Conditions: Bladder Cancer
Keywords: Bladder Cancer Non-muscle invasive bladder cancer Apaziquone TURBT Stage Ta, G1-G2
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: no

Brief summary:
This is a Phase 3, randomized, multicenter, multi-arm, placebo-controlled, double-blind study of apaziquone in participants with ≤4 non-muscle invasive bladder cancer (NMIBC), ≤3.5 centimeters (cm) in diameter, all of which must had been fully resected at TURBT.

In addition to Screening, participants underwent an assessment of urothelial carcinoma of the bladder via cystoscopy for clinically apparent tumor Ta, G1-G2.

Following TURBT on Day 1, eligible participants were randomized to one of three treatment arms in a 1:1:1 ratio.

Arm 1 : One dose of Apaziquone. Arm 2 : Two Doses of Apaziquone. Arm 3 : Placebo. Primary endpoint was to evaluate the Time to Recurrence with either a one instillation of 4 mg apaziquone or two instillations of 4 milligram (mg) apaziquone relative to placebo instillation following TURBT in a participant with NMIBC who received TURBT.

Detailed description:
This is a Phase 3, randomized, multicenter, multi-arm, placebo-controlled, double-blind study of apaziquone in participants with ≤4 non-muscle invasive bladder tumors, ≤3.5 cm in diameter, all of which must have been fully resected at TURBT.

In addition to Screening, participants underwent an assessment of urothelial carcinoma of the bladder via cystoscopy for clinically apparent tumor Ta, G1-G2.

Following TURBT on Day 1, eligible participants were randomized to one of three treatment arms in a 1:1:1 ratio :

Arm 1 : One Dose of Apaziquone:

* Day 1: administration of 4 mg of apaziquone 60±30 minutes post-TURBT
* Day 15 (±5 days): administration of placebo

Arm 2 : Two Doses of Apaziquone :

* Day 1: administration of 4 mg of apaziquone 60±30 minutes post-TURBT
* Day 15 (±5 days): administration of 4 mg of apaziquone

Arm 3: Placebo :

* Day 1 : administration of placebo 60±30 minutes post-TURBT
* Day 15 (±5 days) : administration of placebo

Once randomized, Day 1 study drug instillation occurred 60 ±30 minutes post TURBT. Participants returned on Day 15 (±5 days) for a second instillation unless their pathology results showed non Ta, G1-G2 histology; in the absence of local pathology results by the Day 15 visit, participants received a second instillation of study drug. All histology specimens were reviewed by a local pathology laboratory and all clinical treatment decisions and study analyses were based on the local pathology review. Participants whose pathology was other than Ta, G1-G2 were followed for safety at Day 35 (±5 days) from the last dose of study drug and then discontinued from the study.

Participants with pathology confirmed Ta, G1-G2 disease were followed according to the schedule below :

* Cystoscopic examination and urine cytology every 90 days (±10 days) (calculated from date of TURBT) through 24 months for tumor recurrence and progression.
* If at any time during the 24 months follow up period there was a tumor recurrence, the participant continued on study with follow-up cystoscopic examination and urine cytology every 90 days (±10 days) (calculated from date of TURBT) through the end of 24 months. Participants with a recurrence were permitted to have a follow-up TURBT.
* If at any time during the 24 months follow up period there was a tumor recurrence and/or participant started on another therapy, the participant was followed by telephone, for safety every 90 days (±10 days) (calculated from date of TURBT) through the end of 24 months.

Duration of Study: The duration of the study for each participant was approximately 24 months including:

* Screening Period : 30-days
* Treatment Period : Day 1 and Day 15 (±5 days)
* Safety and Follow-up Period: 24-months

Arms:
arm 1: Participants were randomized to receive first dose of 4 mg of apaziquone by intravesical administration into the bladder at 60 ± 30 minutes post transurethral resection of bladder tumor (TURBT) on Day 1 via an indwelling 100% Silicone Foley catheter. Followed by second dose of placebo by intravesical administration via an indwelling catheter on Day 15 (±5 days). arm 2: Participants were randomized to receive first dose of 4 mg of apaziquone by intravesical administration into the bladder at 60 ± 30 minutes post TURBT on Day 1 via an indwelling 100% Silicone Foley catheter. Followed by second dose of 4 mg of apaziquone by intravesical administration via an indwelling catheter on Day 15 (±5 days). arm 3: Participants were randomized to receive first dose of matching placebo by intravesical administration into the bladder at 60 ± 30 minutes post TURBT on Day 1 via an indwelling 100% Silicone Foley catheter. Followed by second dose of matching placebo by intravesical administration via an indwelling catheter on Day 15 (±5 days).

Interventions: intervention 1: Apaziquone intervention 2: Placebo
Intervention descriptions: intervention 1: One dose of apaziquone administered by intravesical administration intervention 2: Matching placebo (containing 12 mg FD\&C red #40, 15 mg sodium chloride, and 10 mg mannitol was supplied in identical appearing vials) by intravesical administration.

Protocol document:
Prot_000.pdf: 
 
Offici al Titl e:  
A M ultic e nt er, M ulti Ar m, R a n d o miz e d, M ulti -D os e, Pl ac e b o -C o ntr oll e d, 
D o u bl e -Bli n d, P h as e 3 St u d y of I ntr a v esic al A p azi q u o n e ( E O q ui n ®)  as a 
S ur gic al A dj u v a nt i n t h e I m m e di at e P ost o p er ati v e P eri o d i n P ati e nts 
U n d er g oi n g Tr a ns ut h er al R es ecti o n f or N o n -M uscl e  I n v asi v e Bl a d d er 
C a nc er  
N C T N u m b er:  
N C T 0 2 5 6 3 5 6 1  
D oc u m e nt  D at e : 
Pr ot oc ol  V ersi o n 1. 0 : 0 6-A u g ust -2 0 1 5  
 
 
 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
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 M ultice nter, M ulti -A r m, R a n d o mi ze d, M ulti -D ose, Pl ace b o -
C o ntr olle d, D o u ble -Bli n d, P h ase 3 St u d y of I ntr a vesic al 
A p azi q u o ne ( E O q ui n ® ) as a S ur gic al A dj u v a nt i n t he I m me di ate 
P ost o pe r ati ve Peri o d i n P ati e nts U n der g oi n g Tr a ns uret hr al 
Resecti o n f or N o n -M uscle I n v asi ve Bl a d der C a ncer  
St u d y N u m ber:  
S PI -E O Q -1 3 -3 0 5  
St u d y P h ase:  
P hase  3  
St u d y Dr u g:  
A pazi q u o ne ( E O q ui n ® ) 
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/ 0 6 A u g  2 0 1 5   
 
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 h e 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
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- E O Q - 1 3- 3 0 5 
A M ultice nter, M ulti- A r m, R a n d o mi ze d, M ulti- D ose, Pl ace b o- C o ntr oll e d, D o u ble- Bli n d, 
P h ase 3 St u d y of I ntr a vesic al A p azi q u o ne ( E O q ui n ® ) as a S ur gic al A dj u v a nt i n t he 
I m me di ate P ost o pe r ati ve Peri o d i n P ati e nts U n der g oi n g Tr a ns uret hr al Resecti o n f or N o n-
M uscle I n v asi ve Bl a d der C a ncer 
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 dy 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 
S Y N O P SI S 
Title of St u d y: A M ultice nter, M ulti -Ar m , Ra n d o mize d, M ulti -D ose, Place b o -C o ntr olle d, D o u ble -Bli n d P hase 3 
St u d y of I ntra vesical A pazi q u o ne ( E O q ui n ® ) as a S ur gical A dj u va nt i n t he I m me diate P ost o perati ve P eri o d i n 
P atie nts U n der g oi n g Tra ns uret hral  Resecti o n f or N o n -M uscl e I n vasi ve Bla d der Ca ncer  
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:  A pazi q u o ne ( E O q ui n ®)  
Pl a n ne d N u m ber of P atie nts:  A p pr o xi matel y  1 8 6 9  patie nts will be e nr olle d t o o btai n 1 5 5 7 e val ua ble patie nts  
acr oss t hree treat me nt ar ms . 
St u d y Ce nters:  A p pr o xi matel y 1 0 0 st u d y ce nters  
D ur ati o n of St u d y : A p pr o xi matel y 5 years ( 3 years accr ual  +  2 years 
f oll o w-u p)  
Cli nic al P h ase:  3  
O bjecti ves:  
Pri m ar y O bjecti ve(s)  
 
T o e val uate t he Ti me t o Rec urre nce  wit h eit her a o ne i nstill ati o n of 4 m g a pazi q u o ne or t w o 
i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o  i nstillati o n f oll o wi n g T U R B T i n patie nts wit h n o n -
m uscle i n vasi ve bla d der ca ncer ( N MI B C) w h o recei ve t ra ns uret hral resecti o n bla d der t u m or (T U R B T )  
Sec o n d ar y O bjecti ves  
1.  T o e val uate t he 2 -Ye a r  Rec urre nce R ate  wit h eit her o ne  i nstillati o n of 4 m g apazi q u o ne or t w o 
i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o  i nstillati o n f oll o wi n g T U R B T i n patie nts wit h 
N MI B C w h o recei ve T U R B T . 
2.  T o e val uate t he  1 -Ye a r  Rec urre nce R ate  wit h eit her o ne  i nstillati o n of 4 m g apazi q u o ne or t w o 
i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o  i nstillati o n f oll o wi n g T U R B T i n patie nts wit h 
N MI B C  w h o recei ve  T U R B T . 
3.  T o e val uate t he Ti me t o Pr o gressi o n  wit h eit her o ne  instillati o n of 4 m g apazi q u o ne or t w o i nstillati o n s 
of 4 m g a pazi q u o ne relati ve t o place b o  i nstillati o n f oll o wi n g T U R B T i n patie nts wit h N MI B C w h o 
recei ve T U R B T  
4.  T o e val uate t he safet y wit h eit her o ne  i nstillati o n of 4 m g ap azi q u o ne or t w o i nstillati o n s of 4 m g 
a p azi q u o ne relati ve t o place b o  i nstillati o n f oll o wi n g T U R B T i n patie nts wit h N MI B C   
St u d y Desi g n  a n d Tre at me nt Pl a n : 
T his is a P hase 3, ra n d o mize d, m ultice nter, m ulti -ar m, place b o -c o ntr olle d, d o u ble -bli n d st u d y of a pazi q u o ne i n 
patie nts wit h ≤4  n o n -m uscle i n vasi ve bla d der t u m ors, ≤3. 5 c m i n dia meter , all of w hic h m ust ha ve bee n f ull y 
resecte d at T U R B T .  
I n a d diti o n t o S cree ni n g , patie nts will u n der g o a n assess me nt of ur ot helial carci n o ma of t he bla d der via 
c yst osc o p y f or cli nicall y a p pare nt t u m or  T a,  G 1 -G 2.   
F oll o wi n g T U R B T  o n D a y 1 , eli gi ble patie nts will be ra n d o mize d t o o ne of t hree treat me nt ar ms i n a 1: 1: 1 rati o: 
 
Ar m 1 - O ne  D ose of A p azi q u o ne : 
 
D a y 1 : a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0  ±  3 0  mi n ut es p ost -T U R B T  
 
D a y 1 5  (± 5 da ys) : a d mi nistrati o n of place b o   
 
Ar m 2 - T w o D oses of A p azi q u o ne : 
 
D a y 1 : a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0  ±  3 0 mi n ut es p ost -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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 
 
D a y 1 5  (± 5 da ys) : a d mi nistrati o n of 4 m g of a pazi q u o ne  
 
Ar m 3 - Pl ace b o :  
 
D a y 1 : a d mi nistrati o n of place b o 6 0  ±  3 0 mi n utes p ost -T U R B T  
 
D a y 1 5  (± 5 da ys) : a d mi nistrati o n of place b o  
O nce ra n d o mize d, D a y 1  st u d y dr u g i nstillati o n will occ ur 6 0  ±  3 0 mi n utes  p ost  T U R B T . P atie nts will ret ur n o n 
D a y 1 5  (± 5 da ys ) f or a sec o n d i nstillati o n u nless t heir pat h ol o g y res ults are a vaila ble a n d s h o w n o n T a , G 1 -G 2 
hist ol o g y ; i n t he a bse nce of l ocal p at h ol o g y res ults b y t he D a y 1 5 visit, patie nts will recei ve a sec o n d i nstillati o n 
of st u d y dr u g . All hist ol o g y s p eci me ns will b e re vie we d b y a l ocal pa t h ol o g y la b orat or y a n d a ll cli nical 
treat me nt d ecisi o ns a n d st u d y a nal yses will be base d o n t he l ocal pat h ol o g y r e vie w. P atie nts w h ose pat h ol o g y is 
ot her t ha n T a, G 1 -G 2 will be f oll o we d f or safet y at D a y 3 5  ( ± 5 da ys ) fr o m t he last d ose of st u d y dr u g  a n d t he n 
disc o nti n ue d fr o m t he st u d y .  
P atie nts wit h pat h ol o g y c o nfir me d T a , G 1 -G 2 disease will b e f oll o we d acc or di n g t o t he sc he d ule bel o w:  
 
C yst osc o pic e xa mi nati o n a n d uri ne c yt ol o g y e ver y 9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m dat e of T U R B T ) 
t hr o u g h 2 4 m o nt hs  f or t u m or rec urre nce a n d pr o gressi o n. 
 
If at a n y ti me d uri n g t he 2 4 m o nt h  f oll o w u p peri o d t here is a tu m or rec urre nce, t he patie nt will c o nti n ue 
o n st u d y wit h f oll o w -u p c yst osc o pic e xa mi nati o n  a n d uri ne c yt ol o g y e ver y 9 0 da ys ( ± 1 0 da ys) 
(calc ulate d fr o m date of T U R B T ) t hr o u g h t he e n d of 2 4 m o nt hs . P atie nts wit h a rec urre nc e are per mitte d 
t o ha ve a f oll o w-u p T U R B T.  
 
If at a n y ti me d uri n g t he 2 4 m o nt h  f oll o w u p peri o d t here is a tu m or rec urre nce a n d / or patie nt is starte d 
o n a n ot her t hera p y, t he patie nt will be  f oll o we d b y tele p h o ne, f or safet y e ver y 9 0 da ys ( ± 1 0 da ys) 
(calc ulate d fr o m date of T U R B T ) t hr o u g h t he e n d of 2 4 m o nt hs .  
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 a p pr o xi matel y 2 4  m o nt hs  i ncl u di n g: 
 
Scree ni n g Peri o d : 3 0 -da y s  
 
Tre at me nt  Peri o d : D a y 1  a n d  D a y 1 5  ( ± 5 da ys)  
 
S afet y a n d F oll o w -u p Peri o d : 2 4 -m o nt h s  
P atie nt Re pl ace me nt Str ate g y:  P atie nts w h o disc o nti n ue fr o m t he st u d y after t he i nitial T U R B T a n d st u d y dr u g 
i nstillati o n will n ot b e re place d.  
I ncl usi o n & E xcl usi o n Crite ri a:  
I ncl usi o n Criteri a: 
1.  P atie nt m ust ha ve a  dia g n os is wit h ur ot helial carci n o ma of t he bla d der wit h cli nicall y a p pare nt t u m or 
T a,  G 1 -G 2.  
2.  P atie nt will ha ve ≤4 t u m ors, n o ne of w hic h e xcee ds 3 . 5 c m i n dia meter.  
3.  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. 
4.  P atie nt is at least 1 8 years of a ge at ra n d o mizati o n.  
5.  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 t he last d ose of t he st u d y dr u g . 
6.  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 a n acti ve c o nc urre nt mali g na nc y/life -t hreate ni n g disease. If t here is a hist or y of pri or 
mali g na ncies/life -t hreate ni n g diseases, t he patie nt is t o be disease free f or at least 5 years. P atie nts wit h 
ot her pri or mali g na ncies less t ha n 5 years bef ore st u d y e ntr y ma y still be e nr olle d if t he y ha ve recei ve 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 
treat me nt res ulti n g i n c o m plet e res ol utio n of t he ca ncer a n d c urre ntl y ha ve n o cli nical, ra di ol o gic, or 
la b orat or y e vi de nce of acti ve or rec urre nt disease. 
2.  P atie nt has  p ositi ve uri ne c yt ol o g y  f or mali g na nc y at Scree ni n g . 
3.  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 pr ot oc ol 
treat me nt. 
4.  P atie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gics, or de vices wit hi n 3 0 da ys  pri or t o st u d y treat me nt 
or 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.  
5.  P atie nt has ha d a n y pri or i ntra vesical 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 ur e t o 
a p azi q u o ne.  
6.  P atie nt has or has e ver ha d  
 
U p per tract Tra nsiti o nal Cell Carci n o ma ( T C C).  
 
U ret hral t u m or ( pr ostatic uret hra i ncl u de d).  
 
A n y i n vasi ve bla d der t u m or k n o w n t o be ot her t ha n t u m or Ta, G 1 -G 2.  
 
A n y e vi de nce of l y m p h n o de or dista nt metastasis .  
 
A n y bla d der t u m or wit h hist ol o g y ot her t ha n T C C.  
 
Carci n o ma i n sit u ( CI S ). 
7.  P atie nt has a t u m or i n a bla d der di vertic ul u m.  
8.  P atie nt has recei ve d a n y pel vi 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.)  
9.  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. 
1 0.  P atie nt has scree ni n g he m o gl o bi n < 1 0 m g/ d L.  
1 1.  P atie nt has a n y u nsta ble me di cal c o n diti o n  t hat w o ul d ma ke it u nsafe t o u n der g o T U R B T. 
1 2.  P atie nt has a hist or y of i nterstitial c ystitis.  
1 3.  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.  
1 4.  F or patie nts wit h rec urre nt t u m or, t he patie nt ha d at least a 6 -m o nt h c yst osc o picall y -c o nfir me d t u m or -
free i nter val bet wee n t he last t u m or rec urre nce a n d scree ni n g c yst osc o pic e xa mi nati o n.  
1 5.  P atie nt is pre g na nt or breast -fe e di n g. 
D ose a n d R o ute of A d mi nist r ati o n:  
T he first d ose of eit her 4 m g/ 4 0 m L a p azi q u o ne  or 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 (ra n d o miz ati o n date,  D a y 1 ) via a n i n d welli n g 1 0 0 % S ilic o ne 
F ole y cat heter . T he sec o n d d ose of eit her 4 m g/ 4 0 m L a pazi q u o ne or place b o will a d mi nistere d b y i ntra vesical 
a d mi nistrati o n via a n i n d welli n g cat heter o n D a y 1 5  (± 5 da ys ).  
Effic ac y Assess me nts:  
C yst osc o p y e ver y 9 0  da ys ( ± 1 0 da ys ) calc ulate d fr o m t he date of T U R B T  t hr o u g h 2 4 m o nt hs . 
Pri m ar y E n d p oi nt:  
 
Ti me t o Rec urre nce  i n patie nts wit h eit her o ne  i nstillati o n of 4 m g a pazi q u o ne or t w o i nstillati o n s of 4 
m g a p azi q u o ne relati ve t o plac e b o i nstillati o n f oll o wi n g T U R B T . 
Sec o n d ar y E n d p oi nts:  
1.  T he 2 -Ye a r  R ec urre nce R ate  of bla d der ca ncer  
2.  T he 1 -Ye a r  R ec urre nce R ate  of bla d der ca ncer  
3.  Ti me t o Pr o gressi o n  t o hi g her sta ge  
S afet y Assess me nts:  
Safet y will be assesse d b y re p orte d/elicite d A Es, la b orat or y assess me nts, a n d p h ysical e xa mi nati 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 
S afet y E n d p oi nts  
 
All a d verse e ve nts  
 
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  
 
Vital si g ns (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 para meters ( c o m plete 
bl o o d c o u nt wit h 3 -part differ e ntial , 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:  
All a d verse e ve nts fr o m t he ti me of ra n d o mizati o n u ntil 3 5 da ys after t he last d ose of st u d y treat me nt  will be 
rec or de d. After 3 5 da ys a n d t hr o u g h 2 4 m o nt hs , o nl y S A Es a n d A Es ≥Gra de 3 will be rec or de d. 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. 
St atistic al M et h o ds:  
A f or mal statistical a nal ysis pl a n ( S A P) will be pr o vi de d wit h f ull tec h nical details of t he met h o ds of a nal ysis of 
st u d y data.  
T he pri mar y a nal ysis p o p ulati o n is t he T ar g et (T a , G 1 -G 2 ) P o p ul ati o n . T he T ar get  ( T a, G 1-G 2) P o p ul ati o n  
i ncl u des all patie nts w h o have  u n der g o ne T U R B T a n d ha ve l ocal pat h ol o g y c o nfir me d T a , G 1 -G 2 N MI B C.  T he 
S afet y P o p ul ati o n  i ncl u des all p atie nts wit h T U R B T a n d ha ve recei ve d at least o ne i nstillati o n of st u dy dr u g 
(a p azi q u o ne  or place b o).  
T he e nr olle d patie nts will be  ra n d o mize d i n a 1: 1: 1 rati o i nt o o ne of t he f oll o wi n g t hree tr eat me nt ar ms: Ar m 1: 
o ne d ose of apazi q u o ne , Ar m 2: t w o d ose s of apazi q u o ne , or Ar m 3: place b o , usi n g a per m ute d bl oc k desi g n.  
T he pri mar y e n d p oi nt of t he st u d y is Ti me t o Rec urre nce  i n t he T ar get ( T a, G 1-G 2) P o p ul ati o n . T he pri mar y 
e n d p oi nt a nal ysis i n v ol ves t w o pair wise tests of c o m paris o ns: o ne d ose  of  4 m g apazi q u o ne vs. place b o a n d t w o 
d ose s of 4 m g apazi q u o ne vs. place b o. N o c o m paris o n of Ar m  1  (o ne d ose  of  apazi q u o ne ) vs.  Ar m 2  (t w o d ose s 
of  apazi q u o ne ) will be perf or me d.  T he pri mar y a nal yses of tests of pair wise c o m paris o ns of Ar m 1  (o ne d ose  of 
a p azi q u o ne)  vs. Ar m 3  (place b o ) a n d Ar m 2  (t w o d ose s of a pazi q u o ne) vs. Ar m 3  (place b o ) ar ms will be 
perf or me d usi n g 2 -si de d l o g-r a n k test eac h at 5 % le vel of si g nifica nce.  
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. H oc h ber g 
pr oce d ure will b e use d t o c o ntr ol t he o verall T y pe I err or rate d ue t o m ulti ple c o m paris o ns f or t he pri mar y 
e n d p oi nt. If t he lar ger p -v al ue of t he t w o c o m paris o ns ( o ne d ose of a pazi q u o ne vs place b o, t w o d ose s of 
a p azi q u o ne  vs . place b o) is ≤0. 0 5, t he n b ot h c o m paris o ns will be c o nsi dere d sta tisticall y si g nifica nt. If t he lar ger 
p -val ue of t he t w o c o m paris o ns is > 0. 0 5 b ut t he s maller p -val ue is ≤0. 0 2 5, t he c o m paris o n ass ociate d wit h t he 
s maller p-val ue will be c o nsi dere d statistical l y si gnifica nt . If t he lar ger p-val ue of t he t w o c o m paris o ns i s > 0. 0 5 
a n d t he s maller p -val ue is > 0. 0 2 5, t he n neit her c o m paris o n will be c o nsi dere d statistical l y si g nifica nt. If b ot h 
c o m paris o ns are statisticall y si g nifica nt, t he T y pe I err or will be use d t o test t he list of sec o n dar y e n d p oi nts f or 
eac h pair wise c o m p aris o n i n t he or der liste d u ntil t he p -val ue of a partic ular c o m paris o n is > 0. 0 5.  
A p pr o xi matel y 1 8 6 9  patie nts will b e 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 3 6 m o nt hs  
a n d f oll o w-u p ti me as 2 4 m o nt hs . Ass u mi n g 5 4 % of patie nts will  be rec urre nce-free f or place b o a n d 6 0. 5 %  
rec urre nce-free f or t he a p azi q u o ne treat me nt ar ms (ass u me d t o be t he sa me f or eac h ar m) at t he e n d of  2 4 m o nt h  
f oll o w-u p , sa m ple sizes of 5 1 9  c o nfir me d T a, G 1 -G 2 patie nts per treat me nt ar m will ac hie ve 8 0 % p o wer t o  
detect s u peri orit y i n eac h c o m paris o n, usi n g l o g -ra n k test at 5 % le vel of si g nifica nce. At t he 2 year f oll o w u p, 
t his t otal n u m ber of patie nts is ass u me d t o pr o vi de 3 3 6 rec urre nce e ve nts i n t he P l ace b o Tre at me nt Ar m  a n d 
2 9 5 e ve nts i n eac h A p azi q u o ne Tre at me nt Ar m . Base d o n t he data fr o m pri or st u dies o n misclassificati o n of 
sta ge a n d gra de dia g n osis at S cree ni n g  f or e nr oll me nt, a n a d diti o nal 2 0 % of patie nts nee d t o be e nr olle d.  
T heref ore, t he st ud y will e nr oll a n d ra n d o mize 6 2 3  patie nts per  ar m f or a t otal of 1 8 6 9  patie nts.   
T o deter mi ne w het her e nr oll me nt s h o ul d be disc o nti n ue d i n a n i nefficaci o us ar m, a f utilit y a nal ysis will be 
c o n d ucte d o nce 1 0 0 of t he e x p ecte d 3 3 6  rec urre nce e ve nt s are o bser ve d i n t he Pl ace b o Tre at me nt Ar m  of  t he 
st u d y. T he re q uire d n u m ber of e ve nts will be deter mi ne d b y i n de pe n de nt, u n bli n de d data m o nit ori n g pers o n nel. 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
7 
T he fi nal a nal ysis of T i me t o R ec urre nce  will be c o n d ucte d o nce all 3 3 6 rec urre nce e ve nts i n t he Pl ace b o 
Tre at me nt Ar m  are accr ue d.  
If b ot h pri mar y e n d p oi nt c o m paris o ns are statisticall y si g nifica nt, sec o n dar y a nal yses will be c o n d ucte d usi n g 
pair wise c o m paris o n s bet wee n t he A p azi q u o ne Tre at me nt Ar ms  vs. t he Pl ace b o Tre at me nt Ar m  usi n g t he 
sa me pr oce d ure as a b o ve. All treat me nt e mer ge nt a d verse e ve 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 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. 03 , 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 p er patie nt.  
Ori gi n al Pr ot oc ol:  0 6 A u g  2 0 1 5  
 
