o n ger or u ntil y o u start y o ur ne xt treat me nt.  
M ore detaile d i nf or mati o n a b o ut t he st u d y pr oce d ures ca n be f o u n d u n der “ W hat e xtra tests a n d 
pr oce d ures will I ha ve if I ta ke part i n t his st u d y?”  
 
Is t here a n y w a y bei n g i n t his st u d y c o ul d be b a d f or me ? 
Yes. I n a d diti o n t o t he r o uti ne si de effects of C PI, w hic h is c o nsi dere d sta n dar d f or patie nts li ke 
y o u, t his trial i n v ol ves t he p ote ntial f or ca ncer gr o wt h. T his ca ncer gr o wt h c o ul d be faster t ha n if 
y o u sta ye d o n t hera p y.  
A d diti o nall y, C PI has its o w n set of ris ks, w hic h are detaile d bel o w. T hese si de effects are n ot 
i ncrease d c o m pare d t o if y o u were n ot o n st u d y. W hile m ost patie nts treate d wit h C PI t hera p y 
ha ve s o me mil d t o m o derate effects, s o me ca n ha ve si g nifica nt si de  effects. M ore detaile d 
i nf or mati o n a b o ut t he ris ks of t his st u d y ca n be f o u n d bel o w. T he rest of y o ur me dical care will 
be acc or di n g t o o ur sta n dar d practice.  
M ore detaile d i nf or mati o n a b o ut t he ris ks of t his st u d y ca n be f o u n d u n der “ W hat p ossi ble ris ks 
ca n I e x pect fr o m ta ki n g part i n t his st u d y?”  
 
W h at p ossi ble be nefits c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
We ca n n ot k n o w if y o u will ha ve a n y be nefit as a res ult of y o ur partici pati o n i n t he st u d y; it is 
p ossi ble t he st u d y treat me nt ma y relief s o me s y m pt o ms relate d t o treat me nt, i m pr o ve y o ur 
q ualit y of life, lesse n t he a m o u nt of me dicati o ns or visits f or t he treat me nt of C PI relate d si de 


 
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effects, a n d decrease d ris k of h os pitalizati o n f or rare c o m plicati o ns of C PI use.  
 
H o we ver, it is p ossi ble t hat y o ur c o n diti o n c o ul d w orse n.  Y o ur partici pati o n i n t his st u d y will 
hel p t o o btai n i nf or mati o n a b o ut treati n g s u bjects wit h bla d der ca ncer.  
 
W h at is t he us u al a p pr o ac h t o m y bl a d der c a ncer ?  
T he sta n dar d of care is f or patie nts li ke y o urself t o start C PI t hera p y. Y o u w o ul d c o nti n ue t his 
me dicati o n i n defi nitel y, u ntil disease pr o gressi o n or i nt olera ble si de effects.  
 
W h at are m y ot her c h oices if I d o n ot t a ke p art i n t his st u d y ?  
If y o u deci de n ot t o ta ke part i n t his st u d y, y o u ha ve ot her c h oices. F or e xa m ple: 
 y o u ma y c h o ose t o ha ve t he us ual a p pr oac h descri be d a b o ve 
 y o u ma y c h o ose t o ta ke part i n a differe nt st u d y, if o ne is a vaila ble 
 y o u ma y c h o ose n ot t o be treate d f or ca ncer. F or e xa m ple: c o mf ort/ palliati ve care  
 
Det aile d I nf or m ati o n: T he f oll o w i n g is m ore detaile d i nf or mati o n a b o ut t his st u d y i n a d diti o n 
t o t he i nf or mati o n liste d a b o ve. 
 
W h at are t he st u d y gr o u ps ?   
All st u d y partici pa nts will get t he sa me st u d y i nter ve nti o n. It will i ncl u de h ol di n g C PI t hera p y if 
sca ns s h o w a si g nifica nt decrease i n t u m or size after 2 4 wee ks of treat me nt wit h C PI t hera p y.   
 
W h at e xtr a tests a n d pr oce d ures will I h a ve if I t a ke p art i n t his st u d y ?  
M ost of t he e xa ms, tests, a n d pr oce d ures y o u will ha ve are part of t he us ual a p pr oac h f or y o ur 
ca ncer. H o we ver, t here ma y be s o me e xtra tests t hat y o u will nee d t o ha ve if y o u ta ke part i n t his 
st u d y. 
  
Bi o m ar kers: At s pecifie d ti me p oi nts, bl o o d sa m ples will be c ollecte d t o see w het her t he st u d y 
dr u g is pr o d uci n g c ha n ges t o t he ge nes a n d pr otei ns relate d t o y o ur ca ncer.  
 
I m m u n o ge nicit y (I G) tests deter mi ne if y o ur b o d y’s i m m u ne s yste m is m o u nti n g a res p o nse t o 
t he st u d y dr u g. At eac h ti me p oi nt, a b o ut 3 teas p o o ns of bl o o d will be dra w n f or researc h 
p ur p oses. 
 
