A Randomized, Multicenter, Two-Arm, Single-Dose, Double-Blind, Placebo-CONtrolled Phase 3 Study of Intravesical Qapzola™ (Apaziquone) as a Chemotherapy Adjuvant to TransUrEthral Resection of Bladder Tumors in Patients With Low- to Intermediate-Risk Non-Muscle Invasive Bladder Cancer (CONQUER)
Phase: PHASE3
Conditions: Bladder Cancer
Sponsor: Spectrum Pharmaceuticals, Inc

 
Offici al Titl e:  
 
A R a n d o miz e d, M ultic e nt er, T w o -Ar m, Si n gl e -D os e, D o u bl e - Bli n d, Pl ac e b o -
C O Ntr oll e d P h as e 3 St u d y of I ntr a v esic al Q a pz ol a ™ ( A p azi q u o n e) as a 
C h e m ot h er a p y A dj u v a nt t o Tr a ns Ur Et hr al  R es ecti o n of Bl a d d er T u m ors i n 
P ati e nts wit h L o w - t o I nt er m e di at e-Ris k N o n -M uscl e I n v asi v e Bl a d d er 
C a nc er  ( C O N Q U E R) 
 
N C T N u m b er:  
N C T 0 3 2 2 4 1 8 2  
 
D oc u m e nt  D at e : 
 
C li nic al St u dy Pr ot oc ol Ori gi n al : 2 2  D ec e m b er  2 0 1 6 
 
 
 
 
 
 
 
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 
 
 
C O N FI D E N TI A L 
C LI NI C A L S T U D Y P R O T O C O L 
TI T L E P A G E 
St u d y Title:  
A R a n d o miz e d, M ultice nter, T w o -Ar m, Si n gle -D ose, D o u ble -Bli n d, 
Pl ac e b o -C O N tr olle d P h ase 3 St u d y of I ntr a vesic al Q a pz ol a ™ 
( A p azi q u o ne) as a C he m ot her a p y A dj u v a nt t o Tr a nsU ret hr al 
Resecti o n of Bl a d der T u m ors i n P atie nts wit h L o w - t o 
I nter me di atE -R is k N o n-M uscle I n v asi ve Bl a d der C a ncer 
( C O N Q U E R) 
St u d y N u m ber:  
S PI -Q A P -3 0 6  
St u d y P h ase:  
P hase  3  
St u d y Dr u g:  
Qa pz ola ™ ( A pazi q u o ne) 
I N D N u m ber: 
7 3, 5 7 2  
S p o ns or(s):  
S pectr u m P har mace uticals, I nc.  
1 5 7 Tec h n ol o g y Dri ve  
Ir vi ne, C A, U S A 
 
Pr ot oc ol V ersi o n/ D ate:  
Ori gi nal/ 2 2  Dec  2 0 1 6  
 
T his st u d y is t o be c o n d u cte d acc or di n g t o U S a n d i nter nati o nal sta n dar ds of G o o d Cli nical 
Practice ( F D A Title 2 1 part 3 1 2 a n d I nter nati o nal C o nfere nce o n Har m o nizati o n g ui deli nes), 
a p plica ble g o ver n me nt re g ulati o ns a n d I nstit uti o nal researc h p olicies a n d pr oce d ures. 
 
C o nfi de nti alit y St ate me nt 
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt, partic ularl y u n p u blis he d d ata, is t he pr o pert y or 
u n der c o ntr ol of S pe ctr u m P har mace uticals, I n c. a n d is pr o vi de d t o y o u i n c o nfi de nce as a n 
I n v esti gat or, p ote ntial I n vesti gat or, or c o ns ulta nt, f or re vie w b y y o u, y o ur staff, a n d a n a p plica ble 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee. T he i nf or mati o n is o nl y t o b e use d b y y o u i n 
c o n necti o n wit h a ut h orize d cli nical st u dies of t he i n vesti gati o nal dr u g d escri be d i n t he pr ot oc ol. 
Y o u will n ot discl ose a n y of t he i nf or mati o n t o ot hers wit h o ut writte n a ut h orizati o n fr o m 
S pectr u m P har mace uticals, I nc. e x ce pt t o t he e xte nt necessar y t o o btai n I nf or me d C o nse nt fr o m 
t h ose pers o ns t o w h o m t he dr u g ma y be a d mi nistere d. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 
I N V E S TI G A T O R SI G N A T U R E  
 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
A R a n d o miz e d, M ultice nter, T w o- Ar m, Si n gle- D ose, D o u ble- Bli n d, Pl ace b o- C O Ntr olle d 
P h ase 3 St u d y of I ntr a vesic al Q a pz ol a ™ ( A p azi q u o ne) as a C he m ot her a p y A dj u v a nt t o 
Tr a ns Uret hr al Res ecti o n of Bl a d der T u m ors i n P ati e nts wit h L o w- t o I nter me di at E- Ris k 
N o n- M uscle I n v asi ve Bl a d der C a ncer ( C O N Q U E R) 
I h a ve rea d t his pr ot oc ol a n d a gree t hat it c o ntai ns all t he necess ar y details f or perf or mi n g t he 
st u d y i n acc or da n ce wit h t he Declarati o n of Helsi n ki a n d t he I nter n ati o nal C o nfere n ce o n 
Har m o nizati o n (I C H) f or G o o d Cli nical Practice ( G C P). 
I will pr o vi de c o pies of t he pr ot oc ol a n d of t h e cli nical a n d precli nical i nf or mati o n o n t he 
i n vesti gati o nal pr o d u ct, w hic h was f ur nis he d t o me b y t he S p o ns or ( S pectr u m P har mace uticals, 
I n c.), t o all me m bers of t he st u d y te a m res p o nsi bl e t o me w h o partici pat e i n t he st u d y. I will 
disc uss t his material wit h t he m t o ass ure t hat t he y are f ull y i nf or m e d re gar di n g t he st u d y dr u g 
a n d t he c o n d uct of t h e st u d y. 
I will perf or m t he st u d y acc or di n g t o s pecifi cati o ns o utli ne d i n t he pr ot oc ol a n d a gree t o 
i m ple me nt pr ot oc ol re q uire me nts o nl y after t he pr ot oc ol a n d patie nt i nf or m ati o n/I nf or me d 
C o nse nt f or m ha ve bee n a p pr o ve d b y t he I nstit uti o nal Re vie w B o ar d/ Et hics C o m mittee 
(I R B/ E C). I will s u b mit a n y pr ot oc ol m o dificati o ns (a me n d me nts) a n d/ or a n y I nf or me d C o nse nt 
f or m m o dificati o ns t o t he I R B/ E C, a n d a p pr o val will be o btai ne d bef ore a n y m o dificati o ns are 
i mple me nte d. 
I u n d ersta n d t hat t he i nf or mati o n prese nte d i n t his st u d y pr ot oc ol is c o nfi d e ntial, a n d I h ere b y 
ass ure t hat n o i nf or mati o n base d o n t he c o n d u ct of t he st u d y will be releas e d wit h o ut pri or 
c o nse nt fr o m S pectr u m P har mace uticals, I nc., u nl ess t his re q uire me nt is s u perse de d b y a 
re g ulat or y a ut h orit y (e g, F D A). 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I n vesti g at or N a me ( P L E A S E P RI N T):  
 
Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 
S Y N O P SI S 
Title of St u d y: A Ra n d o mize d, M ultice nter, T w o -Ar m , Si n gle -D ose , D o u ble-Bli n d , Place b o-C O N tr olle d P hase 
3 St u d y of I ntra vesical Q a p z ol a ™ (A pazi q u o ne ) as a C he m ot hera p y  A dj u va nt t o Tra ns U ret hral Resecti o n of 
Bla d der T u m ors i n P atie nts wit h L o w - t o I nter me diatE -R is k N o n -M uscle I n vasi ve Bla d der Ca ncer  
(C O N Q U E R ) 
N a me of S p o ns or: S pectr u m P har mace uticals, I nc . 
N a me of I n vesti g ati o n al Pr o d uct:  Qa p z ola ™ (apazi q u o ne ) 
Pl a n ne d N u m ber of P atie nts:  A p pr o xi matel y 5 0 0  patie nts will be e nr olle d t o o btai n 4 2 5  tar get disease  patie nts  
i n t w o treat me nt ar ms. 
St u d y Ce nters:  A p pr o xi matel y 7 0  st u d y ce nters gl o ball y.  
D ur ati o n of St u d y : A p pr o xi matel y 5  years ( 2 . 5 years accr ual + 2. 5  years f oll o w -u p )  
Cli nic al P h ase:  3  
O B J E C TI V E S:  
Pri m ar y O bjecti ve(s)  
 
T o e val uate t he Ti me t o Rec urre nce i n patie nts wit h l o w - t o i nter me diate-ris k n o n-m uscle i n vasi ve 
bla d der ca ncer ( N MI B C) w h o recei ve eit her 8  m g  Qa p z ola  or place b o p ost t ra ns uret hral resecti o n of 
bla d der t u m or (T U R B T ).  
Sec o n d ar y O bjecti ves  
T o e val uate t he f oll o w in g i n p atie nts wit h l o w- t o i nter me diate-ris k N MI B C w h o recei ve eit her 8 m g  Qa p z ola or 
place b o p ost -T U R B T:  
1.  2 -Year Rec urre nce Rate  
2.  E xte nt of Disease at Rec urre n ce  ( n u m ber, a n d l ocati o n of t u m ors) 
3.  Ti me t o Disease Pr o gressi o n  ( base d o n t he t u m or sta ge) 
4.  S afet y  
S T U D Y D E SI G N  A N D T R E A T M E N T P L A N : 
T his is a ra n d o mize d, m ultice nter, t w o-ar m, d o u ble -bli n d, place b o -c o ntr olle d st u d y of Qa pz ola  i n patie nts wit h 
l o w- t o i nter me diate-ris k N MI B C, assesse d acc or di n g t o t he 2 0 1 6 A merica n Ur ol o g y Ass ociati o n ( A U A) 
G ui deli nes . S pecificall y, o nl y patie nts wit h t u m or c haracteristics i n b ol d te xt  i n t he l o w- t o i nter me diate-ris k 
c ol u m ns of t he ta ble bel o w will be i ncl u de d i n t he st u d y.  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
5 
D ur ati o n of St u d y:  T he d urati o n of t he st u d y  f or eac h patie nt will be as f oll o ws : 
 
Scree ni n g Peri o d:  u p t o 3 0 -da y s  
 
Tre at me nt : Da y 1   
 
S afet y F oll o w -u p : Da y 3 5 ( ± 5 da ys)  ( n o n-T ar get P o p ulati o n) or M o nt h 3 F oll o w -u p  Visit ( T ar get 
P o p ulati o n)  
 
F oll o w -u p Peri o d:  N o f oll o w -u p i n n o n -T ar get P o p ulati o n. U ntil eit her a c o nfir me d t u m or rec urre nce or 
t he E n d -of -St u d y , w hic he ver occ urs first i n T ar get P o p ulati o n. 
P atie nt Re pl ace me nt Str ate g y:  If a patie nt is c o nfir me d t o ha ve  n o n -tar get disease  after T U R B T , t he patie nt 
will n ot be c o nsi dere d e val ua ble f or a nal ysis. E nr oll me nt will c o nti n ue u ntil t he st u d y reac hes t he re q uire d 
n u m ber of tar get-disease e val ua ble patie nts.   
I N C L U SI O N & E X C L U SI ON C RI T E RI A:  
I ncl usi o n Criteri a: 
1.  P atie nt m ust ha ve a  cli nical di a g n os is of  l o w- t o i nter me diat e-ris k n o n-m uscle i n vasi ve bla d der ca ncer 
acc or di n g t o t he 2 0 1 6 A meric a n Ur ol o gical Ass ociati o n ( A U A) G ui deli nes  
2.  P atie nt m ust b e willi n g t o gi ve writte n i nf or me d c o nse nt a n d m ust be a ble t o a d here t o d osi n g a n d visit 
sc he d ules, a n d meet all st u d y r e q uire me nts. 
3.  P atie nt is at least 1 8 years of a ge a n d < 9 0 years of a ge  at t he ti me I nf or me d C o nse nt is si g ne d. 
4.  P atie nt m ust b e  willi n g t o practice t w o f or ms of c o ntrace pti o n, o ne of w hic h m ust be a barrier met h o d, 
fr o m st u d y e ntr y u ntil at least 3 5  da ys  after st u d y treat me nt. P atie nts s ur gicall y sterilize d  or w h o are 
p ost me n o pa usal f or at least 1 year ( defi ne d as m ore t ha n  1 2  m o nt hs  si nce last me nses) d o n ot re q uire 
c o ntrace pti o n.  
5.  Fe males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test wit hi n 3 0 da ys  pri or t o 
ra n d o mizati o n. Fe males w h o are p ost me n o pa usal f or at least 1 year ( defi ne d as m ore t ha n 1 2  m o nt hs  
si nce last me nses) or are s ur gi call y sterilize d d o n ot re q uire t his test.  
E xcl usi o n Criteri a:  
1.  P atie nt  has mali g na nc y or life -t hreate ni n g s yste mic disease or a hist or y of a d va nce d, seri o us, life-
t hreate ni n g mali g na nc y/ diseas e wit hi n t he last 5 yea rs, e xcept ver y l o w-ris k pr ostate ca nc er 
2.  P atie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gics ( vacci nes, a nti b o dies), or de vices wit hi n 3 0 da ys 
pri or t o st u d y treat me nt or has pla ns t o use a n y of t hese d uri n g t he c o urse of t he st u d y  
3.  P atie nt has recei ve d a n y pel v i c ra di ot hera p y (i ncl u di n g e xter nal bea m a n d/ or brac h yt hera p y). 
4.  P atie nt has a hist or y of aller g y t o re d c ol or f o o d d ye or a n y ot her c o m p o ne nt of Qa p z ola, place b o, or 
t heir dil ue nt s  
5.  P atie nt has ha d a s ur gical pr oce d ure 4 wee ks pri or t o T U R B T or will ha ve  o t her s ur gical pr oce d ures 
perf or me d  at t he ti me of T U R B T or  wit hi n 4  wee ks after  T U R B T  
6.  P atie nt has a n y u nsta ble or u nc o ntr olle d me dical c o n diti o n t hat w o ul d ma ke it p ote ntiall y u nsafe t o 
u n der g o T U R B T i ncl u di n g a pre vi o us str o ke or m y ocar dial i nfarcti o n wit hi n 6  m o nt hs  
7.  P atie nt has a n acti ve u nc o ntr olle d i nfecti o n, i ncl u di n g a uri nar y tract i nfecti o n, u n derl yi n g me dical 
c o n diti o n, or ot her seri o us ill ness t hat w o ul d i m pair t he a bilit y of t he patie nt t o recei ve st u d y treat me nt 
or  u n der g o st u d y pr oce d ures   
8.  P atie nt has a blee di n g dis or der or a scree ni n g platelet c o u nt  < 1 0 0 × 1 0 9/ L, or re q uires c o nti n u o us 
a ntic oa g ulati o n or bri d gi n g a ntic oa g ulati o n d uri n g t he pr oce d ure   
9.  P atie nt has a he m o gl o bi n  val ue  < 1 0  g/ d L  at Scree ni n g  
1 0.  P atie nt has e ver ha d c o nfir me d e xtra vesi cal ur ot helial disease ( u p per tract  a n d  uret hral  i ncl u di n g 
pr ostatic uret hral ) 
1 1.  P atie nt wit h a hist or y of pre vi o us bla d der ca ncer:  
 
Hi g h -Ris k N MI B C as classifi e d per t he 2 0 1 6 A U A G ui deli nes  
 
Bla d der ca ncer t hat was m uscl e i n vasi ve or p ositi ve f or l y m p h n o de or dista nt metastasis  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
6 
1 2.  P atie nt has recei ve d a n y pre vi o us i ntra vesical t hera p y f or bla d der ca ncer - c he m ot hera p y, 
i m m u n ot hera p y, or pre vi o us e x p os ure t o Qa p z ola i n t he last 3 years 
1 3.  P atie nt has a t u m or i n t he bla d der di vertic ul u m 
1 4.  P atie nt has a hist or y of i nterstitial c ystitis 
1 5.  P atie nt is pre g na nt or breast -fe e di n g  
D O S E A N D R O U T E O F A D MI NI S T R A TI O N:  
O ne d ose of eit her 8  m g /5 0 m L  Qa p z ola  or v ol u me a n d a p peara nce matc he d place b o will be a d mi nistere d b y 
i ntra vesical a d mi nistrati o n i nt o t he bla d der  at 6 0  ±  3 0 mi n utes p ost  T U R B T ( Da y 1)  via a n i n d welli n g 1 0 0 % 
Silic o ne F ole y cat heter  a n d will be retai ne d i n t he bla d der f or 6 0 ±  5 mi n utes .  
E F FI C A C Y A S S E S S M E N T S : 
C yst osc o pic e xa mi nati o n  a n d uri ne c yt ol o g y  test e ver y 3  m o nt hs  ( ±3 0 da ys) (calc ulate d fr o m date of T U R B T) 
f or t he first 2  years  f or t u m or r ec urre nce a n d pr o gressi o n a n d t he n e ver y 6  m o nt hs  (± 6 0  da ys ) u ntil eit her a 
c o nfir me d t u m or rec urre nce or t he E n d -of -St u d y , w hic he ver occ urs first. P at h ol o g y re vie w will be perf or me d b y  
l ocal la b orat ories o n tiss ue/t u m or s peci me ns fr o m c yst osc o p y or  T U R B T , w hic he ver is c o n d ucte d f or t he 
f oll o w-u p assess me nt . 
Pri m ar y E n d p oi nt:  
 
Ti me t o Rec urre nce  i n patie n ts wit h l o w- t o i nter me diate-ris k N MI B C w h o recei ve eit her 8  m g  Qa p z ola  
or place b o f oll o wi n g T U R B T . 
T he p ri mar y a nal ysis will be c o n d ucte d o nce a t otal of 2 0 8 rec urre nce e ve nts ha ve occ urre d i n t he st u d y.  
Sec o n d ar y E n d p oi nts:  
1.  2 -Year Rec urre nce Rate  
2.  E xte nt of Disease at Rec urre n ce  ( n u m ber a n d l ocati o n of t u m ors)  
3.  Ti me t o Disease Pr o gressi o n  (base d o n t he t u m or sta ge ) 
4.  Safet y   
S A F E T Y A S S E S S M E N T S:  
Safet y will be assesse d b y re p orte d/elicite d a d verse e ve nts ( A Es ), la b orat or y test assess me nts, a n d p h ysical 
e xa mi nati o ns.  
S afet y E n d p oi nts  
 
All A Es  
 
Treat me nt -relate d a d verse e ve nts  
 
Seri o us A d verse E ve nts ( S A Es)  
 
A Es lea di n g t o disc o nti n uati o n  
 
A Es of s pecial i nterest ( ≥gra d e 3 d ys uria a n d he mat uria)  
 
Vital si g ns (b o d y te m perat ure, bl o o d press ure a n d heart rate ) a n d r o uti ne la b orat or y test para meters 
(c o m plete bl o o d c o u nt a n d bl o o d c he mistr y) 
 