 
 








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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 1  
g)  
All a d vers e e ve nts fr o m t h e ti me of ra n d o mizati o n u ntil 3 5 da ys aft er t h e last d ose of st u d y treat me nt will be rec or de d. After 3 5 da ys a n d t hr o u g h 2 4 m o nt hs, o nl y S A Es a n d A Es ≥Gra de 3 will be 
rec or de 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 2  
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 SI S ...................................................................................................................................... 3  
T A B L E O F C O N T E N T S ............................................................................................................ 1 2  
List of T a bles .......................................................................................................................... 1 5  
List of Fi g ure s ......................................................................................................................... 1 5 
LI S T O F  A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S .......................................... 1 6 
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 8  
1. 1  
N o n- M uscle I n v asi ve Bl a d der C a ncer ..................................................................... 1 8  
1. 2  
A p azi q u o ne f or I ntr a vesic al I nstill ati o n .................................................................. 1 9  
1. 3  
S u m m ar y of N o ncli nic al St u dies wit h A p azi q u o ne................................................. 1 9  
1. 3. 1  
I n vitr o A p azi q u o ne Acti vit y i n Ur ot heli al C a ncer Cell Li nes ...................... 1 9  
1. 3. 2  
De r m al Ir rit ati o n St u d y .................................................................................... 2 0  
1. 4  
Cli nic al St u dies wit h A p azi q u o ne ............................................................................. 2 0  
1. 4. 1  
I ntr a ve n o us A d mi nistr ati o n St u dies ................................................................ 2 0 
1. 4. 2  
I ntr a vesic al St u dies ........................................................................................... 2 0 
1. 4. 2. 1  
P h ase 1 M ar ker Lesi o n St u dy ( N D 0 1 9 9 0 3) .................................................. 2 0  
1. 4. 2. 2  
P h ase 2 M ar ker Lesi o n St u dy ( N D 0 3 0 2 0) .................................................... 2 1  
1. 4. 2. 3  
P h ase 2 Hi g h-ris k St u dy ( S PI- 0 5- 0 0 3) ......................................................... 2 1  
1. 4. 2. 4  
Pil ot  St u dy- S afety a n d P K of Si n gle I nstill ati o n of A p azi q u o ne 
I m m e di ately After T U R B T ( S PI- 5 1 5) ........................................................... 2 2 
1. 4. 2. 5  
P h ase 3 St u dies of a Si n gle, I m m e di ate, P ost- T U R B T I nstill ati o n of 
A p azi q u o ne ( St u dies S PI- 6 1 1 a n d S PI- 6 1 2) ................................................ 2 2  
1. 4. 2. 6  
P h ase 3 St u dies of M ulti- D ose, P ost- T U R B T I nstill ati o n of 
A p azi q u o ne .................................................................................................... 3 0  
1. 5  
R ati o n ale ..................................................................................................................... 3 0  
1. 5. 1  
S u m m ar y of Ris ks a n d Be nefits ....................................................................... 3 2  
1. 5. 1. 1  
P ote nti al Ris ks ............................................................................................... 3 2  
1. 5. 1. 2  
P ote nti al Be nefits ........................................................................................... 3 2  
1. 5. 2  
J ustific ati o n of t he D ose, Sc he d ule a n d R o ute of A d mi nistr ati o n of 
A p azi q u o ne ...................................................................................................... 3 3  
2  
S T U D Y O B J E C TI V E S ........................................................................................................ 3 4  
2. 1  
Pri m ar y O bjecti ve(s) ................................................................................................. 3 4  
2. 2  
Sec o n d ar y O bjecti ves................................................................................................. 3 4  
3  
I N VE S TI G A TI O N A L P L A N .............................................................................................. 3 4  
3. 1  
St u d y Desi g n a n d Tre at me nt Pl a n............................................................................ 3 4  
3. 2  
St u d y D ur ati o n ........................................................................................................... 3 5  
4  
P A TI E N T P O P U L A TI O N ................................................................................................... 3 5  
4. 1  
I ncl usi o n Criteri a ....................................................................................................... 3 5 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 3  
4. 2  
E xcl usi o n Criteri a ...................................................................................................... 3 6  
4. 3  
P ati e nt Disc o nti n u ati o n/ Wit h dr a w al Criteri a ......................................................... 3 7  
5  
S T U D Y P R O C E D U R E S ...................................................................................................... 3 8  
5. 1  
Scree ni n g ..................................................................................................................... 3 9  
5. 2  
P ati e nt Assi g n me nt .................................................................................................... 4 0  
5. 3  
Ti mi n g of Assess me nts a n d Pr oce d ures ................................................................... 4 0  
5. 3. 1  
S cree ni n g ............................................................................................................ 4 0  
5. 3. 2  
T re at me nt Peri o d Visit 1 ( D a y 1) ..................................................................... 4 1  
5. 3. 3  
T re at me nt Peri o d Visit 2 ( D a y 1 5 [ ± 5 d a ys]) .................................................. 4 1  
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 ( E ver y 9 0 d a ys [ ± 1 0 d a ys] 
P ost- T U R B T) ................................................................................................... 4 1  
5. 3. 5  
S afet y F oll o w- u p Visit ( D a y 3 5 ( ± 5 d a ys) After D ate of E arl y 
Disc o nti n u ati o n or L ast D ose of St u d y Dr u g) .............................................. 4 1  
5. 4  
Descri pti o n of St u d y Assess me nts a n d Pr o ce d ures................................................. 4 2  
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.................................. 4 2  
5. 4. 2  
M e dic al Hist or y ................................................................................................. 4 2  
5. 4. 3  
Re vie w I ncl usi o n/ E xcl usi o n Criteri a ............................................................... 4 2  
5. 4. 4  
P h ysic al E x a mi n ati o n ........................................................................................ 4 2  
5. 4. 5  
Vit al S i g n Assess me nts ...................................................................................... 4 2 
5. 4. 6  
Cli n ic al L a b or at or y Tests ................................................................................. 4 2 
5. 4. 7  
Ur i ne C yt ol o g y ................................................................................................... 4 3 
5. 4. 8  
C yst osc o p y .......................................................................................................... 4 3  
5. 4. 9  
T U R B T ............................................................................................................... 4 3  
5. 4. 1 0  
A d v erse E ve nt .................................................................................................... 4 3  
5. 4. 1 1  
C o nc o mit a nt Me dic ati o ns ................................................................................. 4 4  
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 ..................................... 4 4  
6. 1  
A p azi q u o ne a n d Pl ace b o ........................................................................................... 4 4  
6. 1. 1  
C o m p ositi o n of A p azi q u o ne.............................................................................. 4 4  
6. 1. 2  
C o m p ositi o n of Pl ace b o ..................................................................................... 4 4  
6. 1. 3  
C o m p ositi o n of Dil ue nt f or A p azi q u o ne a n d Pl ace b o .................................... 4 4  
6. 1. 4  
S hi p pi n g a n d St or a ge of St u d y Dr u g ............................................................... 4 4  
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................................ 4 4  
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 ......................................... 4 4 
6. 2. 2  
S c he d ule of St u d y Dr u g A d mi nistr ati o n ......................................................... 4 4  
6. 2. 2. 1  
Pre p ar ati o n of St u dy Dr u g ............................................................................ 4 5  
6. 2. 2. 2  
I nstill ati o n of t he First d ose of t he St u dy Dr u g o n D ay 1 ............................ 4 5 
6. 2. 2. 3  
I nstill ati o n of t he Sec o n d D ose of t he St u dy Dr u g o n D ay 1 5 ( ± 5 
d ays) p ost- T U R B T ......................................................................................... 4 6  
6. 3  
Dis p os al of St u d y Dr u g .............................................................................................. 4 6  
6. 4  
P r o d uct Acc o u nt a bilit y .............................................................................................. 4 6  
6. 5  
Tre at me nt Bli n di n g Pr oce d ures ............................................................................... 4 7  
6. 6  
N o n- St u d y Tre at me nts .............................................................................................. 4 7  
6. 6. 1  
Pri o r a n d C o nc o mit a nt Me dic ati o ns ............................................................... 4 7  
6. 6. 2  
P r o hi bite d Me dic ati o ns ..................................................................................... 4 8  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 4  
7  
S A F E T Y A S S E S S M E N T ..................................................................................................... 4 8  
7. 1  
S afet y Me as ures ......................................................................................................... 4 8  
7. 2  
A d verse E ve nts ........................................................................................................... 4 8  
7. 3  
G ui deli nes f or Rec or di n g a n d Attr i b uti o n Sc ori n g of A d verse E vents ................ 4 9  
7. 3. 1  
Re c or di n g of A d verse E ve nts ........................................................................... 4 9  
7. 3. 2  
G r a di n g of A d verse E ve nts ............................................................................... 5 0  
7. 4  
F oll o w- u p of A d verse E ve nts .................................................................................... 5 0  
7. 5  
Rel ati o ns hi p ................................................................................................................ 5 0  
7. 6  
E x pecte d ness ............................................................................................................... 5 1  
7. 7  
S eri o us A d verse E ve nts ............................................................................................. 5 1  
7. 7. 1  
S eri o us A d verse E ve nt Re p o rti n g .................................................................... 5 1  
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 .................... 5 2  
7. 8  
Re pr o d ucti ve Ris ks .................................................................................................... 5 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 ...................................................................... 5 3  
8. 1  
S a m ple Size ................................................................................................................. 5 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 ............................................... 5 4  
8. 3  
A n al ysis P o p ul ati o ns .................................................................................................. 5 5  
8. 4  
Ge n er al St atistic al Met h o ds ...................................................................................... 5 5  
8. 5  
Effic ac y A n al yses ....................................................................................................... 5 5  
8. 5. 1  
E ffic ac y Assess me nts ......................................................................................... 5 5 
8. 5. 2  
P ri m ar y E n d p oi nt .............................................................................................. 5 6  
8. 5. 3  
S ec o n d ar y E n d p oi nts ......................................................................................... 5 6  
8. 5. 4  
De fi niti o ns .......................................................................................................... 5 6 
8. 5. 5  
P ri m ar y E n d p oi nt - Ti me t o Rec urre nce ........................................................ 5 6  
8. 5. 6  
S ec o n d ar y E n d p oi nts ......................................................................................... 5 7  
8. 5. 6. 1  
S ec o n d ary E n d p oi nt - Rec urre nce R ates ...................................................... 5 7  
8. 5. 6. 2  
S ec o n d ary E n d p oi nt - Ti m e t o Pr o gressi o n .................................................. 5 8  
8. 6  
S afet y E v al u ati o n ....................................................................................................... 5 8  
8. 6. 1  
S afet y E n d p oi nts ................................................................................................ 5 8  
8. 6. 1. 1  
A dverse Eve nts ............................................................................................... 5 8  
8. 6. 1. 2  
De at hs ............................................................................................................ 5 8  
8. 6. 2  
Ot h er Seri o us A d verse E ve nts .......................................................................... 5 8  
8. 6. 3  
Cli nic al L a b or at or y E v al u ati o ns ...................................................................... 5 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 ........................ 5 9  
9. 1  
I n vesti g at or Res p o nsi bilities ..................................................................................... 5 9 
9. 1. 1  
G o o d Cli nic al Pr a ctice ...................................................................................... 5 9  
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 .............................. 5 9 
9. 1. 3  
I nf or me d C o nse nt .............................................................................................. 5 9 
9. 1. 4  
St u d y Files a n d Rete nti o n of Rec or ds .............................................................. 5 9  
9. 2  
Rec or di n g a n d C ollecti n g of D at a ............................................................................ 5 9  
9. 2. 1  
C ase  Re p ort F or ms ............................................................................................ 6 0 
9. 2. 2  
Dr u g Acc o u nt a bilit y .......................................................................................... 6 0  
9. 3  
Pr ot oc ol C o m pli a nce .................................................................................................. 6 0  
9. 4  
S p o ns or Res p o nsi bilities ............................................................................................ 6 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 5  
9. 4. 1  
St u d y M o nit ori n g ............................................................................................... 6 0  
9. 4. 2  
S afet y M o nit ori n g .............................................................................................. 6 0  
9. 5  
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities ............................................................ 6 1  
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 ..................................... 6 1  
9. 5. 2  
T er mi n ati o n of t he St u d y .................................................................................. 6 1  
9. 5. 3  
P u blic ati o n P olic y .............................................................................................. 6 1  
9. 6  
C o nfi de nti alit y ............................................................................................................ 6 2  
1 0  R E F E R E N C E S ..................................................................................................................... 6 3  
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 ............ 6 5  
 
List of T a bles 
T a ble 1  
Sc he d ule of St u d y Assess me nts a n d Pr oce d ures .................................................... 1 0  
T a ble 2  
Res p o nse t o I ntr a vesic al Tre at me nt i n t he D ose- Esc al ati o n a n d Fi xe d- D ose 
C o h orts ....................................................................................................................... 2 1  
T a ble 3  
I n di vi d u al St u d y Pri m a r y E n d p oi nt- 2- Ye ar Rec urre nce R ate i n t he T a, G 1- G 2 
P o p ul ati o n ( S PI- 6 1 1, S PI- 6 1 2) ................................................................................. 2 3  
T a ble 4  
I nte gr ate d St u d y Pri m a r y E n d poi nt D at a- 2- Ye ar Rec urre nce  R ate i n t he 
T a, G 1 -G 2 P o p ul ati o n ( S PI- 6 1 1 + S PI- 6 1 2) ........................................................... 2 4  
T a ble 5  
I n di vi d u al St u d y Pri m a r y E n d p oi nt D at a- 2- Ye ar Rec urre nce R ate i n t he 
T a, G 1 -G 2 P o p ul ati o n i n t he 3 1 t o 9 0 Mi n ute P ost- T U R B T Wi n d o w  ( S PI- 6 1 1 
a n d S PI- 6 1 2) .............................................................................................................. 2 5  
T a ble 6  
I n di vi d u al St u d y Ke y Sec o n d ar y E n d p oi nt- Ti me t o Rec urre nce i n t he T a, G 1-
G 2 P o p ul ati o n ( S PI- 6 1 1, S PI- 6 1 2) ........................................................................... 2 6  
T a ble 7  
I nte gr ate d St u d y Sec o n dar y E n d p oi nt- Ti me t o Rec urre n ce i n t he T a, G 1 - G 2 
P o p ul ati o n ( S PI- 6 1 1 + S PI- 6 1 2) ............................................................................... 2 8  
T a ble 8  
I n di vi d u al St u d y Ke y Seco n d ar y E n d p oi nt i n t he T a, G 1- G 2 P o p ul ati o n f or t he 
3 1- t o 9 0- Mi n ute P ost- T U R B T I nstill ati o n Wi n d o w  (S PI- 6 1 1 a n d S PI- 6 1 2) ...... 2 9  
T a ble 9  
I n vesti g at or Assess me nt of A d verse E ve nt C a us alit y ............................................ 5 0 
 