Rese arc h bi o psies  
T u m or bi o psies are rec o m me n de d at differe nt p oi nts i n t he st u d y t o c hec k t he c haracteristics of 
y o ur t u m or. Y o ur t u m or cells c o ul d be affecte d b y t he dr u g . If y o ur t u m or is accessi ble, a t u m or 
bi o ps y will be d o ne . Pri or t u m or bi o psies o btai ne d wit hi n 6 m o nt hs of e nr oll me nt are all o we d.  
 
A t u m or bi o ps y is t he re m o val of a s mall ( pe ncil eraser -size d) circle of t u m or usi n g a c o o kie 
c utter-li ke i nstr u me nt. T he d urati o n of t he bi o ps y pr oce d ure is a p pr o xi matel y 3 0 mi n utes. T he 
bi o ps y i nstr u me nt ma y be place d i nt o t he t u m or b y y o ur p h ysicia n eit her i n t he office or i n 
ra di ol o g y. T he pr oce d ure will be d o ne usi n g l ocal a nest hesia t o mi ni mize disc o mf ort fr o m t he 
bi o ps y. D uri n g a bi o ps y of t he a b d o me n (f or e xa m ple, bi o ps y of t he li ver or l y m p h n o des i n t he 
bell y), y o u will be as ke d t o lie flat a n d a d oct or will clea n t he area o n y o ur bell y. T he d oct or will 
t he n n u m b t he area wit h a l ocal a nest hetic s o t hat y o u d o n ot feel t he bi o ps y. T he d oct or will as k 


 
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y o u t o h ol d y o ur breat h a n d n ot m o ve w hile he or s he places t he nee dle i nt o y o ur t u m or a n d 
wit h dra ws a s mall c ore of tiss ue w hic h re mai ns tra p pe d i nsi de t he nee dle. It is ver y i m p orta nt 
t hat y o u n ot m o ve or breat he d uri n g t he bi o ps y. 
 
Bef ore y o u be gi n t he st u d y:  
Y o u will nee d t o ha ve t he f oll o wi n g e xa ms tests a n d pr oce d ures t o fi n d o ut if y o u ca n be i n t he 
st u d y: 
 C T ( C o m p ute d t o m o gra p h y) sca n of c hest, a b d o me n, a n d pel vis t o meas ure t u m ors 
 B o ne sca n a n d/ or brai n sca n if y o ur d oct or t hi n ks it necessar y  
 Bl o o d tests ( bl o o d c o u nts, c he mistries, t h yr oi d tests, a n d researc h sa m ples) 
 W o me n of c hil d beari n g p ote ntial m ust ha ve a bl o o d or uri ne pre g na nc y test.  
 B o ne sca n t o meas ure t u m ors if prese nt.  
 C T or Ma g netic Res o na nce I ma gi n g t o meas ure brai n t u m ors if prese nt.  
 
A n e xtra bl o o d sa m ple (a b o ut 3 teas p o o ns) will be ta ke n f or t he st u d y . T his sa m ple is re q uire d i n 
or der f or y o u t o ta ke part i n t his st u d y beca use t he researc h o n t he sa m ple is a n i m p orta nt part of 
t he st u d y.  
 
Neit her y o u n or y o ur healt h care pla n/i ns ura nce carrier will be bille d f or t he c ollecti o n of t he 
researc h bi o mar ker a n d i m m u n o ge nicit y bl o o d dra ws t hat will be use d f or t his st u d y. 
 
D uri n g t he st u d y t he f oll o wi n g will be a d diti o n al rese arc h pr oce d ures:  
 
 Researc h b l o o d tests eac h ti me y o u ha ve C T sca ns  
 
W h at p ossi ble ris ks c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
If y o u c h o ose t o ta ke part i n t his st u d y, t here is a ris k t hat: 
 Y o u ma y l ose ti me at w or k or h o me a n d s pe n d m ore ti me i n t he h os pital or d oct or’s office 
t ha n us ual 
 Y o u ma y be as ke d se nsiti ve or pri vate q uesti o ns w hic h y o u n or mall y d o n ot disc uss 
 T here is t he p ote ntial f or ra pi d gr o wt h of y o ur ca ncer. 
 T here is a ris k s o me o ne c o ul d get access t o t he pers o nal i nf or mati o n i n y o ur me dical 
rec or ds or ot her i nf or mati o n researc hers ha ve ke pt a b o ut y o u. S o me o ne mi g ht be a ble t o 
trace t his i nf or mati o n bac k t o y o u. T he researc hers belie ve t he c ha nce t hat s o me o ne will 
i de ntif y y o u is ver y s mall, b ut t he ris k ma y c ha n ge i n t he f ut ure as pe o ple c o me u p wit h 
ne w wa ys of traci n g i nf or mati o n. I n s o me cases, t his i nf or mati o n c o ul d be use d t o ma ke it 
har der f or y o u t o get or kee p a j o b. T here are la ws a gai nst mis use of ge netic i nf or mati o n, 
b ut t he y ma y n ot gi ve f ull pr otecti o n. T he researc hers belie ve t he c ha nce t hese t hi n gs will 
ha p pe n is ver y s mall, b ut ca n n ot pr o mise t hat t he y will n ot occ ur . 
 