Deat hs  
A d verse E ve nt a n d Seri o us A d verse E ve nt Re p orti n g:  
Fr o m t he ti me t he st u d y I nf or me d C o nse nt is si g ne d t hr o u g h t he da y of st u d y dr u g a d mi nistrati o n, o nl y S A Es 
t hat are relate d t o st u d y pr oce d ures are t o be rec or de d. F or all n o n -T ar get p o p ulati o n  patie nts, a ll a d verse e ve nts 
fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil Da y 3 5 ( ± 5  da ys ) p ost -T U R B T  will be rec or de d . F or T ar get 
p o p ulati o n  patie nts , all a d vers e e ve nts will be rec or de d fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil t he 
3 -m o nt h F oll o w -u p Visit . O nl y deat hs a n d A Es relate d t o st u d y pr oce d ures will be rec or de d  f or t he re mai n der of 
t he f oll o w-u p peri o d . 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
7 
I n de pe n de nt D at a M o nit ori n g C o m mittee (I D M C) 
T he safet y of t he 8  m g / 5 0 m L Qa p z ola  d ose will be e val uate d  b y a n I D M C  f or t he first 30 patie nts treate d  i n t he 
st u d y. C o nti n uati o n of t he st u d y at t his d ose le vel will be deter mi ne d base d o n t he I D M C e val uati o n. T he I D M C 
is als o res p o nsi ble f or t he re vi e w of t he u n bli n de d f utilit y a nal ysis.   
S T A TI S TI C A L M E T H O D S:  
T he pri mar y a nal ysis p o p ulati o n is t he T ar get P o p ulati o n , w hic h will c o nsist of all patie nts wit h c o nfir me d l o w- 
t o i nter me diate-ris k N MI B C. T he sta ge a n d gra de deter mi nati o n f or t he T ar get  P o p ulati o n will c o me fr o m  t he 
pat h ol o g y re vie w. T u m ors will b e gra de d usi n g 2 0 0 4 W H O/I S U P criteria.  
T he Safet y P o p ulati o n i ncl u des all patie nts w h o ha ve ha d a  T U R B T a n d ha ve recei ve d treat me nt of st u d y dr u g 
(Qa p z ola  or place b o).  
T he e nr olle d patie nts will be  ra n d o mize d i n a 2 : 1 rati o t o eit her Qa p z ola  or  place b o . T he p ri mar y e n d p oi nt is 
Ti me t o Rec urre nce  i n t he T ar get P o p ulati o n. T he pri mar y e n d p oi nt a nal ysis i n v ol ves a test of c o m paris o n: 8  m g  
Qa p z ola  vs. place b o usi n g 2 -si de d l o g-ra n k test at 5 % le vel of si g nifica nce.  
T he Ti me t o Rec urre nce is defi ne d as ti me fr o m Da y 1 Treat me nt t o t he date of t he first hist ol o gicall y c o nfir me d 
rec urre nce ( usi n g t he date of c orres p o n di n g c yst osc o p y) of t he patie nt’s bla d der t u m or.  P atie nts wit h o ut 
recurre nce at t he ti me of t he pri mar y  a nal ysis will be ce ns or e d at t he last a vaila ble  date of c yst osc o p y . P atie nts 
w h o die d d ue t o a n y ca use bef ore c o nfir me d rec urre nce will be ce ns ore d at t he last a vaila ble date of c yst osc o p y.   
T he f oll o wi n g se nsiti vit y a nal yses will be perf or me d f or t he pri mar y a nal ysis.  
1.  A nal ysis of ti me t o rec urre nce b y e xcl u di n g patie nts w h o miss 2 c o nsec uti ve c yst osc o pies or l ost t o 
f oll o w-u p  eit her pri or t o rec urre nce or pri or t o t he date of t he pri mar y  a nal ysis –  C o m pleter a nal ysis  
2.  A nal ysis of ti me t o rec urre nce b y e xcl u di n g patie nts w h o miss 2 c o nsec uti ve c yst osc o p ies or l ost t o 
f oll o w-u p  eit her  pri or t o rec urre nce or pri or t o patie nt’s f oll o w -u p d urati o n of 2 4  m o nt hs  –  C o m pleter 2 4 
M o nt h a nal ysis  
3.  A nal ysis of ti me t o rec urre nce b y c o nsi deri n g patie nts wit h n o rec urre nce w h o miss 2 c o nsec uti ve 
c yst osc o pies or l ost t o  f oll o w-u p pri or t o date of t he pri mar y  a nal ysis as rec urre d.  
T he pri mar y a nal ysis will be c o n d ucte d usi n g a hierarc hical pr oce d ure of h y p ot hesis testi n g  at a 5 % le vel of 
si g nifica nce. T he pri mar y e n d p oi nt , Ti me t o Rec urre nce , will be e xa mi ne d first, a n d if si g nifica nt, t he sec o n dar y 
e n d p oi nt , 2 -Year Rec urre nce Rate , will be e xa mi ne d ne xt, a n d if als o si g nifica nt, E xte nt of Disease at 
Rec urre nce, a n d Ti me t o Dise ase Pr o gressi o n will t he n be e xa mi ne d  i n t hat or der. 
A p pr o xi matel y 5 0 0  patie nts will be e nr olle d a n d treate d i n t his st u d y. Accr ual ti me is esti mate d as 2 4  m o nt hs  
a n d f oll o w-u p ti me as a p pr o xi matel y 2 4  m o nt hs . F or t he sa m ple size calc ulati o n, a hazar d rati o ( H R) of 0. 6 5 is 
ass u me d f or t he i m pr o ve me nt i n T i me t o R ec urre nce i n fa v or of Qa p z ola as c o m p are d t o t he place b o  wit h a 
hazar d rate of 0. 3  i n place b o ar m. I n a 2: 1 ra n d o mizati o n of Qa p z ola a n d place b o, sa m ple sizes of 2 8 4 i n A P Z 
a n d 1 4 1 i n P B O T ar get diseas e  patie nts  (t otal of 4 2 5) will pr o vi de 8 5 % p o wer. T his sa m pl e size is esti mate d t o 
pr o vi de  a t otal of 2 0 8 rec urre nce e ve nts d uri n g t he f oll o w-u p  d urati o n of at least 2 4  m o nt hs . T he pri mar y  
a nal ysis will be c o n d ucte d o nc e a t otal of 2 0 8 rec urre nce e ve nts are o bser ve d.  T he e ve nts will be m o nit ore d i n a 
bli n de d fas hi o n re gar dless of t he treat me nt as si g n me nt t o deter mi ne t he ti mi n g of t he pri mar y a nal ysis. All 
sec o n dar y e n d p oi nt a nal yses will b e c o n d ucte d at t he ti me of t he pri mar y a nal ysis.   
Si nce t he T ar get p o p ulati o n is c o nfir me d b y t he pat h ol o g y re vie w a n d t his will be perf or me d after patie nts are  
ra n d o mize d a n d ha ve u n der g o ne T U R B T pr oce d ure, t he st u d y will acc o u nt f or misclassifi cati o n i n T ar get 
disease p o p ulati o n.  Acc o u nti n g f or 1 5 % misclassificati o n of ra n d o mize d patie nts, t he st u d y will e nr oll 
a p pr o xi matel y 5 0 0 patie nts. H o we ver, t he st u d y wil l c o nti n ue t o e nr oll patie nts u ntil t he re q uire d n u m ber of 
T ar get disease patie nts are accr ue d.   
A f utilit y a nal ysis will be perf or me d d uri n g t he st u d y c o n d uct t o deter mi ne t he st u d y c o nti n uati o n. T he f utilit y 
a nal ysis will be c o n d ucte d i n t he T ar get patie nts o nce 6 0 e ve nts are o bser ve d. T he st u d y will be st o p pe d f or 
f utilit y if t he calc ulate d z-val ue fr o m t he l o g -ra n k test of H R is > 1. 0. N o a dj ust me nt f or m ulti plicit y of 
c o m paris o n will be ma d e f or f utilit y a nal ysis a n d t he fi nal a nal ysis will be perf or me d at 5 % le vel of si g nifica nce.  
T he i nteri m a nal ysis will als o be use d t o deter mi ne if a d diti o nal s u bj ects s h o ul d be r ecr uite d t o ens ure t hat 
e n o u g h e ve nts w o ul d be acc u m ulate d at a p pr o xi matel y 2 -ye ar  f oll o w-u p  fr o m dr u g i nstillati o n. Base d o n t he 
e x pecte d e ve nts of 2 0 8 o ut of 4 2 5 s u bj ects after 2 -year f oll o w-u p , we a ntici pate t hat t he first 1 2 3 s u bj ects s h o ul d 
ha ve c o m plete d  2 -year f oll o w-u p  visits at t he f utilit y a nal ysis w he n 6 0 e ve nts are o bser ve d. H o we ver, if l o wer 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
8 
o verall rec urre nce rate is o bser ve d, a d diti o nal patie nts i n t he T ar get P o p ulati o n  will be recr uite d i n or der t o 
accr ue re q uire d n u m ber of e ve nts.  
T he i nte ri m a nal ysis will be perf or me d b y a n I n de pe n de nt D ata M o nit ori n g C o m mittee (I D M C)  t hat will ha ve 
access t o t he u n bli n de d data. T he st u d y tea m will be bli n de d t o t he treat me nt all ocati o n d uri n g t he f oll o w -u p 
peri o d.   
All treat me nt -e mer ge nt a d vers e e ve nts wi ll be gra de d acc or di n g t o Nati o nal Ca ncer I nstit ut e C o m m o n 
T er mi n ol o g y Criteria f or A d verse E ve nts ( N CI C T C A E) versi o n 4. 0 3 , a n d gr o u pe d b y t he Me d D R A S yste m 
Or ga n Class a n d P referre d T er m, a n d s u m marize d b y w orst gra de se verit y per patie nt.  
Ori gi n al Pr ot oc ol:  2 2  Dec  2 0 1 6  
 
 
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
9 
St u d y Fl o w C h art 
 
 
 
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 1  
T A B L E O F C O N T E N T S 
TI T L E P A G E ................................................................................................................................. 1  
I N V E S TI G A T O R SI G N A T UR E  .................................................................................................. 2 
S Y N O P S I S ...................................................................................................................................... 3 
T A B L E O F C O N T E N T S ............................................................................................................ 1 1  
List of Fi g ures ......................................................................................................................... 1 4  
LI S T O F A B B R E VI A TI O N S A N D D E F I NI TI O N S O F T E R M S .......................................... 1 5 
1  
I N T R O D U CTI O N A N D B A C K G R O U N D ........................................................................ 1 7  
1. 1  
N o n- M uscle I n v asi ve Bl a d der C a ncer ..................................................................... 1 7  
1. 2  
Q a pz ol a f or I ntr a vesic al I nstill ati o n ........................................................................ 1 7  
1. 3  
Cli n ic al St u dies wit h Q a pz ol a ................................................................................... 1 8 
1. 3. 1  
Cli n ic al Effic ac y of Q a pz ol a ............................................................................. 1 8 
1. 3. 1. 1  
2 - Y e ar Rec urre nce R ate ................................................................................ 1 9 
1. 3. 1. 2  
Ti m e t o Rec urre nce ....................................................................................... 1 9  
1. 3. 1. 3  
Ot h er Sec o n d ary Effic acy P ar a m eters ......................................................... 2 1  
1. 3. 1. 4  
Ti m e t o I nstill ati o n ........................................................................................ 2 1  
1. 3. 2  
Cli n ic al S afet y of Q a pz ol a ................................................................................. 2 2 
1. 4  
St u d y R ati o n ale .......................................................................................................... 2 3  
2  
S T U D Y O B J E C TI V E S ........................................................................................................ 2 6  
2. 1  
Pri m ar y O bjecti ve(s) ................................................................................................. 2 6  
2. 2  
Sec o n d ar y O bjecti ves................................................................................................. 2 6  
3  
I NV E S TI G A TI O N A L P L A N .............................................................................................. 2 6  
3. 1  
St u d y Desi g n a n d Tre at me nt Pl a n............................................................................ 2 6  
3. 2  
St u d y D ur ati o n ........................................................................................................... 2 7  
4  
P A TI E N T P O P U L A TI O N ................................................................................................... 2 8  
4. 1  
I ncl usi o n Criteri a ....................................................................................................... 2 8 
4. 2  
E x cl usi o n Criteri a ...................................................................................................... 2 8  
4. 3  
P ati e nt Disc o nti n u ati o n/ Wit h dr a w al Criteri a ......................................................... 2 9  
5  
S T U D Y P R O C E D U R E S ...................................................................................................... 2 9  
5. 1  
Scree ni n g ..................................................................................................................... 3 0  
5. 2  
P ati e nt Assi g n me nt .................................................................................................... 3 1  
5. 3  
Ti mi n g of Assess me nts a n d Pr oce d ures ................................................................... 3 1 
5. 3. 1  
S cree ni n g ............................................................................................................ 3 1  
5. 3. 2  
Tre at me nt Peri o d: Visit 1 ( D a y 1) .................................................................... 3 2  
5. 3. 3  
S afet y F oll o w- u p Visit: Visit 2 ( D a y 3 5 [ ± 5 d a ys] p ost- T U R B T ( n o n- T ar get 
p atie nt p o p ul ati o n) or Visit 3 ( M o nt h 3 F oll o w- u p Visit) ( T ar get p atie nt 
p o p ul ati o n) ....................................................................................................... 3 2  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 2  
5. 3. 4  
L o n g- Ter m F oll o w- u p Visits - Visits 3 t hr o u g h 1 0 ( Fi rst 2 Ye a rs: E ver y 
3 m o nt hs [ ± 3 0 d a ys] P ost- T U R B T) a n d Visits 1 1 t hr o u g h 1 6 ( Ye ars 3- 5: 
E ver y 6 m o nt hs [ ± 6 0 d a ys]) ............................................................................ 3 2  
5. 4  
Descri pti o n of St u d y Assess me nts a n d Pr o ce d ures................................................. 3 3  
5. 4. 1  
E x pl ai n St u d y a n d O bt ai n Writte n I nf or me d C o nse nt.................................. 3 3  
5. 4. 2  
M e dic al Hist or y ................................................................................................. 3 3  
5. 4. 3  
Re vie w I ncl usi o n/ E xcl usi o n Criteri a ............................................................... 3 3  
5. 4. 4  
P h ysic al E x a mi n ati o n ........................................................................................ 3 3  
5. 4. 5  
Vit al S i g n Assess me nts ...................................................................................... 3 3 
5. 4. 6  
Cli n ic al L a b or at or y Tests ................................................................................. 3 3 
5. 4. 7  
Ur i ne C yt ol o g y ................................................................................................... 3 4 
5. 4. 8  
C yst osc o p y .......................................................................................................... 3 4  
5. 4. 9  
T U R B T ............................................................................................................... 3 4  
5. 4. 1 0  
A d ver se E ve nt .................................................................................................... 3 5 
5. 4. 1 1  
C o nc o mit a nt Me dic ati o ns ................................................................................. 3 5  
6  
S T U D Y D R U G A N D P H A R M A C E U TI C A L I N F O R M A TI O N ..................................... 3 5  
6. 1  
Q a pz ol a a n d Pl ace b o.................................................................................................. 3 5  
6. 1. 1  
C o m p ositi o n of Q a pz ol a .................................................................................... 3 5  
6. 1. 2  
C o m p ositi o n of Pl ace b o ..................................................................................... 3 5  
6. 1. 3  
C o m p ositi o n of Dil ue nt f or Q a pz ol a a n d Pl ace b o .......................................... 3 5  
6. 1. 4  
S hi p pi n g a n d St or a ge of St u d y Dr u g ............................................................... 3 6  
6. 2  
D ose, R o ute of A d mi nistr ati o n, a n d Sc he d ule of St u d y Dr u g................................ 3 6  
6. 2. 1  
D ose  a n d R o ute of A d mi nistr ati o n of St u d y Dr u g ......................................... 3 6 
6. 2. 2  
S c he d ule of St u d y Dr u g A d mi nistr ati o n ......................................................... 3 6  
6. 2. 2. 1  
Pre p ar ati o n of St u dy Dr u g ............................................................................ 3 6  
6. 2. 2. 2  
I nstill ati o n of St u dy Dr u g ............................................................................. 3 6 
6. 3  
Dis p os al of St u d y Dr u g .............................................................................................. 3 7  
6. 4  
P r o d uct Acc o u nt a bilit y .............................................................................................. 3 7  
6. 5  
Tre at me nt Bli n di n g Pr oce d ures ............................................................................... 3 7  
6. 6  
R a n d o miz ati o n ........................................................................................................... 3 8  
6. 7  
N o n- St u d y Tre at me nts  .............................................................................................. 3 8 
6. 7. 1  
P ri o r a n d C o nc o mit a nt Me dic ati o ns ............................................................... 3 8  
6. 7. 2  
P r o hi bite d Me dic ati o ns ..................................................................................... 3 8  
7  
S A F E T Y A S S E S S M E N T ..................................................................................................... 3 8  
7. 1  
S afet y Me as ures ......................................................................................................... 3 8  
7. 2  
A d verse E ve nts ........................................................................................................... 3 9  
7. 3  
G ui deli nes f or Rec or di n g a n d Attri b u ti o n Sc ori n g of A d verse E ve nts ................ 4 0 
7. 3. 1  
Re c or di n g of A d verse E ve nts ........................................................................... 4 0  
7. 3. 2  
Gr a di n g of A d verse E ve nts ............................................................................... 4 0  
7. 4  
F oll o w- u p of A d verse E ve nts .................................................................................... 4 0  
7. 5  
Rel ati o ns hi p ................................................................................................................ 4 1  
7. 6  
E x pecte d ness ............................................................................................................... 4 1  
7. 7  
Se ri o us A d verse E ve nts ............................................................................................. 4 1  
7. 7. 1  
S eri o us A d verse E ve nt Re p o rti n g .................................................................... 4 2  
7. 7. 2  
E xcl usi o ns t o Seri o us A d verse E ve nt Re p orti n g Re q uire me nts .................... 4 3  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 3  
7. 8  
Re pr o d ucti ve Ris ks .................................................................................................... 4 3  
8  
S T A TI S TI C A L D E SI G N A N D A N A L Y SI S ...................................................................... 4 3  
8. 1  
S a m ple Size ................................................................................................................. 4 3  
8. 2  
Met h o d of Tre at me nt Assi g n me nt, R a n d o miz ati o n ............................................... 4 4  
8. 3  
A n al ysis P o p ul ati o ns .................................................................................................. 4 5  
8. 4  
G e ner al St atistic al Met h o ds ...................................................................................... 4 5  
8. 5  
Effic ac y A n al yses ....................................................................................................... 4 5  
8. 5. 1  
E ffic ac y Assess me nts ......................................................................................... 4 5 
8. 5. 2  
P ri m ar y E n d p oi nt .............................................................................................. 4 5  
8. 5. 3  
S ec o n d ar y E n d p oi nts ......................................................................................... 4 6  
8. 5. 4  
De fi niti o ns .......................................................................................................... 4 6 
8. 5. 5  
P ri m ar y E n d p oi nt - Ti me t o Rec urre nce ........................................................ 4 6  
8. 5. 6  
S ec o n d ar y E n d p oi nts ......................................................................................... 4 7  
8. 5. 6. 1  
2 - Y e ar Rec urre nce R ate ................................................................................ 4 7 
8. 5. 6. 2  
E xte nt of Dise ase at Rec urre nce ................................................................... 4 7  
8. 5. 6. 3  
Ti m e t o Dise ase Pr o gressi o n ......................................................................... 4 7  
8. 6  
S afet y E v al u ati o n ....................................................................................................... 4 7  
8. 6. 1  
S afet y E n d p oi nts ................................................................................................ 4 7  
8. 6. 1. 1  
A dverse Eve nts ............................................................................................... 4 8  
8. 6. 1. 2  
De at hs ............................................................................................................ 4 8  
8. 6. 2  
Ot h er Seri o us A d verse E ve nts .......................................................................... 4 8  
8. 6. 3  
Cli n ic al L a b or at or y E v al u ati o ns ...................................................................... 4 8 
9  
A D MI NI S T R A TI V E P R O C E D U R E S A N D S T U D Y M A N A G E M E N T ........................ 4 8  
9. 1  
I n vesti g at or Res p o nsi bilities ..................................................................................... 4 8 
9. 1. 1  
G o o d Cli nic al Pr a ctice ...................................................................................... 4 8  
9. 1. 2  
I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee A p pr o v al .............................. 4 8 
9. 1. 3  
I nf or me d C o nse nt .............................................................................................. 4 9 
9. 1. 4  
S t u d y Files a n d Rete nti o n of Rec or ds .............................................................. 4 9 
9. 2  
Rec or di n g a n d C ollecti n g of D at a ............................................................................ 4 9  
9. 2. 1  
C ase  Re p ort F or ms ............................................................................................ 4 9 
9. 2. 2  
Dr u g Acc o u nt a bilit y .......................................................................................... 4 9  
9. 3  
Pr ot oc ol C o m pli a nce .................................................................................................. 5 0  
9. 4  
S p o ns or Res p o nsi bilities ............................................................................................ 5 0  
9. 4. 1  
S t u d y M o nit ori n g ............................................................................................... 5 0 
9. 4. 2  
S afet y M o nit ori n g .............................................................................................. 5 0  
9. 5  
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities ............................................................ 5 0  
9. 5. 1  
Ac cess t o I nf or m ati o n f or M o nit ori n g a n d A u diti n g ..................................... 5 0  
9. 5. 2  
T er mi n ati o n of t he St u d y .................................................................................. 5 0  
9. 5. 3  
P u blic ati o n P olic y .............................................................................................. 5 0  
9. 6  
C o nfi de nti alit y ............................................................................................................ 5 1  
1 0  R E F E R E N C E S ..................................................................................................................... 5 2  
A P P E N DI X 1:  S C H E D U L E O F S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ............ 5 4  
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 4  
List of T a bles 
T a ble 1  
T w o- Ye ar Rec urre nce R ate after a Si n gle I ntr a vesic al A d mi nistr ati o n of 
Q a pz ol a P ost- T U R B T  ( T a, G 1 - G 2 T ar get P o p ul ati o n)......................................... 1 9 
T a ble 2  
2 0 1 6 A meric a n Ur ol o gic al Ass oci ati o n Str atific ati o n f or N o n- M uscle I n v asi ve 
Bl a d der C a ncer ......................................................................................................... 2 6  
T a ble 3  
I n vesti g at or Assess me nt of A d verse E ve nt C a us alit y ............................................ 4 1  
 
List of Fi g ures 
Fi g ur e 1  
K a pl a n- Meier Esti m ates of Ti me t o Rec urre nce i n t he Q a pz ol a Pi v ot al St u dies 
S PI- 6 1 1 a n d S PI- 6 1 2 ( T a, G 1 - G 2 T ar get P o p ul ati o n) ........................................... 2 0 
Fi g ure 2  
K a pl a n- Me ier Esti m ates of Ti me t o Rec urre nce b y Ti me of I nstill ati o n 
( T a, G 1 -G 2 T ar get P o p ul ati o n) ............................................................................... 2 5  
Fi g ure 3  
St u d y Desi g n Di a gr a m  .............................................................................................. 3 0 
 