List of Fi g ures 
Fi g u re 1  
St u d y Desi g n Di a gr a m ................................................................................................ 8  
Fi g ure 2  
St u d y Fl o w C h art ........................................................................................................ 9  
Fi g ur e 3  
I n di vi d u al St u d y Ti me t o Rec urre nce i n t he T a, G 1- G 2 P o p ul ati o n ( S PI- 6 1 1) .. 2 6  
Fi g ure 4  
I n di vi d u al St u d y Ti me t o Rec urre nce i n t he T a, G 1- G 2 P o p ul ati o n ( S PI- 6 1 2) .. 2 7  
Fi g ure 5  
I nte gr ate d St u d y- Ti me t o Rec urre nce ( S PI- 6 1 1 + S PI-6 1 2) ................................ 2 8  
Fi g ure 6  
I n di vi d u al St u d y Ti me t o Rec urre nce- I nstill ati o n Wi n d o w 3 1 t o 9 0 Mi n utes 
p ost- T U R B T ( S PI- 6 1 1, S PI- 6 1 2) ............................................................................. 3 0  
Fi g ure 7  
St u d y Desi g n Di a gr a m .............................................................................................. 3 8  
F i g ure 8 
St u d y Fl o w C h art ...................................................................................................... 3 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 8  
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 In v asi ve Bl a d der C a ncer 
I n t he U S, 7 4, 0 0 0 ne w cases of bla d der ca n cer a n d 1 6, 0 0 0 deat hs are pr ojecte d t o occ ur i n 2 0 1 5 
[1 ]. T he me dia n a ge at dia g n osis is 7 3 years a n d t he treat me nt of bl a d der ca ncer is fre q u e ntl y 
c o m plicate d b y t he prese nce of si g nifica nt c o m or bi dities [2 ]. 
T he  cli nical s pectr u m of bla d der ca ncer ca n be di vi de d i nt o 3 br oa d cate g ories t hat differ i n 
pr o g n osis a n d m a na ge me nt . T he first cate g or y c o nsists of n o n- m uscle i n vasi ve bla d der ca ncer 
( N MI B C), f or w hic h treat me nt is directe d at l ocal treat me nt a n d re d uci n g rec urre nces a n d 
pre ve nti n g pr o gressi o n t o m ore a d va n ce d sta ges. T hese N MI B Cs ca n b e f urt her s u b di vi de d, 
base d o n t heir relati ve ris k of pr o g ressi o n, i nt o l o w, i nter me diate or hi g h ris k gr o u ps. T h e sec o n d 
cate g or y of t u m ors is c o m prise d of t he  l ocall y a d va nce d, m uscle i n v asi ve lesi o ns. F or t hese 
patie nts, s ur gic al re m o v a l of t he bla d der a n d a djace nt or ga ns, c yste ct o m y wit h uri nar y di v ersi o n, 
is t he sta n dar d of care wit h preve nti o n of metastasis. F or t he t hir d cat e g or y, metastatic disease, 
s yste mic treat me nt is ai me d at atte m pti n g t o pr ol o n g s ur vi val. N u m er o us c he m o- a n d 
i m m u n ot hera pies ha ve s h o w n acti vit y i n t his disease, yet t o d ate, patie nts wit h metastatic bla d der 
ca ncer are lar gel y i nc ura ble. T he iss ue f or t he cli nicia n is h o w best t o use t he a vaila ble a ge nts t o 
ac hie ve t h e m ost satisfac t or y o utc o me f or t he patie nt, w hile ne w a ge nts are bei n g d e vel o pe d t o 
a d dress t he u n met me dical nee d f or t he tre at me nt of bla d der ca ncers. 
M ore t ha n t w o-t hir ds of ne wl y di a g n ose d cases of bla d der ca ncer are tra nsiti o nal cell carci n o mas 
wit h a n e x o p h yti c pa pillar y a p peara n ce. A p pr o xi matel y 7 0 % of t hese t u m ors are c o nfi ne d t o t he 
e pit heli u m ( Ta), w hile a p pr o xi matel y 3 0 % reac h t he la mi na pr o pria ( T 1) [3 ]. T he nat ur al hist or y 
of t he se t u m ors is c haract erize d b y a te n de n c y t o r ec ur at t he s a me or differe nt l o cati o n i n t he 
bla d der. A p pr o xi matel y o ne- half t o t w o-t hir ds of t hese patie nts will e x perie nce a rec urre nce 
wit hi n 5 years [3 ]. As t h ese t u m ors are hi g hl y rec urre nt, patie nts re q uire fre q ue nt f oll o w u p 
s ur veilla nce a n d retr eat m e nt, res ulti n g i n si g nifica nt e x pe nse a n d m or bi dit y. Healt h o utc o me dat a 
i n dicate t hat bla d der can cer is t he m ost e x pe nsi ve t u m or t o treat o n a per lifeti me basis [4 , 5 ]. 
T u m or rec urre n ce is attri b ute d t o a c o m bi nati o n of misse d t u m ors, a n i nc o m plete resecti o n, a n d 
i m pla ntati o n of t u m or cells release d d uri n g tr a ns uret hral res ecti o n bla d der t u m or ( T U R B T) or 
gr o wt h of a ne w t u m or. T he i niti al treat me nt f or N MI B C is a g o o d q ualit y T U R B T f oll o we d b y 
a n i m me diate p ost o perati ve i nstillati o n of a c he m o- or i m m u n ot hera pe utic, as rec o m me n d e d b y 
A merica n Ur ol o gical Ass ociati o n ( A U A) a n d E ur o pea n Ass ociati o n of Ur ol o g y ( E A U) 
g ui deli nes [6- 8 ]. F urt her m ore, Nati o nal C o m pre h e nsi ve Care Net w or k ( N C C N) g ui deli nes 
rec o m me n d “i n a d diti o n t o o bser vati o n, t he cli nicia n s h o ul d c o nsi der a d mi nisteri n g a si n gle d os e 
of i m me diate i ntra vesic al c he m ot hera p y ( n ot i m m u n ot hera p y) wit hi n 2 4 h o urs of res ecti o n” [9 ]. 
T he  i m me diate p ost o perati ve i nstillati o n of a c he m ot hera pe utic a ge nt is t h o u g ht t o me diate its 
effect b y destr o yi n g fl oati n g t u m or cells releas e d d uri n g T U R B T t hat p ote ntiall y ca n i m pla nt i n 
t he bla d der wall a n d/ or b y a bl ati n g resi d ual t u m ors cells at t he res ecti o n site.  
T he pri mar y o bje cti ve of a d di n g i m me diate p ost o p erati ve i ntra v esical t hera p y after T U R B T i n 
patie nts wit h N MI B C is t o de la y rec urre nce of bla d der ca n cer, he nce e n a bli n g patie nts t o ha v e 
t he l o n gest p ossi ble “rec urre nce free” i nter val. Re d uci n g rec urre n ce rates, w o ul d lea d t o a 
re d uce d n ee d f or s u bse q u ent s ur gi cal i nter ve nti o n a n d a nest hesia, w hic h w o ul d f urt her fa v ora bl y 
i m pact patie nts’ q ualit y of life, red u ci n g t h e ris ks of pr o gressi o n, a n xiet y, a n d ec o n o mic b ur de n 
[4 ]. A d diti o nall y, t he re p eate d t u m or resecti o ns re q uire d d ue t o t u m or rec urre nces wit h N MI B C 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
1 9  
ma y res ult i n re d uce d bla d der ca p acit y fr o m s carri n g, w hic h i n t ur n lea ds t o uri nar y s y m pt o ms of 
ur ge nc y, fre q ue n c y, etc., f urt her ne gati vel y i m pacti n g patie nts’ q u alit y of life .  
T he me dical literat ure a n d i nter nati o nal treat me nt 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, b eca use of t he p ote ntial i m pact o n re d uci n g 
t u m or rec urre nce a n d dis ease pr o gressi o n. 
U n derl yi n g t hese treat me nt rec o m me n dati o ns are t he res ults of a p u blis he d meta-a nal ysis of 
se ve n ra n d o mize d trials i ncl u di n g 1 4 7 6 patie nts, t hat de m o nstrate d a 1 2 % decrease i n 
Rec urre n ce R ates  ( 4 8. 4 % T U R B T al o ne vs. 3 6. 7 % T U R B T + si n gle i nstillati o n of a 
che m ot hera p e utic a ge nt) [1 0 ]. T his a nal ysis s u p p orts t he val ue of a si n gle 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 n re d uci n g t he i nci de nce of t u m or 
rec urre nce, w hic h i n tur n lea ds t o fe w er re q uire d s u bse q ue nt s ur gical i nter v e nti o ns [1 0 ].  
T he  First I nter nati o nal C o ns ultati o n o n Bla d der T u m ors ( FI C B T), t he p u blis he d literat ure, a n d 
t he I nt er nati o nal Bla d der Ca ncer Gr o u p (I B C G) als o rec o m me n d T U R B T pl us a n i m me diate 
p ost o perati ve c h e m ot hera pe utic i nstillati o n [1 1 ]. T he g o als of t his treat me nt are: 
1.  T o pr e ve nt r ec urre nce 
2.  T o pr e ve nt pr o gressi o n t o m uscle i n vasi ve diseas e 
3.  De crease t h e nee d f or re p etiti ve i n vasi ve pr oce d ures s uc h as c yst osc o p y a n d T U R B T 
wit h t he i n here nt ris k of i nfecti o n, blee di n g a n d p erf orati o n 
4.  Ulti matel y t o dela y or a v oi d t he nee d f or c ystect o m y 
H o we ver, t here is n o c urre ntl y a p pr o ve d a ge nt f or t his i n dicati o n i n t he U nite d States a n d t here 
re mai ns a hi g h u n met me dical nee d. 
1. 2  
A p azi q u o ne f or I ntr a vesic al I nstill ati o n 
A pa zi q u o ne ( E O q ui n ® , E O 9) is a f ull y s y nt h etic bi ore d ucti ve al k ylati n g i n d ol o q ui n o ne t hat is a 
pr o dr u g acti va t e d b y re d uctase e nz y m es t o ge nerate reacti ve a n d c yt ot o xic i nter me diates. T he 
acti vit y of a pazi q u o ne is e n ha nce d i n t u m or cells w hic h c o ntai n hi g her a m o u nts of re d ucti ve 
e nz y mes c o m pare d t o n or ma l cells; bla d der carci n o ma cells c o ntai n hi g h le vels of s uc h re d u cti ve 
e nz y mes [1 2 ]. T he a ntit u m or acti vit y of a pazi q u o ne has bee n c o nfir me d i n i n vitr o st u dies i n f o ur 
h u ma n tra nsiti o nal cell ca ncer cell li nes [1 3 ] a n d i n viv o i n a rat ort h ot o pic bla d der ca ncer m o del 
[1 4 ]. A d diti o nall y, P hase 1 t o P hase 3 cli nical st u dies c o n d ucte d wit h a p azi q u o ne ha ve 
c o nfir me d its ac ti vit y i n patie nts wit h N MI B C. 
1. 3  
S u m m ar y of N o ncli nic al St u dies wit h A p azi q u o ne 
1. 3. 1  I n vitr o A p azi q u o ne Acti vit y i n Ur ot heli al C a ncer Cell Li nes 
T he c yt ot o xicit y o f a pazi q u o ne a n d ot her c o m m o nl y use d i ntra v esical c he m ot hera pe utic a ge nts 
( mit o m yci n C, e pir u bici n a n d ge mcita bi ne) was i n vesti gate d i n vitr o i n f o ur h u ma n tra nsiti o nal 
cell ca n cer cell li nes ( R T 1 1 2, T 2 4, 2 5 3J, R T 4). I n t hese bla d der ca n cer cell li nes, a pazi q u o ne 
was s h o w n t o be t he m ost p ote nt a ge nt i n ter ms of c yt ot o xicit y c o m pare d t o mit o m yci n C, 
e pir u bici n, a n d ge mcita bi ne. F or e x a m ple, acti vit y of a pazi q u o ne was 5 t o 7 5 f ol d hi g her t ha n 
mit o m yci n C  i n t hese cell li nes [1 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
2 0  
1. 3. 2  Der m al Ir rit ati o n St u d y 
Der mal irritati o n p ote ntial of t he a pazi q u o ne f or m ulati o n was e val uate d i n fe male Ne w Zeala n d 
W hite  ra b bits b y t o pical a d mi nistrati o n ( n o n- occl usi ve) of a pazi q u o ne f or m ulati o n or ve hicle 
c o ntr ol as a si n gle d ose f or 4 h o urs, f oll o we d b y s ki n e xa mi nati o n at Baseli ne a n d at vari o us ti me 
p oi nts f or 3 da ys p ost a d mi nistrati o n, after re m o v al of e x cess material.  
N o m ortalit y or si g nifica nt dr u g-relate d cli nical/ d er mal o bser vati o ns were o bser ve d i n a n y of t he 
treat me nt sites e x p ose d t o a pazi q u o ne or ve hicle c o ntr ol. Sli g ht tra nsie nt er yt he ma res p o nses 
were o bs er ve d at t he 4 h o ur a n d 2 4 h o ur ti me p oi nts p ost e x p os ure i n a pazi q u o ne- a n d ve hicl e-
treate d sites. All er yt h e ma res p o nses were res ol ve d b y 4 8 h o ur e x a mi nati o n ti me p oi nt. N o ot her 
si g nifica nt a d vers e effects were o bs er ve d. (T X 0 9 0 6 8 _ T X ) 
1. 4  
Cli n ic al St u dies wit h A p azi q u o ne 
1. 4. 1  I ntr a ve n o us A d mi nistr ati o n St u dies 
T he i nitial st u dies of i ntra ve n o us a pazi q u o ne i n h u ma ns were c o n d ucte d at a d ose sc he d ul e of 
1 2 m g/ m 2 wee kl y or 2 2 m g/ m 2 e ver y 3 wee ks i n patie nts wit h breast, n o n-s mall cell l u n g ca ncer 
(N S C L C), gastr oi ntesti nal ca ncers a n d carci n o ma of u n k n o w n pri mar y ( C U P). Des pite re p orts of 
3 partial re s p o nses i n o ne P hase 1 st u d y i n 2 patie nts wit h C U P a n d o ne patie nt wit h bile d uct 
carci n o ma, n o res p o nses were o bs er ve d i n s u bse q ue nt P hase 2 st u dies. T he lac k of efficac y of 
a pazi q u o ne was attri b ute d t o its s h ort half-life ( 0. 8 t o 1 9 mi n utes) d ue t o t he a ge nt’s ra pi d 
i nacti vati o n b y t he si g nifica nt re d bl o o d cell fracti o n prese nt i n t he s yste mic circ ulati o n, si nc e it 
was re c o g niz e d t hat re d bl o o d cells ha ve t he a bilit y t o i nacti vate a pazi q u o ne [1 5 ]. Si nce 
apazi q u o ne is i nacti vate d b y re d bl o o d cells, t he dr u g was c o nsi dere d m ore s uita ble f or use wit h 
n o n-i ntra ve n o us a d mi nistrati o n t o t u m or sites i n rea dil y accessi ble c o m part me nts, s uc h as t he 
uri na r y bla d der, w here t h e dr u g c o ul d ha ve direct c o ntact wit h t u m or cells a n d w hic h t y picall y 
has fe w or n o re d bl o o d c ells. He nce, a pazi q u o ne was c o nsi dere d a n i deal ca n di date f or t h e 
treat me nt of bla d der ca ncer b y i ntra vesic al i nstillati o n, w hic h w o ul d all o w f or a 1 h o ur rete nti o n 
time t hat w o ul d i ncrease e x p os ure ti me t o bla d der ca ncer cells. Alt h o u g h mi ni mal s yst e mic 
u pta ke was e x pecte d vi a i ntra vesical a d mi nistrati o n, a n y dr u g reac hi n g t he s yste mic cir c ulati o n 
fr o m t he bla d der, b y w hate ver mec h a nis m, w o ul d be ra pi dl y cleare d, mi ni mizi n g t he ris k of 
s yste mic t o xicit y. 
1. 4. 2  I ntr a vesic al St u dies 
T here h a ve bee n 3 st u dies of a pazi q u o ne a d mi nistere d b y t he i ntr a vesical r o ute.  
1. 4. 2. 1  
P h ase 1 M a r ker Lesi o n St u d y ( N D 0 1 9 9 0 3) 
N D 0 1 9 9 0 3  was a n i ntra p atie nt d ose escalati o n st u d y perf or me d i n p atie nts ( n = 6) wit h rec urre nt 
N MI B C ( Ta- T 1, G 1- G 2) i n w hic h all b ut o ne “ mar ker” lesi o n ha d b ee n re m o ve d at T U R B T . 
A pazi q u o ne was gi ve n wee kl y f or 6 w ee ks b e gi n ni n g 2 wee ks p ost- T U R B T . T he d oses st u die d 
i ncl u ded 0. 5, 1, 2, 4, 8, a n d 1 6 m g i n 4 0 m L. F o ur patie nts recei ve d all d os e le vels u p t o t he 
ma x i m u m d ose of 1 6 m g. T w o of t he 6 patie nts treate d e x perie n ce d l ocal t o xicit y ( Gra de 3 
d ys uria ) at t he 8 m g d ose, b ut t olerate d t heir last i nstillati o n at t he re d uce d d ose of 4 m g . T h us, 
t he 4 m g per i nstillati o n d ose was deter mi ne d t o be t he Ma xi m u m T olerate d D ose ( M T D). M ore 
pa tients ( n = 6) were e nr olle d a n d treat e d wit h t he fi x e d d ose of 4 m g i n 4 0 m L. F o ur of t h ese 
6 patie nts ( 6 7 %) e x perie nce d a c o m plete hist ol o gic res p o nse of t h eir mar ker lesi o ns [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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
2 2  
ha d CI S. All patie nts r ecei ve d a n i n d ucti o n c o urs e of 6 wee kl y i ntra vesic al i nstillati o ns of 
4 m g/ 4 0 m L of a p azi q u o ne, a n d patie nts wit h CI S were f urt her tr eate d wit h 3 wee kl y i nstillati o ns 
of 4 m g / 4 0 m L of a p azi q u o ne e ver y 3 m o nt hs if CI S di d n ot rec ur. T he f oll o w- u p c o nsiste d of 
s ur veilla nce c yst os c o p y e ver y 3 m o nt hs f or 1 8 m o nt hs.  
Of 4 9 patie nts wit h pa pillar y disease, 2 7 patie nts ( 5 5 %) re mai n e d rec urre nce free at t he 1 8-
m o nt h f oll o w u p c yst osc o p y [1 8 ]. T he t w o p atie nts wit h CI S disc o nti n ue d after 6 i nstillati o ns 
eac h a n d di d n ot recei ve a n y m ai nte na nce d ose of a pazi q u o ne d ue t o c ystitis a n d rec urre nt 
pa pillar y  dis ease. T h e ot her 2 patie nts wit h CI S c o m plete d t he i n d ucti o n c o urse. O ne p atie nt 
recei ve d o nl y t hree mai nt e na nce d oses a n d disc o nti n ue d d ue t o uri nar y i nc o nti ne nce. T he ot her 
re mai ni n g p atie nt recei ve d 6 mai nte na nce d os es a n d disc o nti n ue d d ue t o d ys uria after recei vi n g a 
t otal of 1 2 d oses. Of t he 4 patie nts wit h CI S, 3 were disease free at 3 m o nt h f oll o w- u p a n d t he 
ot her 1 patie nt de vel o p e d pr o gressi ve dise ase. All f o ur patie nts wit h CI S ha d a c o m plete 
res p o nse b y histol o g y at 3 m o nt hs, b ut disc o nti n ue d t he st u d y after 6, 6, 9, a n d 1 2 d oses of 
a pazi q u o ne ( 3, 3, 5, a n d 1 2 m o nt hs after st u d y i n cl usi o n, res pecti vel y), d ue t o c ystitis, rec urre nt 
pa pillar y dis ease ( T 1, G 3), uri nar y i nc o nti ne nce, a n d d ys uria, res pecti vel y. 
1. 4. 2. 4  
Pil ot St u d y- S afet y a n d P K of Si n gle I nstill ati o n of A p azi q u o ne I m me di atel y 
A fter T U R B T (S PI- 5 1 5 ) 
S PI- 5 1 5  w as a safet y a n d t olera bilit y st u d y of si n gle d ose a pazi q u o ne ( 4 m g/ 4 0 m L) a d mi nistere d 
wit hi n 6 h o urs of T U R B T i n patie nts wit h Sta ge Ta- T 1, Gra de G 1- G 2 n o ni n vasi ve bla d der 
ca ncer t hat accr ue d 2 0 patie nts. All patie nts ( n = 2 0) d ose d t olerate d a pazi q u o ne i nstillati o n a n d 
rete nti o n in t he bla d de r f or 1 h o ur. T here was n o e vi de nce of i m paire d w o u n d heali n g o n f oll o w 
u p c yst osc o p y p erf or me d at D a y 8 5  o n t he first 1 0 patie nts d ose d. P K st u dies were perf or me d i n 
6 pa tie nts. Bl o o d sa m ples were c ollecte d bef ore i nstillati o n a n d at 5, 1 5, 3 0, 4 5, 6 0 mi n utes after 
i nstillati o n. Neit her t he pare nt dr u g ( a pazi q u o ne) n or its meta b olite E O 5a was detect e d i n plas ma 
sa m ples wit h a l o wer li mit of q ua ntitati o n ( L L O Q) f or E O 9 a n d E O 5a at 0. 5 n g/ m L [1 9 ]. 
1. 4. 2. 5  
P h ase 3 St u dies of a Si n gle, I m me di ate, P ost- T U R B T I nstill ati o n of A p azi q u o ne 
( St u dies S PI- 6 1 1 a n d S PI- 6 1 2) 
T w o lar ge  ra n d o mize d ( 1: 1), d o u ble- bli n d, place b o-c o ntr olle d st u dies of a p azi q u o ne e nr olle d a 
t otal of 1 6 1 5 patie nts (S PI- 6 1 1 , 8 0 2 patie nts; S PI- 6 1 2 , 8 1 3 patie nts) wit h N MI B C dia g n ose d b y 
vis ual a p peara nce at T U R B T as Ta, G 1- G 2 . All p atie nts recei ve d a si n gle i nstillati o n of eit her 
apazi q u o ne or place b o wit hi n 6 h o urs of T U R B T wit h t he st u d y dr u g retai ne d i n t he bla d der f or 
6 0 mi n utes. Ta, G 1- G 2  disease was c o nfir me d b y ce ntral pat h ol o g y f or 5 6 6 patie nts i n S P I- 6 1 1 
a n d 5 8 0 patie nts i n S PI- 6 1 2 . T hese data pr o vi de t h e basis f or t he s electi o n of d ose a n d sc h e d ule 
f or t he ne wl y pr o p ose d P hase 3 st u d y. 
1. 4. 2. 5. 1  Pri m ar y E n d p oi nt A n al ysis- 2- Ye ar Rec urre nce R ates-  
I n divi d ual St u dy A n alysis ( S PI- 6 1 1 a n d S PI- 6 1 2)  
I n S PI- 6 1 1 , t he pri mar y e n d p oi nt of 2 - Ye a r Rec urre nce R ate  i n t he T a, G 1- G 2 P o p ul ati o n  f or 
t he A p azi q u o ne Tre at me nt Gr o u p  ( N = 2 9 5) was 3 8. 0 % ( 9 5 % CI 3 2. 4 t o 4 3. 7) a n d 4 4. 6 % 
( 9 5 % CI 3 8. 6 t o 5 0. 8) i n t he Pl ace b o Tre at me nt Gr o u p  ( N = 2 7 1). T his st u d y de m o nstr ate d a 
cli nically me a ni n gf ul 6. 7 % re d ucti o n i n t he 2- Ye a r Rec urre nce R ate  wit h a pazi q u o ne (χ 2 
P = 0. 1 0 7), alt h o u g h t his differe n ce relati ve t o place b o was n ot statisticall y si g nifica nt (T a ble 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
2 7  
Fi g ure 4 
I ndi vi d u al St u d y Ti me t o Rec urre nce i n t he T a, G 1- G 2 P o p ul ati o n ( S PI- 6 1 2)  
 
I nte gr ate d Stu dy A n alysis ( S PI- 6 1 1 + S PI- 6 1 2)  
Ti me  t o Rec u rre nce- Fr o m Ti me of I nstill ati o n 
T he Ti me t o Rec urre nce , base d o n ti me fr o m T U R B T t o i nstillati o n, was als o s h o w n t o be 
statisticall y differe nt bet wee n treat me nt gr o u ps i n t he i nte grate d a n al ysis, fa v ori n g a pazi q u o ne 
treat me nt wit h a l o g ra n k p- val ue of 0. 0 0 9 8 a n d a hazar d rati o of 0. 7 9 (T a ble 7 ). I nte grate d data 
of t he s ur vi val pr o ba bilit y o ver 2 4 m o nt hs f or pati e nts i n S PI- 6 1 1  a n d S PI- 6 1 2  are prese nte d i n 
t he Ka pla n- M eier gra p h i n  Fi g ure 5 .  