 
Y o u are c urre ntl y recei vi n g o ne of t he a p pr o ve d c hec k p oi nt i n hi bit or t hera pies f or bla d der 
ca ncer: 
•  Atez oliz u ma b ( Tece ntri q)  
•  A vel u ma b ( Be ve nci o) 
•  D ur val u ma b (I mfi nzi)  


 
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•  Ni v ol u ma b ( O p di v o)  
•  Pe m br oliz u ma b ( Ke ytr u da)  
 
T he c hec k p oi nt i n hi bit or i m m u n ot hera pies use d i n t his st u d y ma y affect h o w differe nt parts of 
y o ur b o d y w or k s uc h as y o ur li ver, ki d ne ys, heart, a n d bl o o d. T he st u d y d oct or will be testi n g 
y o ur bl o o d a n d will let y o u k n o w if c ha n ges occ ur t hat ma y affect y o ur healt h.  
 
 
T here is als o a ris k t hat y o u c o ul d ha ve si de effects fr o m t he st u d y dr u g(s)/st u d y a p pr oac h. 
Here are i m p orta nt p oi nts a b o ut si de effects:  
 T he st u d y d oct ors d o n ot k n o w w h o will or will n ot ha ve si de effects. 
 S o me si de effects ma y g o a wa y s o o n, s o me ma y last a l o n g ti me, or s o me ma y ne ver g o 
a wa y. 
 S o me si de effects ma y i nterfere wit h y o ur a bilit y t o ha ve c hil dre n. 
 S o me si de effects ma y be seri o us a n d ma y e ve n res ult i n deat h.  
 
Here are i m p orta nt p oi nts a b o ut h o w y o u a n d t he st u d y d oct or ca n ma ke si de effects less of a 
pr o ble m: 
 Tell t he st u d y d oct or if y o u n otice or feel a n yt hi n g differe nt s o t he y ca n see if y o u are 
ha vi n g a si de effect.  
 T he st u d y d oct or ma y be a ble t o treat s o me si de effects.  
 T he st u d y d oct or ma y a dj ust t he st u d y dr u gs t o tr y t o re d uce si de effects. 
 
T he ta bles bel o w s h o w t he m ost c o m m o n a n d t he m ost seri o us si de effects t hat researc hers k n o w 
a b o ut. T here mi g ht be ot her si de effects t hat researc hers d o n ot yet k n o w a b o ut. If i m p orta nt ne w 
si de effects are f o u n d, t he st u d y d oct or will disc uss t hese wit h y o u. 
 
P ossi ble si de effects of c hec k p oi nt i n hi bit or i m m u n ot hera pies, w hic h is t he us ual a p pr oac h f or t his 
t y pe of ca ncer: 
 
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple recei vi n g C PI t hera p y,  m ore t ha n 2 0 a n d u p t o 1 0 0 ma y ha ve:  
 Fati g ue  
 Water y st o ols  
 S ki n itc hi n g  
 C o u g h  
 
O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple recei vi n g C PI t hera p y , fr o m 4 t o 2 0 ma y ha ve: 
 J oi nt pai n  
 Fe ver  
 Bac k pai n  
 Ras h  
 Pai n i n y o ur bell y  
 L oss of s ki n c ol or  


 
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O C C A SI O N A L, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple recei vi n g C PI t hera p y , fr o m 4 t o 2 0 ma y ha ve: 
 N ot e n o u g h t h yr oi d h or m o ne s o y o u ma y feel tire d, gai n wei g ht, feel c ol d, 
ha ve i nfre q ue nt or har d st o ols  
 L o w le vels of salt i n t he bl o o d t hat ma y ca use y o u t o feel tire d, c o nf use d, ha ve 
a hea dac he, m uscle cra m ps a n d/ or feel sic k t o y o ur st o mac h  
 
 
 
U N C O M M O N SI D E E F F E C T S  
O ut of 1 0 0 pe o ple recei vi n g C PI t hera p y, fr o m 1 t o 5 ma y ha ve: 
•  I nfla m mati o n of t he l u n gs s o y o u ma y feel s h ort of breat h a n d c o u g h.  
•  T o o m uc h t h yr oi d h or m o ne s o y o u ma y feel a n xi o us, a n gr y, ha ve tr o u ble slee pi n g, 
feel wea k, tre m ble, s weat, feel tire d, ha ve l o ose a n d water y st o ols  
•  I nf usi o n reacti o n, w here y o u ma y feel dizz y or fai nt, fl us he d, get a ras h, ha ve a fe ver, 
feel s h ort of breat h or at t he ti me of recei vi n g y o ur i nf usi o n (I V) or j ust after, or pai n 
at t he site of i nf usi o n  
•  I nfla m mati o n of t he b o wels/ g ut w hic h ma y ca use se vere pai n i n y o ur bell y wit h l o ose 
or water y st o ols, a n d blac k, tarr y, stic k y st o ols or st o ols wit h bl o o d or m uc us  
•  I nfla m mati o n of t he s ki n s o y o u ma y ha ve peeli n g of t he s ki n, itc hi ness, a n d/ or s ki n 
re d ness. T he s ki n i nfla m mati o n (i.e. peeli n g, itc hi n g a n d re d ness) c o ul d als o be 
wi des prea d t hr o u g h o ut y o ur b o d y. M ore se vere s ki n reacti o ns ma y i n v ol ve t he i nsi de 
of y o ur m o ut h, t he s urface of y o ur e ye a n d ge nital areas, a n d/ or ma y ca use t he t o p 
la yer of y o ur s ki n t o peel fr o m all o ver y o ur b o d y w hic h ca n ca use se vere i nfecti o n.  