 
 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 7  
1  I N T R O D U C TI O N A N D B A C K G R O U N D 
1. 1  N o n - M uscle I n v asi ve Bl a d der C a ncer 
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 nite d States ( U S) a n d t he f o urt h- m ost 
c o m m o n ca ncer i n me n, a n d is a p pr o xi matel y t hree ti mes m ore pre v ale nt i n me n t ha n i n w o me n. 
Acc or di n g t o t he latest fi g ures fr o m t he S ur veilla nce, E pi de mi ol o g y, a n d E n d Res ults ( S E E R) 
Pr o gra m of t he Nati o nal Ca ncer I nstit ute ( N CI) [1 ], ~ 6 0 0, 0 0 0 pe o ple were li vi n g wit h bla d der 
ca ncer i n t he U S i n 2 0 1 3. I n 2 0 1 6, it is esti mate d t hat ~ 7 7, 0 0 0 pe o ple will be ne wl y dia g n ose d 
wit h bla d der ca n cer a n d ~ 1 6, 0 0 0 pe o ple will die fr o m t he disease. T h e me dia n a ge at dia g n osis is 
7 3 years, a n d m ore t ha n 9 0 % of patie nts are 5 5 years of a ge or ol der [1 ]. Beca use of t he o n g oi n g 
dia g n ostic a n d t h era p e utic re q uir e me nts f or rec urre nt disease, as well as f or disease pr o gressi o n, 
bla d der ca ncer is e x pecte d t o re mai n t he m ost e x pe nsi ve ca n cer t o treat. [2- 3 ]. T he t otal U S 
a n n ual c ost of bla d d er ca ncer is e x pecte d t o rise t o $ 5 billi o n b y 2 0 2 0 [2- 3 ]. 
I n t he U S, ur ot helial (tra nsiti o nal cell) carci n o mas c o m prise 9 0 % of all hist ol o gic s u bt y p es of 
bla d der ca ncer [4 ]. Of t h ese, N MI B C acc o u nts f or 7 0 % of ne wl y dia g n os e d cases (ie, ~ 5 4, 0 0 0 
patie nts t his year). I nitial dia g n osis a n d sta gi n g of N MI B C is base d o n c yst osc o pic e x a mi nati o n 
u n der a nest h esia. Pri mar y treat me nt wit h T U R B T, if i n dicate d, is a n i n vasi ve pr oce d ure t hat ca n 
ha ve a d etri me ntal effect o n a patie nt’s healt h-relat e d q ualit y of life ( H R Q o L). It als o carries 
i n here nt s ur gical ris ks (e g, ble e di n g, i nf ecti o n, perf orati o n) a n d a ris k of m e dical c o m plicati o ns 
arisi n g fr o m a nest hesi a. T hese are i m p orta nt c o nsi derati o ns gi v e n t hat t he maj orit y of patie nts 
w h o u n der g o T U R B T are el derl y a n d li kel y t o ha ve me dical c o m or bi dities [4 ]; the me dia n a ge at 
dia g n osis of bla d d er ca ncer is 7 3 years, a n d m ore t ha n 9 0 % of patie nts are 5 5 years of a ge or 
ol der [1 ]. 
T o r e d uce t he ris k of t u m or rec urre n ce, a n d he nce t he nee d f or re p eat T U R B T, t he Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k ( N C C N) [4 ], t he A merica n Ur ol o gical Ass ociati o n ( A U A) [5 ], 
t he Cana dia n Ur ol o gic al Ass ociati o n ( C U A) [6 ], t he E ur o pea n Ass ociati o n of Ur ol o g y ( E A U) 
[7 ], an d t he E ur o pea n S o ciet y f or Me dical O nc ol o g y ( E S M O) [8 ] rec o m me n d t hat patie nts wit h 
cli nicall y a p p are nt l o w- or i nter me diate-ris k N MI B C recei ve a si n gle i ntr a vesical i nstillati o n of a 
c he m ot hera p e utic a ge nt i m me diatel y f oll o wi n g resecti o n. C o m plia nce wit h t he g ui deli ne 
rec o m me n dati o n is p o or partl y b eca us e t he c urre ntl y a vaila ble a ge nts i ncl u di n g mit o m yci n C 
( M M C) or e pir u bici n are n ot a p pr o ve d f or t his i n dicati o n. A n y a d diti o nal treat me nts or 
i nstillati o ns are g ui de d b y t u m or hist ol o g y b ase d o n s ur gical pat h ol o g y. [4 ]. 
Beca use of t h e hi g h ris k of t u m or rec urre n ce a n d t he p ote ntial ris k f or pr o gressi o n t o m uscle 
i n vasi ve bla d der ca ncer ( MI B C), patie nts wit h N MI B C re q uir e fre q ue nt, dili ge nt f oll o w- u p 
i ncl u di n g re g ul ar 3- t o 4- m o nt h cli nic visits wit h uri ne a nal yses, uri ne mar k ers, a n d re peat 
c yst osc o pi es. Dia g n osis, treat me nt, c o nti n ue d s ur v eilla nce, a n d, if n ecessar y, re peat T U R B T ma y 
t h us c o ntri b ute t o t he si g nifica nt m or bi dit y a n d ec o n o mic b ur de n f or t he m a na ge me nt of N MI B C 
a n d is w h y o n a lifeti me, per- patie nt b asis, bla d der ca ncer is, a n d is e x pecte d t o re mai n, t he m ost 
e x pe nsi ve ca ncer t o treat [3 , 9 - 1 0]. 
1. 2   Q a pz ol a f or I ntr a vesic al I nstill ati o n 
Qa pz ola ™ (a pazi q u o ne, E O 9) is a n o vel, f ull y s y nt hetic, bi ore d ucti ve al k ylati n g i n d ol o q ui n o ne. 
Qa pz ola is a pr o- dr u g t hat is acti vate d b y t h e e nz y me D T- dia p h orase als o k n o w n as N Q O 1 
( N A D( P) H: q ui n o ne o xi d ore d uctas e- 1) a n d ot her re d uctases t o ge n erat e c yt ot o xic s pecies. T he 
mec ha nis m of acti vati o n of Qa pz ola i n v ol ves re d u cti o n b y cell ular e nz y m es t hat tra nsfer o ne or 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
1 8  
t w o electr o ns, f or mi n g a se mi q ui n o ne a n d a h y dr o q ui n o ne, res pecti v el y. O xi dati o n of t he 
se mi q ui n o ne u n der aer o bic c o n diti o ns res ults i n a re d o x c ycl e t hat ca n ca us e cell deat h b y 
f or mi n g reacti ve o x y ge n s pecies or de pl eti o n of N A D H a n d N A D P H. T he se mi q ui n o ne/ 
h y dr o q ui n o n e ca n al k yl ate a n d cr ossli n k D N A a n d ot her macr o m ol ec ules, a pr ocess t hat is 
e n ha nce d u n der h y p o xic c o n diti o ns. I n b ot h pat h wa ys, D N A da m a ge acti vates t he bi oc he mical 
pat h wa ys of a p o pt osis lea di n g t o c ell deat h. 
1. 3  Cli n ic al St u dies wit h Q a pz ol a 
S pectr u m has c o n d uct e d 9 cli nical st u dies wit h Qa pz ola a d mi nistere d b y t h e i ntra vesic al r o ute.  
1. 3. 1  Cli n ic al Effic ac y of Q a pz ol a 
T he effi cac y res ults fr o m t he t w o ra n d o mize d place b o-c o ntr olle d pi v otal P h ase 3 st u dies 
( S PI- 6 1 1 a n d S PI- 6 1 2) are t he basis f or t he N D A a p plicati o n. T he pri mar y o bjecti ve of S PI- 6 1 1 
a n d S PI- 6 1 2 w as t o assess t he 2- Year Rec urre n ce Rate of bla d der ca n cer i n patie nts wit h 
Ta, G 1 -G 2 N MI B C w h o u n der we nt T U R B T ra n d o mize d t o recei ve o ne Qa pz ola i nstillati o n 
( 4 m g / 4 0 mL) vers us t h ose w h o u n der we nt T U R B T a n d recei ve d a matc hi n g place b o i nstillati o n. 
Alt h o u g h S pectr u m i nitiall y desi g ne d t he st u dies wit h Ti me t o Rec urre n ce as t he pri mar y 
e n d p oi nt, t he O nc ol o g y Di visi o n of t he F D A, aft er c o ns ultati o n wit h Di visi o n of Re pr o d ucti ve 
a n d Ur ol o gic Pr o d ucts, r ec o m me n de d 2- Year Rec urre nce Rate as t h e pri mar y efficac y v aria ble 
i n S PI- 6 1 1 a n d S PI- 6 1 2, a n d Ti me t o First Rec urre nce as t he ke y sec o n dar y efficac y varia ble 
( Meeti n g Mi n utes 5 Fe b 2 0 0 7). A d diti o nal sec o n d ar y efficac y e n d p oi nts w ere Pr o gressi o n t o 
hi g her st a ge or gra de, N u m ber of Rec urre n ces per Patie nt, Disease-free I nter val, Disease-free 
S ur vi val, a n d O verall S ur vi val. 
Sa m ple siz e calc ulati o ns f or S PI- 6 1 1 a n d S PI- 6 1 2 were b ase d o n t he treat m e nt effect re p orte d i n 
a meta-a n al ysis c o n d ucte d b y S yl v ester et al ( 2 0 0 4) [1 1 ]. T his meta-a nal ysis s h o we d rec urre n ce 
rates of 4 8. 4 % f or T U R B T al o n e a n d 3 6. 7 % f or T U R B T pl us i ntra vesic al t hera p y, a n a bs ol ute 
differe n ce of 1 1. 7 % a n d relati ve i m pr o ve me nt of 3 9 % ( o d ds rati o [ O R] 0. 6 1, 9 5 % c o nfi de n ce 
i nter val [ CI] 0. 4 9, 0. 7 5; p < 0. 0 0 0 1) f or i ntra vesical t hera p y o ver T U R B T at a me dia n f oll o w- u p 
of 3. 4 years. C o nse q u e ntl y, S PI- 6 1 1 a n d S PI- 6 1 2 were d esi g n e d t o detect a 1 2 % a bs ol ute 
diffe re n ce b et wee n Qa pz ola a n d place b o i n t he pri mar y e n d p oi nt at a 5 % l e vel of si g nifica nce 
a n d p o were d at 8 0 %.  
Eli gi ble patie nts, base d o n a vis ual assess me nt u n der we nt T U R B T at Visit 1 ( Da y 0) after w hic h 
t he y w ere ra n d o mize d t o recei v e eit her Qa pz ola or place b o i nstille d i nt o t he bla d der i m me diatel y 
( withi n 6 h o urs) f oll o wi n g T U R B T. Aft er a 6 0- mi n ute rete nti o n, st u d y dr u g was drai ne d fr o m 
t he bla d der. A p ost o perati ve f oll o w- u p visit was sc he d ule d 3 wee ks later. Patie nts wit h 
c o nfirme d Ta, G 1- G 2 dis ease bas e d o n ce ntral pat h ol o g y re vie w, recei v e d n o f urt her treat me nt 
a n d were f oll o we d c yst osc o picall y e ver y 3 m o nt hs t hr o u g h Year 2 f or t u m or rec urre n ce. Patie nts 
wit h t u m ors ot her t ha n Ta, G 1 or G 2 recei ve d f urt her treat me nt i n acc or da n ce wit h 
c o nte m p ora ne o us treat m e nt g ui deli nes or sta n dar d of care, a n d were als o f oll o we d u p 
c yst osc o pi call y e ver y 3 m o nt hs t hr o u g h Year 2 f or t u m or rec urre n ce. N ot e t hat w hile patie nts 
were  e nr olle d bas e d o n vis ual dia g n osis at c yst osc o p y, t he tar get p o p ulati o n f or t he pri mar y 
effic ac y a n al ysis w as det er mi ne d b y hist ol o gical c o nfir mati o n of Sta ge Ta, G 1- G 2 b y ce ntral 
pat h ol o g y. T h us, patie nts wit h hi g her sta ge diseas e ( T 1, Tis) were e nr olle d b ut were n ot i ncl u de d 
i n t he effic ac y a n al ys es f or t he pre-s p ecifie d Ta, G 1- G 2 Tar get P o p ulati o n ( b ut were i n cl u de d i n 
t he i nte nt-t o-treat [I T T] a nal yses). 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 2  
1. 3. 2  Cli nic al S afet y of Q a pz ol a 
T he maj orit y of data esta blis hi n g t he safet y of a si n gle i ntra v esical i nstillati o n of Qa pz ola i n t he 
p ost- T U R B T setti n g ca m e fr o m t he t w o place b o-c o ntr olle d pi v otal st u dies, S PI- 6 1 1 a n d S PI- 6 1 2 
( N = 8 0 8). T h e me dia n d urati o n of eac h st u d y was ~ 2 years. 
T he i nci de nce a n d t y pe of a d vers e e ve nts ( A Es) re p orte d i n S PI- 6 1 1 a n d S PI- 6 1 2 was si milar f or 
b ot h treat me nt gr o u ps. Re gar dless of treat me nt gr o u p, a p pr o xi matel y 8 0 % of pati e nts i n eac h 
st u d y e x perie nce d at least o ne treat me nt-e m er ge nt A E  ( T E A E); m ost T E A Es ( 7 0 % t o 8 0 %) were 
of Gra d e 1 or Gra de 2 s e verit y . T h e  m ost c o m m o n T E A Es ( occ urri n g i n a p pr o xi matel y 1 0 % t o 
2 0 % of patie nts i n eit her treat me nt gr o u p i n eit her st u d y) were  d ys uria, uri n ar y tract i nfecti o n, 
he mat uria, a n d p olla ki uri a  wit h less c o m m o n T E A Es ( 5 % t o 1 0 % of patie nts) bei n g mict uriti o n 
ur ge nc y, bla d d er pai n, uri nar y rete nt i o n, pr oce d ural pai n a n d bla d der s pas m .  
F e w p atie nts ( 1 0 % t o 1 3 %) ha d T E A Es t h e i n vesti gat or c o nsi dere d treat me nt relate d wit h t he 
i nci de nce of t h ese A Es b ei n g  si milar bet w ee n Q a pz ola a n d place b o.  T he m ost c o m m o n 
treat me nt-relate d A Es ( occ urri n g i n 1 % t o 5 % of patie nts) were d ys uria, bl a d der s pas m, 
mict uriti o n ur ge n c y, bla d der pai n, he mat uria, uri n ar y tract i nfecti o n, a n d p olla ki uria .  
A p pr o xi matel y 2 5 % of patie nts i n S PI - 6 1 1 a n d S PI- 6 1 2 re p orte d a s eri o us a d verse e v e nt ( S A E), 
wit h t he i nci de nce a n d t y pes of S A Es re p ort e d bei n g si milar bet w ee n st u dies a n d bet wee n 
treat me nt gr o u ps. T he m ost c o m m o n S A Es (i n < 3 % of patie nts) were c o n gesti ve car di ac fail ure, 
he mat uria, uri nar y rete nti o n, atrial fi brillati o n, c hr o nic o bstr ucti ve p ul m o nar y dise ase, 
p ne u m o nia, k nee art hr o plast y, a n d c or o nar y art er y disease, m ost of w hic h ma y b e e x pecte d i n a n 
el derl y p o p ulati o n. T w o patie nts e x perie nce d S A Es t hat were c o nsi dere d t o be p ossi bl y relate d t o 
Qa pz ola. B ot h S A Es starte d o n t he da y of st u d y dr u g i nstillati o n, a n d b ot h res ol ve d: o ne patie nt 
ha d Gra d e 3 he mat uri a a n d rec o vere d wit hi n 3 da ys, t he ot her ha d Gra de 3 ac ute re nal f ail ure a n d 
rec o vere d wit hi n 1 8 da ys. A n ot her patie nt w h o recei ve d Qa pz ola die d of ac ute re nal f ail ure 6 2 4 
da ys after Qa pz ola treat me nt; t he e ve nt was ass esse d as n ot relate d t o st u d y treat me nt. He mat uria 
is a c o m m o n prese nti n g si g n of N MI B C [5 , 1 3 ] a n d is a n e x pecte d c o nse q u e nce of t h e T U R B T 
pr oc e d ure.  
Si nce t here w as o nl y o n e i nstillati o n, t here were n o A Es t hat le d t o disc o nti n uati o n of st u d y dr u g 
i nstillati o n. A p pro xi matel y 4 % of patie nts disc o nti n ue d fr o m t he st u dies d u e t o A Es o ver t he 2-
year st u d y peri o d, wit h t he i nci de nce of t hese A Es bei n g si milar bet w ee n st u dies a n d bet wee n 
treat me nt gr o u ps, a n d n o i n di vi d ual A E occ urri n g i n m ore t ha n 1 % of patie nts. N o ne of t he A Es 
lea di n g t o disc o nti n uati o n were assesse d as relat e d t o st u d y treat me nt b y t he I n vesti gat or.  
A p pr o xi m atel y 3 % of patie nts ha d A Es t hat res ulte d i n deat h, n o ne of w hic h t he i n vesti gat or 
assesse d as r elate d t o st u d y dr u g ( Qa pz ola or place b o). T here were n o d eat hs re p orte d i n t he 
i m me diate p ost T U R B T i nstillati o n peri o d ( wit hi n 3 0 da ys). 
Cl i nical la b orat or y assess me nts s h o we d n o cli nicall y mea ni n gf ul differe nces bet wee n patie nts 
recei vi n g Q a pz ola a n d place b o i n a n y h e mat ol o gic, li ver, ki d ne y, or met a b olic para meters a n d i n 
a s u b gr o u p of pa tie nts i n S PI- 6 1 1 ( n = 1 9 1), t here was n o meas ura ble effect o n f u ncti o nal bla d der 
ca pacit y.  
Data fr o m t he ot h er si x st u dies were s u p p orti ve of t he safet y dat a i n S PI- 6 1 1 a n d S PI- 6 1 2. 
A m o n g t he 2 4 5 p atie nts i n t hese st u dies, 1 3 9 recei ve d m ulti ple i nstillati o ns of Qa pz ola. T he 
t y pes of T E A Es i n t hese patie nts were si milar t o t h ose i n SPI - 6 1 1 a n d S PI- 6 1 2, alt h o u g h t he 
i nci de nce of d ys uria, he mat uria, p olla ki uria, a n d mict uriti o n ur ge n c y te n de d t o be hi g h er i n 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 3  
patie nts recei vi n g m ulti ple i nstillati o ns of Qa pz ola ( ~ 1 5 % t o 4 5 %)  t ha n si n gle i nstillati o ns ( ~ 3 % 
t o 1 5 %). Treat me nt-rel ate d S A Es were e x perie nce d b y t hr ee p atie nts w h o recei v e d si n gl e 
i nstillati o ns of Qa pz ola ( pel vic pai n, p ost o perati v e uri nar y rete nti o n, a n d he mat uria) a n d f o ur 
pa tie nts recei vi n g m ulti ple i nstillati o ns of Qa pz ola ( d ys uria, he mat uri a a n d he m orr ha ge uri nar y 
tract, c he mical c ystitis, p olla ki uria); all patie nts rec o vere d. N o patie nts i n t he s u p p orti ve safet y 
st u dies disc o nti n ue d d ue t o A Es a n d n o ne die d.  
1. 4  S t u d y R ati o n ale  
All e x pert ur ol o g y s ocieties rec o m me n d a hi g h q u alit y T U R B T as t he i nitial treat me nt f or 
patie nts wit h N MI B C. H o we ver, d es pite t he i m pr o ve me nts i n i nstr u me ntati o n a n d s ur gi cal 
tech ni q ues, t here c o nti n u es t o be a hi g h fre q ue nc y of t u m or rec urre n ce a n d pr o gressi o n of t he 
disea se t o m ore a d v a nce d sta ges. T heref ore, a ke y f oc us f or i m pr o vi n g t he treat me nt of N MI B C 
is t o i de ntif y ne w treat me nt strate gi es t hat re d u ce t he rate of rec urre nce a n d pr o gressi o n. 
T he me dical literat ure s u p p orts, a n d i nter nati o nal g ui deli nes rec o m me n d, i m me diate i nstillati o n 
of a  c he m ot hera p e utic a ge nt f oll o wi n g T U R B T beca use of its p ote ntial i m pact i n re d uci n g t u m or 
rec urre nce. T he oreticall y, t he hi g h rate of t u m or rec urre nce is attri b ute d t o a n u m ber of p utati ve 
fact ors: 
 In c o m plete i nitial t u m or resecti o n 
 In a bilit y t o vis ualize all t u m ors  
 Im pla ntati o n of fl oati n g t u m or cells, w hic h are release d i nt o t he bla d der d uri n g T U R B T  
 G r o wt h of a n e w t u m or d ue t o u n k n o w n or p o orl y u n derst o o d fact ors pre dis p osi n g t o t he 
de vel o p me nt of bla d der ca ncer.  
T he g o al of i m me diate p ost o perati ve i nstillati o n of a c he m ot hera p e utic a ge nt i nt o t he bla d der is 
t o decrease rec urre nce rates b y destr o yi n g fl oati n g t u m or cells releas e d d uri n g t he T U R B T 
pr oce d ure, w hic h h a ve t h e p ote ntial t o i m pla nt i n t he bla d der wall. P ost o perati ve i nstillati o n of a 
c he m ot hera p e utic a ge nt ma y als o pr o vi de be n efit b y a bl ati n g resi d ual tu m or cells re mai ni n g at 
t he resecti o n site.  
Qa pz ola is a pr o dr u g t hat is s pecificall y acti vat e d i nt o a p ote nt al k yl ati n g a ge nt i n t u m or cells, 
w hic h c o ntai n hi g h a m o u nts of re d ucti ve e nz y mes. T he a ntit u m or acti vit y of Qa pz ola has bee n 
de m o nstrate d i n i n vitro  st u dies i n f o ur h u ma n bla d der ca n cer cell li nes, w here it was s h o w n t o 
be  t he m ost p ote nt c yt ot o xic a ge nt c o m pare d t o mit o m yci n C, e pir u bici n, a n d ge m cita bi ne, wit h 
acti vit y t hat w as 5- t o 7 5- f ol d hi g h er t ha n mit o m yci n C. P hase 1 a n d P has e 2 cli nical st u dies 
s h o wed t he acti vit y of Q a pz ola, f oll o wi n g i ntra v esical i nstillati o n, i n d uci n g t he re gressi o n of 
bla d der ca ncer mar ker lesi o ns wit h C R rates as hi g h as 6 7 % i n hea vil y pretreate d patie nts. P hase 
3 si n gle i nstillati o n st u dies ( S PI- 6 1 1, n = 8 0 2; S PI- 6 1 2, n = 8 1 3) de m o nstrate d cli nicall y 
mea ni n gf ul re d u cti o ns of 6. 7 % a n d 6. 6 %, res pecti vel y, i n t he 2- Year Rec urre nce R ate b y 
Qa pz ola i n t he Ta, G 1- G 2 P o p ulati o n. Alt h o u g h t hese differe n ces were n ot statisticall y 
si g nifica nt i n t he i n di vi d ual st u dies, a n i nte grate d a nal ysis of data fr o m b ot h P hase 3 st u dies 
( n = 1 6 1 5) s h o w e d a cli nic all y me a ni n gf ul 6. 7 % re d ucti o n i n t he 2- Year Rec urre n ce Rate i n t he 
Qa pz ola Treat me nt Gr o u p t hat was als o statisticall y si g nifica nt ( p = 0. 0 2 2). I n a d diti o n, it 
de m o nstrat e d a n a p pr o xi mate 2 4 % re d u cti o n i n t he ris k of t u m or rec urre nce at 2 years base d o n 
t he O d ds Rati o of Rec urre nce. I ntra vesic al treat m e nt wit h Qa pz ola was als o s h o w n t o be well-

