Clinical trial NCT03224182
Conditions: Bladder Cancer
Sponsor: Spectrum Pharmaceuticals, Inc
Start date: 2017-08-04; Completion date: 2019-09-26
Enrollment: 118 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multicenter, two-arm, double-blind, placebo-controlled study of Qapzola in participants with low- to intermediate-risk non-muscle invasive bladder cancer (NMIBC), assessed according to the 2016 American Urology Association (AUA) Guidelines. Specifically, only participants with the following low-to intermediate-risk tumor characteristics were included in the study.

2016 American Urological Association Stratification for Non-Muscle Invasive Bladder Cancer:

Low Risk

* Low grade solitary Ta ≤3 centimeters (cm)
* Papillary urothelial neoplasm of low malignant potential (PUNLMP)

Intermediate Risk

* Recurrence within 1 year, low-grade Ta
* Solitary low-grade Ta \>3 cm
* Low-grade Ta, multifocal
* High-grade Ta, ≤3 cm (solitary tumor)

Detailed description:
In addition to other Screening assessments, participants underwent an assessment of urothelial carcinoma of the bladder via cystoscopy for clinically apparent tumor of Ta histology, including PUNLMP, although participants with strongly suspected PUNLMP at Screening or transurethral resection of bladder tumor (TURBT) were not to be enrolled in the study. The qualifying cystoscopy could be performed up to 45 days prior to signing the informed consent.

Eligible participants were randomized in a 2:1 ratio to either:

* Arm 1: One dose of 8 milligrams (mg) Qapzola
* Arm 2: One dose of placebo

Once approved for randomization, participants underwent TURBT on Day 1 and the study drug instillation occurred at 60 ± 30 minutes post-TURBT and was retained for 60 minutes (±5 minutes) in the bladder. All histology specimens were reviewed by a local pathology laboratory and all clinical treatment decisions were based on the local pathology review. Participant target disease was confirmed and efficacy analyses were performed based on the pathology results. The target study population was low- to intermediate-risk participants who had Ta histology, including PUNLMP, as confirmed by a pathology laboratory. Participants with strongly suspected PUNLMP at Screening or TURBT were not to be enrolled in the study. Participants whose tumor histology did not meet the criteria for eligibility, as confirmed by pathology (Non-Target Population), were to be followed up for safety on Day 35 (±5 days) (Safety Follow-up Visit) and were discontinued from the study. If the pathology results were delayed beyond 35 days, the Safety Follow-up Visit was to be conducted when the results were available for these participants.

Participants who had pathology-confirmed target histology did not receive additional medications to treat NMIBC during the follow-up while on the study. All target disease participants were to be followed until either a confirmed tumor recurrence, additional bladder cancer treatments, or until the End-of-Study, whichever occurred first.

The primary analysis was conducted once the required number of recurrence events were observed. A recurrence was defined as any pathologically confirmed disease of ≥Ta histology or carcinoma in situ (CIS) post-treatment. The number of events needed to perform the final primary endpoint analysis was estimated based on the recurrence rate at 24 months from previous studies. The follow-up schedule is below:

* Cystoscopic examination (all participants) and urine cytology (only participants with a Baseline diagnosis of intermediate-risk NMIBC) every 3 months (±30 days) (calculated from date of TURBT) for 2 years for tumor recurrence and progression and then every 6 months (±60 days) until either a confirmed tumor recurrence or the End-of-Study, whichever occurred first.
* If at any time during the study there was a histologically confirmed tumor recurrence, the participants discontinued from the study at that time and could then be treated per the Investigator's standard of care.

The study was to end (End-of-Study) when the required number of events for the primary endpoint analysis was accrued.

Duration of Study: The duration of the study for each participant was as follows:

* Screening Period: up to 30 days
* Treatment: Day 1
* Safety Follow-up: Day 35 (±5 days) after treatment
* Follow-up Period: No follow-up in non-Target Population. Until either a confirmed tumor recurrence or the End-of-Study, whichever occurred first in the Target Population.