 
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R A R E SI D E E F F E C T S  
O ut of 1 0 0 pe o ple recei vi n g C PI t hera p y, less t ha n 1 ma y ha ve: 
•  
I nfla m mati o n of t he ner ves t hat ma y ca use pai n, wea k ness or ti n gli n g i n y o ur ha n ds 
a n d feet, a n d ma y s prea d t o y o ur le gs, ar ms a n d u p per b o d y lea di n g t o se vere m uscle 
wea k ness a n d p ossi ble te m p orar y paral ysis  
•  
I nfla m mati o n of t he m uscles s o y o u ma y feel wea k or ha ve pai n i n y o ur m uscles 
•  
I nfla m mati o n of t he pa ncreas (a gla n d i n y o ur a b d o me n t hat c o ntr ols s u gar le vels) s o 
y o u ma y ha ve se vere pai n i n t he t o p part of y o ur bell y t hat ma y m o ve t o y o ur bac k, 
feel sic k t o y o ur st o mac h, a n d v o miti n g t hat gets w orse w he n y o u eat  
•  
I nfla m mati o n of t he e ye s o y o u ma y ha ve e ye re d ness, bl urre d visi o n, se nsiti vit y t o 
li g ht, e ye pai n, see fl oaters or ha ve hea dac hes  
•  
I nfla m mati o n of t he li ver t hat ma y ma ke y o u feel sic k t o y o ur st o mac h a n d v o mit, feel 
li ke n ot eati n g, feel tire d, ha ve a mil d fe ver, ha ve a pai n i n t he ri g ht si de of y o ur bell y, 
yell o w e yes a n d s ki n, a n d dar k uri ne  
•  
I nfla m mati o n of t he pit uitar y gla n d (a gla n d i n t he hea d), w hic h ma y ca use y o u t o feel 
sic k t o y o ur st o mac h or ha ve hea dac hes, c ha n ges i n y o ur be ha vi or, d o u ble visi o n, fe w 
t o n o me nstr ual c ycles, wea k ness, v o miti n g a n d dizzi ness or fai nti n g.  
•  
A dre nal gla n ds ( gla n ds o n t o p of t he ki d ne ys) t hat ma y n ot ma ke e n o u g h h or m o ne 
w hic h c o ul d ca use tire d ness, wei g ht l oss, m uscle wea k ness, feeli n g fai nt, j oi nt, 
m uscle a n d bell y ac hes, na usea, v o miti n g, l o ose or water y st o ols, fe ver, salt cra vi n g, 
a n d s o meti mes dar ke ni n g of t he s ki n li ke a s u nta n.  
•  
T y pe 1 Dia betes, a c o n diti o n t hat ca n ca use t o o m uc h s u gar i n y o ur bl o o d, feeli n g 
t hirstier t ha n us ual, fre q ue nt uri nati o n a n d wei g ht l oss. Y o u are li kel y t o nee d re g ular 
i ns uli n s h ots. I nfla m mati o n of t he ki d ne y s o y o u ma y pass less uri ne or ha ve cl o u d y 
or bl o o d y uri ne, s welli n g a n d l o w bac k pai n 
•  
I nfla m mati o n of t he mi d dle la yer of y o ur heart wall t hat ma y ca use y o ur heart t o ha ve 
diffic ult y p u m pi n g bl o o d t hr o u g h o ut y o ur b o d y, w hic h ca n ca use c hest pai n, s h ort ness 
of breat h a n d s welli n g of t he le gs. Y o u ma y e x perie nce a fast or irre g ular heart beat 
t hat ma y ca use dizzi ness or fai nti n g. 
•  
I nfla m mati o n of t he t h yr oi d gla n d, a n or ga n t hat ma kes a n d st ores t h yr oi d h or m o nes. 
T his c o n diti o n ma y lea d t o c ha n ge i n y o ur heart rate, bl o o d press ure, b o d y 
te m perat ure, a n d t he rate at w hic h f o o d is c o n verte d i nt o e ner g y.  
•  
A c o n diti o n t hat ma y ma ke y o u feel wea k a n d tire d a n d mi g ht ha ve dr o o pi n g of t he 
e yeli ds, bl urre d or d o u ble visi o n, diffic ult y s wall o wi n g, sl urre d s peec h, wea k ness i n 
y o ur ar ms a n d le gs, or diffic ult y breat hi n g  
•  
T he f or mati o n of s mall cl usters of i m m u ne cells (calle d gra n ul o mas) i n parts of y o ur 
b o d y s uc h as y o ur l y m p h n o des, e yes, s ki n, or l u n gs  
•  
I nfla m mati o n of t he brai n wit h c o nf usi o n a n d fe ver. T his ma y als o i ncl u de 
dis orie ntati o n, me m or y pr o ble ms, seiz ures (fits), c ha n ges i n pers o nalit y a n d be ha vi or, 
diffic ult y s pea ki n g, wea k ness or l oss of m o ve me nt i n s o me parts of y o ur b o d y, a n d 
l oss of c o nsci o us ness  
 
 
 
 


 
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P ote nti al Ris k or Disc o mf ort fr o m Rese arc h Pr oce d ures  
 
Bl o o d Dra ws  
 
T he i nserti o n of t he nee dle t o dra w bl o o d is pai nf ul; h o we ver, t he disc o mf ort is us uall y brief.  
F or m ost pe o ple, nee dle p u nct ures t o get bl o o d sa m ples d o n ot ca use a n y seri o us pr o ble ms; 
h o we ver, t he y ma y ca use blee di n g, br uisi n g, disc o mf ort, i nfecti o ns, dizzi ness, or fai nti n g. 
 