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 4  
t olerate d wit h t he m ost c o m m o n A Es c o m m o nl y s ee n i n patie nts wit h bla d der ca n cer (e g, 
he mat uria, d ys uria, a n d uri nar y fre q ue n c y). 
Qa pz ola has bee n s h o w n t o be i nacti vate d b y re d bl o o d cells [1 2 ]. Hemat uria, b ot h micr osc o pic 
an d macr os c o pic, is t he m ost c o m m o n a d verse e v e nt i n t he i m me diate p ost- T U R B T p eri o d. 
T heref o re, a n y blee di n g i n t he p ost- o perati ve p eri o d f oll o wi n g T U R B T c o ul d i nacti vate Qa pz ola 
f oll o wi n g its i m me diate, p ost o perati ve i nstillati o n, re d uci n g its effi cac y. T his pr o vi de d t he 
rati o nale f or t h e f urt her a nal ysis of t he P has e 3 st u d y dat a f or S PI- 6 1 1 a n d S PI- 6 1 2 bas e d o n t he 
ti me i nter val of dr u g i nstillati o n p ost- T U R B T ( < 3 0 mi n utes, 3 1 t o 9 0 mi n utes, a n d > 9 0 mi n utes). 
T his a nal ysis  de m o nstr ate d a r o b ust 2 0. 3 % re d ucti o n i n t he 2- Year Rec urre nce Rate i n Qa pz ola-
treate d patie nts i n t he Ta, G 1 - G 2 P o p ulati o n w h o recei ve d treat me nt 3 1 t o 9 0 mi n utes after 
T U R B T, c o m pare d t o patie nts treate d wit h place b o i n t he sa m e ti me i nter val ( 2 3. 3 % vs 4 3. 6 %); 
t his differe nce was statisticall y si g nifica nt ( p = 0. 0 3 4 6), wit h t he o d ds rati o ( 0. 3 9; 9 5 % CI 0. 1 6, 
0. 9 4) i n fa v or of Qa pz ola. Si nce t he ma xi m u m be nefit fr o m i ntra vesic al i nstillati o n was see n i n 
t he gr o u p of patie nts recei vi n g i nstillati o n at 3 1 t o 9 0 mi n utes p ost- T U R B T, t his d osi n g wi n d o w 
was sele ct e d f or i nstillati o n of st u d y dr u g ( Qa pz ola or place b o) ( 6 0 ± 3 0 mi n utes p ost- T U R B T) 
i n t he ne w pr o p ose d P has e 3 st u d y.  
A si n gle i nstillati o n d os e of 8 m g  i n 5 0 m L Qa pz ol a was c h os e n as t he st u d y treat me nt i n t he 
curre nt st u d y. T he 4 m g  i n 4 0 m L d ose of Qa pz ola was esta blis he d i n t he P hase 1 d ose-escal ati o n 
stu d y a n d w as use d i n t h e P hase 2 a n d pre vi o us P hase 3 st u dies. Base d o n t he data fr o m t he 
P hase 1 d ose -es calati o n st u d y, it was f o u n d t hat t h e 8 m g  i n 4 0 m L d ose ( 0. 2 m g / mL) di d n ot 
s h o w a n y cli nicall y rel e v a nt safet y c o n cer ns. Beca use t he 8 m g  d os e of Qa p z ola, at a 
co nce ntr ati o n of 0. 2 m g / m L, was d eter mi ne d t o b e safe, t h e d ose of 8 m g  i n 5 0 m L 
( 0. 1 6 m g / mL) was c h ose n as t he d ose t o be use d i n S PI- Q A P - 3 0 6. As p art of t he safet y 
m o ni t ori n g i n t he st u d y, a n I n de pe n d e nt Data M o nit ori n g C o m mittee (I D M C) will re vie w t he 
u n bli n de d safet y data fr o m t he first 3 0 patie nts t o verif y t hat t he 8 m g / 5 0 m L d ose is safe. 
Bec a use of t h e p ote ntial f or t he i nacti vati o n of Qa pz ola b y bl o o d i n t he i m me diate p ost- T U R B T 
peri o d, t he pr o p ose d Qa p z ola d osi n g is tar gete d t o be deli vere d 6 0 ± 3 0 mi n utes p ost- T U B T. 
T his d osi n g ti me wi n d o w is s u p p orte d b y t he a nal ysis of Ti me t o Rec urre n ce i n t he pre vi o us 
P hase 3 si n gle- d ose st u dies ( S PI- 6 1 1, S PI- 6 1 2) i n patie nts treate d 3 1 t o 9 0 mi n utes p ost- T U R B T. 
T he haza r d rati o f or patie nts w h o were tr eate d 3 1 t o 9 0 mi n utes p ost- T U R B T was 0. 4 4 
( p = 0. 0 2 0 2, l o g-ra n k test; 9 5 % CI 0. 2 2, 0. 9 0) i n fa v or of Qa pz ola i n S PI- 6 1 1 (Fi g u re 2A ) a n d 
0. 5 5 ( p = 0. 0 3 4 4, l o g-ra n k test; 9 5 % CI 0. 3 1, 0. 9 7) i n fa v or of Qa pz ola i n S PI- 6 1 2 (Fi g ure 2 B ).  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 5  
Fi g ure 2 
K a pl a n- Meier Esti m ates of Ti me t o Rec urre nce b y Ti me of I nstill ati o n 
( T a, G 1 -G 2 T ar get P o p ul ati o n) 
A) S PI- 6 1 1 
 
B ) S PI- 6 1 2 
 
T U R =tra ns uret hral resecti o n of bla d der t u m or. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 7  
Eli gi ble patie nts will be ra n d o mize d i n a 2: 1 rati o t o eit her: 
Ar m 1:  O n e d ose of 8 m g  Q a pz ola  
Ar m 2:  O n e d ose of pl ace b o  
O nc e ra n d o mize d, patie nts will u n der g o T U R B T o n Da y 1 a n d t he st u d y dr u g i nstillati o n will 
oc c ur at 6 0 ± 3 0 mi n utes p ost- T U R B T a n d will be retai ne d f or 6 0 mi n utes ( ± 5 mi n utes) i n t he 
bla d der. All hist ol o g y s p eci me ns will be re vi e we d b y a l o cal pat h ol o g y la b orat or y a n d all cli nical 
treat me nt decisi o ns will be base d o n t he l ocal pat h ol o g y re vie w. Patie nt tar get disease will be 
co nfir me d a n d effi cac y a nal yses will be perf or me d base d o n t he pat h ol o g y res ults. T he tar get 
st u d y p o p ulati o n is l o w- t o i nter me diate-ris k p atie nts w h o ha ve Ta hist ol o g y, i ncl u di n g 
P U N L M P, as c o nfir me d b y a p at h ol o g y l a b orat or y. Patie nts w h os e t u m or hist ol o g y d o es n ot 
meet t he criteri a f or eli gi bilit y, as c o nfir me d b y p at h ol o g y ( N o n- Tar get P o p ulati o n), will be 
f oll o wed u p f or safet y o n Da y 3 5 ( ± 5 da ys) ( Safet y F oll o w- u p Visit) a n d will t he n be 
disc o nti n ue d fr o m t he st u d y. If t he pat h ol o g y res ults are dela ye d be y o n d 3 5 da ys, t he S afet y 
F oll o w- u p Visit will be c o n d ucte d w he n t he res ults are a v aila ble f or t hese p atie nts.  
P atie nts w h o ha ve pat h ol o g y c o nfir me d tar get hist ol o g y will n ot recei ve a d diti o nal treat me nt f or 
N M I B C d uri n g t he f oll o w- u p pri or t o rec urre nce. All patie nts will be f oll o we d u ntil eit her a 
co nfir me d t u m or rec urre nce or t he E n d- of- St u d y, w hic he ver occ urs first.  
T he  pri mar y a n al ysis will be c o n d ucte d o nce t he re q uire d n u m ber of rec urre nce e ve nts are 
o bser ve d as d etaile d i n t he Statistical Met h o ds bel o w. T he n u m ber of e ve nts nee de d t o perf or m 
t he fi nal pri mar y e n d p oi nt a nal ysis w as esti mate d base d o n t he rec urre nce rate at 2 4 m o nt hs fr o m 
pre vi o us st u dies. T he f oll o w- u p sc he d ule is b el o w:  
 C yst osc o pic e x a mi nati o n a n d uri ne c yt ol o g y e v er y 3 m o nt hs ( ±3 0 da ys) (calc ulate d fr o m 
date of T U R B T) f or 2 years f or t u m or rec urre n ce a n d pr o gressi o n a n d t h e n e ver y 
6 m o nt hs ( ± 6 0 da ys ) u nti l eit her a c o nfir me d t u m or rec urre n ce or t h e E n d-of - St u d y, 
w hic he ver occ urs first. 
 If at a n y ti me d uri n g t he st u d y t here is a hist ol o gicall y c o nfir me d t u m or rec urre nce, t he 
pa tie nt will be disc o nti n ue d fr o m t he st u d y at t hat ti me a n d ma y t h e n be treate d per t he 
I n v esti gat or’s sta n dar d of care.  
T he st u d y will e n d ( E n d- of- St u d y) w he n t he re q uire d n u m ber of e ve nts f or t he pri mar y e n d p oi nt 
a nal ysis are accr ue d.  
3. 2  S t u d y D ur ati o n 
T he esti mate d d urati o n of t he st u d y is a p pr o xi matel y 5 years ( 2 . 5 years accr ual + a p pr o xi matel y 
2. 5  years f oll o w- u p). 
T he t otal d urati o n of t he st u d y f or eac h patie nt will be a p pr o xi matel y 5 years i ncl u di n g: 
 S cree ni n g Peri o d:  u p t o 3 0- da ys  
 Tre at me nt:  Da y 1  
 S afet y F oll o w- u p : Da y 3 5 ( ± 5 da ys) ( n o n- Tar get P o p ulati o n) or M o nt h 3 F oll o w- u p 
Visi t ( Tar get P o p ulati o n) 
 F oll o w- u p Peri o d:  N o f oll o w- u p i n n o n- Tar get P o p ulati o n. U ntil eit her a c o nfir me d 
t u m or rec urre nce or t he E n d- of- St u d y, w hic he v er occ urs first i n Tar get P o p ulati o n. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 8  
4  P A TI E N T P O P U L A TI O N  
4. 1  I ncl usi o n Criteri a 
1.  Patie nt m ust ha ve a cli nical dia g n os is of l o w- t o i nter me diate-ris k n o n- m uscle i n vasi ve 
bla d de r ca ncer acc or di n g t o t he 2 0 1 6 A merica n Ur ol o gical Ass ociati o n ( A U A) 
G ui de li nes  
2.  P atie nt m ust be willi n g t o gi ve writte n i nf or me d c o nse nt a n d m ust be a ble t o a d here t o 
d osi n g a n d visit sc he d ul es, a n d meet all st u d y re q uire me nts. 
3.  P atie nt is at least 1 8 years of a ge a n d < 9 0 years of a ge at t he ti me I nf or me d C o nse nt is 
si gne d. 
4.  P atie nt m ust be willi n g t o practice t w o f or ms of c o ntrace pti o n, o ne of w hic h m ust be a 
barrier m et h o d, fr o m st u d y e ntr y u ntil at least 3 5 da ys after st u d y tr eat me nt. Patie nts 
s ur gic all y steriliz e d or w h o are p ost me n o pa us al f or at least 1 year ( d efi ne d as m ore t ha n 
1 2 m o nt hs si nce last me nses) d o n ot re q uir e c o ntrace pti o n. 
5.  F e males of c hil d beari n g p ote ntial m ust ha ve a ne gati ve pre g na n c y test wit hi n 3 0 da ys 
pri or t o ra n d o mizati o n. Fe males w h o are p ost me n o pa usal f or at least 1 year ( defi ne d as 
m ore t ha n 1 2 m o nt hs si nce last me nses) or are s ur gicall y steriliz e d d o n ot re q uire t his 
test.  
4. 2  E xcl usi o n Criteri a  
1.  Patie nt has mali g na n c y or life-t hreate ni n g s yste mic disease or a hist or y of a d va nce d, 
seri o us, life-t hreate ni n g mali g na n c y/ disease wit hi n t he last 5 years, e x ce pt ver y l o w-ris k 
pr osta te ca n cer 
2.  P atie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gi cs ( vacci nes, a nti b o dies), or de vices 
wit hi n 3 0 da ys pri or t o st u d y treat me nt or has pla ns t o use a n y of t hese d uri n g t he c o urse 
of t he st u d y  
3.  P atie nt has recei ve d a n y pel vic ra di ot hera p y (i ncl u di n g e xter nal bea m a n d/ or 
brac h yt hera p y) 
4.  P atie nt has a hist or y of aller g y t o re d c ol or f o o d d ye or a n y ot her c o m p o ne nt of Qa pz ola, 
place b o, or t he ir dil ue nts  
5.  P atie nt has ha d a s ur gic al pr oce d ure 4 wee ks pri or t o T U R B T or will ha ve ot her s ur gical 
pr oc e d ures perf or me d at t he ti me of T U R B T or wit hi n 4 wee ks after T U R B T 
6.  P atie nt has a n y u nst a ble or u nc o ntr olle d me dical c o n diti o n t hat w o ul d ma ke it p ote ntiall y 
u nsafe t o u n der g o T U R B T i ncl u di n g a pre vi o us str o ke or m y ocar dial i nfarcti o n wit hi n 
6 m o nt hs 
7.  P atie nt has a n acti ve u n c o ntr olle d i nfecti o n, i ncl u di n g a uri n ar y tract i nfecti o n, 
u n derl yi n g me di cal c o n diti o n, or ot her seri o us ill ness t hat w o ul d i m pair t he a bilit y of t he 
patie nt t o recei v e st u d y tr eat me nt or u n der g o st u d y pr oce d ures  
8.  P atie nt has a blee di n g dis or der or a scree ni n g platelet c o u nt < 1 0 0 × 1 0 9/L, or re q uires 
c o nti n u o us a ntic oa g ulati o n or bri d gi n g a ntic oa g ul ati o n d uri n g t he pr oce d ure  
9.  P atie nt has a he m o gl o bi n val ue < 1 0 g/ d L at Scree ni n g  
1 0.  Patie nt has e ver ha d c o nfir me d e xtra vesical ur ot helial disease ( u p per tract a n d uret hral 
i ncl u di n g pr ostatic uret hr al) 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
2 9  
1 1.  Patie nt wit h a hist or y of pre vi o us bla d der ca ncer:  
 
Hi g h- Ris k N MI B C as classifie d per t he 2 0 1 6 A U A G ui deli nes 
 
B la d der ca n cer t h at was m uscle i n vasi ve or p ositi ve f or l y m p h n o de or dist a nt 
metastasis 
1 2.  Patie nt has recei ve d a n y pre vi o us i ntra vesic al t hera p y f or bla d der ca ncer- c he m ot hera p y, 
i m m u n ot hera p y, or pre vi o us e x p os ure t o Qa pz ola i n t he last 3 years 
1 3.  Pa tie nt has a t u m or i n t he bla d der di vertic ul u m 
1 4.  Patie nt has a hist or y of i nterstitial c ystitis 
1 5.  Patie nt is pre g n a nt or breast-fee di n g  
4. 3  P ati e nt Disc o nti n u ati o n/ Wit h dr a w al Criteri a 
Patie nt s ca n wit h dra w fr o m partici pati o n i n t his st u d y at a n y ti me, f or a n y reas o n, s pecifi e d or 
u ns pe cifie d, a n d wit h o ut prej u dice.  
Patie nts m ust be wit h dra w n fr o m st u d y p artici pati o n f or t he f oll o wi n g reas o ns:  
 It is deter mi ne d b y Da y 1 pat h ol o g y re vie w t hat t h e patie nt has hist ol o g y ot her t ha n l o w- 
t o i nter me diate-ris k N MI B C  
 De vel o p me nt of a n a d verse e ve nt ( A E) t hat i nterferes wit h t he patie nt’s partici pati o n 
 P atie nt wit h dra wal of i nf or me d c o nse nt 
 In v esti gat or decisi o n 
 S p o ns or decisi o n 
 T he  patie nt ref uses f urt h er f oll o w- u p st u d y pr oce d ures, i ncl u di n g c yst osc o p y  
 T he  patie nt is l ost t o f oll o w- u p ( misse d at least t w o c o nsec uti ve f oll o w- u p c yst osc o pi es) 
 P atie nt has a c ystect o m y 
 P atie nt has a hist ol o gicall y-c o nfir me d rec urre n ce  
 De at h 
 P re g n a nc y  
T he reas o n f or t he p atie nt disc o nti n ui n g st u d y treat me nt or ter mi nati n g fr o m t he st u d y m ust be 
rec or de d o n t he case re p ort f or m ( C R F). F or patie nts w h o disc o nti n ue fr o m t he st u d y d uri n g t he 
f oll o w- u p peri o d or w h o are wit h dr a w n, t he dat e of last c o ntact will be t he fi nal visit.  
5  S T U D Y P R O C E D U R E S 
T he st u d y d esi g n dia gra m is prese nte d i n  Fi g ure 3  a n d t he Sc he d ule of St u d y Assess me nts a n d 
P r oce d ures is prese nte d A p pe n di x 1 . 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 0  
Fi g ure 3 
St u d y Desi g n Di a gr a m 
 