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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 1  
disease 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 tr eat 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 ve l 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 
che 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 t u m or cells re mai ni n g at 
t he resecti o n site.  
A pazi q u o ne 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 n z y m es. T he a ntit u m or acti vit y of a pazi q u o ne 
has be e n de m o nstr ate d i n i n vitro  st u dies i n f o ur h u ma n bla d der ca ncer 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 p are 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 her t h a n mit o m yci n C. P hase 1 a n d P hase 2 
cli nical st u dies s h o we d t he acti vit y of a pazi q u o ne, 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- Ye ar  
Re c urre nce R ate  b y a pazi q u o ne i n t he T a, G 1- G 2 P o p ul ati o n . Alt h o u gh t hese differe n ces were 
n ot sta tisticall 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 ha se 3 st u dies ( n = 1 6 1 5) s h o we d a cli nicall y mea ni n gf ul 6. 7 % re d ucti o n i n t he 2- Ye ar 
Re c urre nce R ate i n t he A p azi q u o ne  Tre at 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 bas e d o n t he O d ds Rati o of Rec urre n ce. I ntra vesi cal treat me nt was als o 
s h o w n t o be well t olerate d wit h t he mai n A Es i ncl u di n g t h ose e x pecte d i n p atie nts wit h bla d der 
ca ncer, e g, h e mat uria, d ys uria, a n d uri nar y fre q ue nc y. 
A pazi q u o ne 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 5 ]. He mat uria, b ot h 
mi cr osc o pic a n d ma cr osc o pic, is t he m ost c o m m o n a d verse e ve nt i n t he i m me diate p ost- T U R B T 
pe ri o d. T heref ore, a n y bl ee di n g i n t he p ost- o perati ve peri o d f oll o wi n g T U R B T c o ul d i nacti vate 
a pazi q u o ne 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 efficac y. T his 
pr o vi de d t he rati o nal e f or t he f urt her a nal ysis of t h e P hase 3 st u d y d ata f or S PI - 6 1 1 a n d S PI- 6 1 2  
ba se 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 nstrate d a r o b ust 2 0. 3 % re d ucti o n i n t he 2- Ye ar Rec urre nce 
R at e i n a pazi q u o ne-tr eat e d patie nts i n t he T a, G 1 - G 2 P o p ul ati 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 s a me 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 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 2  
( 0. 3 9; 9 5 % CI 0. 1 6, 0. 9 4) i n fa v or of a pazi q u o ne. Si nce t he ma xi m u m be nefit fr o m i ntra vesical 
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 selecte d f or i nstillati o n of st u d y dr u g (a p azi q u o ne 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 hase 3 st u d y.  
T he pr o p ose d P hase 3 st u d y i ncl u des t w o a pazi q u o ne d osi n g ar ms ; Ar m  1: a si n gle i nstillati o n 
of a pazi q u o ne; a n d Ar m 2:  t w o a pazi q u o ne i nstillati o ns, 2 wee ks a p art. T he rati o nale f or t his 
sec o n d a pazi q u o ne d ose is t w of ol d: 1) it per mits treat me nt at a p oi nt i n ti me w he n t he p ossi bilit y 
of p ost- T U R B T blee di n g is l o w, mi ni mizi n g t he p ote ntial f or a pazi q u o ne i nacti vati o n; a n d 2) 
preli mi nar y data fr o m m ulti-i nstallati o n st u dies wit h a pazi q u o ne ( S PI- 1 0 1 1  a n d S PI- 1 0 1 2 ) 
s u g geste d a n a d diti o nal b e nefit fr o m r e peat a d mi nistrati o n of a pazi q u o ne wit h a 1 9 % t o 2 8 % 
re d ucti o n i n Rec urre nce R ates wit h m ulti- d ose i nstallati o n, vers us 6 % i n t he si n gle- d ose 
st u dies; safet y pr ofil es bet wee n si n gle a n d m ulti-i nstillati o n st u dies were si milar. T h us, t he 
pr o p ose d P hase 3 st u d y is desi g ne d t o i ncl u d e a tr eat me nt ar m ( Ar m 2 ) wit h a pri mar y o bjecti ve 
of assessi n g t he treat me nt be nefit of t w o i ntra vesi cal i nstillati o ns of a pazi q u o ne i n patie nts wit h 
N MI B C, o ne i n t he i m m e diate p ost T U R B T p eri o d a n d t he sec o n d i nstillati o n 2 wee ks later; t his 
d osi n g  strate g y ma y f urt her dela y or pre v e nt t he rec urre nce of N MI B C.  
1. 5. 1  S u m m ar y of Ris ks a n d Be nefits 
1. 5. 1. 1  P ote nti al Ris ks 
A pazi q u o ne has bee n a d mi nistere d t o o ver 1 1 0 0 patie nts as a si n gl e i nstillati o n or as m ulti ple 
i nstillati o ns eit her wit hi n 6 h o urs of T U R B T or starti n g 2 wee ks p ost- T U R B T. T he d e m o nstrate d 
safet y pr ofile of a pazi q u o ne is si milar t o place b o wit h re p orte d a d v erse e v e nts bei n g li mite d t o 
t he bla d der ie, d ys uri a, h e mat uria, uri nar y tract i nfecti o n, a n d bla d der pai n etc. I n t he 1 6 1 5 
pati e nts treate d i n t w o P h ase 3 st u dies (S PI- 6 1 1  a n d S PI- 6 1 2 ), t he 4 m g a pazi q u o ne i nstillati o n 
was retai n e d f or 1 h o ur i n 9 8 % of patie nts. I n st u dies perf or m e d t o date, a pazi q u o ne a p pears t o 
be we ll t olerate d wit h m ost si de effects li mite d t o t he bla d der. 
T he p h ysi cia n is ur ge d t o use cli nical j u d g m e nt re gar di n g t h e a p pr o priate ness of i ntra vesic al 
i nstillati o n i n t he i m me diate p ost- T U RB T  p eri o d. Patie nts wit h a n e xte nsi ve resecti o n, p ossi ble 
bla d de r perf orati o n, or si g nifica nt p ost o perati ve bl ee di n g s h o ul d n ot recei ve a pazi q u o ne 
i nstillati o n. 
1. 5. 1. 2  P ote nti al Be nefits 
As o utli ne d a b o ve, P hase 1 a n d P hase 2 st u dies ha ve de m o nstrate d t u m or re gressi o ns f oll o wi n g 
a pazi q u o ne treat me nt wit h 6 7 % of patie nts ha vi n g hist ol o gicall y pr o ve n c o m plete res p o nses. T he 
t w o c o m plete d P hase 3 si n gle i nstillati o n st u dies of a pazi q u o ne gi ve n i ntra v esicall y i m me diat el y 
after T U R B T ha v e de m o nstrate d a cli nicall y mea ni n gf ul 6. 7/ 6. 6 % re d ucti o n i n 2- Ye ar 
Re c urre nce R ates i n t he i n di vi d ual st u dies, a n d a 6. 7 % re d ucti o n i n 2- Ye a r Rec urre nce R ate 
t hat was statisticall y si g nifica nt ( p = 0. 0 2 2) o n i nte grate d a n al ysis, wit h a n a p pr o xi mate 2 4 % 
red ucti o n i n t he ris k of t u m or rec urre n ce at 2 years base d o n t he O d ds Rati o of Rec urre nce. 
I m p orta ntl y, p atie nts w h o recei v e d treat me nt wit h a pazi q u o ne at 3 1 t o 9 0 mi n utes after T U R B T 
(T a, G 1- G 2 3 1 - 9 0 mi n ute P o p ul ati o n ) were s h o w n t o ha ve a r o b ust 2 0. 3 % re d u cti o n i n 2 - Ye ar 
Rec urre nce R ate  c o m p are d t o patie nts treat e d wit h place b o i n t he sa me ti me i nter val ( 2 3. 3 % vs 
4 3. 6 %); t his differe n ce w as 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 a p azi q u o ne (T a ble 5 ). I ntr a vesical treat me nt wit h a pazi q u o ne was als o 
s h o w n t o be well t olerate d wit h t he mai n A Es i ncl u di n g t h ose e x pecte d i n p atie nts wit h bla d der 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 3  
ca ncer, e g, h e mat uria, d ys uria, a n d uri nar y fre q ue nc y. T h ere is t heref ore, a p ote ntial cli nical 
be nefit f or p atie nts wit h N MI B C w h o recei ve i ntr a vesical a pazi q u o ne i n t he i m me diate p ost-
T U R B T peri o d. 
1. 5. 2  J u stific ati o n of t he D ose, Sc he d ule a n d R o ute of A d mi nistr ati o n of A p azi q u o ne 
As disc usse d a b o ve, t he 4 m g i n 4 0 m L d os e of a pazi q u o ne a d mi nistere d i ntra vesicall y was 
esta blis he d i n a P hase 1 d ose-escalati o n st u d y t hat de m o nstrate d b ot h t he safet y a n d a ntit u m or 
acti vit y of 6 w ee kl y i nstillati o ns of t his a pazi q u o ne d ose i n patie nts wit h N MI B C. T his sa me 
d ose  was use d i n t he t w o s u bse q ue nt si n gle d os e P hase 3 st u dies t hat f urt her de m o nstrate d t he 
anti-t u m or acti vit y of a pazi q u o ne, w hile als o s h o wi n g it t o be safe a n d well t olerate d. T he 
co ncl usi o n fr o m t hese cli nical st u dies was t hat a pazi q u o ne, a d mi nistere d as a si n gle i ntr a vesical 
i nstillati o n of 4 m g i n 4 0 m L was c he m oa bl ati ve wit h a cli nicall y mea ni n gf ul re d ucti o n i n 2-
Ye ar R ec urre nce R ates of a p pr o xi matel y 6. 6 %; t he a d verse e v e nt pr ofile of a pazi q u o ne was 
si milar t o place b o. T hese data pr o vi de t he j ustificati o n f or t he pr o p ose d a p azi q u o ne d ose i n 
T re at me nt Ar m 1 a n d A r m 2 . 
Beca use of t h e p ote ntial f or t he i nacti vati o n of a p azi q u o ne 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 a pazi q u o ne d osi n g is tar gete d t o be d eli vere d 6 0 ± 3 0 mi n utes 
p ost- T U B T. T his d osi n g wi n d o w is s u p p orte d b y t he a nal ysis of 2- Ye ar Rec urre nce R ates  b y 
time i nter val f oll o wi n g T U R B T i n t he P hase 3 si n gle d ose st u dies ( S PI- 6 1 1 , S PI- 6 1 2 ), w hi c h 
de m o nstrate d 2 0. 3 % a n d 2 0. 8 % re d ucti o ns, res pecti vel y, i n 2- Ye a r Rec urre nce R ate  f or 
patie nts w h o recei ve d treat me nt 3 1 t o 9 0 mi n utes p ost- 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 me ti me i nter val; S PI- 6 1 1  ( 2 3. 3 % vs 4 3. 6 %; p = 0. 0 3 4 6) a n d S PI- 6 1 2  
( 3 3. 3% vs 5 4. 1 %; p = 0. 0 2 3 8). T he o d ds rati os f or S PI- 6 1 1  ( 0. 3 9; 9 5 % CI 0. 1 6, 0. 9 4) a n d S PI-
6 1 2  ( 0. 4 2; 9 5 % CI 0. 2 0, 0. 8 9) fa v ore d a pazi q u o ne treat me nt. T heref ore, alt h o u g h pre vi o us 
st u dies i nstille d dr u gs wit hi n 6 h o urs of T U R B T, t he P hase 3 data o btai n e d fr o m S PI- 6 1 1  a n d 
S PI- 6 1 2  cl earl y s u p p ort t he pr o p ose d d osi n g f or a pazi q u o ne i n t his ne w st u d y at 6 0 ± 3 0 mi n utes 
p ost - T U R B T; t hese dat a j ustif y t he pr o p ose d a pazi q u o ne d osi n g re gi me n i n Tre at me nt Ar m 1 
a n d Ar m 2 . 
Preli mi nar y a nal ysis of t he a vaila ble efficac y d ata fr o m t w o m ulti ple i nstillati o n st u dies 
(S PI- 1 0 1 1  a n d S PI- 1 0 1 2 ) s u g geste d a n a d diti o nal be nefit fr o m t he re peat a d mi nistrati o n of 
a pazi q u o ne i n patie nts wit h N MI B C. I n t hese m ulti-i nstillati o n st u dies, a 1 9 % t o 2 8 % re d u cti o n 
i n Re c urre nce R ates  was de m o nstrate d f or a pazi q u o ne c o m pare d t o t he a p pr o xi mately 6 % 
re d ucti o n see n i n t he pri or si n gle- d ose st u dies; safet y pr ofiles bet wee n t he si n gle- a n d m ulti-
i nstillati o n st u dies were si milar. T hese data s u g gest t hat i n a d diti o n t o t he cli nical be nefit 
de m o nstrate d wit h a si n gle p ost- T U R B T i nstillati o n of a pazi q u o ne f or p atie nts wit h N MI B C, a 
sec o n d a pazi q u o ne d ose ma y pr o vi d e f urt her be n efit i n re d uci n g t u m or Rec urre nce R ates  or 
i ncreasi n g Ti me t o T u m or Rec urre nce . T heref ore, t he ne w pr o p ose d P has e 3 st u d y i ncl u des a n 
ad diti o nal ar m ( Ar m 2 ) t hat i ncl u des a sec o n d a pazi q u o ne d ose a d mi nistere d a p pr o xi matel y 2 
wee ks f oll o wi n g t he i nitial p ost- T U R B T d osi n g. A n a d diti o nal rati o nale f or t his sec o n d 
i nstillati o n is t hat it will occ ur 2 w ee ks p ost- T U R B T, w he n h e mat uria is li kel y t o ha ve res ol v e d ; 
t hese data s u p p ort t he pr o p ose d a pazi q u o ne d osi n g re gi me n i n T re at me nt Ar m 2 . I n or der t o 
ens ure t hat treat me nt re m ai ns bli n de d i n t he pr o p ose d 3-ar m st u d y, all patie nts will get t w o d oses 
of e it her st u d y dr u g, a p azi q u o ne or place b o, or o ne of eac h b ase d o n t he ra n d o mize d treat me nt 
ar m.  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 4  
2  
S T U D Y O B J E C TI V E S 
2. 1  
P ri m ar y O bjecti ve(s) 
 T o e val uate t he Ti me t o Rec urre nce  wit h eit her o ne i nstillati o n of 4 m g of a pazi q u o ne 
or t w o i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T 
i n patie nts wit h n o n- m uscle i n vasi ve bla d der ca ncer ( N MI B C) w h o recei ve tra ns uret hr al 
resecti o n bla d d er t u m or ( T U R B T)  
2. 2  
S ec o n d ar y O bjecti ves 
1.  T o e val uate t he 2- Ye a r  Rec urre nce R ate  wit h eit her o ne i nstillati o n of 4 m g a p azi q u o ne 
or t w o i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T 
i n patie nts wit h N MI B C w h o recei ve T U R B T. 
2.  T o e val uate t he 1- Ye a r  Rec urre nce R ate  wit h eit her o ne i nstillati o n of 4 m g a p azi q u o ne 
or t w o i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T 
i n patie nts with N MI B C w h o recei ve T U R B T. 
3.  T o e val uate t he Ti me t o Pr o g ressi o n  wit h eit her o ne i nstillati o n of 4 m g a pazi q u o ne or 
t w o i nstillati o ns of 4 m g a pazi q u o ne relati ve t o pl ace b o i nstillati o n f oll o wi n g T U R B T i n 
patie nts wit h N MI B C w h o recei v e T U R B T 
4.  T o e val uate t he s afet y wit h eit her o ne i nstillati o n of 4 m g a pazi q u o ne or t w o i nstillati o ns 
of 4 m g a pazi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T i n patie nts wit h 
N MI B C  
3  
I N VE S TI G A TI O N A L P L A N 
3. 1  
S t u d y Desi g n a n d Tre at me nt Pl a n 
T his is a P hase 3, ra n d o mize d, m ultice nter, place b o-c o ntr olle d, d o u ble- bli n d st u d y of a p azi q u o ne 
i n patie nts wit h ≤4 n o n- m uscle i n vasi ve bla d der t u m ors, ≤3. 5 c m i n dia meter, all of w hic h m ust 
ha ve bee n f ull y resecte d at T U R B T.  
I n a d diti o n t o Scree ni n g , patie nts will als o u n der g o a n assess me nt of ur ot h elial carci n o ma via 
c yst osc o p y f or cli nic all y a p pare nt t u m or Ta, G 1- G 2. 
F oll o wi n g T U R B T, eli gi ble patie nts will be ra n d o mize d i n a 1: 1 : 1 rati o t o o ne of t he t hree 
f oll o wi n g ar ms: 
 Ar m 1 - O n e D ose of A p azi q u o ne: 
 
D a y 1: a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0  ± 3 0 mi n utes p ost- T U R B T 
 
D a y 1 5 (± 5 da ys) : a d mi nistrati o n of place b o  
 Ar m 2 - T w o D oses of A pazi q u o ne: 
 
D a y 1:  a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0 ± 3 0 mi n utes p ost- T U R B T 
 
D a y 1 5  (± 5 da ys ): a d mi nistrati o n of 4 m g of a pazi q u o ne  
 Ar m 3 - Place b o:  
 
D a y 1:  a d mi nistrati o n of place b o 6 0 ± 3 0 mi n utes p ost- T U R B T 
 
D a y 1 5  (± 5 da ys ): a d mi nistrati o n of place b o  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 5  
O nce ra n d o mize d, D a y 1  st u d y dr u g i nstillati o n will occ ur at 6 0 ± 3 0 mi n ut es p ost T U R B T. 
P atie nts w h ose t u m or is deter mi ne d t o be Ta, G 1- G 2 will ret ur n o n D a y 1 5  (± 5  da ys) f or a 
sec o n d i nstillati o n. If t he pat h ol o g y res ults are a vaila ble a n d s h o w n o n Ta, G 1- G 2 hist ol o g y, t he 
pa tie nt will n ot ret ur n o n D a y 1 5 ( ± 5  da ys) f or a sec o n d i nstillati o n. I n t he a bse nce of l o cal 
pat h ol o g y res ults b y t he D a y 1 5 visit, t he patie nt will recei ve a sec o n d i nstillati o n of st u d y dr u g. 
All hi st ol o g y s peci me ns will be re vie we d b y a l ocal pat h ol o g y la b orat or y a n d all cli nical 
treat me nt decisi o ns a n d st u d y a n al ys es will be bas e d o n t he l ocal pat h ol o g y re vie w. Patie nts 
w h ose  pat h ol o g y is ot her t ha n Ta, G 1- G 2 will be f oll o we d u p f or safet y at D a y 3 5  ( ± 5 da ys) 
fro m t he last d ose of st u d y dr u g a n d will t he n be disc o nti n ue d fr o m t he st u d y at t he E n d of 
S t u d y Visit.  
P atie nts w h o ha ve pat h ol o g y c o nfir me d Ta, G 1- G 2 hist ol o g y will be f oll o we d f or 2 4 m o nt hs 
acc or di n g t o t he s c he d ule bel 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 9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m 
da te of T U R B T) t hr o u g h 2 4 m o nt hs f or t u m or rec urre nce a n d pr o gressi o n. 
 If at a n y ti me d uri n g t he 2 4 m o nt h f oll o w u p peri o d t here is a t u m or rec urre nce, t he 
pa tie nt will c o nti n ue o n st u d y wit h f oll o w- u p c yst osc o pic e x a mi nati o n a n d uri ne c yt ol o g y 
e ver y 9 0 da ys ( ± 1 0 da ys) (calc ulat e d fr o m dat e of T U R B T) t hr o u g h t he e n d of 2 4 
m o nt hs. Patie nts wit h a rec urre nce are per mitte d t o ha ve a f oll o w- u p T U R B T. 
 If at a n y ti me d uri n g 2 4 m o nt h f oll o w u p peri o d t here is a t u m or rec urre n ce a n d/ or patie nt 
is starte d o n a not her i ntra vesical t hera p y, t he patie nt will be f oll o we d b y tel e p h o ne, f or 
safet y e v er y 9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m date of T U R B T) t hr o u g h t he e n d of 2 4 
m o nt hs. 
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 ( 3 years f or accr ual a n d 2 years f or 
treat me nt a n d 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 2 4 m o nt hs i ncl u di n g: 
 S cree ni n g Peri o d : 3 0- da ys  
 T re at me nt  Peri o d: D a y 1  a n d D a y 1 5  ( ± 5 da ys)  
 S afet y F oll o w- u p Peri o d : 2 4- m o nt hs  
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 dia g n osis of ur ot helial carci n o ma of t he bla d der wit h cli nicall y 
a p pare nt t u m or T a, G 1- G 2. 
2.  P atie nt wit h ≤4 t u m ors, n o ne of w hic h e x cee ds 3. 5 c m i n dia meter. 
3.  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 ules,  a n d meet all st u d y re q uire me nts. 
4.  Patie nt is at least 1 8 years of a ge at r a n d o mizati 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 6  
5.  Patie 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 t h e last d ose of t he st u d y 
dr u g . 
6.  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 a n acti ve c o n c urre nt mali g na n c y/life-t hreate ni n g dise ase. If t h ere is a hist or y 
of pri or mali g n a ncies/life-t hreate ni n g dise ases, t he patie nt is t o be disease free f or at least 
5 years. Patie nts wit h ot her pri or mali g na n cies less t ha n 5 years bef ore st u d y e ntr y m a y 
still be e nr olle d if t he y h a ve recei ve d treat me nt r es ulti n g i n c o m plete res ol uti o n of t he 
ca ncer a n d c urre ntl y h a v e n o cli nical, ra di ol o gic, or la b orat or y e vi de nce of acti ve or 
rec urre nt diseas e. 
2.  P atie nt has p ositi ve uri ne c yt ol o g y f or mali g n a nc y at Scree ni n g. 
3.  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 pr ot oc ol treat me nt. 
4.  P atie nt has use d a n y i n vesti gati o nal dr u gs, bi ol o gi cs, or de vices wit hi n 3 0 da ys pri or t o 
st u d y treat me nt or pla ns t o use a n y of t hes e d uri n g t he c o urse of t h e st u d y. 
5.  Patie nt has ha d a n y pri or i ntra vesical c he m ot hera p y, i m m u n ot hera p y, or pre vi o us 
ex p os ure t o a pazi q u o ne. 
6.  P atie nt has or has e ver ha d:  
 
U p per tract Tra nsiti o nal Cell Carci n o ma ( T C C)  
 
Uret hral t u m or ( pr ostatic uret hra i ncl u d e d)  
 
A n y i n vasi v e bla d der t u m or k n o w n t o be ot her t h a n t u m or Ta, G 1- G 2   
 
A n y e vi de nce of l y m p h n o de or dista nt metastasis  
 
A n y bla d d er t u m or wit h hist ol o g y ot her t ha n T C C  
 
C arci n o ma i n sit u ( CI S)  
7.  P atie nt has a t u m or i n a bla d der di vertic ul u m. 
8.  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.) 
9.  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. 
1 0.  Patie nt has scree ni n g h e m o gl o bi n < 1 0 m g/ d L. 
1 1.  Patie nt has a n y u nst a ble me dical c o n diti o n t hat w o ul d ma ke it u nsafe t o u n der g o T U R B T. 
1 2.  Patie nt has a hist or y of i nterstitial c ystitis. 
1 3.  Patie nt has a hist or y of aller g y t o re d c ol or f o o d d ye.  
1 4.  F or patie nts wit h rec urre nt t u m or, t he patie nt ha d at least a 6- m o nt h c yst os c o picall y-
c o nfir me d t u m or-free i nter val bet wee n t he last t u m or rec urre n ce a n d s cree ni n g 
c yst osc o pi c e x a mi nati o n.  
1 5.  Patie nt is pre g n a nt or breast-fee di n g  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
3 7  
4. 3  
P ati e nt Disc o nti n u ati o n/ Wit h dr a w al Criteri a 
Patie nts 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 fi nal pat h ol o g y re vie w t hat t he patie nt has hist ol o g y ot h er t ha n Ta, 
G 1 - G 2  
 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 a f oll o w- u p c yst osc o p y  
 T he  patie nt is l ost t o f oll o w- u p – if t he patie nt has misse d 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 rec urre n ce a n d recei v es t hera p y ( Patie nt will be f oll o we d b y tel e p h o ne f or 
safet y) 
 Deat 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). Patie nts w h o disc o nti n ue treat me nt or w h o are 
wit h dra w n fr o m tr eat me nt will ret ur n f or a S afet y F oll o w- u p Visi t, 3 5 da ys ( ± 5 da ys) after t he 
da te of earl y disc o nti n uati 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 0  
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. T he scree ni n g i ncl u des a c yst osc o pic e x a m i n or der t o assess 
t he sta ge an d gra de of t h e bla d der t u m or. A n e x a m c o n d ucte d as part of t h e sta n dar d practice 
wit hi n 3 0 da y s pri or t o r a n d o mizati o n ma y ser ve as t he assess me nt as l o n g as sta ge a n d gra de of 
t u m or are re p orte d usi n g t he W orl d Healt h Or ga ni zati o n ( W H O) 1 9 7 3 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 e 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. 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 D a y 1  (D a y - 3 0  t o 
D a y - 1 ). 
 Inf or me d C o nse nt 
 C yst osc o pic E x a m ( ma y be o btai ne d pri or t o si g ni n g of I C a n d ma y be us e d f or 
Scree ni n g p ur p os es as l o n g as t he y are perf or me d pri or t o D a y 1 ) 
 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  
 He i g ht a n d wei g ht 
 C o m plete bl o o d c o u nt ( C B C) wit h 3- part differe ntial 
 C he mistr y 
 Uri ne c yt ol o g 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 1  
5. 3. 2  Tre at me nt Peri o d Visit 1 ( D a y 1) 
 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 wit h 3- part differe ntial 
 C he mistr y 
 Ur i ne di pstic k  
 R a n d o mizati o n 
 T U R B T  a n d p at h ol o g y s peci me ns t o be se nt t o l o cal pat h ol o g y 
 Ur i ne c yt ol o g y  
 A pa zi q u o ne or place b o a d mi nistrati o n 
 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. 3  T re at me nt Peri o d Visit 2 ( D a y 1 5 [ ± 5 d a ys] )  
 R e vie w of t u m or pat h ol o g y t o deter mi ne c o nti n ue d patie nt eli gi bilit y bas e d o n Ta, G 1- G 2 
hist ol o g y ( Ca n be perf or me d a n y ti me bet wee n Visit 1  a n d Visit 2 ) 
 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 wit h 3- part differe ntial 
 C he mistr y 
 Uri ne di pstic k  
 Ur i ne c yt ol o g y 
 A pa zi q u o ne or place b o a d mi nistrati o n 
 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 ( E ver y 9 0 d a ys [ ± 1 0 d a ys] P ost-
T U R B T) 
 Ur i ne di p stic k 
 P h ysical e x a m (as nee de d) 
 Uri ne c yt ol o g y  
 C yst osc o p y  
 A d verse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3  ( All A Es will be c ollecte d u ntil 
3 5 da ys after t h e last d ose of st u d y treat me nt. O nl y S A Es a n d A Es ≥Gra d e 3 will 
be rec or de d f or t he rest of t he f oll o w- u p peri o d.) 
 C o nc o mita n t me dicati o ns 
5. 3. 5  S afet y F oll o w- u p Visit ( D a y 3 5 ( ± 5 d a ys) After D ate of E arl y Disc o nti n u ati o n or 
L ast D ose of St u d y Dr u g) 
 P h ysical e x a mi nati 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 2  
 Uri ne di p stic k  
 A d ve rse e ve nts usi n g N CI C T C A E Versi o n 4. 0 3 ( O nl y S A Es a n d A Es ≥Gra de 3) 
 C o nc o mita nt me dicati o ns  
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 pre vi o us t hera p y a n d 
i n vesti gati o ns as well as si g nifica nt p ast a n d all c o-e xisti n g diseases a n d c urre nt me dicati 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 co 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 at t he E n d- of - St u d y Visit (Visit 1 0  or 
da te of disc o nti n uati o n). A p h ysic al e xa mi nati o n is o nl y perf or me d at all ot her visits if it is 
dee me d cli nicall y necess ar y. P h ysic al e xa mi nati o ns are t o be c o m plete d b y a p h ysi cia n or ot her 
healt hcare pr ofessi o nal lice nse d t o perf 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 di cal rec or d a n d o n t he a p pr o priate 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  a n d at eac h treat me nt 
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  - I ncl u di n g W B C wit h 3- part differe ntial. T he res ults of t he la b orat or y ass ess me nts 
s h o uld be e val uate d a n d me dicall y acce pte d b y t h e res p o nsi ble p h ysicia n f or t he 
assess me nt of cli nical si g nifica 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, creati ni ne cle ara nce, A S T/ S G O T, A L T/ S G P T, al kali ne p h os p hatase, t otal 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 3  
bilir u bi n, uric aci d, a n d calci u m. 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 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 S cree ni n g , Tre at me nt Visit 1 , Tre at me nt 
Visit 2 , a n d e ver y 9 0 da ys ± 1 0 da ys, fr o m t he dat e of T U R B T, t hr o u g h 2 4 m o nt hs.  
5. 4. 8  C y st osco p y 
C yst osc o p y will be perf or me d at Scree ni n g  a n d e ver y 9 0 da ys ± 1 0 da ys, fr o m t he date of 
T U R B T, t hr o u g h 2 4 m o nt hs. A n o perati ve re p ort s h o ul d c o ntai n t he n u m ber, size a n d l ocati o n of 
t he rec urre nt t u m ors, if a n y. All lesi o ns s h o ul d be bi o psie d a n d se nt f or pat h ol o gical re vie w; 
rec urre nces are t o be re p orte d o n t he a p 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 v e 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, siz e, 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. All hist ol o g y s peci me ns will be rea d b y a l ocal pat h ol o gist. A c hec k f or si g nifi ca nt 
blee di n g i n t he bl a d der will be perf or me d p ost- T U R B T i n or der t o e v al uate patie nts f or 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 g nifica 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. 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. 
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 d e f or eac h lesi o n re m o ve d usi n g t he 
W H O 1 9 7 3 gra di n g s yste m.  
P ri or t o Tre at me nt Visit 2 , pat h ol o g y will be re vie we d b y t he I n vesti gat or a n d if t he patie nt’s 
t u m or(s) is ot her t ha n Ta, G 1- G 2, t he patie nt will be disc o nti n ue d fr o m t he st u d y a n d will n ot 
recei v e a n y f urt her treat me nt. Patie nts w h o are disc o nti n ue d will ret ur n at D a y 3 5  ( ± 5 da ys) f or a 
S afet y F oll o w- u p Visit . If t he fi nal pat h ol o g y is u na vaila ble at t he ti me of t he sec o n d d ose, t h e 
ori g i nal cli nic al assess me nt t hat q ualifie d t he patie nt f or t he st u d y will be use d a n d t he patie nt 
s h o uld recei ve t h e sec o n d d ose of i n vesti gati o nal pr o d uct. 
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) Scale Versi o n 4. 0 3 f or A E 
g ra di n g, a n d will rec or d t he perti ne nt i nf or mati o n o n t he C R F. All A Es will be rec or de d u ntil 3 5 
da ys after t h e last d ose of st u d y treat me nt. O nl y S A Es a n d A Es ≥Gra de 3 will be rec or de d f or t h e 
rest of t he 2 4 m o nt h f oll o w- u p peri o d. 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 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 4  
t hr o u g h t he d a 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. 
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 t hr o u g h 2 4 m o nt hs p ost 
T U R B T will be rec or de d o n t he C R F. 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  
A p azi q u o ne a n d Pl ace b o 
A pazi q u o ne 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 A p azi q u o ne  
A pazi q u o ne 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 1 0 m L cle ar glass vials. Eac h vial c o ntai ns 4 m g a p azi q u o ne, 5 0 m g ma n nit ol, a n d 5 m g 
s o diu m bicar b o nate. Aft er rec o nstit uti o n, a pazi q u o ne has a re d dis h a p peara nce si milar t o t hat of 
cra n berr 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 s u 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 a pazi q u o ne.  
6. 1. 3  C o m p ositi o n of Dil ue nt f or A p azi q u o ne a n d Pl ace b o 
T he dil ue nt f or a p azi q u o ne a n d place b o is a steril e s ol uti o n s u p plie d i n a 5 0 m L clear T y p e I 
g lass vial. Eac h vial c o nt ai 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 yl e ne 
g l yc ol, dis o di u m E D T A, a n d sterile wat er 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 a pazi q u o ne 4 m g rec o nstit ute d wit h 4 0 m L of dil ue nt or 
matc hi n g pla ce b o. Rec o nstit uti o n pr oce d ures are o utli ne d i n t he P har mac y ma n ual. T he 4 0 m L 
of r ec o nstit ute d 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 % Silic o ne 
F ole y cat heter, w h ere it is t o be retai ne d f or 6 0 mi n utes ( ± 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 
T he first d ose of t he 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. 
T he  sec o n d d os e will be gi ve n o n D a y 1 5  ( ± 5 da ys) p ost- T U R B T f or all patie nts e x ce pt t h ose 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 5  
w h ose pat h ol o g y res ults s h o w n o n Ta, G 1- G 2 dis ease; i n t he a bs e nce of l ocal pat h ol o g y res ults 
b y t he D a y 1 5 visit, patie nts will recei ve a s ec o n d i nstillati o n of st u d y dr u g. Wit hi n t he 
ad 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 
de la 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 g nifica 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. 
6. 2. 2. 1  Pre p ar ati o n of St u d y Dr u g 
E q ui p me nt nee de d: o ne 4 m g vial of a p azi q u o ne or place b o, o n e vial of Dil ue nt , o ne 5 0 m L or 
6 0 m L L uer-l o k s yri n ge, 1 8 ga u ge nee dle, pr otecti ve cl ot hi n g. 
 W ear pr otecti ve cl ot hi n g. 
 Dr a w u p 4 0 m L of dil ue nt i n t he s yri n ge (a p pr o xi matel y 5 m L will re mai n i n t he vial). 
 Inje ct a p pr o xi matel y 5 m L t o 1 0 m L of dil ue nt i nt o t he st u d y dr u g vial. 
 Ge ntl y a gitate t he vial a n d attac he d s yri n ge u ntil n o u n diss ol ve d particles are visi ble ( D o 
n ot detac h t he s yri n ge fr o m t he st u d y dr u g vial). 
 W it h dra w all diss ol ve d st u d y dr u g i nt o t he s yri n ge. 
 W it h dra w t he s yri n ge fr o m t he st u d y dr u g vial. 
 C o ver t he nee dl e wit h ne e dle c o ver. 
 In v ert t he s yri n ge at least 1 0 ti mes t o e ns ure a de q u ate mi xi n g. 
 C aref ull y e x pel all tra p pe d air i n t he s yri n ge. 
 T he  fi nal v ol u me i n t he s yri n ge s h o ul d b e 4 0 m L. 
If st u d y dr u g is rec o nstit ute d, a n d n ot use d wit hi n 6 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. T he f oll o wi n g criteri a are t o be met pri or t o 
dr u g  rec o nstit uti o n: 
 Patie nt has ≤4 t u m ors; 
 N o si n g le t u m or is greater t ha n 3. 5 c m; 
 Vis ua l a p peara nc e c o nsiste nt wit h a Ta, G 1-G 2  hist ol o g y; 
 N o e vi de nce of bla d der perf orati o n; 
 C o m plete he m ostasis is o btai ne d, uri ne a p p ears clear u p o n vis ual i ns pecti o n; 
 P ost- T U R B T di uretic has n ot bee n a d mi nistere d; 
 Patie nts are at 6 0 ± 3 0 mi n utes p ost- T U R B T. 
6. 2. 2. 2  
I nstill ati o n of t he First d ose of t he St u d y Dr u g o n D a y 1 
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 uld 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 
ad 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 4 0 m L 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 6  
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. 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).  
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 
co 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. 2. 2. 3  
I nstill ati o n of t he Sec o n d D ose of t he St u d y Dr u g o n D a y 1 5 ( ± 5 d a ys) p ost-
T U R B T 
A sec o n d d ose of st u d y dr u g is t o be a d mi nistere d t o all patie nts u nless t heir pat h ol o g y res ults 
are a v aila ble a n d s h o w n o n Ta, G 1- G 2 hist ol o g y; i n t he a bse nce of l ocal p at h ol o g y res ults b y t he 
D a y 1 5 visit, patie nts will recei ve a sec o n d i nstillati o n of st u d y dr u g. F or t h e sec o n d d ose 
i nstillati o n, t he patie nt’s bla d der s h o ul d be drai ne d via a 1 0 0 % silic o ne F ole y cat het er f oll o we d 
b y i nstillati o n of t he st u d y dr u g. T h e 4 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. T h e F ole y cat heter s h o ul d b e cla m p e d f or 6 0 mi n utes 
( ± 5 mi n utes).  
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 h e 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 mi n ute ( ± 5 mi n ute s) peri o d of rete nti o n, st u d y dr u g s h o ul d be caref ull y 
dra i 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: 
 Da te 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. 
 I D 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. 
 Dates 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 be 
rea dil y a vaila bl e f or i ns p ecti 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 7  
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 
pe r 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 
aut 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  
T re 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 bli n 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 W R S will be set u p wit h 
a p pr o priate access str uct ure i n or der t o k ee p t he a b o ve st u d y tea 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 1: 1: 1 rati o t o o ne of t hree tr eat me nt 
ar ms: Ar m 1 : o n e i nstillati o n of 4 m g a pazi q u o ne, Ar m 2: t w o i nstillati o ns of a pazi q u o ne or 
Ar m 3 : pla ce b o at eac h st u d y site. A ra n d o mizati o n sc he me usi n g per m ute d bl oc k desi g n will be 
de vel o pe 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 
Patie nt I D t hat h as 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 d ata base.  
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 
In 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.  
T he  st u d y i ncl u d es a f utilit y a nal ysis o nce 1 0 0 of t he e x pecte d 3 3 6 rec urre n ce e v e nts are 
o bse r ve d i n t he Pl ac e b o Tre at me nt Ar m ; t his will e na ble a deter mi nati o n w het her e nr oll me nt 
s h o uld be disc o nti n ue d i n a n i nefficaci o us A p azi q u o ne Tre at me nt A r m. A n i n de pe n de nt, 
u n bli n de d data m o nit ori n g pers o n nel will c o n d uct t h is f utilit y a n al ysis. D ata m o nit ori n g 
pe rs o n nel will recei ve treat me nt all ocati o n i nf or m ati o n directl y fr o m I W R S t o m o nit or e ve nts 
a n d t o perf or m statistical a nal ysis. T h e e ntire st u d y tea m will be u n bli n de d o nl y o nce all data are 
e ntere d a n d l oc ke d a n d rea d y f or fi nal a nal ysis.  
6. 6  
N o n - St u d y Tre at me nts 
6. 6. 1  P ri o r a n d C o nc o mit a nt Me dic ati o ns 
All c o nc o mita nt me dicati o ns, i ncl u di n g o ver t h e c o u nter s u p ple me nts, s h o ul d be rec or de d fr o m 
S cree ni n g  (Visi t - 1) t hr o u g h 2 4 m o nt hs p ost- T U R B T. Patie nts ma y use aceta mi n o p he n or 
anti p yretics t o ma na ge si de effects ass oci ate 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. 
As piri n or pr o d ucts c o ntai ni n g acet yls alic yli c aci d s h o ul d n ot be use d f or 2 4 h o urs after t h e 
i nitial T U R B T. 
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.  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 8  
6. 6. 2  Pr o hi bite d Me dic ati o ns 
Pri or t o rec urre nce, patie nts wit h t u m or hist ol o g y of Ta, G 1- G 2  s h o ul d n ot recei v e ot her 
me dic ati o ns t o treat bla d der ca n cer. If a patie nt starts a n ot her t hera p y f or rec urre nce/ pr o gressi o n, 
t he patie nt will be wit h dra w n fr o m t he st u d y after u n der g oi n g t he e n d of st u d y pr oce d ures, a n d 
f oll o we d u p f or safet y at D a y 3 5  ( ± 5 da ys) fr o m last d ose of st u d y dr u g f or a S afet y F oll o w- u p 
Visit .  
N o di uretics 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 ys.  
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. 
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 ncl 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 de re 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 ( ± 5 da ys) 
after t he l ast d ose of st u d y dr u g a d mi nistrati o n or 3 5 da ys ( ± 5 da ys) after t he date of p atie nt earl y 
disc o nti n ua ti o n. O nl y S A Es a n d A Es ≥Gra d e 3 will be rec or de d f or t he re m ai n der of t he 2 4 
m o nt h f oll o w- u p peri o d. 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 rel ate d t o st u d y pr oce d ures are t o be rec or de d. T h e 
st u dy will rec or d all A Es acc or di n g t o t he i nf or mati o n i n Secti 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. 
 Si 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. 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
4 9  
 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 co nstit ute A Es i ncl u de: 
 Me dical or s ur gic al pr oce 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 it 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 pate 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.  
 Pr 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, 
an 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  Rec or di n g of A d verse E ve nts 
All A Es t hat occ ur fr o m t he ti me of ra n d o mizati o n u ntil 3 5 da ys aft er t he last d ose of st u d y dr u g 
will  be rec or de d o n t he A E C R F. After 3 5 d a ys a n d t hr o u g h 2 4 m o nt hs, o nl y S A Es a n d A Es 
≥Gr a de 3 will be rec or de d. 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 first 
d ose 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.  
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 h e f oll o wi n g c o n v e nti o ns 
s h o ul d be f oll o we d w he n 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.  