C T Sca ns  
If y o u ta ke part i n t his researc h, y o u will ha ve o ne or m ore me dical i ma gi n g st u dies w hic h use 
ra diati o n.  T he ra diati o n d ose we ha ve disc usse d is w hat y o u will recei ve fr o m t his st u d y o nl y, 
a n d d oes n ot i ncl u de a n y e x p os ure y o u ma y n ot ha ve recei ve d or will recei ve fr o m ot her tests. 
T he C T sca n t hat y o u will recei ve i n t his st u d y will e x p ose y o u t o l o w a m o u nts of ra diati o n. 
E ver y da y, pe o ple are nat urall y e x p ose d t o l o w le vels of ra diati o n t hat c o me fr o m t he s u n a n d t he 
e n vir o n me nt. T his t y pe of ra diati o n is calle d “ bac k gr o u n d ra diati o n.” N o o ne k n o ws f or s ure 
w het her e x p os ure t o l o w a m o u nts of ra diati o n is har mf ul f or y o ur b o d y. H o we ver, scie ntists 
belie ve t hat bei n g e x p ose d t o t o o m uc h ra diati o n ca n ca use har mf ul si de effects, i ncl u di n g 
ca usi n g a ne w ca nc er.   T he a m o u nt of ra diati o n t hat scie ntists t hi n k ca n ca use har mf ul si de 
effects e q uals m ore t ha n 1 5 ti mes t he a m o u nt of e xtra ra diati o n y o u w o ul d recei ve fr o m bei n g i n 
t his st u d y. Als o, scie ntists belie ve t he n u m ber of pe o ple w h o w o ul d be at ris k f or de vel o pi n g a 
sec o n d ca ncer fr o m bei n g e x p ose d t o lar ge a m o u nts of ra diati o n t o be a b o ut 1 o ut of e ver y 
1, 0 0 0.  
 
B o ne Sca n  
A b o ne sca n is a test t hat hel ps dia g n ose a n d trac k b o ne disease.  A b o ne sca n will be d o ne w he n 
y o u first start t he st u d y.  F or a b o ne sca n, y o u will recei ve a n i njecti o n of a tracer i nt o a vei n i n 
y o ur ar m.  Y o u will nee d t o lie still o n a ta ble w hile a mac hi ne wit h a n ar m -li ke de vice 
s u p p orti n g t he ca mera passes o ver y o ur b o d y t o rec or d t he patter n of t he tracer bei n g a bs or be d 
b y y o ur b o nes.  T his is pai nless.  A sca n of y o ur e ntire s kelet o n will ta ke u p t o 6 0 mi n utes.  Y o u 
ma y fi n d t he i njecti o n a n d t he nee d t o lie still d uri n g t he sca n ni n g pr oce d ure mil dl y 
u nc o mf orta ble.  T he ris k of a n aller gic reacti o n t o t he tracer is e xtre mel y rare.    
 
Bi o psies 
Ris ks ass ociate d wit h bi o psies i ncl u de pai n, re d ness, s welli n g, l o w bl o o d press ure, 
e xcessi ve  blee di n g, br uisi n g, or drai ni n g at t he nee dle site, a b n or mal w o u n d heali n g, fe ver, 
i nfecti o n, a n d aller gic reacti o n t o t he me dicati o n use d t o n u m b t he s ki n o ver t he bi o ps y site. T w o 
t o 3 % of patie nts re q uire h os pitalizati o n after a t u m or bi o ps y. Rarel y, a n i nfecti o n ca n occ ur .  
Y o u will si g n a se parate c o nse nt f or m bef ore t he bi o ps y is ta ke n. T his will be a sta n dar d s ur gical 
c o nse nt f or m fr o m t he i nstit uti o n w here t he bi o ps y pr oce d ure ta kes place. 
 
Ris ks s pecificall y ass ociate d wit h l u n g bi o ps y are p ne u m ot h ora x (c olla pse of l u n g), air e m b ol us 
(air i n a bl o o d vessel), he m o pericar di u m ( bl o o d ar o u n d t he heart), a n d l u n g t orsi o n (t wisti n g t hat 
i nterr u pts t he bl o o d s u p pl y t o t he l u n g).  
 
Let y o ur st u d y d oct or k n o w of a n y q uesti o ns y o u ha ve a b o ut p ossi ble si de effects. Y o u ca n as k 
t he st u d y d oct or q uesti o ns a b o ut si de effects at a n y ti me.  