5. 1  S cree ni n g 
I nf or me d c o ns e nt is t o be o btai ne d pri or t o t he start of a n y pr ot oc ol-s pecifie d assess me nts or 
pr oce d ures. H o we ver, s o me patie nts ma y c o m plet e c yst osc o p y wit h pat h ol o g y ass ess me nt a n d / or 
uri ne c yt ol o g y t est as part of t he sta n dar d of care pri or t o si g ni n g t he i nf or m e d c o nse nt. T h ose 
test res ults, if t he y are wit hi n 4 5 da ys pri or t o si g ni n g i nf or me d c o nse nt, c o ul d be part of 
eli gi bilit y ass ess me nt. I n t his case, t here is n o n ee d t o re peat sa m e test pr oce d ure. T he pr oce d ures 
an d e val uati o ns r e q uire d f or e nr oll me nt i nt o t he st u d y are s u m marize d bel o w. All p ote ntial st u d y 
patie nts will be scree n e d a n d eli gi bilit y d eter mi ne d pri or t o e nr oll me nt. Scree ni n g assess me nts 
perf or me d pri or t o t he si g ni n g of i nf or me d c o nse nt as part of t he site’s r o uti ne sta n dar d of 
practice will be all o we d at t he discreti o n of S pectr u m. T his i nf or mati o n s h o ul d be disc usse d wit h 
t he Me dical M o nit or bef ore t he patie nt is ra n d o mi ze d a n d e nr olle d i n t he st u d y.  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 1  
All pr oce d ures are t o be perf or me d as o utli ne d i n  A p pe n di x 1  pri or t o t he start of st u d y 
treat me nt, u nless ot her wise n ote d. Scree ni n g i n cl u des a c yst osc o pic e x a m a n d uri ne c yt ol o g y i n 
or der t o assess t he cli nicall y a p pare nt sta ge a n d gra de of t he bla d der t u m or. A c yst osc o pic or 
uri ne c y t ol o g y e x a m c o n d ucte d as part of t he sta n dar d practice wit hi n 4 5 d a ys pri or t o t he 
si g ni n g of t he i nf or m e d c o nse nt ma y s er ve as t he assess me nt as l o n g as sta ge a n d gra d e of t u m or 
are r e p orte d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) 2 0 0 4 gra di n g s yste m.  
5. 2  P ati e nt Assi g n me nt 
C o nfir mati o n of eli gi bilit y is t o be recei v e d b y t he i n vesti gati o nal site fr o m S pectr u m pri or t o 
e nr ollme nt of a patie nt. After a p atie nt has si g ne d t he I C F, t he I n v esti gat or or site staff s h o ul d 
l o g i nt o I W R S a n d o btai n a Patie nt I D. T he Patie nt I D will i ncl u de t w o parts: t he site n u m ber 
c o m prise d of 5 di gits wit h a 2- di git al p h a betic c o u ntr y c o d e [ Refere nce I S O 3 1 6 6] f oll o we d b y a 
3- di git site s pecifi c n u meric c o de a n d a 3- di git patie nt se q ue ntial n u m ber, u ni q ue t o a site, 
separa t e d b y a h y p he n (ie,  
).  
O nce t he I n v esti gat or or site staff ha ve c o m plete d t he re q uire d C R Fs, a n d a p pr o val f or 
ra n d o mizati o n has bee n recei ve d fr o m S pectr u m, t he site will ra n d o mize t he patie nt usi n g a pre-
s pecified ra n d o mizati o n sc he me. Patie nts m ust n ot u n der g o T U R B T u ntil t he y h a ve b ee n 
ra n d o mize d. Please refer t o t he st u d y bi n der f or detaile d i nstr ucti o ns re gar di n g e nr oll me nt.  
5. 3  T i mi n g of Assess me nts a n d Pr oce d ures 
5. 3. 1  S cree ni n g  
T he f oll o wi n g s cree ni n g assess me nts s h o ul d be perf or me d wit hi n 3 0 da ys of Da y 1 ( Da y - 3 0 t o 
Da y  - 1). 
 I nf or me d C o nse nt 
 Ur i ne c yt ol o g y ( Wit hi n 4 5 da ys pri or t o si g ni n g i nf or me d c o nse nt) 
 C yst osc o pic E x a m ( Wit hi n 4 5 da ys pri or t o si g ni n g i nf or m e d c o nse nt) 
 C o m plete me dical hist or y 
 Vital si g ns (te m perat ure, bl o o d press ure, a n d h eart rate) 
 De m o gra p hic d ata 
 P h ysical e x a mi nati o n  
 Hei g ht a n d wei g ht 
 C o m plete bl o o d c o u nt ( C B C)  
 C he mistr y 
 Uri ne di pstic k  
 P re g n a nc y test ( b eta h u m a n c h ori o nic g o na d otr o pi n [ β- h C G]) i n w o me n of c hil d beari n g 
p ote ntial  
 A d ve rse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3 
 C o nc o mita nt Me dicati o ns 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 2  
5. 3. 2  Tre at me nt Peri o d: Visit 1 ( D a y 1) 
If t he scree ni n g ass ess me nts f or t he p h ysi cal e xa mi nati o n, he mat ol o g y, c h e mistr y, uri ne di pstic k 
were p erf or me d wit hi n 3 da ys ( 7 2 h o urs) pri or t o Da y 1/ T U R B T, t hes e ass ess me nts d o n ot nee d 
t o be re peate d at t he D a y 1 Visit. 
 Vital si g ns (te m perat ure, bl o o d press ure, a n d h eart rate) 
 C o m plete bl o o d c o u nt  
 C he mistr y 
 R a n d o mizati o n 
 Ur i ne di pstic k j ust pri or t o dr u g i nstillati o n 
 T U R B T  a n d p ac ka gi n g of pat h ol o g y s p eci me ns t o be se nt t o l ocal pat h ol o g y 
 Vis ua l i ns pecti o n f or gr oss he mat uria p ost- T U R B T b ut pri or t o dr u g i nstillati o n 
 Qa pz ola or place b o a d mi nistrati o n 
 C o nc o mita nt Me dicati o ns  
 A d ve rse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3 
5. 3. 3  S afet y F oll o w- u p Visit: Visit 2 ( D a y 3 5 [ ±5 d a ys] p ost- T U R B T ( n o n- T ar get p atie nt 
p o p ul ati o n) or Visit 3 ( M o nt h 3 F oll o w- u p Visit) ( T ar get p atie nt p o p ul ati o n)  
 Vital si g ns (te m perat ure, bl o o d press ure, a n d h eart rate) 
 P h ysical e x a mi nati o n 
 C o m plete bl o o d c o u nt 
 C he mistr y 
 Ur i ne di pstic k  
 A d ve rse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  
 C o nc o mita nt me dicati o ns  
5. 3. 4  L o n g- Ter m F oll o w- u p Visits - Visits 3 t hr o u g h 1 0 ( Fi rst 2 Ye a rs: E ver y 3 m o nt hs 
[± 3 0 d a ys] P ost- T U R B T) a n d Visits 1 1 t hr o u g h 1 6 ( Ye ars 3- 5: E v er y 6 m o nt hs [ ± 6 0 
d a ys]) 
 P h ysical e x a m (re q uire d at M o nt h 3 F oll o w- u p Visit, as nee de d t hereafter) 
 Vital si g ns (te m perat ure, bl o o d press ure, a n d h eart rate) (re q uir e d at M o nt h 3 F oll o w- u p 
Visit, as nee de d t hereafter) 
 Ur i ne di p stic k pri or t o c yst osc o p y 
 C o m plete bl o o d c o u nt ( M o nt h 3 F oll o w- u p Visit o nl y) 
 C he mistr y ( M o nt h 3 F oll o w- u p Visit o nl y) 
 Ur i ne c yt ol o g y  
 C yst osc o p y 
 O nl y A Es relate d t o st u d y pr oce d ures will be rec or de d u ntil t he E n d- of- St u d y 
 C o nc o mita nt me dicati o ns (I ntra vesic al treat me nt o nl y)  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 3  
 T U R B T a n d p ac ka gi n g of pat h ol o g y s p eci me ns t o be se nt t o l ocal pat h ol o g y (if 
necessar y) 
5. 4  De scri pti o n of St u d y Assess me nts a n d Pr o ce d ures 
5. 4. 1  E x pl ai n St u d y a n d O bt ai n Writte n I nf or me d C o nse nt 
I nf or me d c o ns e nt is t o be o btai ne d pri or t o t he start of a n y pr ot oc ol-s pecifie d assess me nts or 
pr oce d ures (i ncl u di n g re q uire d was h o ut of a n y pr o hi bite d me dicati o ns). T he Pri nci pal 
I n v esti gat or or desi g nee is t o disc uss t he st u d y f ull y wit h t he patie nt a n d o btai n writte n I nf or m e d 
C o nse nt. T he writte n I C F is t o be si g ne d b y t he patie nt a n d t he Pri nci pal I n v esti gat or or 
de si g nee. A c o p y of t he si g ne d I C F is t o be gi ve n t o t he patie nt. 
5. 4. 2  M e dic al Hist or y 
Me dical hist or y i n cl u des t he hist or y of t he n e o plastic disease, its s y m pt o ms, fi n di n gs, pre vi o us 
t hera p y, a n d i n vesti gati o ns as well as si g nifica nt past a n d all c o-e xisti n g diseases a n d c urre nt 
me dic ati o ns f or t he pre vi o us 5 years. 
5. 4. 3  Re vie w I ncl usi o n/ E xcl usi o n Criteri a  
At Scree ni n g a n d pri or t o e nr oll me nt, t he I ncl usi o n a n d E x cl usi o n Criteria will be re vie we d b y 
t he Pri nci pal I n vesti gat or or ot her q ualifie d h ealt h care pr ofessi o nal t o e ns ure t hat t he patie nt 
q ualifies f or t he st u d y.  
5. 4. 4  P h ysic al E x a mi n ati o n 
A c o m plete p h ysical e x a mi nati o n, i ncl u di n g a des cri pti o n of e xter nal si g ns of t he ne o plastic 
disease a n d c o- m or bi dities is perf or me d at Scree ni n g a n d t he Safet y F oll o w- u p/ M o nt h 3 F oll o w-
u p Visi t. A p h ysical e x a mi nati o n is o nl y perf or m e d at all ot her visits if it is dee me d cli nicall y 
necessar y. P h ysic al e x a mi nati o ns are t o be c o m plete d b y a p h ysicia n or ot h er healt hcare 
pr of essi o nal lice nse d t o p erf or m s uc h e x a mi nati o ns. Fi n di n gs will be d oc u me nte d i n t he patie nt's 
me dic al rec or d a n d o n t h e a p pr o pri ate C R F pa ges. A n y a b n or malities after e nr oll me nt are t o b e 
rec or de d o n t he A E C R F. 
5. 4. 5  Vit al S i g n Assess me nts 
Te m perat ur e, bl o o d press ure, a n d heart rat e are t o be rec or de d at Scree ni n g, at t he Treat me nt Visit, 
a n d t he Safet y F oll o w- u p/ M o nt h 3 F oll o w- u p Visit.  
5. 4. 6  Cli n ic al L a b or at or y Tests 
A l ocal la b orat or y will be use d t o pr ocess all cli nical s peci me ns. T h e f oll o wi n g cli nical 
la b orat or y para meters will be e val uate d i n t his st u d y: 
 C B C  - T he res ults of t he la b orat or y ass ess me nts s h o ul d be e val uate d a n d me dicall y 
acce pte d b y t he res p o nsi ble p h ysicia n f or t he assess me nt of cli nical si g nifi ca nt 
a b n or malities.   
 C he mistr y P a nel  - C o m pre he nsi ve c he mistr y a n d electr ol ytes i ncl u di n g B U N, 
creati ni ne, A S T/ S G O T, A L T/ S G P T, al kali ne p h os p hatase, a n d al b u mi n. T he res ults of 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 4  
t he la b orat or y assess me nts s h o ul d be e val uate d a n d me dicall y acce pte d b y t he 
res p o nsi ble p h ysi cia n f or t he assess me nt of cli nical si g nifica nt a b n or malities. 
 Ur i n al ysis - Uri nal ysis will be perf or me d usi n g uri ne di pstic ks. 
5. 4. 7  Ur i ne C yt ol o g y 
Uri ne c yt ol o g y will be o btai ne d f or all patie nts at Scree ni n g ( or u p t o 4 5 da ys pri or t o si g ni n g of 
i nf orme d c o nse nt), Treat me nt Visit 1, e ver y 3 m o nt hs ( ±3 0 da ys) (calc ulat e d fr o m date of 
T U R B T) f or 2 years a n d t he n e ver y 6 m o nt hs ( ± 6 0 da ys ) u nti l eit her a c o nfir me d t u m or 
rec urre nce or t he E n d- of- St u d y, w hic he v er occ urs first. At Scree ni n g, if a p atie nt has a p ositi ve 
cyt ol o g y f or a mali g na n c y, i ma gi n g of t he u p p er ge nit o uri nar y tract s h o ul d be c o n d ucte d t o 
c o nfir m t hat t here is n o u p per tract mali g na ncies. I ma gi n g m o dalit y ca n i ncl u de c o ntrast C T , 
M R I, or ultras o u n d wit h retr o gra d e p yel o gra ms. If a patie nt is c o nfir me d t o ha ve a dise ase of 
u p pe r tract or pr ostatic uret hra, t he patie nt is c o nsi dere d n ot eli gi ble f or t h e st u d y a n d n o ot her 
st u d y rel ate d pr oce d ures s h o ul d ta ke place.  
Si milarl y, at a n y ti me p oi nt d uri n g t he f oll o w- u p, if a patie nt has a p ositi ve c yt ol o g y t hat ca n n ot 
be  e x plai ne d b y bla d d er fi n di n gs or bla d der pat h ol o g y, i ma gi n g s h o ul d be c o n d ucte d t o c o nfir m 
t hat t here are n o u p per tract mali g n a ncies a n d t hat t he pr ostatic uret hr a is e x cl u de d as a reser v oir.  
5. 4. 8  C yst osc o p y 
C yst osc o p y will be perf or me d at Scree ni n g ( or u p t o 4 5 da ys pri or t o si g ni n g of i nf or me d 
co nse nt), e v er y 3 m o nt hs ( ± 3 0 da ys) fr o m t he d ate of T U R B T f or t he first 2 years, a n d e ver y 
6 m o nt hs ( ± 6 0 da ys) u ntil eit her a c o nfir me d t u m or rec urre n ce or t h e E n d- of -St u d y, w hic h e ver 
oc c urs first. A n o p erati ve re p ort s h o ul d c o ntai n t he n u m ber, siz e a n d l ocati o n of t he t u m ors. All 
lesi o ns s h o uld be bi o psie d a n d se nt f or p at h ol o gical re vie w; rec urre n ces are t o be re p orte d o n t he 
ap pr o priate C R F. All cli nical decisi o ns will be ma de base d o n t he l ocal pat h ol o gist’s re p ort. All 
pat h ol o g y re p orts m ust i ncl u de t he t u m or sta ge a n d gra de f or eac h lesi o n re m o ve d.  
5. 4. 9  T U R B T 
T U R B T will be perf or me d acc or di n g t o eac h site’s sta n dar d o perati n g pr oce d ure. A n o perati ve 
re p ort s h o ul d i ncl u de n u m ber, size, a n d l ocati o n of t he t u m ors re m o ve d. T he se ve n bla d der 
regi o ns are: d o me, l eft a n d ri g ht lateral walls, a nteri or a n d p osteri or walls, tri g o ne, a n d bla d der 
ne c k. Eac h t u m or/lesi o n resect e d d uri n g T U R B T s h o ul d be s u b mitte d t o t he l ocal pat h ol o g y la b 
i n a se parate c o ntai ner, n oti n g t he l ocati o n, t o e ns ure t hat t he t u m or sta ge a n d gra de f or eac h 
lesi o n is assesse d. All hist ol o g y s peci me ns will be rea d b y a l o cal pat h ol o gist a n d all pat h ol o g y 
rep orts m ust i ncl u de t he l ocati o n, size, sta ge, a n d gra de f or eac h t u m or/lesi o n re m o ve d acc or di n g 
t o the 2 0 0 4 W H O/I S U P gra di n g s yst e m al o n g wit h t he prese n ce/a bse n ce of m uscle fi ber i n t he 
lesi o n.  
P atie nts wit h si g nifica nt c o m plicati o ns fr o m T U R B T (ie, bla d d er perf orati o n, o n g oi n g blee di n g) 
s h o ul d n ot recei ve st u d y dr u g. Wit hi n t he a d mi nistrati o n wi n d o w ( 6 0 ± 3 0 mi n utes p ost-
T U R B T), st u d y dr u g a d mi nistrati o n s h o ul d be dela ye d t o all o w f or res ol uti o n of si g nifica nt 
blee di n g. If si g nifica nt bl ee di n g d oes n ot st o p, decisi o n t o a d mi nister t he dr u g s h o ul d be left t o 
t he St u d y I n vesti gat or.  
All cli nical decisi o ns will be ma de base d o n t h e l ocal pat h ol o gist’s re p ort. F oll o wi n g st u d y 
treat me nt o n Da y 1, p at h ol o g y will be re vi e we d b y t he St u d y I n vesti gat or a n d if t he patie nt’s 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 5  
t u m or(s) is ot her t ha n l o w- t o i nter me diate-ris k N MI B C, t he patie nt will b e disc o nti n ue d fr o m 
t he st u dy a n d ret ur n at D a y 3 5 ( ± 5 da ys) f or a Safet y F oll o w- u p Visit.  
5. 4. 1 0  A d verse E ve nt  
At e ver y visit, t he I n vesti gat or or desi g nee will q uesti o n t he patie nt a b o ut a d verse e v e nts a n d 
i nterc urre nt ill nesses si nce t he last visit, acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI) 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Versi o n 4. 0 3 f or A E gra di n g, a n d 
will  rec or d t he p erti ne nt i nf or mati o n o n t he C R F.  
Fr o m t he ti me t he st u d y I nf or me d C o nse nt is si g ne d t hr o u g h t he da y of st u d y dr u g 
a d mi nistrati o n, o nl y S A Es t hat are relate d t o st u d y pr oce d ures are t o be rec or de d. F or all n o n-
Tar get p o p ulati o n patie nts, all a d verse e ve nts fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil 
Da y 3 5 ( ± 5 da ys) p ost- T U R B T will be rec or de d. F or Tar get p o p ulati o n patie nts, all a d verse 
eve nts will be rec or de d fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil t he 3- m o nt h F oll o w- u p 
Visit. O nl y deat hs a n d A Es relate d t o st u d y pr oce d ures will be rec or de d fr o m t he 3 m o nt h visit 
u ntil t he E n d- of- St u d y. 
5. 4. 1 1  C o nc o mit a nt Me dic ati o ns 
All me dicati o ns a d mi nistere d fr o m t he ti me I nf or me d C o nse nt is si g ne d u ntil 3 5 da ys p ost 
T U R B T will be rec or de d o n t he C R F. After 3 5 d a ys, u ntil patie nt disc o nti n ues fr o m st u d y, o nl y 
ad diti o nal treat me nt f or N MI B C are t o be rec or de d. Start a n d st o p dates a n d reas o ns f or 
me dicati o n use will be n ote d. 
6  S T U D Y D R U G A N D P H A R M A C E U TI C A L I N F O R M A TI O N 
6. 1  Q a p z ol a a n d Pl ace b o 
Qa pz ola a n d place b o will be s u p plie d b y S pectr u m. 
6. 1. 1  C o m p ositi o n of Q a pz ol a  
Qa pz ola f or i ntra vesi cal i nstillati o n is a sterile, n o n- p yr o ge nic, l y o p hilize d pr o d uct s u p plie d i n 
t w o 1 0 m L cle ar glass vi als. Eac h vial c o nt ai ns 4. 6 m g  a p azi q u o ne, 5 7. 9 m g  ma n nit ol, a n d 
5. 8 m g  s o di u m bicar b o nate. After rec o nstit uti o n, Qa pz ola has a re d dis h a p peara n ce si milar t o 
t hat of cra n b err y j uice. 
6. 1. 2  C o m p ositi o n of Pl ace b o 
Matc hi n g pla ce b o c o ntai ni n g 1 2 m g  F D & C re d # 4 0, 1 5 m g  s o di u m c hl ori de, a n d 1 0 m g  ma n nit ol 
is su p plie d i n i de ntical a p peari n g vials. Rec o nstit uti o n a n d i nstillati o n pr oce d ures f or place b o are 
t he same as f or Qa pz ola.  
6. 1. 3  C o m p ositi o n of Dil ue nt f or Q a pz ol a a n d Pl ace b o 
T he dil ue nt f or Qa pz ola is a sterile s ol uti o n s u p plie d i n a t w o 5 0 m L clear T y pe I glass vials. 
Eac h vial c o ntai ns 4 1. 2 m L of t he dil ue nt c o ntai ni n g s o di u m bicar b o nate, pr o p yle ne gl yc ol, 
dis o di u m E D T A, a n d sterile water f or i njecti o n.  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 6  
T he dil ue nt f or place b o is a sterile s ol uti o n s u p plie d i n a t w o 5 0 m L clear T y pe I glass vials. 
Ea c h vial c o ntai ns 4 1. 2 m L of t he dil ue nt c o ntai ni n g 0. 9 % s o di u m c hl ori d e i n sterile water f or 
i njecti o n. 
6. 1. 4  S hi p pi n g a n d St or a ge of St u d y Dr u g 
St u d y dr u g is s hi p pe d o n c o ol pac ks i n i ns ulate d c o ntai ners, a n d  s h o ul d be st ore d i n a sec ure area 
wit h li mite d access. St u d y dr u g is t o be refri gerat e d (a p pr o xi matel y 2° C t o 8° C) i n a sec ure area 
an d s h o ul d be pr otect e d fr o m direct li g ht. Dil ue nt f or st u d y dr u g ma y be refri gerate d or st ore d at 
r o o m te m perat ur e. 
6. 2  D ose , R o ute of A d mi nistr ati o n, a n d Sc he d ule of St u d y Dr u g 
6. 2. 1  D ose  a n d R o ute of A d mi nistr ati o n of St u d y Dr u g 
Ra n d o mize d patie nts will recei v e eit her Qa pz ola 8 m g  i n 5 0 m L of d ose s ol uti o n or matc hi n g 
plac e b o. Rec o nstit uti o n a n d d ose pre parati o n pr oce d ures are o utli ne d i n t he P har mac y Ma n u al. 
T he  5 0 m L d os e s ol uti o n of st u d y dr u g is t o be i nstille d i nt o t he bla d der via a n i n d welli n g 1 0 0 % 
S ilic o ne F ole y cat h eter, w here it is t o be ret ai ne d f or 6 0 ± 5 mi n utes.  
6. 2. 2  S c he d ule of St u d y Dr u g A d mi nistr ati o n 