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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 2  
S A Es a n d A Es ≥Gra d e 3 will be rec or de d f or t h e re mai n der of t h e 2 4 m o nt h f oll o w- u p peri o d 
an d are t o b e 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 (re gar dless of t heir relati o ns hi p t o st u d y treat me nt) are t o be re p ort e d a n d t he seri o us 
ad verse e ve nt r e 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 v e 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 ur e t he 
timel y 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. 
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 
be c 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). 
T he S pectr u m Cli nical Researc h Ass ociat e ( C R A ) or desi g n ee will c ollect t he ori gi n al S A E R 
fro m t he site. 
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  


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 3  
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 a pazi q u o ne i n pre g na nt w o me n. 
Bec a 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, a pazi q u o ne is n o t 
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 ( ± 5 da ys) after t he 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 he I n v esti gat or has gai n e d k n o wle d ge of t he e ve nt vi a fa x or e- mail (see 
c o ntact i nf or mati o n i n  Secti o n 7. 7. 1 ). F oll o w u p i nf or mati o n re gar di n g t he o utc o me of t he 
pre g na nc y will be re q u este d b y t he S pectr u m P har mac o vi gila n ce 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. A f or mal 
statistical a nal ysis pla n ( S A P) will be fi nalize d bef ore dat a base l oc k.  
8. 1  
S a m ple Size 
I n t w o ra n d o mize d place b o-c o ntr olle d cli nical trials (S PI- 6 1 1  a n d S PI- 6 1 2 ) of a pazi q u o ne i n 
patie nts wit h Ta, G 1 - G 2 bla d der t u m ors ( N = 8 0 2; 8 1 3), t he Rec u rre nce R ate  i n t he Pl ace b o 
Tre at me nt Ar m  was a p pr o xi matel y 4 6 %. B y ta ki n g i nt o acc o u nt t he Rec u rre nce R ates  o verall 
i n t he a b o ve t w o st u dies, t he Rec urre nce R ate  i n t he A p azi q u o ne Tre at me nt Ar m  fr o m t he 
t w o stu dies was ass u me d t o be 3 9. 5 %, w hic h res ults i n a hazar d rati o of a p pr o xi matel y 0. 8 0.  
T he e nr olle d p atie nts will be ra n d o mize d i n a 1: 1: 1 rati o i nt o o ne of t hree treat me nt ar ms 
i ncl u di n g: Ar m 1: o ne d ose of a pazi q u o ne, A r m 2: t w o d oses of a p azi q u o ne, or Ar m 3: 
plac e b o, usi n g a per m ute d bl oc k desi g n. T h e pri m ar y e n d p oi nt of t he st u d y is Ti me  t o 
Rec urre nce . T h e pri mar y e n d p oi nt a n al ysis i n v ol ves 2 pair wise tests of c o m paris o ns: o ne d ose 
of 4 m g a pazi q u o ne vs. place b o a n d t w o d os es of 4 m g a p azi q u o ne vs. place b o. N o c o m paris o n 
of t he treat me nt ar ms t hat recei ve d o n e d ose of a p azi q u o ne vs. t w o d oses of a pazi q u o ne will be 
perf or me d.  
T he pri mar y a n al yses of t ests of pair wise c o m paris o ns of o ne d ose vs. place b o a n d t w o d oses vs. 
place b o a r ms will be perf or me d usi n g 2-si de d l o g-ra n k test eac h at 5 % le v el of si g nifica n ce. T h e 
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. 
H oc h ber g pr oce d ure [2 0 ] will be use d t o c o ntr ol t he o verall T y p e I err or rat e d ue t o m ulti ple 
co m paris o ns f or t he pri mar y e n d p oi nt. If t he l ar ger p- val ue of t h e t w o c o m paris o ns ( o ne d ose vs 
place b o, t w o d ose s vs place b o) is ≤0. 0 5, t he n b ot h c o m paris o ns will be c o nsi dere d statisticall y 
si g nifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 b ut t he s maller p- val u e is 
≤0. 0 2 5, t he c o m paris o n ass ociate d wit h t he s maller p- val ue will be c o nsi dere d statisticall y 
si g nifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 a n d t he s maller p- val u e is 
> 0. 0 2 5, t he n neit her c o m paris o n will be c o nsi dere d statisticall y si g nifica nt.  
T he f oll o wi n g  pr oce d ure will be use d t o test t he list of sec o n dar y e n d p oi nts f or eac h pair wis e 
c o m paris o n:  
1.  If b ot h c o m paris o ns of pri mar y e n d p oi nts ( o ne d os e vs. place b o, t w o d os es vs. place b o) 
are si g nifica nt ( p ≤0. 0 5), t he T y p e I err or will be re use d f or t he pair wise c o m paris o ns 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 4  
eac h sec o n dar y e n d p oi nt u ntil a test p- val ue > 0. 0 5 i n a pair wise c o m p aris o n ( o n e d ose vs. 
plac e b o or t w o d os e vs. place b o). N o c o m paris o n will be ma de after t his p oi nt. 
2.  If o ne of t he c o m paris o ns of pri mar y e n d p oi nts (eit her o ne d ose vs. pl ace b o or t w o d oses 
vs. place b o) is n ot si g nifi ca nt, n o re us e of T y pe I err or will be atte m pte d f or a n y of t he 
sec o n dar y e n d p oi nts.  
T he or der of sec o n dar y e n d p oi nts f or t he test of c o m paris o ns is liste d bel o w :  
1.  T he  2- Ye a r Rec urre nce R ate  of bla d d er ca ncer 
2.  T he  1- Ye a r Rec urre nce R ate  of bla d d er ca ncer 
3.  T i me t o Pr o gressi o n t o hi g her st a ge 
A p pr o xi matel y 1 8 6 9 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 3 years a n d f oll o w- u p ti me as 2 4 m o nt hs. Ass u mi n g 5 4 % of patie nts are rec urre nce-free f or 
plac e b o a n d 6 0. 5 % of patie nts are rec urre nce-free f or t he a p azi q u o ne treat me nt a r ms (ass u me d t o 
be  t he sa me f or eac h ar m) at t he e n d of 2 4 m o nt h f oll o w- u p, sa m ple siz es of 5 1 9 per treat me nt 
ar m will ac hie ve 8 0 % p o wer t o dete ct s u peri orit y i n eac h c o m p aris o n usi n g l o g-ra n k test at 5 % 
le vel of si g nifi ca nce. T he a b o ve sa m ple siz e acc o u nts f or 5 % of patie nts l ost t o f oll o w- u p. At t he 
en d of t he 2- year f oll o w u p, t his t otal is ass u me d t o pr o vi de 3 3 6 rec urre nce e ve nts i n t he P l ace b o 
Tre at me nt Ar m a n d 2 9 5 rec urre nce e v e nts i n eac h A p azi q u o ne Tre at me nt Ar m ( Hi ntze, J 
[2 0 1 3]. P A S S 1 2, N C S S, L L C, Ka ys ville, Ut a h, U S A). T he fi nal a nal ysis of t he pri mar y 
en d p oi nt will be c o n d uct e d o nce all 3 3 6 rec urre n ce e ve nts i n t he P l ace b o Tre at me nt Ar m are 
accr ue d. .  
B ase d o n t h e data fr o m pri or st u dies o n misclassificati o n of sta ge a n d gra d e dia g n osis at t he 
scree ni n g f or e nr oll me nt, a n a d diti o nal 2 0 % patie nts ma y nee d t o be e nr olle d i n or der t o accr ue 
t he re q uire d T ar g et T a, G 1- G 2 P o p ul ati o n  i n t he st u d y. T h eref ore, t he st u d y will e nr oll a n d 
ran d o mize 6 2 3 patie nts per ar m f or a t otal of 1 8 6 9 patie nts.  
T o de ter mi ne w h et her e nr oll me nt s h o ul d be disc o nti n ue d i n a n i nefficaci o us ar m, a f utilit y 
a nal ysis will be c o n d ucte d o nce t he first 1 0 0 of t h e e x pecte d 3 3 6 rec urre nce e ve nts are o bser ve d 
i n t he Pl ac e b o Tre at me nt Ar m i n t he st u d y. T he re q uire d n u m ber of e v e nts nee de d t o deci d e o n 
t he ti mi n g of t he i nteri m f utilit y a nal ysis will be trac ke d b y i n de pe n de nt, u n bli n de d data 
m o nit ori n g pers o n nel. T h e first 1 0 0 of t he e x pecte d 3 3 6 rec urre nce e v e nts i n t he Pl ace b o 
Tre at me nt Ar m will ac hie ve 2 0 % c o n diti o nal p o wer t o detect t he alter nati ve hazar d rati o of 0. 8 
at a si g nifi ca nce le vel of 0. 0 5 usi n g a t w o-si d e d l o g-ra n k test. T he c orres p o n di n g z- val ue 
t hres h ol d of t he data t hat ha ve accr ue d f or t he f utilit y a nal ysis is - 3. 0. T he f utilit y i n de x is 0. 8 0 2. 
If t he z- val ue of a n y of t h e pair wise c o m paris o ns (ie H R) bet wee n si n gle d ose a pazi q u o ne vs. 
place b o or t w o d os es of a pazi q u o ne vs. place b o is less t ha n - 3. 0, t he c orres p o n di n g n o n-
effic aci o us A p azi q u o ne Tre at me nt Ar m will be dr o p pe d a n d t he st u d y will be re-ra n d o mize d 
t o i ncl u de t he re mai ni n g A p azi q u o ne Tre at me nt Ar m a n d P l a ce b o Tre at me nt Ar m i n a 1: 1 
rati o. N o a dj ust me nt t o T y p e I err or will be ma de f or t he f utilit y a n al ysis as t he fi nal a nal ysis will 
be c o n d ucte d usi n g a T y pe I err or of 0. 0 5 as state d i n t he pr ot oc ol. 
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 
pa tie 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 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 5  
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 1: 1 : 1 t o recei ve o n e 
i nstillati o n of 4 m g a pazi q u o ne, t w o i nstillati o ns of a pazi q u o ne, or t wo i nstillati o ns 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 1 vial of a pazi q u o ne a n d 1 vial of place b o, 2 vials of a pazi q u o ne, or t w o 
vials of pla ce 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 nter. Patie nt 
n u m ber s will be assi g n e d se q ue ntiall y at eac h site.  
S t u d y dr u g s h o ul d n ot be pre pare d u ntil t he n u m ber, siz e, a n d a p peara n ce of all bla d der t u m ors 
are c o nfir me d at T U R B T. If f or a n y reas o n, f oll o wi n g T U R B T t he patie nt d oes n ot recei ve st u d y 
dr u g, t he M e dical M o nit or s h o ul d be n otifie d i m me diatel y via fa x.  
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 ( T a G 1 - G 2) P o p ul ati o n: all ra n d o mize d patie nts wit h a l ocal la b orat or y 
co nfir me d pat h ol o g y of Ta, G 1 -G 2 N MI B C, cl assifie d acc or di n g t o t he treat me nt ar ms 
i nt o w hic h t he y w ere ra n d o mize d, re gar dless of t h e act ual tr eat me nt recei v e d. T he 
a nal ysis p o p ulati o n f or all efficac y e n d p oi nts will be t he T ar get ( T a , G 1 -G 2 ) 
P o p ul ati o n  base d o n l oc al 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 wit h a l ocal la b orat or y c o nfir me d n o n-
Ta , G 1 -G 2 N MI B C, cl assifie d acc or di n g t o t he treat me nt ar ms i nt o w hic h t he y were 
ra n d o mize d, re gar dl ess of t he act ual tr eat me nt r ecei ve d. N o pri mar y effi cac y e n d p oi nt 
anal ysis will be pr o vi d e 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.  
 P er- Pr ot oc ol 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 ual 
treat me nt recei ve d w h o h a ve l ocal p at h ol o g y c o nfir me d Ta, G 1-G 2 , regar dl ess of ra n d o m 
assi g n me nt. Ra n d o miz e d patie nts w h o recei ve n o treat me nt or ha v e maj or pr ot oc ol 
de viati o ns will be e x cl u de d fr o m t he a n al ys es of efficac y.  
 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 hist ol o gicall y d o c u me nte d rec urre nce re p orte d 
i n patie nts with hist ol o gicall y c o nfir me d T a, G 1 -G 2  hist ol o g y b y l ocal pat h ol o g y, w h o recei ve d 
o ne  or t w o i nstillati o ns of a pazi q u o ne or place b o. T hese patie nts will be ass esse d c yst osc o picall y 
a n d b y uri ne c yt ol o g y at 9 0 da y ( ± 1 0 da ys) i nter vals calc ulate d fr o m t he d ate of T U R B T.  T he 
date of t he bi o ps y pr oce d ure at w hic h t he bl a d der t u m or was c o nfir m e d hist ol o gicall y will be 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 6  
use d as t he date of rec urre nce. Patie nts wit h Ta, G 1- G 2 hist ol o g y w h o rec ur a n d d o n ot recei ve 
a n y f urt her i ntra vesic al t hera p y will c o nti n ue t o b e f oll o we d f or t w o years after ra n d o mizati o n. 
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 eit her o ne i nstillati o n of 4 m g a pazi q u o ne or t w o 
i nstillati o ns of 4 m g a pazi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T  
8. 5. 3  S ec o n d ar y E n d p oi nts 
1.  T he 2- Ye a r  Rec urre nce R ate  of bla d d er ca ncer  
2.  T he  1- Ye a r  Rec urre nce R ate  of bla d d er ca ncer 
3.  T i me t o Pr o gressi o n t o hi g her st a ge  
8. 5. 4  De fi niti o ns 
 Re c urre nce : a n y p at h ol o g y c o nfir me d bla d d er ca ncer i n t he patie nt’s bla d der 
 P r o g ressi o n : a n y pat h ol o g y c o nfir me d bla d d er ca ncer i n t he p atie nt’s bla d der wit h a 
hi g her st a ge 
8. 5. 5  Pri m ar y E n d p oi nt - Ti me t o Rec urre nce 
Ti m e t o Rec u rre nce  is t he ti me fr o m date of ra n d o mizati o n t o t he date of first d oc u me ntati o n of 
recurre nt diseas e. Ti me t o Rec urre nce  of patie nts wit h n o d oc u me nte d rec urre nce w hile o n 
st u dy will be ce ns ore d at t he date of last e v al ua ble visit (c yst osc o p y or T U R B T) o n-st u d y. Ti me 
t o Rec urre nce of patie nts wit h n o e val ua ble visit o n-st u d y will be ce ns ore d at ra n d o mizati o n.  
T he pri mar y e n d p oi nt of Ti me t o Rec u rre nce  will be a nal yz e d usi n g t he T ar get ( T a, G 1 - G 2) 
P o p ul ati o n  as defi ne d a b o ve. T he fi nal a nal ysis of Ti m e t o Rec u rre nce  will be c o n d ucte d o nce 
all 3 3 6 of t he e x pecte d rec urre n ce e ve nts i n t he Pl ace b o Tre at me nt Ar m  are accr ue d. T he 
pri ma r y e n d p oi nt a nal ysis i n v ol ves 2 pair wise tests of c o m paris o ns: o ne d ose of 4 m g 
apazi q u o ne vs. place b o a n d t w o d ose s of 4 m g a pazi q u o ne vs. place b o. N o c o m paris o n of t he 
treat me nt ar ms t hat recei ve d o ne d ose of a pazi q u o ne vs. t w o d oses of a p azi q u o ne will be 
pe rf or me d. T he pri mar y a nal ys es of tests of pair wise c o m paris o ns of o ne d ose vs. place b o a n d 
t w o d oses vs. place b o ar ms will be perf or me d usi n g 2-si de d l o g-ra n k test eac h at 5 % le v el of 
si gnifica n ce.  
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. 
H oc h be r g pr oce d ure [2 0 ] will be use d t o c o ntr ol t he o verall T y p e I err or rat e d ue t o m ulti ple 
c o m paris o ns f or t he pri mar y e n d p oi nt. If t he l ar ger p- val ue of t h e t w o c o m paris o ns ( o ne d ose vs 
place b o, t w o d oses vs place b o) is ≤0. 0 5, t he n b ot h c o m paris o ns will be c o nsi dere d statisticall y 
si gnifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 b ut t he s maller p- val u e is 
≤0. 0 2 5, t he c o m paris o n ass ociate d wit h t he s maller p- val ue will be c o nsi dere d statisticall y 
si g nifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 a n d t he s maller p- val u e is 
> 0. 0 2 5, t he n neit her c o m paris o n will be c o nsi dere d statisticall y si g nifica nt. 
I n a d diti o n, t he f oll o wi n g a d diti o nal a nal ys es will be pr o vi de d: 
 A nal ysis of Ti me t o Rec urre nce  i n T ar get ( T a, G 1- G 2) P o p ul ati o n w h o recei v e d o nl y 
o ne d ose of a p azi q u o ne 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 7  
 A nal ysis of Ti me t o Rec urre nce  i n T ar get ( T a, G 1- G 2) P o p ul ati o n  w h o recei v e d b ot h 
d ose s of a pazi q u o ne 
 A na l ysis of Ti me t o Rec urre nce  i n t he Pe r- pr ot oc ol P o p ul ati o n  i n T ar get ( T a , G 1 -
G 2 ) P o p ul ati o n recei vi n g o ne d os e of a p azi q u o ne a n d t h ose recei vi n g b ot h d oses of 
apazi q u o ne  
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 a d dress e d i n t he 
anal ysis of Ti me t o Rec urre nce  usi n g t he Pe r- Pr ot oc ol P o p ul ati o n  as e x pl orat or y:  
 A na l ysis of Ti me t o Rec urre nce  wit h D a y 1  i nstillati o n t hat d o n ot occ ur bet wee n 3 1 
a n d 9 0 mi n utes p ost- T U R B T 
 A na l ysis of Ti me t o Rec urre nce  i n patie nts w h os e f oll o w u p c yst osc o p y o cc urs o utsi de 
t he ± 1 0- da y wi n d o w 
F or t he a b o ve a n al ys es, t he f oll o wi n g d ata ha n dli n g r ules will be use d: 
 P atie nts w h o c ha n ge t hera p y pri or t o rec urre nce will be ce ns ore d at t he last assess me nt 
pri or t o c ha n ge i n t hera p y.  
 P atie nts wit h t w o or m ore missi n g assess me nts i m me diatel y pri or t o t he ne xt visit wit h a 
d oc u me nte d rec urre nce will be ce ns ore d at t he last assess me nt wit h d oc u me ntati o n of n o 
rec urre nce.  
T he pri mar y a n al ysis will i ncl u de all patie nts i n t he T a, G 1- G 2 T ar get P o p ul ati o n  irres pecti ve 
of l ost pat h ol o g y or n o sa m ple.  
Dist ri 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- Meier pr o d uct-li mit 
met h o d. T he  me dia n ti mes t o rec urre n ce wit h t w o-si de d 9 5 % c o nfi d e nce i nter vals 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 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 h e o nl y c o variate a n d teste d usi n g a l o g-ra n k test at t he l e vel of si g nifica nce 
de scri be d a b o ve. A d diti o nal e x pl orat or y a nal 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 % c o nfi de nce i nter val. T he m o d el will i ncl u de 
treat me nt effect, st u d y ce nter, pri mar y vs. rec urre nt disease as stratificati o n fact or i n a d diti o n t o 
an y ot h er bas eli ne or de m o gra p hi cs fact ors.  
8. 5. 6  S ec o n d ar y E n d p oi nts 
8. 5. 6. 1  Sec o n d ar y E n d p oi nt - Rec urre nce R ates 
1- Ye ar an d  2 - Y e ar R ec urre nce R ates  will be esti mate d usi n g t he Ka pl a n- Meier pr o d u ct-li mit 
met h o d a l o n g wit h t w o-si de d 9 5 % c o nfi de n ce i nter vals a n d will be c o m pare d usi n g a t w o-si de d 
l o g-ra n k test eac h at 5 % l e vel of si g nifica n ce. Si nce visits d o n ot ofte n occ ur at t he s pecifi e d 
i nter vals, a c ut- off u p per li mit of 3 7 5 or 7 6 5 da ys fr o m ra n d o mizati o n will be use d f or t he 1 2 or 
2 4 m o nt h visits, res pecti vel y. 
F or t he mai n a n al ysis, t he Rec urre nce R ate  calc ulati o n i ncl u des patie nts w h o met rec urre n ce 
criteria as c o nfir me d b y pat h ol o g y at eac h visit. A n a d diti o nal a nal ysis will be pr o vi de d b y 
c o u nti n g patie nts w h o dr o p o ut pri or t o t he a b o ve ti me p oi nt as ha vi n g a rec urre n ce. T h e 
Rec urre nce R ates  will b e c u m ulati ve at eac h visit fr o m t he ti me of st u d y ra n d o mizati 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 8  
8. 5. 6. 2  Sec o n d ar y E n d p oi nt - Ti me t o Pr o gressi o n 
Ti me t o Pr o gressi o n  is t he ti me fr o m ra n d o mizati o n t o t he first d oc u me ntati o n of sta ge 
pr o gr essi o n as c o nfir me d b y pat h ol o g y i n t he T ar get ( T a, G 1- G 2) P o p ul ati o n . Ti me t o 
P r o g ressi o n  of patie nts wit h n o d oc u me nte d pr o gressi o n o n-st u d y will be ce ns ore d at t he ti me of 
last eval ua ble visit o n-st u d y. Ti me t o Pr o gressi o n  of patie nts wit h n o e val u a ble visit o n-st u d y 
will  be ce ns ore d at ra n d o mizati o n. 
Distri b uti o n of Ti me t o Pr o g ressi o n  will be esti mate d usi n g t he Ka pla n- Meier met h o d. A nal ysis 
of T i me t o Pr o g ressi o n will be si milar t o t he a nal ysis of T i me t o Rec urre nce, 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 ( S afet y 
P o p ul ati o n ), a n d classifi e d acc or di n g t o t he treat me nt recei v e d. 
8. 6. 1  S afet y E n d p oi nts  
 All A Es  
 R elate 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 ( bl o o d press ure a n d heart rate ) an d r o uti ne la b orat or y para meters 
( he mat 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 
All 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 h er 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 nic 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 pretreat me nt a n d t hr o u g h o ut st u d y. 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 marize d b y 
w or st gra de p er patie nt a n d treat me nt ar m. 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
5 9  
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 mitte e 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. 
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 
writte 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 a t 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. 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 0  
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. C o m me nt fiel ds o n t he 
C R Fs will be use d as a m ea ns of cl arificati o n a n d c o m m u nicati o n bet wee n t he I n v esti gat or a n d 
S pectr u m; h o we ver, c o m me nts e ntere d i n t hese fiel ds will n ot be e dite d or clarifie d. 
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 a pazi q u o ne 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 a pazi q u o ne are t o b e acc o u nte d f or at t he site a n d mai nt ai n e 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 a pazi q u o ne 
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 dy c o n cl usi o n, all u n use d vials of a pazi q u o ne ma y b e destr o ye d at t he site, f oll o wi n g 
ve rificati o n of acc o u nt a bilit y b y a S p o ns or re prese ntati ve. 
9. 3  
P r 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 proce 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. I n a d diti o n, a c u m ulati ve re vi e w of all S A Es fr o m all s o urces will be assesse d 
peri o dicall 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 1  
9. 5  
J oi nt 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 e 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 e 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 e 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  T er 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 
partici 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 ter mi 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 st aff. 
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 
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 m et 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:  
1.  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;  
2.  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  
3.  Fi 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. 