 
C A S E 6 8 1 9   
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9 
 
 
Re pr o d ucti ve ris ks 
Y o u s h o ul d n ot get pre g na nt, breastfee d, or fat her a ba b y w hile i n t his st u d y. T h e C PI t hera p y  
use d i n t his st u d y c o ul d be ver y da ma gi n g t o a n u n b or n ba b y. C hec k wit h t he st u d y d oct or a b o ut 
w hat t y pes of birt h c o ntr ol, or pre g na nc y pre ve nti o n, t o use w hile i n t his st u d y.  
 
W h at h a p pe ns t o t he i nf or m ati o n c ollecte d f or t he rese arc h ? 
Y o ur i nf or mati o n or sa m ples t hat are c ollecte d as part of t his researc h will n ot be use d or 
distri b ute d f or f ut ure researc h st u dies, e ve n if all of y o ur i de ntifiers are re m o ve d. 
 
C a n I st o p t a ki n g p art i n t his st u d y ?  
Yes. Y o u ca n deci de t o st o p at a n y ti me. If y o u deci de t o st o p f or a n y reas o n, it is i m p orta nt t o let 
t he st u d y d oct or k n o w as s o o n as p ossi ble s o y o u ca n st o p safel y. If y o u st o p, y o u ca n deci de 
w het her or n ot t o let t he st u d y d oct or c o nti n ue t o pr o vi de y o ur me dical i nf or mati o n t o t he 
or ga nizati o n r u n ni n g t he st u d y. 
 
T he st u d y d oct or will tell y o u a b o ut ne w i nf or mati o n or c ha n ges i n t he st u d y t hat ma y affect 
y o ur healt h or y o ur willi n g ness t o c o nti n ue i n t he st u d y. 
 
T he st u d y d oct or ma y ta ke y o u o ut of t he st u d y: 
 If y o ur healt h c ha n ges a n d t he st u d y is n o l o n ger i n y o ur best i nterest 
 If ne w i nf or mati o n bec o mes a vaila ble 
 If y o u d o n ot f oll o w t he st u d y re q uire me nts 
 If t he st u d y is st o p pe d b y t he s p o ns or, I nstit uti o nal Re vie w B oar d (I R B) or F D A.  
 
W h at are m y ri g hts i n t his st u d y ?  
Ta ki n g part i n t his st u d y is y o ur c h oice. N o matter w hat decisi o n y o u ma ke, a n d e ve n if y o ur 
decisi o n c ha n ges, t here will be n o pe nalt y t o y o u. Y o u will n ot l ose me dical care or a n y le gal 
ri g hts.  
 
W h at are t he c osts of t a ki n g p art i n t his st u d y ?  
Y o ur i n v ol ve me nt i n t his researc h st u d y is v ol u ntar y a n d y o u will n ot be pai d f or y o ur 
partici pati o n.  
 
Y o u a n d/ or y o ur healt h pla n/i ns ura nce c o m pa n y will nee d t o pa y f or s o me or all of t he c osts of 
treati n g y o ur ca ncer i n t his st u d y (i.e., me dical hist or y, re vie w of me dicati o ns, p h ysical e xa ms, 
perf or ma nce stat us, r o uti ne bl o o d tests, pre g na nc y test, x- ra ys a n d/ or sca ns f or t u m or 
meas ure me nt).  S o me healt h pla ns will n ot pa y t hese c osts f or pe o ple ta ki n g part i n st u dies. 
C hec k wit h y o ur healt h pla n or i ns ura nce c o m pa n y t o fi n d o ut w hat t he y will pa y f or. Ta ki n g 
part i n t his st u d y ma y or ma y n ot c ost y o ur i ns ura nce c o m pa n y m ore t ha n t he c ost of getti n g 
re g ular ca ncer treat me nt. 
 
F or m ore i nf or mati o n o n cli nical trials a n d i ns ura nce c o vera ge, y o u ca n visit t he Nati o nal Ca ncer 
I nstit ute’s We b site at htt p:// w w w.ca ncer. g o v/cli nicaltrials/lear ni n ga b o ut . 
 
 


 
C A S E 6 8 1 9   
C o nse nt versi o n date  2 6 F E B 2 0 2 0  
1 0  
 
W h at h a p pe ns if I a m i nj ure d or h urt bec a use I t o o k p art i n t his st u d y ?  
 
If y o u belie ve t hat y o u are i nj ure d as a res ult of t he researc h pr oce d ures bei n g perf or me d, please 
i m me diatel y c o ntact t he st u d y d oct or. 
 
If i nj ur y occ urs as a res ult of y o ur i n v ol ve me nt i n t his researc h, me dical treat me nt is a vaila ble 
fr o m Cle vela n d  Cli nic  or a n ot her me dical facilit y b ut y o u/ y o ur me dical i ns ura nce will be 
res p o nsi ble f or t he c ost of t his treat me nt.  A researc h i nj ur y is a n i nj ur y t hat ha p pe ns as a res ult 
of ta ki n g part i n t his researc h st u d y.  If y o u are i nj ure d b y a me dical treat me nt or proce d ure t hat 
y o u w o ul d ha ve recei ve d e ve n if y o u were n’t i n t he st u d y, t hat is n ot c o nsi dere d a “researc h 
i nj ur y”. T here are n o pla ns f or pa y me nt of me dical e x pe nses or ot her pa y me nts, i ncl u di n g l ost 
wa ges, f or a n y researc h relate d i nj ur y.  T o hel p a v oi d i nj ur y, it is ver y i m p orta nt t o f oll o w all 
st u d y directi o ns. 
 