A si n gle d ose of st u d y dr u g o n D a y 1 is t o be a d mi nistere d at 6 0 ±  3 0 mi n utes p ost- T U R B T. 
Wit hi n t he a d mi nistrati o n wi n d o w ( 6 0 ± 3 0 mi n utes p ost T U R B T), st u d y dr u g a d mi nistrati o n 
s h o ul d be dela ye d t o all o w f or res ol uti o n of si g nifica nt blee di n g. Patie nts n ot ca n di dates f or p ost-
o perati ve i ntra v esical c h e m ot hera p y aft er fr o m T U R B T (ie, e xte nsi ve res ecti o n, bla d der 
pe rf orati o n, o n g oi n g ble e di n g) s h o ul d n ot recei ve st u d y dr u g. 
6. 2. 2. 1  Pre p ar ati o n of St u d y Dr u g 
Pre parati o n of st u d y dr u g d ose s ol uti o n s h o ul d f oll o w directi o ns as des cri be d i n t he P har mac y 
Ma n ual. E q ui p me nt nee d e d: Dr u g kit ( T w o 4. 6 m g  vials of Qa pz ola or place b o a n d t w o vials of 
Dil ue nt), o ne 5 0 m L or 6 0 m L L uer-l o k s yri n ge, o ne 1 0 m L s yri n ge wit h 0. 2 m L mar ki n g, o n e 5-
1 0 m L s yri n ge, 1 8 ga u ge nee dle, pr ote cti ve cl ot hi n g. 
If st u d y dr u g is rec o nstit ute d, a n d n ot use d wit hi n 2 h o urs, it m ust  be discar de d; res u p pl y of ne w 
st u dy dr u g kits ma y n ot al wa ys b e p ossi ble i n a reas o na ble ti me. T heref ore, patie nt eli gi bilit y 
s h o uld be c o nfir me d pri or t o dr u g rec o nstit uti o n.  
6. 2. 2. 2  
I nstill ati o n of St u d y Dr u g  
F oll o wi n g drai na ge, st u d y dr u g is t o be i nstille d i nt o t he bla d der via a 1 0 0 % Silic o ne F ole y 
cat heter at 6 0 ± 3 0 mi n ut es p ost- T U R B T. A de q uate he m ostasis s h o ul d be o btai ne d, a n d t he uri ne 
s h o ul d a p pear vis uall y cl ear ( N o macr osc o pic e vi de nce of bl ee di n g) b ef ore st u d y dr u g 
i nstillati o n. Wit hi n t he a d mi nistrati o n wi n d o w ( 6 0 ± 3 0 mi n utes p ost T U R B T), st u d y dr u g 
a d mi nistrati o n s h o ul d be dela ye d t o all o w f or res ol uti o n of si g nifica nt blee di n g. Patie nts wit h 
si gnifica nt c o m plicati o ns fr o m T U R B T (ie, bla d der perf orati o n, o n g oi n g bl ee di n g) s h o ul d n ot 
recei v e st u d y dr u g. T he bla d der s h o ul d be e m ptie d bef ore i nstilli n g t he st u d y dr u g. T h e 5 0 m L of 
t he st u d y dr u g s h o ul d be sl o wl y i nstille d i nt o t he bla d der ta ki n g care n ot t o i ntr o d uce air. W he n 
i nstillati o n is c o m plete, t he F ole y cat heter s h o ul d be cla m pe d f or 6 0 mi n utes ( ± 5 mi n utes).  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 7  
If d uri n g t he rete nti o n peri o d, t here is a n y lea ka ge ar o u n d t he cat heter, t h e a m o u nt of st u d y dr u g 
lea ke d s h o ul d be esti mat e d a n d rec or de d. After 6 0 mi n utes ( ± 5 mi n utes) of rete nti o n, t he bla d der 
c o nte nts s h o ul d be drai ne d a n d t he drai ne d bl a d der c o nte nts dis p ose d of acc or di n g t o 
i nstit uti o nal p olic y. T he i nstit uti o n’s r o uti ne g ui deli nes f or t he p ost o perati v e care s h o ul d be 
f oll o we d. 
N o di uretics are all o we d pri or t o i nstillati o n o n t he st u d y dr u g i nstillati o n da ys. St u d y dr u g 
s h o ul d n ot be i nstille d if a s u bcli nical or cli nical bla d der perf orati o n is s us pecte d. 
6. 3  Dis p os al of St u d y Dr u g 
At t he e n d of t he 6 0 ± 5 mi n utes peri o d of rete nti o n, st u d y dr u g s h o ul d be caref ull y 
drai ne d / v oi de d i nt o a s uita ble c o ntai ner, a n d dis p ose d of acc or di n g t o t he i nstit uti o n’s p olicies 
f or dis p osal of hazar d o us waste. 
6. 4  P r o d uct Acc o u nt a bilit y 
T he site a n d/ or t he p har mac y m ust mai ntai n acc urate acc o u nti n g of i n vesti gati o nal pr o d u ct. 
D uri n g  t h e st u d y, t he f oll o wi n g i nf or m ati o n m ust be rec or de d: 
 Date of recei pt, q ua ntit y a n d i de ntificati o n of t he pr o d uct recei ve d fr o m t he S p o ns or. 
 ID n u m ber of t h e patie nt t o w h o m t he pr o d uct is dis pe nse d. 
 T he  date(s) a n d q ua ntit y of t he pr o d uct dis pe nse d. 
 Da tes a n d q ua ntit y of pr o d uct ret ur ne d, l ost or acci de ntall y or deli beratel y d estr o ye d. 
Acc o u nta bilit y Rec or ds will be pr o vi de d b y t h e S p o ns or. T he y m ust be ke pt c urre nt a n d m ust b e 
rea dil y a vaila bl e f or i ns p ecti o n. 
T he I n vesti gat or s h o ul d n ot ret ur n cli nical st u d y materials t o t he S p o ns or u nless s pecificall y 
i nstr ucte d t o d o s o b y t he S p o ns or. All use d vials of st u d y dr u g a n d dil ue nt s h o ul d be destr o ye d 
per t he  i nstit uti o n’s p olic y. 
All e x pire d vials of st u d y dr u g a n d dil ue nt s h o ul d be retai ne d. T he Cli nical Researc h Ass ociate 
(C R A ) will peri o dicall y c o n d uct a n acc o u nta bilit y of t he e x pire d st u d y dr u g a n d dil ue nt a n d 
a ut h orize t heir destr ucti o n. If t he partici p ati n g p h ar mac y is pr o hi bite d b y i nstit uti o nal p olic y 
fr o m retai ni n g e x pire d vi als, t he i n vesti gati o nal p h ar macist will t he n be res p o nsi ble f or 
d oc u me nti n g t he d estr ucti o n of t he vials. 
6. 5  Tre at me nt Bli n di n g Pr oce d ures 
T his st u d y is d o u ble- bli n d wit h res pect t o treat me nt assi g n me nt; all st u d y p artici pa nts (ie, 
s u bject, st u d y staff i ncl u di n g t he p h ysicia n, a n d all n o n-st u d y i n di vi d uals) a n d t he S p o ns or 
re mai n blin de d u ntil t he st u d y is c o m plete a n d u n bli n de d. A n i n de pe n de nt d ata m o nit ori n g 
c o m mittee (I D M C) will be esta blis he d t o re vie w safet y data f or t he first 3 0 treate d patie nts i n t he 
st u dy. T he I D M C will als o c o n d uct t he f utilit y a n al ysis of t he u n bli n de d d ata as des cri be d i n 
Secti o n 8. 1 . T he details f or t he I D M C will be pr o vi de d i n a se parate C hart er. A n I W R S will be 
set u p wit h a p pr o priate access str uct ur e i n or der t o kee p t he a b o v e st u d y t ea m bli n de d. P har mac y 
will ha ve access t o t he I W R S t o get t he treat me nt all ocati o n.  
T he patie nts e nr olle d i n t his st u d y will be ra n d o mi ze d i n a 2 : 1 rati o t o eit her:  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 8  
 Ar m 1 : o n e i nstillati o n of 8  m g  Qa pz ola 
 Ar m 2: o n e i nstillati o n of place b o   
I n t he cas e of a si g nifica nt safet y c o ncer n, a p atie nt’s treat me nt ma y be u n bli n de d. T he 
I n v esti gat or s h o ul d first c o ntact t he Me dical M o nit or i m me diatel y t o disc uss a n d a gree o n t he 
mer its a n d nee d f or u n bli n di n g a p atie nt’s treat me nt. T he reas o ns a n d rati o nale f or brea ki n g t he 
treat me nt bli n d will be d oc u me nte d i n writi n g a n d mai ntai ne d i n t he st u d y file.  
6. 6  R a n d o miz ati o n 
After patie nts ha v e bee n f o u n d t o be eli gi ble f or i ncl usi o n i n t he st u d y a n d pri or t o T U R B T t he 
site will re q uest ra n d o mi zati o n a p pr o val fr o m t he Me dical M o nit or. T he patie nt m ust n ot 
u n der g o T U R B T u ntil t he y h a ve b ee n ra n d o mize d. 
A ra n d o mizati o n sc he me usi n g per m ute d bl o c k desi g n will be de vel o p e d. A n I V R S/I W R S 
s yste m will be use d t o assi g n ra n d o mizati o n I D o nce patie nts meet eli gi bilit y criteria a n d are 
rea d y t o be ra n d o mize d. T he ra n d o mizati o n c o de will be differe nt t ha n Pati e nt I D t hat has bee n 
assi g ne d t o a patie nt a n d a ma p pi n g of ra n d o mizati o n I D- Patie nt I D will be ke pt i n a sec ure d 
data base.  
6. 7  N o n - St u d y Tre at me nts 
6. 7. 1  P ri o r a n d C o nc o mit a nt Me dic ati o ns 
All me dicati o ns a d mi nistere d fr o m t he ti me I nf or me d C o nse nt is si g ne d u ntil 3 5 da ys p ost 
T U R B T will be rec or de d o n t he C R F. After 3 5 d a ys, u ntil patie nt is disc o nti n ue d, o nl y 
me dic ati o ns t o treat N MI B C are t o b e rec or de d. St art a n d st o p dates a n d reas o ns f or me dicati o n 
use  will be n ote d. Patie nts ma y use aceta mi n o p he n or a nti p yretics t o ma na ge si de effects 
ass ociate d wit h T U R B T a n d a d mi nistrati o n of st u d y dr u g.  
T he I n vesti gat or ma y als o prescri be st a n dar d p ost- o perati ve m e dicati o ns.  
6. 7. 2  P r o hi bite d Me dic ati o ns 
F oll o wi n g D a y 1 treat me nt a n d pri or t o rec urre n ce, patie nts i n t he Tar get P o p ulati o n s h o ul d n ot 
recei v e ot her me dicati o ns t o treat bla d der ca ncer. If a patie nt starts a n ot her t hera p y f or bl a d der 
ca ncer d uri n g t he f oll o w- u p peri o d, t he patie nt will be wit h dra w n fr o m t he st u d y.  
N o di ur etics are all o we d pri or t o i nstillati o n o n st u d y dr u g i nstillati o n da y. Patie nts s h o ul d ha ve 
at least a 7- t o 1 0- d a y was h o ut peri o d f or all a ntic oa g ul a nts, i ncl u di n g l o w- d ose as piri n. 
7  S A F E T Y A S S E S S M E N T 
7. 1  S afet y Me as ures 
It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o o versee t he s afet y of t he s u bjects at t heir 
site a n d t o re p ort all A Es/ S A Es t hat are o bser ve d or re p orte d d uri n g t he st u d y, re gar dl ess of 
relati o ns hi p t o st u d y dr u g or cli nical si g nifi ca nce.  
Safet y d ata will als o be re vie we d o n a re g ular basis b y S pectr u m’s st u d y m o nit ori n g tea m, w hic h 
i ncl u des a Cli nical Researc h Ass ociate ( C R A), t he Me dical M o nit or, a n d ot her pers o n nel fr o m 
t he c o m pa n y or its desi g nee. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
3 9  
A d verse e ve nts will be c haract erize d b y i nte nsit y (se verit y), ca usalit y, a n d seri o us ness b y t he 
I n v esti gat or base d o n t h e re g ulat or y defi niti o ns i n cl u de d bel o w. 
T his st u d y will utilize t he Nati o nal Ca ncer I nstit ute ( 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) Scale Versi o n 4. 0 3 f or A E gra di n g. 
7. 2  A d ver se E ve nts 
A n A E is defi ne d as a n y u nt o war d me dical o cc urre nce i n a patie nt or cli nical i n vesti gati o n 
patie nt, te m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct or st u d y pr oce d ure, w het h er or 
n ot c o nsi dere d relate d t o t he me dici nal pr o d uct. T heref ore, a n A E ca n be a n y u nfa v ora bl e a n d 
u ni nte n de d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or 
e x acer bate d) te m p orall y ass ociate d wit h t he use of a me dici nal pr o d u ct. A treat me nt-e mer ge nt 
A E ( T E A E) is a n y A E t h at occ urs fr o m t he first d ose of st u d y tr eat me nt u ntil 3 5 da ys aft er t he 
last d ose of st u d y dr u g a d mi nistrati o n.  
Fr o m t he ti me t he st u d y I nf or me d C o nse nt is si g ne d t hr o u g h t he da y of st u d y dr u g 
a d mi nistrati o n, o nl y S A Es t hat are relate d t o st u d y pr oce d ures are t o be rec or de d. F or all n o n-
Tar get p o p ulati o n patie nts, all a d verse e ve nts fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil 
Da y 3 5 ( ± 5 da ys) p ost- T U R B T will be rec or de d. F or Tar get p o p ulati o n patie nts, all a d verse 
e vents will be rec or de d fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil t he 3- m o nt h F oll o w- u p 
Visit. O nl y deat hs a n d A Es relate d t o st u d y pr oce d ures will be rec or de d fr o m t he 3 m o nt h visit 
u ntil t he E n d- of- St u d y. T he st u d y will rec or d all A Es acc or di n g t o t he i nf or mati o n i n 
S ecti o n 7. 3 . 
E x a m ples of A Es i ncl u de: 
 E x acer bati o n of a c hr o ni c or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
 Ne w c o n diti o ns detect e d or dia g n os e d after i n vesti gati o nal pr o d u ct a d mi nistrati o n. 
 S i g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g i nteracti o n. 
 S i g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her 
i n vesti gati o nal pr o d u ct or a c o nc urre nt me di cati o n. 
 A Es ma y i n cl u de pre-treat me nt or p ost-treat me nt e ve nts t hat occ ur as a res ult of pr ot oc ol-
ma n date d pr oce d ures, ie, i n vasi ve pr oce d ures. 
A b n or mal la b orat or y res ults are t o be rec or de d as A Es, if a n y of t he f oll o wi n g c o n diti o ns are 
met: 
 T he  a b n or mal la b orat or y val ue lea ds t o a t hera p e utic i nter ve nti o n. 
 T he a b n or mal la b orat or y val ue is c o nsi dere d t o b e cli nicall y si g nifica nt b y t he 
I n v esti gat or. 
 T he a b n or mal la b orat or y val ue is pre defi ne d as a n A E i n t he pr ot oc ol or i n a n ot her 
d oc u me nt c o m m u nicate d t o t he I n v esti gat or b y S pectr u m or desi g nee. 
E x a m ples of e ve nts t hat d o n ot c o nstit ute A Es i ncl u de: 
 Me dical or s ur gic al pr oc e d ures (e g, e n d osc o p y, a p pe n dect o m y); t he c o n diti o n t hat lea ds 
t o t he pr oce d ure is a n A E. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 0  
 Sit uati o ns w here a n u nt o war d me dical occ urre n ce d oes n ot occ ur (e g, s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital). 
 A ntici pa te d da y-t o- d a y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n. 
 P la n ne d a n d pres c he d ule d h os pitalizati o ns a n d pr oce d ures.  
 P r o gressi ve disease. 
7. 3  G ui deli nes f or Rec or di n g a n d Attri b uti o n Sc ori n g of A d verse E ve nts 
Ti mel y a n d c o m plete re p orti n g of all A Es is re q uire d f or all patie nts. M o nit ori n g a n d 
d oc u me ntati o n of all A Es all o ws f or i de ntificati o n of p ote ntial st u d y- dr u g or d ose-relate d A Es, 
a n d f or a d h ere n ce t o r e g ulat or y re q uire m e nts. Please refer t o t he C R F C o m pleti o n G ui deli nes 
l ocate d i n t he st u d y bi n d er f or detaile d i nstr ucti o ns f or A E re p orti n g. 
7. 3. 1  Re c or di n g of A d verse E ve nts 
Fr o m t he ti me t he st u d y I nf or me d C o nse nt is si g ne d t hr o u g h t he da y of st u d y dr u g 
a d mi nistrati o n, o nl y S A Es t hat are relate d t o st u d y pr oce d ures are t o be rec or de d. F or all n o n-
Tar get p o p ulati o n patie nts, all a d verse e ve nts fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil 
Da y 3 5 ( ± 5 da ys) p ost- T U R B T will be rec or de d. F or Tar get p o p ulati o n patie nts, all a d verse 
e ve nts will  be rec or de d fr o m t he ti me of st u d y dr u g a d mi nistrati o n u ntil t he 3- m o nt h F oll o w- u p 
Visit. O nl y A Es rel ate d t o st u d y pr oce d ures a n d d eat hs will be rec or de d fr o m t he 3 m o nt h visit 
u ntil a rec urre nce or t he re mai n der of t h e f oll o w- u p peri o d, w hic he v er c o m es first.  
All A Es s h o ul d i ncl u de res ol uti o n at t he E n d- of- St u d y f or a patie nt. T he f oll o wi n g c o n ve nti o ns 
s h o ul d be f oll o we d w hen patie nt c o m pletes or disc o nti n ues fr o m t he st u d y 
 If a patie nt dies, t he d ate of deat h s h o ul d be t he d ate of A E st o p f or all o n g oi n g A Es at 
t he ti me of deat h. 
 If a patie nt disc o nti n ues st u d y dr u g d u e t o a n A E(s), t he o utc o me of t he A E is t o be 
f oll o we d f or 3 5 d a ys ( ± 5 da ys) fr o m t he d ate of disc o nti n uati o n or u ntil t he A E has 
ret ur ne d t o Gra de ≤1 or ret ur ne d t o baseli ne c o n diti o ns f or t he patie nt.  
T he stat us of t he A E a n d t he date of last c o nt act wit h t he patie nt will be ca pt ure d. If t he A E has 
n ot ret ur ne d t o Gra de ≤1 or t o Bas eli ne c o n diti o ns f or t he patie nt b y t he E n d- of- St u d y, t h e A E 
st o p date s h o ul d be left as o n g oi n g. 
All A Es will be classifie d b y i nte nsit y/s e verit y (S ecti o n 7. 3. 2 ), relati o ns hi p t o st u d y dr u g 
(Secti o n 7. 5 ), a n d as seri o us or n o nseri o us (Secti o n 7. 7 ). 
7. 3. 2  G r a di n g of A d verse E ve nts 
T his st u d y will utilize t he N CI C T C A E Versi o n 4. 0 3 f or A E gra di n g. 
7. 4  F oll o w- u p of A d verse E ve nts 
All A Es a n d si g nifica nt a b n or mal la b orat or y v al ues are t o be f oll o w e d u p i n acc or da nce wit h t he 
I nter natio nal C o nfere nce o n Har m o nizati o n (I C H) G o o d Cli nical Practice ( G C P) g ui deli nes, a n d 
ot her a p plic a ble re g ulat or y re q uire m e nts (e g, U nit e d States [ U S ] C o de of Fe deral Re g ul ati o ns 
[ C F R]). 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 2  
( 2 1 C F R 3 1 2. 3 2, I C H of Tec h nical Re q uir e me nts f or Re gistrati o n of P har mace uticals f or H u ma n 
Use E 2 A G ui deli ne) as t h ose A Es t hat meet a n y of t he f oll o wi n g criteri a: 
 Res ults i n deat h 
 Is life-t hreate ni n g ( Gra de 4): ie, a n y e ve nt t hat, i n t he o pi ni o n of t he I n vesti gat or, p os es 
a n i m me diate ris k of deat h fr o m t hat e ve nt 
 Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n (e x cl u di n g 
h os pitaliz ati o ns f or st u d y t hera p y, diseas e-relate d pr oce d ures, or place me nt of a n 
i n d welli n g cat heter, u nless ass ociate d wit h ot her S A Es) 
 R es ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 R es ults i n a c o n ge nital a n o mal y/ birt h defect 
 In cl u des i m p orta nt me dic al e ve nts t hat ma y n ot be i m me diatel y life t hr eate ni n g or res ult 
i n deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt or ma y re q uir e i nter ve nti o n t o 
pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n 
A d ve rse e ve nts t hat d o n ot meet a n y of t he a b o v e criteria f or seri o us s h o ul d be re gar de d as n o n-
seri o us. 
7. 7. 1  S eri o us A d verse E ve nt Re p orti n g 
Fr o m t he ti me t he I nf or m e d C o nse nt is si g ne d u ntil Da y 1 of t he st u d y, o nl y S A Es relate d t o 
st u d y pr oce d ures will be rec or de d. All S A Es t hat occ ur fr o m t he first d ose of st u d y dr u g 
a d mi nistrati o n u ntil Da y 3 5 ( ± 5 da ys) p ost- T U R B T will be rec or de d. All S A Es relate d t o st u d y 
pr oc e d ures will be rec or de d f or t he re mai n der of t he f oll o w- u p peri o d a n d are t o be re p orte d t o 
S pectr u m wit hi n 2 4 h o urs of k n o wle d ge of t h e e v e nt.  
S A Es are t o be re p orte d a n d t he seri o us a d v erse e ve nt re p ort ( S A E R) fa x e d or e maile d wit hi n 2 4 
h o urs of  k n o wle d ge of t he e ve nt t o: 
S pectr u m P h ar m ace uti c als, I nc. 
P ri m ar y C o nt a ct: P h ar m a c o vi gil a nce De p art me nt 
F a x: 
 
