A Multicenter, Multi-Arm, Randomized, Multi-Dose, Placebo-Controlled, Double-Blind, Phase 3 Study of Intravesical Apaziquone (EOquin®) as a Surgical Adjuvant in the Immediate Postoperative Period in Patients Undergoing Transurethral Resection for Non- Muscle Invasive Bladder Cancer
Phase: PHASE3
Conditions: Bladder Cancer
Sponsor: Spectrum Pharmaceuticals, Inc

 
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 
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1 1.  
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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  
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