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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 2  
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 c e 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 3  
1 0  R E F E R E N C E S 
1.   
Sie gel R L, Miller K D, J e mal A. Ca ncer Statistics, 2 0 1 5. C A Ca ncer J Cli n. 2 0 1 5; 6 5( 1): 5-
2 9. 
2.  
H o wla der N N A, Kra pc h o M, Ne y m a n N, A mi n o u R, Wal dr o n W, Alte kr use S F, K osar y 
C L, R u hl J, Tatal o vic h Z, C h o H, Mari ott o A, Eis ner M P, Le wis D R, C he n H S, Fe uer EJ, 
Cr o ni n K A (e ds). . Se er Ca ncer Statistics Re vie w, 1 9 7 5- 2 0 0 9 ( Vi nta ge 2 0 0 9 P o p ulati o ns) 
Bet hes d a, M D: Nati o nal Ca ncer I nstit ute; [ u p date d base d o n N o ve m b er 2 0 1 1 S E E R data 
s u b missi o n, p oste d t o t he S E E R we b site, A pril 2 0 1 2]. A vaila ble fr o m: 
htt p://seer.ca ncer. g o v/csr/ 1 9 7 5 _ 2 0 0 9 _ p o ps 0 9/. 
3.  
De Vita V T, Hell ma n S, R ose n ber g S A. Ca ncer: Pri nci ples & Practice. 7t h e d: Li p pi nc ott 
W illia ms & Wil ki ns; 2 0 0 4. 
4.   
B otte ma n M F, Pas h os C L, Re d aelli A, Las ki n B, Ha user R. T he Healt h Ec o n o mics of 
Bla d der Ca ncer: A C o m pre he nsi ve Re vie w of t he P u blis he d Literat ur e. 
P har mac oec o n o mics. 2 0 0 3; 2 1( 1 8): 1 3 1 5- 3 0. 
5.  
Ste nzl A, He n ne nl otter J, Sc hilli n g D. Ca n We Still Aff or d Bla d der Ca ncer? C urr O pi n 
Ur ol. 2 0 0 8; 1 8( 5): 4 8 8- 9 2. 
6.  
Ba bj u k M, O osterli nc k W, S yl vester R, Kaasi ne n E, B o hle A, Pal o u- Re d orta J, et al. Ea u 
G ui de li nes o n N o n- M uscle-I n vasi ve Ur ot helial Carci n o ma of t he Bla d der, t he 2 0 1 1 
U p da te. E ur Ur ol. 2 0 1 1; 5 9( 6): 9 9 7- 1 0 0 8. 
7.  
E d uar d o S. Earl y Si n gl e I nstillati o n C he m ot hera p y Is V er y Be n eficial a n d S h o ul d Be t he 
S ta n dar d A p pr oac h i n N o n – M uscle-I n vasi v e Bla d der Ca ncer. E ur o pea n Ur ol o g y 
S u p ple me nts. 2 0 0 9; 8( 5): 4 6 4- 9. 
8.  
Hall M C, C ha n g S S, Dal ba g ni G, Pr ut hi R S, Sei g ne J D, S ki n ner E C, et al. G ui deli ne f or 
t he Mana ge me nt of N o n m uscle I n vasi ve Bla d der Ca ncer ( Sta ges Ta, T 1, a n d Tis): 2 0 0 7 
U p date. J Ur ol. 2 0 0 7; 1 7 8( 6): 2 3 1 4- 3 0. 
9.  
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: 
B la d der Ca ncer ( V ersi o n 2. 2 0 1 4) [J u ne 4, 2 0 1 4]. 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 0.  
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 
Instillati o n of C he m ot hera p y Decreas 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 M eta- 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 1.  
Bra usi M, Witjes J A, La m m D, Persa d R, Pal o u J, C ol o m bel M, et al. A Re vie w of 
C urre nt G ui deli nes a n d Best Practice Rec o m me n dati o ns f or t he Ma na ge m e nt of 
N o n m uscle I n vasi ve Bla d der Ca ncer b y t he I nt er nati o nal Bla d der Ca ncer Gr o u p. J Ur ol. 
2 0 1 1; 1 8 6( 6): 2 1 5 8- 6 7. 
1 2.   
C h o u dr y G A, Ste wart P A, D o u ble J A, Kr ul M R, Na yl or B, Fla n ni ga n G M, et al. A N o vel 
Strate g y f or N q o 1 ( Na d( P) H: Q ui n o ne O xi d ore d uctase, Ec 1. 6. 9 9. 2) Me diate d T hera p y of 
Bla d der Ca ncer Base d o n t he P har mac ol o gical Pr o perties of E o 9. Br J Ca ncer. 
2 0 0 1; 8 5( 8): 1 1 3 7- 4 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- E O Q- 1 3 - 3 0 5 
Ori gi n al/ 0 6 A u g 2 0 1 5 
C o nfi de nti al 
6 4  
1 3.   
va n der Heij de n A G, V er hae g h G, J a nse n C F, Sc h al ke n J A, Witjes J A. Effect of 
H y p ert her mia o n t h e C yt ot o xicit y of 4 C he m ot hera pe utic A ge nts C urre ntl y Use d f or t he 
Treat me nt of Tra nsiti o nal Cell Carci n o ma of t he Bla d der: A n i n Vitr o St u d y. J Ur ol. 
2 0 0 5; 1 7 3( 4): 1 3 7 5- 8 0. 
1 4.  
Are ntse n H C, H e n dric ks e n K, H uls ber ge n- va n d e Kaa C A, Re d d y G, O ost er wij k E, 
Alfr e d Witjes J. T he Ort h ot o pic Fisc her/ A y- 2 7 Rat Bla d der Ur ot helial Cell Carci n o ma 
M o de l t o Test t he Efficac y of Differe nt A pazi q u o n e F or m ulati o ns. Ur ol O n c ol. 
2 0 1 2; 3 0( 1): 6 4- 8. 
1 5.  
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 ol e q ui n o ne Bi ore d u cti ve Dr u gs Base d o n t h e 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. 
1 6.  
P uri R, Palit V, L oa d m a n P M, Fla n ni ga n M, S ha h T, C h o u dr y G A, et al. P h ase I/Ii Pil ot 
S t u d y of I ntr a vesical A p azi q u o ne ( E o 9) f or S u perficial Bla d der Ca n cer. J Ur ol. 
2 0 0 6; 1 7 6( 4 P t 1): 1 3 4 4- 8. 
1 7.  
va n der Heij de n A G, M o o ne n P M, C or nel E B, Ver g u nst H, de Reij ke T M, va n B o ve n E, 
et al. P hase Ii Mar k er Lesi o n St u d y wit h I ntr a vesi cal I nstillati o n of A pazi q u o ne f or 
S u perficial Bl a d der Ca n cer: T o xicit y a n d Mar ker Res p o nse. J Ur ol. 2 0 0 6; 1 7 6( 4 Pt 
1): 1 3 4 9- 5 3; disc ussi o n 5 3. 
1 8.  
He n dric kse n K, C or nel E B, de Reij ke T M, Are nts e n H C, C ha wla S, Witjes J A. P hase 2 
S t u d y of A dj u va nt I ntr a v esical I nstillati o ns of A pazi q u o ne f or Hi g h Ris k N o n m uscle 
I n v asi ve Bla d der Ca n cer. J Ur ol. 2 0 1 2; 1 8 7( 4): 1 1 9 5- 9. 
1 9.  
He n dric kse n K, Gleas o n D, Y o u n g J M, Saltzstei n D, Gers h ma n A, Ler ner S, et al. Safet y 
an d Si de Effects of I m me diate I nstillati o n of A pazi q u o ne F oll o wi n g Tra ns uret hral 
Resecti o n i n Patie nts wit h N o n m uscle I n vasi ve Bl a d der Ca n cer. J Ur ol. 2 0 0 8; 1 8 0( 1): 1 1 6-
2 0. 
2 0.  
H oc h ber g Y. A S har per B o nferr o ni Pr oce 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. 



SAP_001.pdf: 
 
Offici al Titl e:  
A M ultic e nt er, M ulti Ar m, R a n d o miz e d, M ulti -D os e, Pl ac e b o -C o ntr oll e d, 
D o u bl e -Bli n d, P h as e 3 St u d y of I ntr a v esic al A p azi q u o n e ( E O q ui n ®) as a 
S ur gic al A dj u v a nt i n t h e I m m e di at e P ost o p er ati v e P eri o d i n P ati e nts 
U n d er g oi n g Tr a ns ut h er al R es ecti o n f or N o n -M uscl e  I n v asi v e Bl a d d er 
C a nc er  
N C T N u m b er:  
N C T 0 2 5 6 3 5 6 1  
D oc u m e nt  D at e : 
S A P  V ersi o n 1. 0 : 0 6-A u g ust -2 0 1 5  
 
 
 




S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
2 
T A B L E O F C O N T E N T S 
T A B L E O F C O N T E N T S  ..............................................................................................................2  
1  
I N T R O D U CTI O N .................................................................................................................. 4  
2  
S T U D Y O B J E C TI V E S .......................................................................................................... 4  
2. 1  
Pri m ar y O bjecti ve(s) ................................................................................................... 4  
2. 2  
Sec o n d ar y O bjecti ves................................................................................................... 4  
3  
I N VE S TI G A TI O N A L P L A N ................................................................................................ 4  
3. 1  
St u d y P o p ul ati o n .......................................................................................................... 4  
3. 2  
St u d y Desi g n ................................................................................................................. 4  
3. 3  
Visit Defi niti o ns ............................................................................................................ 5  
3. 4  
St u d y E n d p oi nts ........................................................................................................... 6  
3. 4. 1  
P ri m ar y Effic ac y E n d p oi nt ................................................................................. 6  
3. 4. 2  
S ec o n d ar y Effic ac y E n d p oi nts ............................................................................ 6  
3. 4. 3  
S afet y E n d p oi nts .................................................................................................. 6  
4  
D E F I NI TI O N S A N D A L G O RI T HM S  ................................................................................. 7 
4. 1  
Deri ve d V ari a bles......................................................................................................... 7  
5  
S T A TI S TI C A L C O N SI D E R A TI O N S .................................................................................. 7  
5. 1  
Ge ner al A n al ysis C o nsi der ati o ns................................................................................ 7  
5. 2  
S a m ple Size ................................................................................................................... 8  
5. 3  
R a n d o miz ati o n ................................................................................................ ............. 9 
5. 4  
B aseli ne Me as ure me nts ............................................................................................... 9  
5. 5  
H a n dli n g of Missi n g D at a ............................................................................................ 9  
5. 6  
I nteri m A n al ysis ......................................................................................................... 1 0 
5. 7  
Fi n al A n al ysis ............................................................................................................. 1 0  
6  
S T U D Y P A TI E N T S .............................................................................................................. 1 1  
6. 1  
Dis p ositi o n of P atie nts ............................................................................................... 1 1  
6. 2  
Pr ot oc ol D e vi ati o ns .................................................................................................... 1 1  
7  
E F F I C A C Y E V A L U A TI O N................................................................................................ 1 1 
7. 1  
D at asets A n al yze d ...................................................................................................... 1 1  
7. 2  
Pretre at me nt C h ar acteristics .................................................................................... 1 2  
7. 3  
E v al u ati o n Criteri a  .................................................................................................... 1 2 
7. 3. 1  
Al g or it h m f or t he Deri v ati o n of Rec urre nce R ate, Ti me t o Rec urre nce, 
Pr o g ressi o n a n d Ti me t o Pr o g ressi o n ............................................................ 1 2  
7. 4  
Effic ac y Res ults .......................................................................................................... 1 4  
7. 4. 1  
E ffic ac y V ari a bles .............................................................................................. 1 4 
7. 4. 2  
Ti me t o Rec u rre nce ........................................................................................... 1 4  
7. 4. 3  
Re c urre nce R ates ............................................................................................... 1 5  
7. 4. 4  
Ti me t o Pr o gressi o n ........................................................................................... 1 5  
7. 4. 5  
S u b gr o u p A n al yses ............................................................................................ 1 6  
8  
S A F E T Y E V A L U A TI O N .................................................................................................... 1 6  


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
3 
8. 1  
E xte nt of E x p os ure ..................................................................................................... 1 6  
8. 2  
C o nc o mit a nt Me dic ati o n s ......................................................................................... 1 6 
8. 3  
A d verse E ve nts ................................................................................................ ........... 1 6 
8. 4  
De at hs, Ot her Seri o us A d verse E ve nts, Ot her Si g nific a nt A d verse E ve nts ......... 1 6  
8. 4. 1  
De at hs ................................................................................................................. 1 7  
8. 4. 2  
Ot h er Seri o us A d verse E ve nts .......................................................................... 1 7  
8. 4. 3  
Ot h er Si g nific a nt A d verse E ve nts .................................................................... 1 7  
8. 5  
Cli nic al L a b or at or y E v al u ati o ns  .............................................................................. 1 7 
8. 6  
Vit al Si g ns ................................................................................................................... 1 7  
9  
R E F E R E N C E S ..................................................................................................................... 1 8  
 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
4 
1  
I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) i ncl u des i nf or mati o n o n statistical desi g n of t his cli nical 
st u d y, defi niti o ns of efficac y a n d safet y e n d p oi nts, a n d pla ns f or t he a nal ysis of pri mar y a n d 
sec o n dar y e n d p oi nts of t he st u d y. T h e statistical met h o ds a n d a nal yses descri be d here are bas e d 
o n t h ose prese nte d i n t he cli nical st u d y pr ot o c ol, a n d s u perse de d efi niti o ns a n d pr oce d ures 
descri be d i n a n y ot h er past a n d/ or prese nt d oc u m e nts re gar di n g t he statistical a nal yses of t he 
effic ac y a n d s afet y e n d p oi nts of st u d y S PI- E O Q- 1 3- 3 0 5 . 
2  
S T U D Y O B J E C TI V E S 
2. 1  
Pr im ar y O bjecti ve(s) 
 T o e val uate t he Ti me t o Rec urre nce  wit h eit her o ne i nstillati o n of 4 m g A pazi q u o ne or 
t w o i nstillati o ns of 4 m g a pazi q u o ne relati ve t o pl ace b o i nstillati o n f oll o wi n g T U R B T i n 
patie nts wit h n o n- m uscle i n vasi ve bla d der ca ncer ( N MI B C) w h o recei ve tra ns uret hral 
resecti o n bla d d er t u m or ( T U R B T). 
2. 2  
S ec o n d ar y O bjecti ves 
1.  T o e val uate t he 2- Ye a r  Rec urre nce R ate  wit h eit her o ne i nstillati o n of 4 m g a p azi q u o ne 
or t w o i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T 
i n patie nts wit h N MI B C w h o recei ve T U R B T 
2.  T o e val uate t he 1- Ye a r  Rec urre nce R ate  wit h eit her o ne i nstillati o n of 4 m g a p azi q u o ne 
or t w o i nstillati o ns of 4 m g a p azi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T 
i n patie nts wit h N MI B C w h o recei ve T U R B T 
3.  T o e val uate t he Ti me t o Pr o g ressi o n  wit h eit her o ne i nstillati o n of 4 m g a pazi q u o ne or 
t w o i nstillati o ns of 4 m g a pazi q u o ne relati ve t o pl ace b o i nstillati o n f oll o wi n g T U R B T i n 
patie nts wit h N MI B C w h o recei v e T U R B T 
4.  T o e val uate t he s afet y wit h eit her o ne i nstillati o n of 4 m g a pazi q u o ne or t w o i nstillati o ns 
of 4 m g a pazi q u o ne relati ve t o place b o i nstillati o n f oll o wi n g T U R B T i n patie nts wit h 
N MI B C. 
3  
I N V E S TI G A TI O N A L P L A N 
3. 1  
St u d y P o p ul ati o n 
Patie nts wit h pri mar y or rec urre nt ≤4 n o n- m uscle n o ni n vasi ve bla d der t u m ors, w h o satisf y all 
pr ot oc ol- defi ne d e nr oll m e nt criteria, are eli gi ble t o e nr oll i n t his ra n d o mize d st u d y. 
3. 2  
St u d y Desi g n 
T his is a P hase 3, ra n d o mize d, m ultice nter, m ulti-ar m, m ulti- d ose, place b o-c o ntr olle d, d o u ble-
bli n d st u d y i n patie nts wit h ≤4 n o n- m uscle i n vasi ve bla d der t u m ors, ≤3. 5 c m i n dia meter, all of 
w hic h m ust ha ve bee n f ull y res ecte d at T U R B T.  
In a d diti o n t o scree ni n g, patie nts will u n der g o a n assess me nt of ur ot helial carci n o ma of t he 
bla d der f or cli nicall y a p p are nt t u m or Ta, G 1 -G 2.  
F oll o wi n g T U R B T o n D a y 1 , eli gi ble patie nts will be ra n d o mize d t o o ne of t he t hree tr eat me nt 
ar ms i n a 1: 1: 1 rati o: 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
5 
 Ar m 1- O ne D os e of A p azi q u o ne: 
 D a y 1 : a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0 ± 3 0 mi n utes p ost- T U R B T 
 D a y 1 5  ( ± 5 da ys): a d mi nistrati o n of place b o  
 Ar m 2- T w o D oses of A p azi q u o ne: 
 D a y 1 : a d mi nistrati o n of 4 m g of a pazi q u o ne 6 0 ± 3 0 mi n utes p ost- T U R B T 
 D a y 1 5  ( ± 5 da ys): a d mi nistrati o n of 4 m g of a pazi q u o ne  
 Ar m 3- Pl ac e b o:  
 D a y 1 : a d mi nistrati o n of place b o 6 0 ± 3 0 mi n utes p ost- T U R B T 
 D a y 1 5  ( ± 5 da ys): a d mi nistrati o n of place b o  
O nce ra n d o mize d, D a y 1  st u d y dr u g i nstillati o n will occ ur at 6 0 ± 3 0 mi n utes p ost T U R B T. 
P atie nts will ret ur n o n D a y 1 5  ( ± 5 da ys) f or a sec o n d i nstillati o n. All hist ol o g y s peci me ns will be 
revie we d b y a l ocal p at h ol o g y la b orat or y. All cli nical treat me nt decisi o ns a n d st u d y a n al ys es will 
be base d o n t he p at h ol o g y re vie w. Patie nts w h ose pat h ol o g y is ot her t ha n T a, G 1- G 2 will be 
f oll o wed f or safet y at D a y 3 5  ( ± 5 da ys) fr o m t he l ast d ose of st u d y dr u g a n d disc o nti n ue d fr o m 
t he st u dy.  
Patie nts wit h pat h ol o g y c o nfir me d Ta, G 1- G 2 hist ol o g y will be f oll o we d acc or di n g t o t he 
sche d ule bel 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 9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m 
date of T U R B T) t hr o u g h 2 4 m o nt hs f or t u m or rec urre nce a n d pr o gressi o n. 
 