E- m ail: 
 
S pectr u m or its desi g n ee ma y re q uest a d diti o nal i nf or mati o n fr o m t he I n v esti gat or t o e ns ure t he 
ti mely c o m pleti o n of acc urate safet y re p orts. Safet y dat a t hat are critical t o t he re p ort a bilit y of a n 
S A E, s uc h as ca us alit y assess me nt a n d seri o us criteria, s h o ul d be i ncl u de d i n t he i nitial fa x e d 
S A E R. If o mitte d, a ti mel y res p o ns e t o dr u g safet y dat a q ueries recei ve d fr o m S pectr u m or a 
S pectr u m desi g n ee is e x pecte d. 
T he I n vesti gat or is t o ta k e all a p pr o pri ate t hera pe utic meas ures necessar y f or res ol uti o n of t he 
S A E. A n y me di cati o ns necessar y f or tr eat me nt of t he S A E are t o be rec or de d i n t he c o nc o mita nt 
me dic ati o n secti o n of t he patie nt’s C R F. 
S A Es t hat are st u d y-treat me nt relate d will be f oll o we d u ntil res ol uti o n or u ntil t he y ha ve ret ur n e d 
t o Baseli ne/ Gra de 1, w hi c he ver is l o n ger, or u ntil it is deter mi ne d t hat t he o utc o me will n ot 
c ha n ge wit h f urt her f oll o w- u p. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 3  
A d diti o nall y, t he S A E is t o be e ntere d i n t he A E s ecti o n of t he C R F. F oll o w- u p S A E Rs nee d t o 
be s u b mitte d t o S pectr u m wit hi n 2 4 h o urs, o nce a d diti o nal i nf or mati o n re gar di n g t h e e ve nt 
bec o mes a v aila ble (e g, dia g n osis is ma de, la b orat or y or test res ults, e ve nt c o urse, o utc o me, et c).  
S pectr u m/ desi g n ee will b e res p o nsi ble f or re p orti n g S A Es t o t he re g ulat or y a ut h orities i n 
acc or da nce wit h a p plica ble e x pe dite d re p orti n g re g ulat or y g ui deli nes. T he I n v esti gat or is 
res p o nsible f or s u b mitti n g S A Es t o his/ her I nstit uti o nal Re vie w B o ar d (I R B)/ Et hics C o m mittee 
(E C ). C o pies of eac h S A E R, a n d d oc u me ntati o n of I R B/ E C n otificati o n a n d ac k n o wle d ge me nt 
of re cei pt, will be ke pt i n t he Site’s Re g ulat or y Bi n der. 
7. 7. 2  E xcl usi o ns t o Seri o us A d verse E ve nt Re p orti n g Re q uire me nts 
T he f oll o wi n g are n ot c o nsi dere d S A Es: 
 S it uati o ns w here a n u nt o war d me dical occ urre n ce di d n ot occ ur (e g, s o cial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital, h os pitalizati o n f or dia g n ostic tests s uc h as C T 
sca ns) 
 A ntici pa te d da y-t o- d a y fl uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d pri or t o first st u d y treat me nt a d mi nistrati o n t hat d o n ot w orse n 
 P la n ne d a n d pres c he d ule d h os pitalizati o ns a n d pr oce d ures  
 P r o gressi ve disease  
7. 8  Re pr o d ucti ve Ris ks 
T o date, t here are n o a de q uate a n d w ell-c o ntr olle d st u dies of Qa pz ola i n pre g n a nt w o me n. 
Be ca use t he re pr o d ucti ve ris ks ha ve n ot bee n st u di e d i n pre g na nt w o me n, Qa pz ola is n ot 
rec o m me n de d f or use d uri n g pre g na n c y. 
Pre g n a ncies i n v ol vi n g a st u d y patie nt or a patie nt’s part ner, t hat occ ur fr o m t he first d ose of 
st u d y treat me nt t hr o u g h 3 5 da ys after t h e last d ose of st u d y treat me nt, m ust be re p orte d wit hi n 
2 4 h o urs after t h e I n vesti gat or h as gai ne d k n o wle d ge of t he e v e nt via fa x or e- mail (see c o ntact 
i nf or mati o n in  Secti o n 7. 7. 1 ). F oll o w- u p i nf or m ati o n re gar di n g t he o ut c o me of t he pre g na nc y 
will be  re q ueste d b y t he S pectr u m P har mac o vi gil a nce De part me nt.  
All patie nts w h o bec o me pre g na nt d uri n g partici pati o n i n t his st u d y are t o be wit h dra w n fr o m t he 
st u d y. 
8  S T A TI S TI C A L D E SI G N A N D A N A L Y SI S 
T his secti o n c o ntai ns a brief o ver vie w of t he statistical a nal yses pla n ne d f or t his st u d y i ncl u di n g 
t he pre-s pecifie d p o w er a n d sa m ple siz e calc ulati o n as well as t he met h o ds f or t he pri mar y 
e n d p oi nt  a nal ysis. A f or mal statistical a nal ysis pl a n ( S A P) will be fi nalize d bef ore d ata bas e l oc k.  
8. 1  S a m ple Size 
T he e nr olle d p atie nts will be ra n d o mize d i n a 2: 1 rati o t o eit her Qa pz ola or place b o. T he pri mar y 
e n d p oi nt is Ti me t o Rec urre nce i n t he Tar get P o p ulati o n. T he pri mar y e n d p oi nt a nal ysis i n v ol ves 
a test of c o m paris o n: 8 m g  Q a pz ola vs. place b o usi n g 2-si de d l o g-ra n k test at 5 % le vel of 
si g nifica n ce.  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 4  
T he sa m ple siz e calc ulati o n ass u mes a hazar d rati o ( H R) of 0. 6 5 bas e d o n t he res ults fr o m 
pre vi o us P hase 3 st u dies of Qa pz ola a n d place b o c o m paris o ns o verall a n d i n t he dr u g i nstillati o n 
ti me wi n d o w 3 1- 9 0 mi n utes p ost- T U R B T as d escri be d i n Secti o n 1. 3. 1. 2  a n d Secti o n 1. 3. 1. 4  
res pecti vel y.  
A p pr o xi matel y 5 0 0 p atie nts will be e nr olle d a n d treate d i n t his st u d y. Accr ual ti me is esti mate d 
as 2 4 m o nt hs a n d f oll o w- u p ti me as 2 4 m o nt hs. F or t he sa m ple siz e calc ulati o n, t he H R of 0. 6 5 is 
ass u med f or t he i m pr o ve me nt i n ti me t o rec urre n ce i n fa v or of Qa pz ola as c o m pare d t o t he 
Place b o wit h a hazar d rat e of 0. 3. I n a 2: 1 ra n d o mizati o n of Qa pz ola a n d Place b o, sa m ple siz es 
of 4 2 5 Tar get disease patie nts ( 2 8 4 i n Qa pz ola a n d 1 4 1 i n Place b o) will pr o vi de 8 5 % p o wer. 
T his sa m ple siz e is esti mate d t o pr o vi de a t otal of 2 0 8 rec urre nce e v e nts d uri n g t he f oll o w- u p 
d urati o n of  at least 2 4 m o nt hs. T he sa m ple siz e calc ulati o n was bas e d o n P A S S 1 4 ( N C S S, L L C, 
Ka ys vil le, Uta h). 
Si nce t he Tar get p o p ulati o n is c o nfir me d b y pat h ol o g y re vi e w a n d t his will be perf or me d after 
patie nts are ra n d o mize d a n d ha ve u n d er g o ne T U R B T pr oce d ure, t he st u d y will acc o u nt f or 
misclassificati o n i n t he Tar get diseas e p o p ulati o n. Acc o u nti n g f or 1 5 % misclassificati o n of 
ra n d o mize d patie nts, t he st u d y will e nr oll a p pr o xi matel y 5 0 0 p atie nts. H o we ver, t he st u d y will 
c o nti n ue t o e nr oll patie nts u ntil t he re q uire d n u m ber of Tar get diseas e patie nts are accr ue d.  
A f utilit y a nal ysis will be perf or me d d uri n g t he st u d y c o n d u ct t o deter mi ne t he st u d y 
c o nti n uati o n. T he f utilit y a nal ysis will be c o n d uct e d i n t he Tar get patie nts o nce 6 0 e v e nts are 
o bser ve d. T he st u d y will be st o p pe d f or f utilit y if t he calc ul ate d z- val ue fr o m t he l o g-ra n k test of 
H R is > 1. 0. N o a dj ust me nt f or m ulti plicit y of c o m paris o n will be ma de f or f utilit y a nal ysis a n d 
t he fi nal a nal ysis will be perf or me d at 5 % le v el of si g nifica n ce.  
At t he ti me of f utilit y a nal ysis, t he decisi o n will be ma de if a d diti o nal s u bjects s h o ul d be 
recr uite d t o e ns ure t hat e n o u g h e v e nts w o ul d be acc u m ulate d at a p pr o xi matel y 2- year f oll o w- u p 
fr o m dr u g i nstillati o n. Base d o n t he e x pecte d e v e nts of 2 0 8 o ut of 4 2 5 s u bjects after 2- year 
f oll o w- u p, it is a ntici pate d t hat t he first 1 2 3 s u bjects s h o ul d ha ve c o m plete d 2- year f oll o w- u p at 
t he time of t he f utilit y a n al ysis. H o we ver, if l o w er o verall rec urre nce rate is o bser ve d, a d diti o nal 
pati e nts i n t he Tar get P o p ulati o n will be recr uite d i n or der t o accr ue t h e re q uire d n u m ber of 
e ve nts.  
T he f utilit y a n al ysis f or t he decisi o n of st u d y c o nti n uati o n a n d a dj ust me nt t o sa m ple siz e will be 
pe rf or med b y t h e I D M C t hat will ha ve access t o t he u n bli n de d data. T he st u d y tea m will be 
bli n de d t o t he treat me nt all ocati o n d uri n g t he f oll o w- u p peri o d. 
8. 2  M et h o d of Tre at me nt Assi g n me nt, R a n d o miz ati o n  
Patie nts w h o meet all eli gi bilit y criteria ma y b e c o nsi dere d f or ra n d o mizati o n. Eli gi bilit y of all 
patie nts will be re vie we d a n d a p pr o ve d f or ra n d o mizati o n b y t he S p o ns or’s Me dical M o nit or, or 
desi g nee. Patie nts a p pr o v e d f or ra n d o mizati o n will be ra n d o mize d 2: 1 t o recei ve o ne i nstillati o n 
of 8 m g  Q a pz ola  or o ne i nstillati o n of place b o.  
T he  ra n d o mizati o n pla n will use a per m ute d bl oc k desi g n a n d will n ot be stratifie d. St u d y dr u g 
kits will c o ntai n eit her vials of Qa pz ola, or place b o a n d will be patie nt s pecific. Patie nts will be 
ra n d o mize d wit hi n a ce nt er. Patie nt n u m bers will be assi g n e d se q u e ntiall y at eac h site.  