F urt her i nf or mati o n a b o ut researc h -relate d i nj uries is a vaila ble b y c o ntacti n g t he Cle vela n d  
Cli nic I nstit uti o nal Re vie w B oar d at ( 2 1 6) 4 4 4- 2 9 2 4. 
 
 
HI P A A A U T H O RI Z A TI O N  
A ut h oriz ati o n t o Use or Discl ose ( Rele ase) He alt h I nf or m ati o n t h at I de ntifies Y o u f or a 
Rese arc h St u d y   
 
If y o u v ol u nteer t o partici pate i n t his researc h, y o ur pr otecte d healt h i nf or mati o n ( P HI) t hat 
i de ntifies y o u will be use d or discl ose d t o M os he C. Or nstei n , M D  M A a n d  t he researc h st u d y 
staff at Cle vela n d Cli nic a n d/ or U ni versit y H os pitals f or t he p ur p oses of t his researc h a n d t o Case 
Wester n Reser ve U ni versit y f or a d mi nistrati o n.  
 
T he P HI t hat we ma y use or discl ose (release) f or t his researc h ma y i ncl u de y o ur na me, a d dress, 
p h o ne n u m ber, date of birt h, S ocial Sec urit y n u m ber, i nf or mati o n fr o m y o ur me dical rec or d, la b 
tests, or certai n i nf or mati o n relatin g t o y o ur healt h or c o n diti o n. 
 
S o me of t he tests a n d pr oce d ures d o ne s olel y f or t his researc h st u d y ma y als o be place d i n y o ur 
me dical rec or d s o ot her d oct ors k n o w y o u are i n t his st u d y.  U p o n c o m pleti o n of t he st u d y, y o u 
ma y ha ve access t o t he researc h i nf or mati o n t hat is c o ntai ne d i n y o ur me dical rec or d.   
 
I n a d diti o n t o t he i n vesti gat ors a n d researc h staff liste d a b o ve, y o ur P HI ma y be l o o ke d at b y 
ot her gr o u ps i n v ol ve d wit h t he st u d y s uc h as t he Cle vela n d Cli nic I nstit uti o nal Re vie w B oar d, 
a n d t he Case C o m pre he nsi ve Ca ncer Ce nter Pr ot oc ol Re vie w a n d M o nit o ri n g C o m mittee.  Y o ur 
P HI ma y als o be use d b y a n d/ or discl ose d (release d) t o: 
 
 Case C o m pre he nsi ve Ca ncer Ce nter me m bers a n d c olla b orat ors 
 T he F o o d a n d Dr u g A d mi nistrati o n; 
 T he De part me nt of Healt h a n d H u ma n Ser vices;  
 T he Nati o nal Ca ncer I nstit ute ( N CI);  
 Ot her I nstit uti o nal Re vie w B oar ds;  
 Data Safet y a n d M o nit ori n g B oar ds;  


 
C A S E 6 8 1 9   
C o nse nt versi o n date  2 6 F E B 2 0 2 0  
1 1  
 
 
O nce y o ur pers o nal healt h i nf or mati o n is release d it ma y be re- discl ose d a n d n o l o n ger pr otecte d 
b y pri vac y la ws.  
 
Y o ur researc h i nf or mati o n ma y be use d a n d discl ose d i n defi nitel y, b ut y o u ma y st o p t hese uses 
a n d discl os ures at a n y ti me b y writi n g t o: 
 
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 
9 5 0 0 E ucli d A ve.  
Cle vela n d, O H 4 4 1 9 5  
 
Y o ur partici pati o n i n t he researc h will st o p, b ut a n y i nf or mati o n pre vi o usl y rec or de d a b o ut y o u 
ca n n ot be re m o ve d fr o m t he rec or ds a n d will c o nti n ue t o be use d as part of t his researc h.  Als o, 
i nf or mati o n alrea d y discl ose d outsi de t he Cle vela n d Cli nic  ca n n ot be retrie ve d.  T his will n ot 
affect y o ur ri g hts t o treat me nt or be nefits o utsi de t he researc h st u d y.    
 
T he Cle vela n d Cl i nic will n ot use y o ur i nf or mati o n c ollecte d i n t his st u d y f or a n ot her researc h 
p ur p ose wit h o ut y o ur writte n per missi o n; u nless t he Cle vela n d Cli nic I nstit uti o nal Re vie w B oar d 
(I R B) ass ures y o ur pri vac y a n d c o nfi de ntialit y is pr otecte d.  T he I R B is a c o m mittee w h ose j o b it 
is t o pr otect t he safet y a n d welfare of researc h s u bjects. 
 
B y si g ni n g t his i nf or me d c o nse nt f or m, y o u are a ut h orizi n g s uc h access t o y o ur researc h a n d 
me dical rec or d i nf or mati o n.  If y o u c h o ose n ot t o si g n t his c o nse nt f or m, y o u will n ot be a ble t o 
partici pate i n t his researc h st u d y.  T his A ut h orizati o n d oes n ot ha ve a n e x pirati o n date. 
 