If at a n y ti me d uri n g 2 4 m o nt h f oll o w u p peri o d t here is a t u m or rec urre n ce, t he patie nt 
will c o nti n ue o n st u d y wit h f oll o w- u p c yst osc o pic e x a mi nati o n a n d uri ne c yt ol o g y e ver y 
9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m date of T U R B T) t hr o u g h t he e n d of 2 4 m o nt hs.  
Patie nts wit h a rec urre nce are p er mitte d t o ha ve a f oll o w- u p T U R B T.  
 If at a n y ti me d uri n g 2 4 m o nt h f oll o w u p peri o d t here is a t u m or rec urre n ce a n d/ or patie nt 
is starte d o n a n ot her t hera p y, t h e patie nt will be f oll o we d b y tel e p h o ne, f or safet y e v er y 
9 0 da ys ( ± 1 0 da ys) (calc ulate d fr o m date of T U R B T) t hr o u g h t he e n d of 2 4 m o nt hs. 
D urati 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 a p pr o xi matel y 2 4 m o nt hs 
i ncl u di n g: 
1.  Scree ni n g Peri o d:  3 0 da ys  
2.  Tre at me nt Peri o d:  D a y 1  a n d D a y 1 5  ( ± 5 da ys) 
3.  S afet y F oll o w- u p Peri o d:  2 4- m o nt hs 
T he  f ull i n vesti gati o nal pla n is detaile d i n t he cli nical pr ot oc ol. 
3. 3  Visi t Defi niti o ns  
Data will be s u m marize d b y visit. A patie nt ma y or ma y n ot h a ve c o m e t o t he cli nic at t he 
sc he d ule d visit ti me per pr ot oc ol. T heref ore, n o n- o verla p pi n g i nter vals are defi ne d f or visits. 




S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
7 
4  
D E FI NI TI O N S A N D A L G O RI T H M S 
4. 1  De ri ve d V ari a bles 
B aseli ne : Da y of Tra ns ur et hral Resecti o n of Bla d der T u m or ( T U R B T) p erf or me d o n D a y 1 . 
St u d y D ur ati o n : Date of t he last patie nt visit mi n us date of ra n d o mizati o n. 
Rec urre nce : A p p eara nce of ne w, hist ol o gicall y c o nfir me d, bla d der t u m or w hile o n st u d y. 
Rec urre nce R ate : T he pr o p orti o n of patie nts wit h hist ol o gicall y c o nfir me d rec urre nce of t he 
bla d der t u m or at a n y ti m e after ra n d o mizati o n a n d o n or bef ore Ye ar 2. T h e first rec urre nce will 
be use d f or Rec urre nce R ate . 
D ate of Rec urre nce : T h e date of t he first c yst osc o picall y c o nfir me d rec urre nce. T h e 
c o nfir mati o n of t he rec urre nce will be ma de usi n g a n i n de pe n de nt p at h ol o g y re p ort. T he d etaile d 
al g orit h m of deter mi nati o n of rec urre n ce a n d Ti me t o Rec urre nce  is pr o vi de d i n Secti o n 7. 3. 1 . 
Ti me t o Rec u rre nce : Ti me fr o m ra n d o mizati o n t o date of first hist ol o gicall y c o nfir m e d 
rec urre nce of t he p atie nts’ bla d der t u m or. Patie nts wit h o ut rec urre nce b y M o nt h 2 4  c yst osc o p y 
assess me nt visit will be c o nsi dere d t o be ce ns ore d at t he last a vaila ble visit/c o ntact. Patie nts w h o 
die d d ue t o a n y ca use bef ore c o nfir m e d rec urre nce b y M o nt h 2 4  c yst osc o p y ass ess me nt visit 
will  be c o nsi dere d t o be ce ns ore d o n t h e date of d eat h. If t he d ate of d eat h is after M o nt h 2 4  
c yst osc o p y assess me nt visit wit h o ut a rec urre nce, t he patie nt will be ce ns ore d at 2 4 m o nt hs. If a 
patie nt ha d a s us pe cte d lesi o n a n d die d bef ore hist ol o gical c o nfir mati o n, t he date of s us p ecte d 
rec urre nce will be use d as t he date of rec urre nce. T he detaile d al g orit h m f or t he deter mi nati o n of 
rec urre nce a n d Ti me t o Rec u rre nce  is pr o vi de d i n Secti o n 7. 3. 1 .  
Ti me t o Pr o gressi o n : Ti me fr o m ra n d o mizati o n t o date of first hist ol o gicall y c o nfir m e d 
pr o gressi o n t o hi g h er sta ge of t he patie nts’ bla d der t u m or. Patie nts wit h o ut rec urre nce will be 
c o nsi dere d t o be ce ns or e d at t he last a vaila ble visit/c o ntact. 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 c o nsi dere d t o be ce ns ore d o n t he dat e of deat h. 
5  
S T A TI S TI C A L C O N SI D E R A TI O N S 
5. 1  
G e ner al A n al ysis C o nsi der ati o ns 
T he statistical a nal yses will be re p orte d usi n g s u m mar y t a bles, fi g ures, a n d data listi n gs. All 
anal ys es a n d ta b ul ati o ns will be perf or me d usi n g S A S ®  Versi o n 9. 3 or hi g her. All ta bles, 
listin gs, a n d fi g ures will be vali date d a n d re vie we d bef ore b ei n g fi nalize d. I n d e pe n de nt 
pr o gra m mi n g will be c o n d ucte d t o verif y ta bl es a n d listi n gs as a p pr o priat e f or efficac y 
e n d p oi nt a nal ysis. T a bles will be re vie we d f or acc urac y, c o nsiste n c y wit h t his pla n, c o nsiste nc y 
wit hi n ta bles, a n d c o nsiste nc y wit h c orres p o n di n g o ut p ut. 
F or t he c o nti n u o us varia bles, n u m ber of n o n- missi n g val ues a n d mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m will be ta b ulate d b y tr eat me nt ar m. F or t he cate g ori cal 
varia bles, t he  c o u nts a n d perce nt f or eac h p ossi ble val ue will be ta b ulate d b y treat me nt ar m. 
Treat me nt ar ms will be c o m pare d usi n g c hi-s q uare ( wit h c o nti n uit y c orrecti o n) or C oc hra n-
Ma ntel- Ha e nszel test a n d t w o-si de d 9 5 % c o nfi d e n ce i nter vals will be pr o vi de d f or pr o p orti o ns 
a n d differe nce i n pr o p orti o ns. F or ti me t o e ve nt data, t he l o g ra n k test will be use d. T he 
distri b uti o n of  ti me will be dis pla ye d usi n g Ka pla n- Meier c ur ves. H azar d rati o a n d its 9 5 % 
c o nfi de nce i nter val will be pr o vi de d. 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
8 
5. 2  
S a m ple Size 
I n t w o ra n d o mize d, place b o-c o ntr olle d cli nical trials (S PI- 6 1 1  a n d S PI- 6 1 2 ) of a pazi q u o ne i n 
patie nts wit h Ta, G 1- G 2 bla d der t u m ors ( N = 8 0 2; 8 1 3), t he Rec u rre nce R ate  i n t he P l ace b o 
Tre at me nt Ar m  was a p pr o xi matel y 4 6 %. B y ta ki n g i nt o acc o u nt t he Rec urre nce R ates  o verall 
i n the a b o ve t w o st u dies, t he Rec urre nce R ate  i n t he A p azi q u o ne Tre at me nt Ar m  fr o m t he 
t w o st u dies was ass u me d t o be 3 9. 5 %, w hic h res ults i n a hazar d rati o of a p pr o xi matel y 0. 8 0.  
T he  e nr olle d p atie nts will be ra n d o mize d i n a 1: 1: 1 rati o i nt o o ne of t hree treat me nt ar ms 
i ncl u di n g: Ar m 1: o ne d ose of a pazi q u o ne, A r m 2: t w o d oses of a p azi q u o ne, or Ar m 3: 
place b o, usi n g a per m ute d bl oc k desi g n. T h e pri m ar y e n d p oi nt of t he st u d y is Ti m e t o 
Rec urre nce  i n t he T ar g et ( T a, G 1- G 2) P o p ul ati o n . T he pri mar y e n d p oi nt a nal ysis i n v ol ves 
2 pair wise tests of c o m paris o ns: o ne d ose of 4 m g a pazi q u o ne vs. place b o a n d t w o d oses of 4 m g 
apazi q u o ne vs. place b o. N o c o m paris o n of t he tr eat me nt ar ms t hat recei ve d o ne d ose of 
a pazi q u o ne vs. t w o d oses of a pazi q u o ne will be perf or me d.  
T he pri mar y a n al yses of t ests of pair wise c o m paris o ns of o ne d ose vs. place b o a n d t w o d oses vs. 
place b o ar ms will be perf or me d usi n g 2-si de d l o g-ra n k test eac h at 5 % le v el of si g nifica n ce. T h e 
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. 
H oc h ber g pr oce d ure [ 1] will be use d t o c o ntr ol t he o verall T y p e I err or rat e d ue t o m ulti ple 
co m paris o ns f or t he pri mar y e n d p oi nt. If t he l ar ger p- val ue of t h e t w o c o m paris o ns ( o ne d ose vs 
place b o, t w o d oses vs place b o) is ≤0. 0 5, t he n b ot h c o m paris o ns will be c o nsi dere d statisticall y 
si g nifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 b ut t he s maller p- val u e is 
≤0. 0 2 5, t he c o m par is o n ass ociate d wit h t he s maller p- val ue will be c o nsi dere d statisticall y 
si g nifica nt. If t he lar ger p- val ue of t he t w o c o m paris o ns is > 0. 0 5 a n d t he s maller p- val u e is 
> 0. 0 2 5, t he n neit her c o m paris o n will be c o nsi dere d statisticall y si g nifica nt.  
T he f oll o wi n g pr oce d ure will be use d t o test t he list of sec o n dar y e n d p oi nts f or eac h pair wis e 
c o m paris o n:  
1.  If b ot h c o m paris o ns of pri mar y e n d p oi nts ( o ne d os e vs. place b o, t w o d os es vs. place b o) 
are si g nifica nt ( p ≤0. 0 5), t he T y p e I err or will be re use d f or t he pair wise c o m paris o ns of 
eac h sec o n dar y e n d p oi nt u ntil a test p- val ue > 0. 0 5 i n a pair wise c o m p aris o n ( o n e d ose vs. 
plac e b o or t w o d os e vs. place b o). N o c o m paris o n will be ma de after t his p oi nt. 
2.  If o ne of t he c o m paris o ns of pri mar y e n d p oi nts (eit her o ne d ose vs. pl ace b o or t w o d oses 
vs. pla ce b o) is n ot si g nifi ca nt, n o re us e of T y pe I err or will be atte m pte d f or a n y of t he 
seco n dar y e n d p oi nts.  
T he or der of sec o n dar y e n d p oi nts f or t he test of c o m paris o ns is liste d bel o w:  
1.  T he  2- Ye a r Rec urre nce R ate  of bla d d er ca ncer 
2.  T he  1- Ye a r Rec urre nce R ate  of bla d d er ca ncer 
3.  T i me t o Pr o gressi o n t o hi g her st a ge 
A p pr o xi matel y 1 8 6 9 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 3 years a n d f oll o w- u p ti me as 2 4 m o nt hs. Ass u mi n g 5 4 % of patie nts are rec urre nce-free f or 
place b o a n d 6 0. 5 % of patie nts are rec urre nce-free f or t he a p azi q u o ne treat me nt ar m (ass u me d t o 
be t he sa me f or eac h ar m) at t he e n d of 2 4- m o nt h f oll o w- u p, sa m ple siz es of 5 1 9 per treat me nt 
ar m will ac hie ve 8 0 % p o wer t o dete ct s u peri orit y i n eac h c o m p aris o n usi n g l o g-ra n k test at 5 % 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
9 
le vel of si g nifi ca nce. T he a b o ve sa m ple siz e acc o u nts f or 5 % of patie nts l ost t o f oll o w- u p. At t he 
e n d of t he 2- year f oll o w u p, t his t otal is ass u me d t o pr o vi de 3 3 6 rec urre nce e ve nts i n t he Pl ace b o 
T re at me nt Ar m a n d 2 9 5 rec urre nce e v e nts i n eac h A p azi q u o ne Tre at me nt Ar m  ( Hi ntze, J. 
[2 0 1 3]. P A S S 1 2, N C S S, L L C, Ka ys ville, Ut a h, U S A). T he fi nal a nal ysis of t he pri mar y 
e n d p oi nt will be c o n d uct e d o nce all 3 3 6 rec urre n ce e ve nts i n t he Pl ace b o Tre at me nt Ar m  are 
accr ue d.  
Base d o n t h e data fr o m pri or st u dies o n misclassificati o n of sta ge a n d gra d e dia g n osis at t he 
scree ni n g f or e nr oll me nt, a n a d diti o nal 2 0 % patie nts ma y nee d t o be e nr olle d i n or der t o accr ue 
t he re q uire d T ar g et T a, G 1- G 2 P o p ul ati o n  i n t he st u d y. T h eref ore, t he st u d y will e nr oll a n d 
ran d o mize 6 2 3 patie nts per ar m f or a t otal of 1 8 6 9 patie nts.  
5. 3  
R a n d o miz ati o n 
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 e it her 1 vial of a pazi q u o ne pl us 1 vial of place b o, 2 vials of a pazi q u o ne, or t w o 
vials of plac e 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 nter. Patie nt 
n u m bers will be  assi g n e d se q ue ntiall y at eac h site. Patie nts will be ra n d o mize d wit hi n a ce nter 
wit h a bl oc k size of 9. Patie nt n u m bers will be assi g ne d s e q ue ntiall y at eac h site. T he st u d y dr u g 
will be s hi p pe d t o st u d y sites i n bl oc ks of t w o t o e ns ure bala nce at eac h site. T he st u d y dr u g will 
be la bele d wit h t he ra n d o mizati o n n u m bers, w hic h will c o nsist of f o ur di gits t hat start fr o m 1 0 0 1 
a n d i ncre ase se q u e ntiall y. 
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 wi ll 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 1: 1 : 1 t o recei ve eit her o ne 
i nstillati o n of 4 m g a pazi q u o ne (D a y 1 ) pl us o ne d ose of place b o (D a y 1 5  [ ± 5 da ys]) or t w o 
i nstillati o ns of a pazi q u o ne, or t w o d oses of place b o. F oll o wi n g a f utilit y a n al ysis, if a n o n-
effic aci o us A p azi q u o ne Tre at me nt Ar m  is dr o p pe d, t he st u d y will be re-ra n d o mize d t o i ncl u de 
t he re mai ni n g A p azi q u o ne Tre at me nt Ar m  a n d Pl ace b o Tre at me nt Ar m  i n a 1: 1 rati o as 
de scri be d i n Secti o n 5. 6  bel o w.  
S t u d y dr u g s h o ul d n ot be pre pare d u ntil t he n u m ber, siz e a n d a p peara n ce of all bla d der t u m ors 
are c o nfir me d at T U R B T. If f or a n y reas o n, f oll o wi n g T U R B T t he patie nt d oes n ot recei ve st u d y 
dr u g, t he M e dical M o nit or s h o ul d be n otifie d i m me diatel y via fa x.  
5. 4  
B aseli ne Me as ure me nts 
B aseli ne m eas ur e me nt of a n y v aria ble f or eac h p atie nt will be t he last a vaila ble val ue of t h e 
varia ble o n or b ef ore t he date of Visit 1 , D a y 1 , w hic h is t he da y o n w hic h t he patie nt u n der g oes 
T U R B T a n d first st u d y dr u g i nstillati o n. 
5. 5  
H a n dli n g of Missi n g D at a 
E x ce pt f or partial dates, missi n g data will n ot be i m p ute d. T hat is, t he a nal ys es will be p erf or me d 
c o nsi deri n g all o bser ve d data. T he effect of missi n g dat a o n t he pri mar y e n d p oi nt of Ti me t o 
Re c urre nce will be e val uate d t hr o u g h a series of pre-s pecifie d se nsiti vit y a nal ys es (Se cti o n 
7. 4. 2 ). 
F or t he d ate of hist orical e ve nts pri or t o t he st u d y, if t he m o nt h a n d da y are missi n g, t he date will 
b e i m p ute d as J ul y 1. If t he da y is missi n g, it w o ul d be i m p ute d as t he 1 5 t h of t he m o nt h. 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 0  
F or start d ate of a d v erse e ve nts a n d c o n c o mita nt me dicati o ns, if t he m o nt h is missi n g a n d t he 
year is t he sa me as t he year of ra n d o mizati o n, it is ass u me d t hat t he e ve nt i s treat me nt-e mer ge nt, 
a n d t hat t he me dicati o n is ta ke n d uri n g t he st u d y, u nless t he st o p date occ urs pri or t o t he first 
d ose date. I n s u c h cas es, t he start date is i m p ute d as t he date of first d ose of st u d y dr u g.  
If t he year is missi n g, n o i m p utati o n will be d o ne f or t he year, a n d t he e ntire date varia bl e will be 
set t o missi n g, a n d t he A E is ass u me d t o be treat me nt e mer ge nt, a n d c o nc o mita nt me dicati o n is 
ass u me d t o be starte d d uri n g t he st u d y. 
T he i m p ute d date val ue will o nl y b e use d f or t he cal c ulati o n of deri ve d varia bles. T he ori gi nall y 
c ollecte d date v al ue will be prese nt e d i n t he data listi n gs. 
F or t he d ates of e v e nts w hic h occ urre d d uri n g t he st u d y, a missi n g d a y is set t o t he 1 5 t h of t he 
m o nt h. N o i m p utati o n will be perf or me d if m o nt h a n d/ or year are missi n g, h o we ver missi n g 
val ues will be q uerie d. 
5. 6  
I nteri m A n al ysis 
T o deter mi ne w h et her e nr oll me nt s h o ul d be disc o nti n ue d i n a n i nefficaci o us ar m, a f utilit y 
a nal ysis will be c o n d ucte d o nce t he first 1 0 0 of t h e e x pecte d 3 3 6 e v e nts are o bser ve d i n t he 
Pl ac e b o Tre at me nt Ar m i n t he st u d y. T he re q uire d n u m ber of e ve nts ne e de d t o deci de o n t he 
ti min g of t he i nteri m f utilit y a nal ysis will be trac ke d b y i n de pe n de nt, u n bli n de d data m o nit ori n g 
pers o n nel. T he first 1 0 0 of t he e x pecte d 3 3 6 rec urre nce e ve nts i n t he Pl ac e b o Tre at me nt A r m 
will ac hie ve 2 0 % c o n diti o nal p o wer t o detect t he alter nati ve hazar d rati o of 0. 8 at a si g nifica n ce 
le vel of 0. 0 5 usi n g a t w o-si de d l o g-ra n k test. T he c orres p o n di n g z- val ue t hres h ol d of t he data 
t hat ha ve accr ue d f or t he f utilit y a nal ysis is - 3. 0. T he f utilit y i n de x is 0. 8 0 2. If t he z- val ue of a n y 
of t he pa ir wise c o m paris o ns (ie H R) bet wee n si n gle d ose a pazi q u o ne vs. pl ace b o or t w o d oses of 
a pazi q u o ne vs. place b o is less t ha n - 3. 0, t he c orres p o n di n g n o n-efficaci o us A p azi q u o ne 
Tre at me nt Ar m will be dr o p pe d a n d t he st u d y will be re-ra n d o mize d t o i ncl u de t he re m ai ni n g 
A p azi q u o ne Tre at me nt Ar m a n d Pl a ce b o Tre at me nt Ar m i n a 1: 1 rati o. N o a dj ust me nt t o 
T y pe I err or will be ma d e f or t he f utilit y a nal ysis as t he fi nal a n al ysis will be c o n d ucte d usi n g a 
T y pe I err or of 0. 0 5 as state d i n t he pr ot oc ol 
5. 7  
F i n al A n al ysis 
T he fi nal a n al ysis of t he pri mar y e n d p oi nt will be c o n d ucte d o nce all 3 3 6 rec urre nce e ve nts i n 
t he Pl ac e b o Tre at me nt Ar m  are accr ue d. T he a b o ve re q uir e d n u m ber of e ve nts nee de d t o 
de ci de o n t he ti mi n g of t he fi nal a nal ysis will be trac ke d b y i n d e pe n de nt, u n bli n de d data 
m o nit ori n g pers o n nel. 
Statistical tests of si g nifica nce will n ot be stratifie d. All statistical tests will be c o n d ucte d at t he 
t w o-si de d 5 % le vel of si g nifica nce f or tr eat me nt effects. Statistical tests f or pri mar y e n d p oi nt 
anal ysis are c o n d ucte d usi n g t he met h o d des cri be d i n Secti o n 5. 2 . 
In t he e ve nt t hat t he pri mar y a nal ys is is perf or me d bef ore all patie nts c o m plete t heir 2 4 - M o nt h 
F oll o w- u p Visit , a fi nal a nal ysis will be c o n d ucte d o n f ull data after all patie nts ha ve t he 
o p p ort u nit y t o c o m plete t he 2 4 m o nt h d urati o n of st u d y. T he fi nal a nal ysis i n t his case will be 
c o nsidere d t o be a se nsiti vit y a nal ysis.  


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 1  
6  
S T U D Y P A TI E N T S 
6. 1  
Dis p ositi o n of P atie nts 
Patie nts will be e nr olle d after gra nti n g i nf or me d c o nse nt. T he f oll o wi n g will be s u m marize d o n 
all ra n d o ml y assi g n e d patie nts b y treat me nt ar ms: 
 Ac cr ual b y c o u ntr y a n d t he Pri nci pal I n vesti gat or (site) 
 A ccr ual b y v ersi o n of t he pr ot oc ol (if a p plica bl e) 
 P atie nt s wit h t he tar get t u m or hist ol o g y ( Ta, G 1 -G 2) 
 P atie nts c o m pleti n g t he 2 4 - M o nt h F oll o w- u p Visit 
 P atie nts wit h dra w n bef ore t he 2 4- M o nt h F oll o w- u p Visit  a n d reas o ns f or 
disc o nti n uati o n 
6. 2  
P r ot oc ol D e vi ati o ns 
De viati o ns will be deter mi ne d b y a n i nter nal r e vie w of cli nical d ata. T he s e res ults will be e ntere d 
i nto t he cli nical data base a n d l oc ke d pri or t o brea ki n g t he st u d y bli n d. All i m p orta nt de viati o ns 
relate d t o st u d y i ncl usi o n or e x cl usi o n criteria, c o n d uct of t he trial, patie nt ma na ge me nt or 
patie nt assess me nt will be rec or de d, s uc h as: 
 T h ose  w h o e ntere d t he st u d y e v e n t h o u g h t he y di d n ot satisf y t he e ntr y criteria  
 T h ose  w h o de vel o p e d wit h dra wal criteria d uri n g t he st u d y b ut w ere n ot wit h dra w n. 
 T h ose w h o recei ve d t he wr o n g treat me nt or wit h d ose c o m plia nce o utsi de 8 0 % t o 1 2 0 % 
of t he tar get d ose. 
 T h ose  w h o recei ve d a n e x cl u de d c o nc o mita nt treat me nt. 
All re mai ni n g d e viati o ns t hat are mi n or will be liste d.  
7  
E F FI C A C Y E V A L U A TI O N 
7. 1  
D at a sets A n al yze d  
F o ur datas ets will be a nal yz e d: 
 T ar get ( T a,  G 1 - G 2) P o p ul ati o n: all ra n d o mize d patie nts wit h a l ocal la b orat or y 
co nfir me d pat h ol o g y of Ta, G 1- G 2 N MI B C, cl assifie d acc or di n g t o t he treat me nt ar ms 
i nt o w hic h t he y w ere ra n d o mize d, re gar dless of t h e act ual tr eat me nt recei v e d. T he 
a nal ysis p o p ulati o n f or all efficac y e n d p oi nts will be t he T ar get ( T a, G 1- G 2) 
P o p ul ati o n  base d o n l oc al pat h ol og y . 
 N o n- T ar get P o p ul ati o n : all ra n d o mize d patie nts wit h a pat h ol o g y la b orat or y c o nfir me d 
n o n - Ta, G 1- G 2 N MI B C, classifie d acc or di n g t o t h e treat me nt ar ms i nt o w hic h t he y were 
ra n d o mize d, re gar dl ess of t he act ual tr eat me nt r ecei ve d. N o pri mar y effi cac y e n d p oi nt 
a nal ysis will be pr o vi d e 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.  
 P er- Pr ot oc ol ( P P) 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 ual 
treat me nt recei ve d w h o h a ve l ocal p at h ol o g y c o nfir me d Ta, G 1- G 2 , regar dl ess of ra n d o m 
assi g n me nt. Ra n d o miz e d patie nts w h o recei ve n o treat me nt or ha v e i m p orta nt pr ot oc ol 
de viati o ns will be e x cl u de d fr o m t he a n al ys es of efficac y.   