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 5  
8. 3  A n al ysis P o p ul ati o ns 
F o ur datas ets will be a nal yz e d: 
 T ar get ( L o w- t o I nter me di ate- Ris k) P o p ul ati o n: all ra n d o mize d patie nts wit h 
co nfir me d l o w- or i nter m e diate-ris k N MI B C as p er t he A U A G ui d eli nes. T he a nal ysis 
p o p ulati o n f or  all effi cac y e n d p oi nts will be t he T ar get (l o w- or i nter me diate-ris k 
N M I B C) P o p ulati o n base d o n l ocal pat h ol o g y.  
 N o n -T a r get P o p ul ati o n : all ra n d o mize d patie nts ot her t ha n t he Tar get P o p ulati o n 
defi ne d a b o v e. N o pri mar y efficac y e n d p oi nt a nal ysis will be pr o vi de d i n t his p o p ulati o n 
as t he y will n ot be u n der f oll o w- u p. O nl y s afet y a nal ysis will be perf or me d usi n g t his 
p o p ulati o n.  
 P er- Pr ot oc ol P o p ul ati o n:  patie nts i n t he Tar get P o p ulati o n e xcl u di n g patie nts wit h 
maj or pr ot oc ol de viati o ns a n d w h o recei ve d a d diti o nal me dicati o ns f or N MI B C d uri n g 
t he f oll o w- u p a n d pri or t o rec urre nce.  
 S afet y P o p ul ati o n : all ra n d o mize d patie nts classifie d acc or di n g t o t he act u al treat me nt 
recei v e d, re gar dless of ra n d o m assi g n me nt.  
8. 4  Ge ner al St atistic al Met h o ds 
S pectr u m’s Bi ostatistics a n d Data Ma n a ge me nt ( B D M) gr o u p will be res p o nsi ble f or data 
ma na ge me nt a n d statistical a nal ysis of t his st u d y. All statistical a nal yses will be perf or me d usi n g 
S A S f or Wi n d o ws ( versi o n 9. 3 or hi g h er). Patie nt data listi n gs a n d ta b ular prese ntati o ns of 
res ults b y tr eat me nt ar ms will be pr o vi de d. F urt h er details of t he criteria a n d c o n d uct of t he 
statistical a nal ys es will be i ncl u de d i n t he Statistical A nal ysis Pla n f or t his st u d y. 
8. 5  Effic ac y A n al yses 
8. 5. 1  E ffic ac y Assess me nts 
T he pri mar y effic ac y ass ess me nt will be ti me t o rec urre nce wit h a n y pat h ol o gicall y c o nfir me d 
disea se of ≥Ta hist ol o g y or CI S p ost-treat me nt. T hese patie nts will be assesse d c yst osc o picall y 
an d b y uri ne c yt ol o g y at 3 m o nt hs ( ±3 0 da ys) i nter vals calc ul ate d fr o m t he date of T U R B T f or 
t he first 2 years a n d t he n e ver y 6 m o nt hs ( ±6 0 da ys) f or t he re mai n der of t he f oll o w- u p or u ntil 
rec urre nce, w hic h e ver occ urs first. T he d ate of t he c yst osc o p y or T U R B T pr oce d ure w he n t h e 
bla d de r t u m or was d etect e d a n d w hic h was c o nfir me d hist ol o gicall y b y pat h ol o g y re vie w will be 
use d as t he date of rec urre nce. O nl y t he first d oc u me nte d rec urre n ce will b e use d t o assess t he 
pri mar y efficac y.  
T he disease rec urre n ce will be deter mi ne d e x cl usi vel y usi n g t he pat h ol o g y re vie w of bi o psie d 
t u m ors w he n detect e d b y t he c yst os c o p y. T he c urre nt st u d y e x cl u des patie nts wit h disease of 
u p pe r tract or pr ostatic uret hra. If t h e uri ne c yt ol o g y is p ositi ve b ut t he pat h ol o g y re vi e w of t he 
bi o ps y is ne gati ve, t his ma y l ea d t o t he e x a mi nati o n of u p per tract disease. A uri ne c yt ol o g y ma y 
be perf or me d t o r ule o ut t he u p per tract ur ot helial carci n o ma at a n y f oll o w- u p ti me p oi nt.  
8. 5. 2  P ri m ar y E n d p oi nt 
 T i me t o Rec u rre nce i n patie nts wit h l o w- t o i nter me diate-ris k n o n- m us cle i n vasi ve 
bla d der ca ncer ( N MI B C) w h o recei ve eit her 8 m g  Qa pz ola or place b o p ost tra ns uret hr al 
resecti o n of bla d d er t u m or ( T U R B T) 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 6  
8. 5. 3  Sec o n d ar y E n d p oi nts 
1.  2- Year Rec urre nce Rat e 
2.  E x te nt of Disease at Rec urre nce ( n u m ber a n d l ocati o n of t u m ors) 
3.  Ti me t o Disease Pr o gressi o n ( base d o n t he t u m or sta ge) 
8. 5. 4  De fi niti o ns 
 Re c urre nce : a n y p at h ol o gic all y c o nfir me d disease of ≥Ta hist ol o g y or CI S p ost-
treat me nt 
 P r o g ressi o n : a n y pat h ol o gic all y c o nfir me d disease of ≥T 2  
8. 5. 5  P ri m ar y E n d p oi nt - Ti me t o Rec urre nce 
T he Ti me  t o Rec urre nce is defi ne d as ti me fr o m Da y 1 tr eat me nt t o t he dat e of t he first 
hist ol o gica ll y c o nfir me d rec urre nce as d escri be d i n Secti o n 8. 5. 1  a b o ve. P atie nts wit h o ut a 
rec ur re nce at t he ti me of t he pri mar y a n al ysis will be ce ns ore d at t he last a v aila ble date of 
c yst osc o p y. Patie nts w h o die d d ue t o a n y ca use bef ore c o nfir me d rec urre nce will be ce ns ore d at 
t he last a vaila ble dat e of c yst osc o p y.  
T he pri mar y a n al ysis will be c o n d ucte d usi n g a hi erarc hical pr o ce d ure of h y p ot hesis testi n g at a 
5 % le vel of si g nifica n ce. T he pri mar y e n d p oi nt, Ti me t o Rec urre n ce, will b e e x a mi ne d first, a n d 
if si g nifica nt, t he s ec o n d ar y e n d p oi nt, 2-Y e ar Rec urre nce Rate, will be e x a mi ne d ne xt, a n d if 
als o si g nifica nt, E xte nt of Disease at Rec urre nce, a n d Ti me t o Disease Pr o gressi o n will t he n be 
e x ami ne d.  
T he pri ma r y e n d p oi nt of Ti me t o Rec urre n ce will be a nal yz e d usi n g t h e Tar get P o p ulati o n as 
defi ne d i n  Secti o n 8. 3 . T he pri mar y a n al ysis of Ti me t o Rec urre n ce will be c o n d ucte d o nce a 
t otal of 2 0 8 rec urre n ce e ve nts are accr ue d i n t he st u d y. T he pri mar y e n d p oi nt a nal ysis i n v ol ves a 
2-si de d l o g-ra n k test of ti me t o rec urre nce bet w ee n t w o treat me nt gr o u ps at 5 % le vel of 
si gnifica n ce. Distri b uti o n of Ti me t o Rec urre nce will be esti mate d usi n g t he Ka pla n- M eier 
pr o d uct-li mit met h o d. T he me dia n ti mes t o rec urre nce wit h t w o-si de d 9 5 % c o nfi de nce i nter vals 
( CI) will be esti mate d, t o get h er wit h t he esti mates at 6, 1 2, 1 8 a n d 2 4 m o nt hs. T he hazar d rati o 
a n d c orr es p o n di n g 9 5 % CI of t he treat me nt effect will be esti mate d fr o m a C o x pr o p orti o nal 
hazar d re gressi o n m o del wit h treat me nt ar m as t he o nl y c o v ariate a n d teste d usi n g a li keli h o o d 
rati o test at t he le vel of si g nifica nce d escri b e d a b o ve. A d diti o nal e x pl orat or y a n al ysis of C o x 
pr o p orti o nal hazar d re gressi o n will be use d t o esti mate t he hazar d rati o a n d its 9 5 % CI. T he 
m o del will i ncl u de treat me nt effect, st u d y ce nter, l o w vs i nter me diate ris k, pri mar y vs. rec urre nt 
disease as stratifi cati o n fact or i n a d diti o n t o a n y ot her baseli ne or de m o gra p hics fact ors.  
I n a d diti o n, t he f oll o wi n g a d diti o nal se nsiti vit y a n al yses of Ti me t o Rec urre nce will be pr o vi d e d: 
a. E x cl u di n g patie nts w h o miss 2 c o nsec uti ve c yst osc o pies or l ost t o f oll o w- u p eit her pri or 
t o recurre nce or pri or t o t he date of t he pri mar y a n al ysis – C o m pleter a n al ysis 
b.  E x cl u di n g patie nts w h o miss 2 c o nsec uti ve c yst osc o pies or l ost t o f oll o w- u p eit her pri o r 
t o recurre nce or pri or t o patie nt’s f oll o w- u p d urati o n of 2 4 m o nt hs – C o m pleter 2 4 M o nt h 
anal ysis 
c. Treati n g patie nts wit h n o rec urre nce w h o miss 2 c o nsec uti ve c yst osc o pies or l ost t o 
f oll o w- u p pri or t o date of t he pri mar y a n al ysis as rec urre d. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 7  
T he f oll o wi n g p atie nts will be c o nsi dere d as pr ot oc ol de viati o ns a n d will be e x cl u de d fr o m t he 
a nal ysis of Ti me t o Rec urre nce usi n g t h e Per- Pr ot oc ol P o p ulati o n as e x pl orat or y:  
 P atie nts wit h Da y 1 i nstillati o n t hat d o n ot occ ur b et wee n 3 0 a n d 9 0 mi n utes p ost-
T U R B T 
 Pa tie nts w h ose f oll o w- u p c yst osc o p y o cc urs o utsi de t he ± 3 0- da y wi n d o w 
 P atie nts w h o recei v e d ot her treat me nt f or N MI B C pri or t o rec urre nce will be ce ns ore d at 
t he last assess me nt pri or t o t he treat me nt  
8. 5. 6  Sec o n d ar y E n d p oi nts 
8. 5. 6. 1  2- Ye ar Rec urre nce R ate 
T he  2 - Ye a r Rec urre nce R ate is t he pr o p orti o n of patie nts w h o ha ve a c o nfir me d rec urre nce 
be f ore or at t he 2- year f oll o w- u p visit ( Visit 1 0) f or eac h st u d y ar m. T he tr eat me nt effect will be 
anal yze d o nl y if a si g nifi ca nt treat me nt effect ( p < 0. 0 5) is i de ntifie d f or t he pri mar y e n d p oi nt, 
Ti me t o Rec u rre nce . T h e a nal ysis will calc ulate o d ds rati o wit h 9 5 % CI a n d a p pl y C oc hra n-
Ma ntel- Hae nszel c hi-s q uare test. T he rec urre nce rate will als o be esti mate d usi n g t he Ka pla n-
Meier pr o d uct-li mit met h o d al o n g wit h 9 5 % CI. Si nce visits d o n ot ofte n occ ur at t he s pecifie d 
i nter vals, a c ut- off u p per li mit of 7 6 5 da ys fr o m Da y 1 tr eat me nt will be us e d f or t he 2 4 m o nt h 
visits.  
8. 5. 6. 2  E xte nt of Dise ase at Rec urre nce 
E xte nt of disease at rec urre nce, i n cl u di n g c ha n ges i n n u m ber a n d i n l ocati o ns of t u m ors fr o m 
Da y 1 t o rec urre n ce, will be e x a mi ne d f or patie nts wit h rec urre nce o nl y b y eac h treat me nt ar m. 
T he c ha n ge i n n u m ber will be s u m marize d usi n g q ua ntiles. T he l ocati o n of all t u m ors will be 
rec or de d at D a y 1 a n d at rec urre nce f or eac h patie nt. L ocati o ns i ncl u de bas e, d o me, nec k, 
tri g o ne, a nteri or wall, p osteri or wall, left w all, a n d ri g ht w all. F or eac h l ocati o n, t he n u m ber of 
patie nts (a n d perce nta ge) w h o ha d t u m or at t hat l ocati o n will be s u m marize d b y at Da y 1 o nl y, at 
rec urre nce o nl y, at b ot h Da y 1 a n d rec urre nce, a n d at neit her. T he disc or da nce rat e of eac h 
l ocatio n will als o be calc ulate d.  
8. 5. 6. 3  Ti me t o Dise ase Pr o gressi o n 
Ti me t o Pr o gressi o n is t h e ti me fr o m Da y 1 t o t he first d oc u me ntati o n of sta ge pr o gressi o n as 
c o nfirme d b y pat h ol o g y. O nl y t he d e vel o p me nt of ≥T 2 disease  will be i ncl u de d i n t he 
assess me nt of ti me t o disease pr o gressi o n. Ce ns ori n g of patie nts wit h n o d oc u me nte d 
pr o gressi o n will be t he sa me as descri b e d f or rec urre nce i n  Secti o n 8. 5. 5  a b o ve. 
Dist ri b uti o n of Ti me t o Pr o gressi o n will be esti mate d usi n g t he Ka pla n- Mei er met h o d. A nal ysis 
of Ti me t o Pr o gressi o n will be si milar t o t he a nal ysis of Ti me t o Rec urre n ce, a b o ve. 
8. 6  S afet y E v al u ati o n 
Patie nts will be e val uate d f or safet y if t h e y ha ve recei ve d a n y st u d y treat m e nt ( Safet y 
P o p ulati o n), a n d classifie d acc or di n g t o t he tr eat m e nt recei ve d. 
8. 6. 1  S afet y E n d p oi nts  
 All A Es 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 8  
 Relate d A d vers e E ve nts 
 S eri o us A d verse E v e nts ( S A Es) 
 A E s lea di n g t o dr u g disc o nti n uati o n 
 Vital si g ns ( b o d y te m perat ure, bl o o d press ure, a n d heart rate ) an d r o uti ne l a b orat or y 
para meters ( he m at ol o g y, c he mistr y) 
 De at hs 
8. 6. 1. 1  A d verse E ve nts 
All treat me nt e mer ge nt a d verse e v e nts will be gra de d acc or di n g t o Nati o nal Ca ncer I nstit ute 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI C T C A E) versi o n 4. 0 3, a n d gr o u pe d b y 
t he Me d D R A Preferre d Ter m, a n d s u m marize d b y w orst gra de s e verit y per patie nt. 
8. 6. 1. 2  De at hs 
Al l deat hs re p orte d d uri n g t he st u d y will be ta b ulate d a n d s u m marize d b y tr eat me nt ar m. 
8. 6. 2  Ot her Seri o us A d verse E ve nts 
Seri o us a d verse e ve nts will be ta b ulate d a n d s u m marize d b y Me d D R A Preferre d T er m a n d 
treat me nt ar m. 
8. 6. 3  Cli n ic al L a b or at or y E v al u ati o ns 
Cli nical la b orat or y res ults will be c ollecte d at Scree ni n g, Da y 1, a n d at t he Safet y F oll o w- u p 
Visi t. All la b orat or y res ults will be classifie d acc or di n g t o t he N CI C T C A E versi o n 4. 0 3, a n d 
will be s u m mariz e d b y w orst gra de per patie nt a n d treat me nt ar m. 
9  A D MI NI S T R A TI V E P R O C E D U R E S A N D S T U D Y M A N A G E M E N T  
9. 1  I nvesti g at or Res p o nsi bilities  
9. 1. 1  G o o d Cli nic al Pr a ctice  
It is t he res p o nsi bilit y of t he Pri nci pal I n vesti gat or t o o versee t he s afet y of t he patie nts at t heir 
site. T he I n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o m plia nce wit h t he 
pri nc i ples of t he “ D eclarati o n of Helsi n ki” (as a me n de d i n T o k y o, Ve nice, H o n g K o n g, a n d 
S o ut h Africa), I C H g ui d eli nes, or wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n w hi c h t he 
researc h is c o n d u cte d. B y si g ni n g t he U S F or m F D A 1 5 7 2, “ State me nt of I n v esti gat or”, t he 
I n v esti gat or c o m mits t o a d here t o a p plica ble secti o ns of t he U S C F R parts 5 0 “ Pr otecti o n of 
H u ma n Patie nts”, 5 4 “ Fi na ncial Discl os ure b y Cli nical I n vesti gat ors”, 5 6 "I nstit uti o nal Re vie w 
B oar ds ”, a n d 3 1 2 s u b part D “ Res p o nsi bilities of S p o ns ors a n d I n vesti gat ors ”. All I n v esti gat or s 
will e ns ure a d here nce t o I C H g ui deli nes f or G C P a n d Cli nical Safet y Data Ma na ge me nt. 
9. 1. 2  I nstit uti o n al Re vie w B o ar d/ Et hics C o m mittee A p pr o v al 
T he I n vesti gat or s hall ass ure t hat t he I R B/ E C will pr o vi de i nitial a n d c o nti n ui n g re vi e w of t he 
st u d y. Pri or t o scree ni n g a n d e nr oll me nt of st u d y patie nts, d oc u me nte d I R B/ E C a p pr o val of t h e 
pr ot oc ol, I C F a n d a n y patie nt materials m ust be o btai ne d a n d pr o vi de d t o S pectr u m or its 
desi g nee. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
4 9  
9. 1. 3  I nf or me d C o nse nt  
T he i n vesti gat or will e ns ure t hat t he met h o d of o btai ni n g a n d d o c u me nti n g t he I nf or me d C o nse nt 
c o m plies wit h I C H- G C P a n d all a p plica ble re g ulat or y re q uire m e nt(s). I nf or me d C o nse nt m ust be 
o btai ne d bef ore st u d y pr oce d ures are p erf or me d, u nless perf or m e d as sta n dar d of care. T he 
s u bject’s s o urce d oc u me nts s hall d oc u me nt t he i nf or me d c o nse nt pr ocess a n d t hat I nf or me d 
C o nse nt was o btai ne d pri or t o st u d y partici pati o n. A c o p y of eac h si g ne d I C F m ust be pr o vi de d 
t o the patie nt or t he patie nt’s le gall y a ut h orize d re prese ntati ve. All si g ne d I C F s m ust re mai n i n 
eac h p atie nt’s st u d y file a n d m ust be a vaila ble f or verificati o n at a n y ti me. 
9. 1. 4  S t u d y Files a n d Rete nti o n of Rec or ds 
T he I n vesti gat or will ret ai n all st u d y rec or ds u ntil at least 2 years after t he l ast a p pr o val of a 
mar keti n g a p plicati o n or at least 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of cli nical 
de vel o p me nt of t he i n vesti gati o nal pr o d uct. T h ese d oc u me nts will be retai n e d f or a l o n ger 
peri o d, h o we v er, if re q uire d b y t he a p plica ble re g ulat or y re q uire m e nts or b y a n a gree me nt wit h 
S pectr u m. If t he I n v esti gat or rel oc ates, or f or a n y reas o n desir es t o dis p ose of t he rec or ds, t he 
st u dy rec or ds ma y b e tra nsferre d t o a n ot her i nstit uti o n, a n ot her i n vesti gat or, or t o S pectr u m u p o n 
wr itte n a gree me nt bet w ee n t he I n vesti gat or a n d S pectr u m.  
9. 2  Re c or di n g a n d C ollecti n g of D at a 
I n acc or da n ce wit h I C H a n d G C P g ui deli nes, t he I n v esti gat or will mai ntai n c o m plete, acc urat e, 
le gi ble, a n d easil y retrie v a ble data, a n d will all o w pers o n nel a ut h orize d b y S pectr u m access t o all 
st u dy data at a n y ti me. S uc h data s hall als o be s ec ure d i n or der t o pre ve nt l oss of data. 
9. 2. 1  C ase  Re p ort F or ms 
At sc he d ule d m o nit ori n g visits, C R Fs will be verifie d a gai nst s o urce d o c u m e ntati o n a n d 
s u b mitte d as fi nal data. A n y s u bse q u e nt c ha n ges t o t he C R Fs are t o be p erf or me d i n acc or da n ce 
wit h S pectr u m’s sta n dar d o perati n g pr oce d ures f or e diti n g a n d clarif yi n g C R Fs. Data e ntr y will 
be perf or me d b y t he sites usi n g a n electr o nic d ata ca pt ure ( E D C) s yste m.  
9. 2. 2  Dr u g Acc o u nt a bilit y 
I n acc or da n ce wit h all a p plica ble re g ulat or y re q uir e me nts, t he I n vesti gat or or desi g n ate d site 
staff is t o mai ntai n st u d y treat me nt acc o u nta bilit y rec or ds t hr o u g h o ut t he c o urse of t he st u d y. 
T his per s o n(s) will d oc u me nt t he a m o u nt of Qa pz ola a d mi nistere d t o patie nts. T he C R A will 
revie w i n ve nt or y a n d acc o u nta bilit y d o c u me ntati o n d uri n g m o nit ori n g visits. 
T he I n vesti gat or will n ot s u p pl y i n vesti gati o nal st u d y dr u gs t o ot her i n vesti gat ors n ot liste d o n 
t he US F or m F D A 1 5 7 2 or e q ui vale nt. I n v esti gati o nal st u d y dr u g us e, ot her t ha n as directe d b y 
t his pr ot oc ol, is n ot all o we d. 
All u n use d vials of Qa pz ola are t o be acc o u nte d f or at t he site a n d mai ntai ne d i n a sec ure d, 
l oc ked st ora ge area wit h access li mite d t o a ut h orize d st u d y p ers o n nel o nl y. Use d Qa pz ola vials 
will  be destr o ye d per i nstit uti o n, l ocal, a n d all a p plica ble p olicies a n d pr oce d ures. After st u d y 
co ncl usi o n, all u n use d vials of Qa pz ola ma y be d estr o ye d at t he site, f oll o wi n g verificati o n of 
acc o u nta bilit y b y a S p o ns or re prese ntati ve. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
5 0  
9. 3  Pr ot oc ol C o m pli a nce 
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y is c o n d uct e d i n acc or da nce wit h 
t he pr oce d ures a n d e val u ati o ns descri be d i n t his pr ot oc ol. 
9. 4  S p o ns or Res p o nsi bilities 
9. 4. 1  S t u d y M o nit ori n g 
T he st u d y will be m o nit ore d b y e m pl o yees or re prese ntati ves of S pectr u m. C R As will m o nit or 
eac h site o n a p eri o dic b asis a n d perf or m v erificati o n of s o urce d o c u me ntati o n f or eac h patie nt as 
well as ot her r o uti ne c o m plia nce re vi e ws. S pectr u m’s Me dical M o nit or a n d P har mac o vi gila nce 
De part me nt will re vi e w s afet y data a n d be res p o nsi ble f or e ns uri n g ti mel y re p orti n g of e x pe dite d 
S A E Rs t o re g ulat or y a ge ncies a n d I n v esti gat ors. 
9. 4. 2  S afet y M o nit ori n g 
T he cli nical dr u g safet y of st u d y tr eat me nt will be c o nti n u o usl y e val u ate d b y t he st u d y Me dical 
M o nit or or desi g n ee o n a n o n g oi n g basis d uri n g t h e c o urse of t his cli nical st u d y. All S A Es 
relate d t o st u d y treat me nt i n t his st u d y a n d all ot her o n g oi n g cli nical st u dies wit h st u d y treat me nt 
will be pr ocesse d i n c o m plia nce wit h c urre nt re g ulat or y g ui deli nes b y S pectr u m’s 
P har mac o vi gila nce De part me nt. T his pr ocessi n g will i ncl u de a f or mal ass ess me nt of eac h S A E 
b y dr u g s afet y. A n I n de p e n de nt Data M o nit ori n g C o m mittee (I D M C) will re vie w t he u n bli n de d 
safet y data fr o m t he first 3 0 patie nts t o verif y t hat t he 8 m g / 5 0 mL d ose is s afe. I n a d diti o n, a 
cu m ulati ve re vie w of all S A Es fr o m all s o urces will be assesse d peri o dicall y  
9. 5  J oi n t I n vesti g at or/ S p o ns or Res p o nsi bilities 
9. 5. 1  Ac cess t o I nf or m ati o n f or M o nit ori n g a n d A u diti n g 
I n acc or da n ce wit h I C H G C P g ui deli nes a n d 2 1 C F R 3 1 2, t he C R A/a u dit or is t o ha ve direct 
access t o t he patie nt’s s o urce d oc u m e ntati o n i n or der t o verif y t he data rec or de d i n t he C R Fs. 
T he C R A is res p o nsi ble f or r o uti ne re vie w of t he C R Fs at re g ular i nter vals t hr o u g h o ut t he st u d y 
a n d t o verif y a d h ere n ce t o t he pr ot oc ol, as well as t he c o m plete ness, c o nsist e nc y, a n d acc urac y of 
t he data bei n g rec or de d. T he C R A/a u dit or is t o ha ve access t o a n y patie nt r ec or ds nee de d t o 
ve rif y t he e ntri es o n t he C R Fs, as well as access t o all ot her st u d y-relat e d d oc u me ntati o n a n d 
mate rials. T he I n v esti gat or a grees t o pr o vi de t he m o nit or wit h s ufficie nt ti me a n d facilities t o 
co n d uct m o nit ori n g. 
9. 5. 2  Ter mi n ati o n of t he St u d y 
F or reas o na bl e ca us e, eit her t he I n v esti gat or  or S pectr u m ma y ter mi nate t h e I n vesti gat or’s 
pa rtici pati o n i n t his st u d y. I n a d diti o n, S pectr u m P har mace uticals I nc. m a y ter mi nate t he st u d y at 
a n y ti me u p o n i m me diate n otice f or a n y reas o n, i n cl u di n g b ut n ot li mite d t o, S pectr u m’s belief 
t hat termi nati o n is necess ar y f or t he s afet y of patie nts. 
9. 5. 3  P u blic ati o n P olic y 
T o c o or di nate t he disse mi nati o n of data fr o m t his st u d y, S pectr u m e n c o ura ges t he f or mati o n of a 
p u blicati o n c o m mittee c o nsisti n g of t he Pri nci pal I n vesti gat or a n d a p pr o priate S pectr u m staff. 
T he c o m mittee is e x pecte d t o s olicit i n p ut a n d assista nce fr o m ot her I n vesti gat ors a n d S p o ns or 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
5 1  
staff as a p pr o priate. M e m bers hi p o n t he c o m mittee ( b ot h f or I n vesti gat ors a n d Staff) d o es n ot 
g uara nte e a ut h ors hi p- t he criteria d escri be d b el o w s h o ul d be met f or e ver y p u blicati o n. 
A ut h or s hi p of a n y p u blicati o ns res ulti n g fr o m t his st u d y will be deter mi ne d o n t he basis of t he 
U nif or m Re q uire me nts f or Ma n uscri pt S u b mitte d t o Bi o me dical J o ur nals (I nter nati o nal 
C o m mittee of Me dical J o ur nal E dit ors, 2 0 0 5), w hi c h states: 
 A ut h or s hi p cre dit s h o ul d be base d o n t he f oll o wi n g; a ut h ors s h o ul d meet all t hree 
co n diti o ns:  
 S u bsta ntial c o ntri b uti o ns t o c o nce pti o n a n d desi g n, ac q uisiti o n of data, or a n al ysis 
a n d i nter pret ati o n of data;  
 Dr afti n g t he article or re visi n g it criticall y f or i m p orta nt i ntellect ual c o nte nt; a n d  
 F i nal a p pr o val of t he versi o n t o be p u blis he d.  
 W he n a lar ge, m ultice nter gr o u p has c o n d u cte d t h e w or k, t he gr o u p s h o ul d i de ntif y t he 
i n di vi d uals w h o acce pt direct res p o nsi bilit y f or t h e ma n uscri pt. T hes e i n di vi d uals s h o ul d 
f ull y meet t he criteri a f or a ut h ors hi p defi ne d a b o v e.  
 Ac q uisiti o n of f u n di n g, c ollecti o n of data, or ge neral s u per visi o n of t he res earc h gr o u p 
al o ne d oes n ot c o nstit ute a ut h ors hi p. 
 All pers o ns desi g n ate d as a ut h ors s h o ul d q ualif y f or a ut h ors hi p, a n d all t h ose w h o q ualif y 
s h o ul d be liste d. 
 Eac h a ut h or s h o ul d ha v e partici pate d s ufficie ntl y i n t he w or k t o ta ke p u blic res p o nsi bilit y 
f or a p pr o priate p orti o ns of t he c o nte nt. 
All p u blicati o ns (e g, m a n uscri pts, a bstracts, or al/sli de prese ntati o ns, b o o ks c ha pters) base d o n 
t his st u d y m ust be s u b mitte d t o S pectr u m wit hi n 3 0 da ys ( b ut n o less t ha n 1 0 da ys) pri or t o 
s u b missi o n or p u blicati o n f or c or p orate re vie w.  
9. 6  C o nf i de nti alit y 
All i nf or mati o n pr o vi de d t o t he I n v esti gat or b y S pectr u m, i ncl u di n g n o n cli nical data, pr ot oc ols, 
C R Fs, a n d ver bal a n d writte n i nf or mati o n, will be ke pt strictl y c o nfi de ntial a n d c o nfi ne d t o t he 
cli nical pers o n nel i n v ol v e d i n c o n d ucti n g t his st u d y, a n d n o dis cl os ure s hall be ma de e x ce pt i n 
acc or da nce wit h a n y ri g ht of p u blicati o n gra nte d t o t he I n v esti gat or. All pers o n nel will ha n dle 
patie nt data i n a c o nfi de ntial ma n ner i n acc or da n ce wit h a p plica ble re g ulati o ns g o ver ni n g cli nical 
researc h. U p o n re q uest b y a re g ulat or y a ut h orit y s uc h as t he U S F D A a n d ot her re g ulat or y 
a ut h orities w orl d wi de, t h e I n vesti gat or/i nstit uti o n is t o ma ke a vaila ble f or direct access all 
req ueste d st u d y-relate d rec or ds or re p orts ge n erate d as a res ult of a patie nt’s partici pati o n i n t his 
st u d y. T his i nf or mati o n ma y b e relat e d i n c o nfi de nce t o t he I R B/ E C or ot h er c o m mittee 
f u ncti o ni n g i n a si milar ca pacit y. I n a d diti o n, n o r e p orts or i nf or mati o n a b o ut t he st u d y or its 
pr o gress will be pr o vi de d t o a n y o n e n ot i n v ol ve d i n t he st u d y ot her t h a n t o S pectr u m, or i n 
c o nfi de nce t o t he I R B/ E C or si milar c o m mittee, e x ce pt if re q uire d b y la w. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
5 2  
1 0  R E F E R E N C E S 
1.   
H o wla der N, N o o ne A M, Kra pc h o M, Miller D, Bis h o p K, Alte kr use S F, et al. (e ds). 
S E E R Ca ncer Statistics Re vie w, 1 9 7 5- 2 0 1 3, Nati o nal Ca ncer I nstit ute. Bet hes da, M D, 
htt p://seer.ca ncer. g o v/csr/ 1 9 7 5 _ 2 0 1 3/, base d o n N o ve m ber 2 0 1 5 S E E R dat a s u b missi o n, 
p ost e d t o t he S E E R we b site, A pril 2 0 1 6. 
2.  
Leal J, L ue n g o- Fer na n dez R, S ulli va n R, Witjes J A. Ec o n o mic B ur de n of Bla d der Ca ncer 
Ac r oss t he E ur o pea n U ni o n. E ur Ur ol. 2 0 1 6; 6 9( 3): 4 3 8- 4 7. 
3.  
Ye u n g C, Di n h T, Lee J. T he healt h ec o n o mics of bla d der ca ncer: a n u p dat e d re vie w of 
t he p u blis he d literat ure. P har mac oec o n o mics. 2 0 1 4; 3 2( 1 1): 1 0 9 3- 1 0 4. 
4.   
Net w or k N C C. Cli nical Practice G ui deli nes i n O nc ol o g y: Bla d der Ca ncer ( Versi o n 
2. 2 0 1 5): Nati o nal C o m pre he nsi ve Ca ncer Net w or k; 2 0 1 5 [ A u g ust 2 1, 2 0 1 5]. A vaila ble 
fr o m: htt p:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ bla d der. p df. 
5.  
C ha n g S S, B o orjia n S A, C h o u R, Clar k P E, Da nes h ma n d S, K o net y B R, et al. Dia g n osis 
A n d T reat me nt Of N o n- M uscle I n vasi ve Bla d der Ca ncer: A U A/ S U O G ui deli ne. 
A merica n Ur ol o gical Ass ociati o n. 2 0 1 6. 
6.  
Kass o uf W, A pri kia n A, Blac k P, K ul kar ni G, Iz a wa J, Ea pe n L, et al. Rec o m me n dati o ns 
f or t he i m pr o ve me nt of bla d der ca ncer q ualit y of care i n Ca na d a: A c o nse ns us d oc u me nt 
re vie we d a n d e n d orse d b y Bl a d der Ca ncer Ca na d a ( B C C), Ca n a dia n Ur ol o gic O n c ol o g y 
Gr o u p ( C U O G), a n d Ca n a dia n Ur ol o gical Ass o ciati o n ( C U A), Dece m ber 2 0 1 5. Ca n Ur ol 
Ass oc J. 2 0 1 6; 1 0( 1 - 2): E 4 6- 8 0. 
7.  
Ba bj u k M, B ö hle A, B ur ger M, C o m pérat E, K aasi ne n E, Pal o u J, et al. G ui deli nes o n 
N o n -m uscle -i n vasi ve Bla d der Ca ncer ( T a, T 1 a n d CI S) I n: E A U G ui deli nes. E d n. 
prese nte d at t he E A U A n n ual C o n gress Ma dri d 2 0 1 5. E ur o pea n Ass o ciati o n of Ur ol o g y, 
Ar n he m, T he N et herla n ds. . 2 0 1 5.  
8.  
Bell m u nt J, Ors ola A, Le o w JJ, Wie gel T, D e Sa ntis M, H or wic h A. Bl a d der ca ncer: 
E S M O Practice G ui deli n es f or dia g n osis, treat me nt a n d f oll o w- u p. A n n O nc ol. 2 0 1 4; 2 5 
S u p pl 3:iii 4 0- 8. 
9.  
A vritsc her E B, C o o ksle y C D, Gr oss ma n H B, Sa bi c hi A L, Ha m bli n L, Di n n e y C P, et al. 
C li nical m o del of lifeti me c ost of treati n g bla d der ca ncer a n d ass ociate d c o m plicati o ns. 
Ur ol o g y. 2 0 0 6; 6 8( 3): 5 4 9- 5 3. 
1 0.  
J a mes A C, G ore J L. T h e c osts of n o n- m uscle i n vasi ve bla d der ca ncer. Ur ol Cli n N ort h 
A m. 2 0 1 3; 4 0( 2) : 2 6 1- 9. 
1 1.  
S yl v ester RJ, O osterli nc k W, va n der Meij de n A P. A si n gle i m me diate p ost o perati ve 
i nstillati o n of c he m ot hera p y d ecreas es t he ris k of rec urre nce i n patie nts wit h sta ge Ta T 1 
bla d der ca ncer: a meta-a nal ysis of p u blis he d res ults of ra n d o mize d cli nical trials. J Ur ol. 
2 0 0 4; 1 7 1( 6 Pt 1): 2 1 8 6- 9 0, q uiz 4 3 5. 
1 2.   
L oa d m a n P M, Bi b b y M C, P hilli ps R M. P har mac ol o gical a p pr oac h t o war ds t he 
de vel o p me nt of i n d ole q ui n o ne bi ore d ucti ve dr u gs base d o n t he cli nicall y i n acti ve a ge nt 
E O 9. Br J P har mac ol. 2 0 0 2; 1 3 7( 5): 7 0 1- 9. 

S pectr u m P h ar m ace utic als, I nc. 
M o d ule 5 Cli nic al Pr ot oc ol 
A p azi q u o ne 
Pr ot oc ol N u m ber: S PI- Q A P- 3 0 6  
Ori gi n al/ 2 2 Dec 2 0 1 6 
C o nfi de nti al 
5 3  
1 3.   
Nati o nal C o m pre he nsi ve Ca ncer Net w or k. Cli nical Practice G ui deli nes i n O nc ol o g y: 
Bla d der Ca ncer ( V ersi o n 1. 2 0 1 6) [ A pril 4, 2 0 1 6]. A vaila ble fr o m: 
htt p:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ bla d der. p df. 
1 4.  
H oc h ber g Y. A s har per B o nferr o ni pr o ce d ure f or m ulti ple tests of si g nifica nce. 
B i o metri ka. 1 9 8 8; 7 5( 4): 8 0 0- 2.