Arms: arm 1: Participants were randomized to receive a single dose of Qapzola 8 mg by intravesical administration into the bladder at 60 ± 30 minutes post transurethral resection of bladder tumor (TURBT) on Day 1 via an indwelling 100% Silicone Foley catheter and retained in the bladder for 60 ± 5 minutes. arm 2: Participants were randomized to receive a single dose of Qapzole-matching placebo by intravesical administration into the bladder at 60 ± 30 minutes post TURBT on Day 1 via an indwelling 100% Silicone Foley catheter and retained in the bladder for 60 ± 5 minutes.
Interventions: intervention 1: Qapzola intervention 2: Placebo
Intervention descriptions: intervention 1: Qapzola administered by the intravesical route. intervention 2: Qapzole-matching placebo administered by the intravesical route.

Protocol documents:
Prot_000.pdf: 
 
Offici al Titl e:  
 
A R a n d o miz e d, M ultic e nt er, T w o -Ar m, Si n gl e -D os e, D o u bl e - Bli n d, Pl ac e b o -
C O Ntr oll e d P h as e 3 St u d y of I ntr a v esic al Q a pz ol a ™ ( A p azi q u o n e) as a 
C h e m ot h er a p y A dj u v a nt t o Tr a ns Ur Et hr al  R es ecti o n of Bl a d d er T u m ors i n 
P ati e nts wit h L o w - t o I nt er m e di at e-Ris k N o n -M uscl e I n v asi v e Bl a d d er 
C a nc er  ( C O N Q U E R) 
 
N C T N u m b er:  
N C T 0 3 2 2 4 1 8 2  
 
D oc u m e nt  D at e : 
 
C li nic al St u dy Pr ot oc ol Ori gi n al : 2 2  D ec e m b er  2 0 1 6 
 
 
 
 
 
 
 
 


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


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


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




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


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


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


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


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




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


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


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


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






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


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








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


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


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


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




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


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


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


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


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


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


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


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


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


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


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


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


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


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




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


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


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


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


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


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


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


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


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


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


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


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



SAP_001.pdf: 
 
Official Title: 
 
A Randomized, Multicenter, Two-Arm, Single-Dose, Double- Blind, Placebo-
CONtrolled Phase 3 Study of Intravesical Qapzola™ (Apaziquone) as a 
Chemotherapy Adjuvant to TransUrEthral Resection of Bladder Tumors in 
Patients with Low- to Intermediate-Risk Non-Muscle Invasive Bladder 
Cancer (CONQUER) 
 
NCT Number: 
NCT03224182 
 
Document Date: 
 
SAP Version 1.0: 30 May 2019 
 
 
 
 
 
 
 
 




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Spectrum Pharmaceuticals, Inc. 
Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
Summary of Changes from protocol 
 
The SAP is to accommodate the early termination of the study due to business reason. Important 
changes are summarized below. 
 
1. All efficacy objectives are removed. 
2. All efficacy endpoints are removed, including all corresponding analysis. 
3. The following Analysis Populations are removed. 
• Target Population 
• Non-Target Population 
• Per-Protocol (PP) Population 
4. Interim Analysis is removed. 
5. Sensitivity analysis and subgroup analysis are removed. 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................. 3 
1 
INTRODUCTION .................................................................................................................. 4 
2 
STUDY OBJECTIVES .......................................................................................................... 4 
2.1 
Primary Objective ........................................................................................................ 4 
3 
INVESTIGATIONAL PLAN ................................................................................................ 4 
3.1 
Study Population .......................................................................................................... 4 
3.2 
Study Design ................................................................................................................. 4 
3.3 
Study Duration ............................................................................................................. 5 
3.4 
Study Endpoints ........................................................................................................... 5 
3.4.1 
Efficacy Endpoints ............................................................................................... 5 
3.4.2 
Safety Endpoints .................................................................................................. 5 
4 
STATISTICAL CONSIDERATIONS .................................................................................. 5 
4.1 
General Analysis Considerations................................................................................ 5 
4.2 
Sample Size ................................................................................................................... 5 
4.3 
Randomization ............................................................................................................. 6 
4.4 
Baseline Measurements ............................................................................................... 6 
4.5 
Handling of Missing Data ............................................................................................ 6 
4.6 
Analysis Population ..................................................................................................... 7 
4.7 
Final Analysis ............................................................................................................... 7 
5 
STUDY PATIENTS ................................................................................................................ 7 
5.1 
Disposition of Patients ................................................................................................. 7 
5.2 
Pretreatment Characteristics ...................................................................................... 7 
6 
EFFICACY EVALUATION .................................................................................................. 7 
7 
SAFETY EVALUATION ...................................................................................................... 7 
7.1 
Extent of Exposure ....................................................................................................... 7 
7.2 
Concomitant Medications ........................................................................................... 7 
7.3 
Adverse Events ............................................................................................................. 7 
7.3.1 
Treatment Emergent Adverse Events................................................................ 7 
7.3.2 
Treatment-Related Adverse Events ................................................................... 8 
7.3.3 
Serious Adverse Events ....................................................................................... 8 
7.3.4 
Other Important Adverse Events ....................................................................... 8 
7.4 
Clinical Laboratory Evaluations ................................................................................ 8 
8 
REFERENCES ....................................................................................................................... 8 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) includes information on statistical design of this clinical 
study, definitions of efficacy and safety endpoints, and plans for the analysis of primary and 
secondary endpoints of the study. The statistical methods and analyses described here are based 
on those presented in the clinical study protocol, and supersede definitions and procedures 
described in any other past and/or present documents regarding the statistical analyses of the 
efficacy and safety endpoints of study SPI-EOQ-13-306. 
 