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 2  
 S afet y ( S A F) 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 ual 
treat me nt recei ve d, re gar dless of ra n d o m assi g n m e nt. 
7. 2  
P retre at me nt C h ar acteristics 
De m o gra p hics a n d ot her B aseli ne  c haract eristics will be s u m marize d f or all ra n d o mize d patie nts 
b y treat me nt ar ms. T his i ncl u des, a m o n g ot hers, a ge, ge n der, race, as w ell as t u m or sta ge a n d 
g ra de bas e d o n pat h ol o g y re vie w. 
7. 3  
E v al u ati o n Criteri a 
After t w o i nstillati o ns of st u d y treat me nt, patie nts will be cl osel y f oll o we d f or t he rec urre nce 
an d/ or pr o gressi o n of bl a d der t u m ors wit h assess me nts a n d e x a mi nati o ns i ncl u di n g c yst osc o p y, 
uri ne  c yt ol o g y, a n d bi o ps y (if i n dicate d) at 9 0 da y ( ± 1 0 da ys) i nter vals calc ulate d fr o m t he dat e 
of T U R B T t hr o u g h o ut t h e 2 4- m o nt h st u d y partici pati o n. 
All bi o psies/sli des will be rea d b y t h e l ocal pat h ol o g y la b orat or y a n d t h e res ults will be use d i n 
t he anal yses of effic ac y e n d p oi nts. Fail ure e v e nts i n t his st u d y will be d efi n e d as: 
 Re c urre nce: a n y bla d der ca ncer, c o nfir me d b y pat h ol o g y, i n t he patie nt’s bla d der 
 P r o g ressi o n:  a n y bla d d er ca ncer, c o nfir me d b y p at h ol o g y, i n t he patie nt’s bla d der wit h a 
hi g her st a ge 
7. 3. 1  Al g or it h m f or t he Deri v ati o n of Rec urre nce R ate, Ti me t o Rec urre nce, Pr o g ressi o n 
a n d Ti me t o Pr o g ressi o n 
T he st u d y effic ac y d ataset f or t he st u d y will ha ve t he f oll o wi n g v aria bles: 
1.  Ti me of  I nstillati o n relati ve t o T U R B T 
a. Date/ti me of T U R B T at D a y 1  – T his s h o ul d be t he ra n d o mizati o n ti me p oi nt or 
B aseli ne  
b.  Da te/ti me of i nstillati o n at D a y 1   
T his Date/ Ti me will be use d t o calc ulate t h e ti me of i nstillati o n relati ve t o T U R B T. 
2.  Re c urre nce R ate a n d T i me t o R ec urre nce –  f oll o wi n g varia bles will be use d. 
a. Date a n d ti me of ra n d o miz ati o n/ T U R B T  
b.  Da te of T U R ma y b e a vaila ble at a n y p ost-D a y 1  visits – T his will be t he ti me of 
resecti o n if patie nt u n d er g oes s u bs e q ue nt res ecti o n.  
c. Da te of C yst osc o p y – t o be perf or me d e v er y 3 m o nt hs. If t u m or s ee n, bi o ps y will be 
pe rf or me d a n d sa m ples s e nt t o t he l ocal pat h ol o g y la b orat or y.  
d.  Da te of Uri ne C yt ol o g y - t o be perf or m e d e ver y 3 m o nt hs.  
e. Pat h ol o g y re p ort date f or all visits – w he n c yst osc o p y is perf or me d, if t u m or is see n 
b y c yst osc o p y, a bi o ps y will be perf or me d a n d t h e sa m ples will be se nt t o t he l ocal 
pat h ol o g y la b orat or y. T his will be t he re p ort date. T he re p ort d ate ma y be m uc h 
la g ged i n ti me d ue t o re vie w a n d re p ort creati o n at t he pat h ol o g y la b.  
f. P at h ol o g y c ollecti o n date – a vaila ble f or all ti me p oi nts w he n sa m ples c ollecte d fr o m 
bi o ps y a n d se nt t o t he l oc al pat h ol o g y la b orat or y. It is t he c ollecti o n date at t he 
pa t h ol o g y la b orat or y.  


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 3  
g.  T u m or see n ( Y/ N) at e v er y visit – t his is t he Site I n vesti gat or’s o bser vati o n of 
w he t her t u m or is see n at t he c yst os c o p y.  
h.  Hist ol o gic gra d e a n d sta ge at e ver y visit – base d o n t he pat h ol o g y c o nfir mati o n u p o n 
revie w.  
T he al g orit h m s h o ul d be t he f oll o wi n g 
1.  Re c urre nce 
a. A n y re- o cc urre nce of eit her hist ol o gic gra de or sta ge or b ot h at a n y p ost b aseli ne visit 
s h o ul d be c o nsi dere d as r ec urre nce. T his ca n i ncl u de sta ge ( Ta, T 1, T 2, Cis) or gra d e 
( G1, G 2, G 3, l o w gra de or hi g h gra de).  
b.  T he baseli ne is t he D ate of T U R B D T at D a y 1 .  
c. Use  t he date of rec urre nce i n t he f oll o wi n g s e q ue nce  
d.  D ate  of cyst osc o py of a visit w he n t he t u m or is hist ol o gic ally c o nfir me d by p at h ol o gy.  
e. If t he d ate of cyst osc o py is n ot av ail a ble b ut hist ol o gic st a ge or gr a de is p ositive, use 
t he d ate of p at h ol o gy c ollecti o n f or t h at p atie nt.  
f. If t he d ate of p at h ol o gy c ollecti o n is n ot av ail a ble b ut hist ol o gic st a ge or gr a de is 
p ositive a n d T U R is perf or me d, use t he T U R d ate f or t h at p atie nt. T he re p ort d ate is 
very l ate a n d t his sce n ari o s h o ul d be very r are.  
g.  If a patie nt d o es n ot ha ve a rec urre n ce i n 2 years i e w he n 2 4 m o nt h c yst osc o p y f oll o w 
u p is c o m plete d (s h o ul d be t he cas e f or ~ 5 0 % of patie nts), t he patie nt s h o ul d be 
ce ns ore d wit h rec urre n ce is ‘ N o’ a n d t he date of t he last meas ure m e nt s h o ul d be as 
f oll o ws 
h.  D ate  of l ast cyst osc o py p erf or me d i n t h at p atie nt by 2 4 m o nt hs.  
i. If d ate of cyst osc o py is n ot av ail a ble, use t he d ate of p at h ol o gy c ollecti o n d ate.  
j. If a b ove t w o are n ot av ail a ble, ie, if a p atie nt d oes n ot h ave a ny f oll o w u p cyst osc o py, 
t he p atie nt s h o ul d be ce ns ore d at b aseli ne.  
k.  If a patie nt die d wit h o ut a n y rec urre n ce or pri or t o rec urre nce, t he patie nt w o ul d be 
ce ns ore d usi n g d ate of deat h. 
l. If a patie nt die d after 2 4 m o nt h f oll o w u p wit h o ut a n y rec urre n ce, t he date of 2 4 
m o nt h f oll o w u p will be c o nsi dere d as t he date wit h patie nt bei n g ce ns ore d.  
2.  P r o g ressi o n 
a. Disease pr o gressi o n s h o ul d be c o nsi dere d b y re vie wi n g o nl y o ne hist ol o gic Sta ge 
o nl y.  
b.  S e q ue nce of pr o gressi o n f or sta ge is Cis - > Ta - > T 1 - > T 2.  
c. P atie nt is c o nsi dere d pr o gresse d if sta ge pr o gressi o n is o bser ve d.   
d.  T he  date of pr o gressi o n uses t he sa me date al g orit h m as t he It e m ( 1) a b o ve f or 
rec urre nce.  
e. If a patie nt die d wit h o ut a n y rec urre n ce or pri or t o rec urre nce, t he patie nt w o ul d be 
c o nsi dere d pr o gresse d wit h date of deat h as t he dat e. 
f. If a patie nt die d after 2 4 m o nt h f oll o w u p wit h o ut a n y rec urre n ce, t he date of 2 4 
m o nt h f oll o w u p will be c o nsi dere d as t he date wit h patie nt bei n g ce ns ore d.  
T he effi cac y a nal ysis will be perf or m e d usi n g d ata fr o m t he l ocal pat h ol o g y la b orat or y.  


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 4  
7. 4  
Effic ac y Res ults 
7. 4. 1  E ffic ac y V ari a bles 
T he pri mar y effic ac y varia ble of t he st u d y is Ti me t o Rec urre nce , d oc u m e nte d b y a l ocal 
pat h ol o g y re vie w. T h e fi nal a nal ysis of T i me t o Rec urre nce will be c o n d ucte d o nce all 3 3 6 
rec urre nce e v e nts i n t he Pl ac e b o Tre at me nt Ar m  are accr ue d. Sec o n dar y efficac y varia bles i n 
t his st u d y are Rec urre nce R ates  at 1 2 a n d 2 4 m o nt hs, a n d T i me t o Pr o gressi o n, all d oc u me nte d 
b y l oc al pat h ol o g y re vie w. 
Da ta fr o m c yst os c o p y a n d pat h ol o g y re vie w will be a nal yz e d f or t h e d urati o n of ti me bet wee n 
visits, a n d t he n u m ber a n d perce nt of patie nts wit h missi n g or n ot e val ua ble visits. A “ missi n g 
visi t” is a misse d sc he d ule d c yst osc o p y. A “ n ot e v al ua ble visit” is a visit wit h a “l ost” or 
“i na de q uat e” bi o ps y s peci me n. 
T he f oll o wi n g a nal yses are i nte n de d t o e ns ure t hat misse d e val uati o ns are u nif or m o n b ot h ar ms 
i n a pair wise c o m p aris o ns a n d e x pl ore w het her differe n ces i n assess m e nt ti me i nter vals e xist, 
a n d if s o, w het her or n ot t hese differe nces ma y acc o u nt ( or partiall y acc o u nt) f or a n y o bser ve d 
i mpr o ve me nt i n Ti me t o Rec urre nce . Data will b e s u m marize d b y tr eat me nt ar ms: 
 P atie nts wit h o ne, t w o, t hree, … missi n g or “ n ot e val ua ble” f oll o w- u p visits 
 P r o d uct li mit esti mates of ti me fr o m ra n d o mizati o n t o t he date of first, sec o n d, t hir d, … 
e val ua ble visit 
F or t hese l ast set of se nsiti vit y a nal yses, w hic h e v al uate t he i m pact of assess me nt sc he d ules o n 
T i me t o Rec u rre nce, distri b uti o n of ti me t o t he n t h e val ua ble visit will be esti mate d usi n g t he 
Ka pla n- Mei er met h o d. Patie nts wit h n o n t h e val ua ble visit will be e x cl u de d. 
7. 4. 2  T i me t o Rec u rre nce 
Ti me t o Rec u rre nce  is t he ti me fr o m date of ra n d o mizati o n t o t he date of first d oc u me ntati o n of 
rec urre nt diseas e. T he d etaile d al g orit h m of Ti me t o Rec urre nce  is pr o vi de d i n S ecti o n 7. 3. 1 . 
T i me t o Rec u rre nce of patie nts wit h n o d oc u me nte d rec urre n ce w hile o n st u d y will be ce ns ore d 
at t he date of last e val ua ble visit (c yst osc o p y or T U R B T) o n-st u d y. Ti me t o Rec urre nce  of 
patie nts wit h n o e val ua bl e visit o n-st u d y will be ce ns ore d at r a n d o mizati o n. A n e val ua ble visit is 
a visit at w hic h t he res ults of pat h ol o g y re vie w are a vaila ble. 
T he pri mar y e n d p oi nt of Ti me t o Rec u rre nce  will be a nal yz e d usi n g t he T ar get ( T a, G 1 - G 2) 
P o p ul ati o n  as defi ne d a b o ve. 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 ys es will be 
pr o vi de d: 
 A na l ysis of Ti me t o Rec urre nce  i n T ar get ( T a, G 1- G 2) P o p ul ati o n w h o recei v e d 
o nl y o ne d os e of a p azi q u o ne 
 A na l ysis of Ti me t o Rec urre nce  i n T ar get ( T a, G 1- G 2) P o p ul ati o n  w h o recei v e d 
b ot h d os es of a pazi q u o ne 
 A na l ysis of Ti me t o Rec urre nce  i n t he Pe r- pr ot oc ol P o p ul ati o n  i n T ar get ( T a, G 1-
G 2) P o p ul ati o n  recei vi n g o ne d os e of a p azi q u o ne a n d t h ose recei vi n g b ot h d oses of 
a pazi q u o ne 
 If a patie nt u n d er g oes a c ha n ge i n treat me nt d uri n g t he f oll o w u p wit h o ut a rec urre nce, 
patie nt is c o nsi dere d t o h a ve a n e ve nt 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 5  
 If a patie nt dr o ps o ut pri or t o c o m pleti o n of f oll o w u p or rec urre n ce, p atie nt is 
c o nsi dere d t o ha v e a n e v e nt.  
T he  f oll o wi n g p atie nt dat a will be c o nsi dere d as pr ot oc ol de viati o ns a n d will be a d dresse d i n t he 
a nal ysis of Ti me t o Rec urre nce  usi n g t he Pe r- Pr ot oc ol P o p ul ati o n .  
 A na l ysis of Ti me t o Rec urre nce  wit h D a y 1  i nstillati o n t hat d o n ot occ ur bet wee n 3 1 
a n d 9 0 mi n utes of T U R B T 
 A n al ysis of Ti me t o Rec urre nce  i n patie nts w h os e f oll o w u p c yst osc o p y o cc urs 
o utsi de t he ± 1 0 da y wi n d o w 
F or t he a b o ve a n al ysis, f oll o wi n g data ha n dli n g r ules will be use d. 
 P atie nts w h o c ha n ge t hera p y pri or t o rec urre nce will be ce ns ore d at t he last assess me nt 
pri or t o c ha n ge i n t hera p y.  
 P atie nts wit h t w o or m ore missi n g assess me nts i m me diatel y pri or t o t he ne xt visit wit h 
a d oc u me nte d rec urre n ce will be ce ns ore d at t he last assess me nt wit h d oc u me ntati o n of 
n o rec urre nce.  
T he pri mar y a n al ysis will i ncl u de all patie nts i n t he T a, G 1- G 2 T ar get P o p ul ati o n  irres pecti ve 
of l ost pat h ol o g y or n o sa m ple.  
Dist ri 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- Meier pr o d uct-li mit 
met h o d. T he  me dia n ti mes t o rec urre n ce wit h t w o-si de d 9 5 % c o nfi d e nce i nter vals 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 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 h e o nl y c o variate a n d teste d usi n g a l o g-ra n k test at t he l e vel of si g nifica nce 
descri be d a b o ve. A d diti o nal e x pl orat or y a nal 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 % c o nfi de nce i nter val. T he m o d el will i ncl u de 
treat me nt effect, st u d y ce nter, pri mar y vs. rec urre nt disease as stratificati o n fact or i n a d diti o n t o 
a n y ot h er bas eli ne or de m o gra p hi cs fact ors.  
7. 4. 3  Re c urre nce R ates 
1- Ye ar an d  2 - Y e ar R ec urre nce R ates  will be esti mate d usi n g t he Ka pl a n- Meier pr o d u ct-li mit 
met h o d a l o n g wit h t w o-si de d 9 5 % c o nfi de n ce i nter vals a n d will be c o m pare d usi n g a t w o-si de d 
l o g-ra n k test eac h at 5 % l e vel of si g nifica n ce. Si nce visits d o n ot ofte n occ ur at t he s pecifi e d 
i nter vals, a c ut- off u p per li mit of 3 7 5 or 7 6 5 da ys fr o m ra n d o mizati o n will be use d f or t he 1 2 or 
2 4 m o nt h visits, res pecti vel y. 
F or t he mai n a n al ysis, t he Rec urre nce R ate  calc ulati o n i ncl u des patie nts w h o met rec urre n ce 
criteria as c o nfir me d b y pat h ol o g y at eac h visit. A n a d diti o nal a nal ysis will be pr o vi de d b y 
c o u nti n g patie nts w h o dr o p o ut pri or t o t he a b o ve ti me p oi nt as ha vi n g a rec urre n ce. T h e 
Rec urre nce R ates  will b e c u m ulati ve at eac h visit fr o m t he ti me of st u d y ra n d o mizati o n. 
7. 4. 4  T i me t o Pr o gressi o n 
Ti me t o Pr o gressi o n  ( or pr o gressi o n-free i nter val, P FI) is t he ti me fr o m ra n d o mizati o n t o t he 
first d oc u me ntati o n of pr o gressi o n as c o nfir m e d b y pat h ol o g y re vie w i n t he T ar get ( T a, G 1- G 2) 
P o p ul ati o n . Ti me t o Pr o gressi o n  of patie nts wit h n o d oc u me nte d pr o gressi o n o n-st u d y will be 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 6  
ce ns ore d at t he ti me of last e val ua ble visit o n-st u d y. Ti me t o Pr o gressi o n  of patie nts wit h n o 
eval ua ble visit o n-st u d y will be ce ns ore d at ra n d o mizati o n. 
Distri b uti o n of Ti me t o Pr o g ressi o n  will be esti mate d usi n g t he Ka pla n- Meier met h o d. T he 
me dia n ti mes t o pr o gressi o n wit h t w o-si de d 9 5 % c o nfi de nce i nter vals will be esti mate d, t o get her 
wit h t he esti mates at 6, 1 2, 1 8 a n d 2 4 m o nt hs. A l o g-ra n k test will be use d as t he pri mar y 
a nal ysis f or treat me nt c o m paris o n. A C o x pr o p orti o nal hazar ds m o del will be use d t o esti mate 
t he hazar d rati o, a n d its 9 5 % c o nfi de n ce i nter val. 
7. 4. 5  S u b gr o u p A n al yses 
Ti me t o Rec u rre nce  a n d t he 1- Ye ar  a n d 2 - Ye ar Rec urre nce R ates  will als o be a nal yze d b y t h e 
stratificati o n fact ors a n d ot her rele v a nt pretr eat me nt c haracteristics i ncl u di n g a ge, ge n d er, 
pri ma r y or rec urre nt disease, t u m or sta ge a n d gra d e at e ntr y, a n d ot h er i m p orta nt fact ors li ke 
w hite li g ht T U R B T a n d bl ue li g ht T U R B T, a n d t he res ulti n g h azar d or o d ds rati os, wit h 
c orres p o n di n g 9 5 % c o nfi de nce i nter vals, will be s u m marize d b y treat me nt ar ms. 
8  
S A F E T Y E V A L U A TI O N 
Patie nts will be e val uate d f or safet y if t h e y recei v e a n y i nstillati o n of st u d y treat me nt ( S afet y 
P o p ul ati o n ), a n d will be classifie d acc or di n g t o t h e treat me nt recei v e d. 
8. 1  
E xte nt of E x p os ure 
N u m ber of i nstillati o ns per patie nt, i nstillati o n i nterr u pti o ns a n d dela ys, wit h dra wals, a n d reas o ns 
f or e x p os ure m o dificati o ns will be s u m marize d b y treat me nt ar ms. 
8. 2  
C o nc o mit a nt Me dic ati o ns 
C o nc o mita nt me dicati o ns will be classifie d b y W H O Dr u g Dicti o nar y, a n d s u m marize d b y t he 
W H O preferre d n a me a n d A nat o mical T hera pe uti c C he mical ( A T C) classificati o n a n d b y 
treat me nt ar ms. 
8. 3  
A d ver se 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 Med D R A preferre d t er m, a n d s u m marize d b y w orst gra de s e verit y per patie nt b y tr eat me nt 
ar ms. Si milar s u m maries will be ge n erat e d f or tr eat me nt-relate d a d v erse e v e nts, w hic h are 
ad verse e ve nts de e me d t o be p ossi bl y, pr o ba bl y, or defi nitel y relat e d t o st u d y treat me nt. 
Treat me nt e mer ge nt a d v erse e ve nts are t h ose a d verse e ve nts t hat occ ur or w orse n o n or after t h e 
i nitial p ost- T U R B T i nstillati o n of a pazi q u o ne, t hr o u g h 3 5 da ys after t he last i nstillati o n of 
apazi q u o ne, a n d/ or treat me nt-relate d a d verse e ve nts, re gar dless of t h e o ns et date. After 3 5 da ys 
an d t hr o u g h 2 4 m o nt hs, o nl y S A Es a n d A Es ≥Gra de 3 will be rec or de d. 
8. 4  
De at hs, Ot her Seri o us A d verse E ve nts, Ot her Si g nific a nt A d verse E ve nts 
Seri o us a d verse e ve nts are t h ose e ve nts t hat r es ult i n deat h, are life-t hreate ni n g, re q uire or 
pr ol o n g i n patie nt h os pitalizati o n, res ult i n persiste nt or si g nifica nt disa bilit y/i nca p acit y, or ca use 
c o n ge nital a n o mal y/ birt h defect. 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 7  
8. 4. 1  De at hs 
All 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 ms. 
8. 4. 2  Ot h er Seri o us A d verse E ve nts 
Ot her seri o us a d v erse e v e nts will be ta b ulate d a n d s u m marize d b y Me d D R A preferre d ter m a n d 
treat me nt ar m. Si milar s u m maries will be ge nerate d f or treat me nt-relat e d seri o us a d verse e ve nts. 
8. 4. 3  Ot h er Si g nific a nt A d verse E ve nts 
All ot her e ve nts lea d i n g t o disc o nti n uati o n of st u d y t hera p y or a n y ot her pre mat ure i nterr u pti o n 
will be ta b ulate d a n d s u m marize d b y treat me nt ar m. 
8. 5  
Cli n ic al L a b or at or y E v al u ati o ns 
C li nical la b orat or y sa m ples are c ollecte d pretreat me nt a n d t hr o u g h o ut st u d y. Bl o o d sa m ples are 
t o be a nal yz e d at ce ntral la b orat ories. Cli nicall y si g nifica nt la b orat or y a b n or malities are t o be 
re p orte d as a d verse e v e nts. 
W here a p plica ble, a ll 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. Res ults will be s u m mariz e d b y w orst gra de p er patie nt a n d treat me nt ar ms. S hifts i n 
la b orat or y C T C A E gra d es fr o m baseli ne gra de t o t he w orst gra d e t o xicit y o n-st u d y will be 
su m marize d. 
8. 6  
Vit al S i g ns 
Data o n Vital si g ns at eac h ti me p oi nt a n d c ha n ge fr o m baseli ne will be s u m marize d b y treat me nt 
ar m.  
 


S pectr u m P h ar m ace utic als, I nc. 
St atistic al A n al ysis Pl a n 
A p azi q u o ne 
St u d y S PI- E O Q- 1 3 -3 0 5  
C o nfi de ntial 
 
1 8  
9  
R E F E R E N C E S 
1.   
H oc h ber g Y. A S har per B o nferr o ni Pr oce d ure f or M ulti ple Tests of Si g nifica nce. 
Bi o metri ka. 1 9 8 8; 7 5( 4): 8 0 0- 2.