V ol u nt ar y P artici p ati o n  
Y o ur partici pati o n i n t his researc h st u d y is v ol u ntar y. C h o osi n g n ot t o partici pate will n ot alter 
y o ur us ual healt h care or i n v ol ve a n y pe nalt y or l oss of be nefits t o w hic h y o u are ot her wise 
e ntitle d. If y o u deci de t o j oi n t he st u d y, y o u ma y wit h dra w at a n y ti me a n d f or a n y reas o n 
wit h o ut pe nalt y or l oss of be nefits. If i nf or mati o n ge nerate d fr o m t his st u d y is p u blis he d or 
prese nte d, y o ur i de ntit y will n ot be re veale d.   
 
I n t he e ve nt ne w i nf or mati o n bec o mes a vaila ble t hat ma y affect t he ris ks or be nefits ass ociate d 
wit h t his st u d y or y o ur willi n g ness t o partici pate i n it, y o u will be n otifie d s o t hat y o u ca n deci de 
w het her or n ot t o c o nti n ue partici pati n g.   
 
Q uesti o ns a b o ut t he Rese arc h  
If y o u ha ve a n y q uesti o ns, y o u ca n as k t he Pri nci pal I n vesti gat or a n d/ or researc h staff at at 2 1 6-
4 4 4- 9 5 6 7.  
 
E mer ge nc y or after - h o urs c o ntact i nf or mati o n  
 
If y o u are a Cle vela n d Cli nic patie nt, y o u s h o ul d c o ntact t he pa ge o perat or at 
 or 
t oll free at
, a n d as k f or t he o nc ol o gist (ca ncer d oct or) t hat is o n call. 


C A S E 6 8 1 9   
C o nse nt versi o n date  2 6 F E B 2 0 2 0  
1 2  
W h ere C a n I Get M ore I nf or m ati o n ?  
If t he researc hers ca n n ot be reac he d, or if y o u w o ul d li ke t o tal k t o s o me o ne ot her t ha n t he 
researc her(s) a b o ut: c o ncer ns re gar di n g t he st u d y, researc h partici pa nt’s ri g hts; researc h-relate d 
i nj ur y; or ot her h u ma n s u bjects iss ues, y o u ma y c o ntact t he I nstit uti o nal Re vie w B oar d (I R B) at 
Cle vela n d Cli nic I R B 2 1 6- 4 4 4-.  
Y o u ma y call t he Nati o nal Ca ncer I nstit ute's Ca ncer I nf or mati o n Ser vice at:  
1- 8 0 0- 4- C A N C E R ( 1 - 8 0 0- 4 2 2- 6 2 3 7)
Y o u m a y als o visit t he N CI We b site at htt p://ca ncer. g o v/ 

F or N CI’s cli nical trials i nf or mati o n, g o t o: htt p://ca ncer. g o v/cli nicaltrials/

F or N CI’s ge neral i nf or mati o n a b o ut ca ncer, g o t o htt p://ca ncer. g o v/ca nceri nf o/
Y o u w ill get a c o p y of t his f or m.  If y o u wa nt m ore i nf or mati o n a b o ut t his st u d y, as k y o ur st u d y 
d oct or.   
U S  N ati o n al I nstit utes of He alt h ( NI H) Cli nic al Tri al D at a b ase:    
A descri pti o n of t his cli nical trial will be a vaila ble o n htt p:// w w w. Cli nical Trials. g o v , if 
a p plica ble, as re q uire d b y U. S. La w. T his We b site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y 
y o u. At m ost, t he We b site will i ncl u de a s u m mar y of t he res ults. Y o u ca n searc h t his We b site at 
a n y ti me. 
Si g n at ure  
Si g ni n g bel o w i n dicates t hat y o u ha ve bee n i nf or me d a b o ut t he researc h st u d y i n w hic h y o u 
v ol u ntaril y a gree t o partici pate; t hat y o u ha ve as ke d a n y q uesti o ns a b o ut t he st u d y t hat y o u ma y 
ha ve; a n d t hat t he i nf or mati o n gi ve n t o y o u has per mitte d y o u t o ma ke a f ull y i nf or me d a n d free 
decisi o n a b o ut y o ur partici pati o n i n t he st u d y.  B y si g ni n g t his c o nse nt f or m, y o u d o n ot wai ve 
a n y le gal ri g hts, a n d t he i n vesti gat or(s) or s p o ns or(s) are n ot relie ve d of a n y lia bilit y t he y ma y 
ha ve.  A c o p y of t his c o nse nt f or m will be pr o vi de d t o y o u. 
Si g nat ure of Partici pa nt 
Date  
Pri nte d Na me of Partici pa nt  
I have disc usse d t he i nf or mati o n c o ntai ne d i n t his d oc u me nt wit h t he partici pa nt a n d it is m y 
o pi ni o n t hat t he partici pa nt u n dersta n ds t he ris ks, be nefits, alter nati ves a n d pr oce d ures i n v ol ve d 
wit h t his researc h st u d y.  
Si g nat ure of Pers o n O btai ni n g C o nse nt 
Date  
Pri nte d Na me of Pers o n O btai ni n g C o nse nt