2 
STUDY OBJECTIVES 
2.1 Primary Objective 
• To evaluate the safety in patients with low- to intermediate-risk NMIBC who receive 
either 8 mg Qapzola or placebo post- TransUrEthral Resection of Bladder Tumors 
(TURBT). 
 
3 
INVESTIGATIONAL PLAN 
3.1 Study Population 
Patients with low- to intermediate-risk non-muscle invasive bladder cancer, who satisfy all 
protocol-defined enrollment criteria, are eligible to enroll in this randomized study. 
 
3.2 Study Design 
This is a randomized, multicenter, two-arm, double-blind, placebo-controlled study of Qapzola 
in patients with low- to intermediate-risk NMIBC. 
At Screening, patients will undergo an assessment of urothelial carcinoma of the bladder via 
cystoscopy for clinically apparent tumor of Ta histology, including PUNLMP. 
On Day 1, eligible patients will be randomized to one of the two treatment arms in a 2:1 ratio: 
• Arm 1- One Dose of 8 mg Qapzola 
• Arm 2- One Dose of Placebo 
Once randomized, patients will undergo TURBT on Day 1 and the study drug instillation will 
occur at 60 ± 30 minutes post-TURBT and will be retained for 60 minutes (±5 minutes) in the 
bladder. All histology specimens will be reviewed by a local pathology laboratory and all clinical 
treatment decisions will be based on the local pathology review. The target study population is 
low- to intermediate-risk patients who have Ta histology, including PUNLMP, as confirmed by a 
pathology laboratory. Patients with strongly suspected PUNLMP at Screening or TURBT should 
not be enrolled in the study. Patients whose tumor histology does not meet the criteria for 
eligibility, as confirmed by pathology (Non-Target Population), will be followed up for safety 
on Day 35 (±5 days) (Safety Follow-up Visit) and will then be discontinued from the study. If 
the pathology results are delayed beyond 35 days, the Safety Follow-up Visit will be conducted 
when the results are available for these patients. 
Patients who have pathology confirmed target histology will not receive additional treatment for 
NMIBC during the follow-up prior to recurrence. All patients will be followed until either a 
confirmed tumor recurrence or the End-of-Study, whichever occurs first. 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
3.3 Study Duration 
The total duration of the study for each patient will be approximately 5 years including: 
• Screening Period: up to 30-days 
• Treatment: Day 1 
• Safety Follow-up: Day 35 (±5 days) (non-Target Population) or Month 3 Follow-up 
Visit (Target Population) 
• Follow-up Period: No follow-up in non-Target Population. Until either a confirmed 
tumor recurrence or the End-of-Study, whichever occurs first in the Target Population. 
The study was terminated early due to business reason and no patient was followed more than 24 
months. 
 
3.4 Study Endpoints 
3.4.1 Efficacy Endpoints 
The study was terminated early due to business reason and analysis for efficacy endpoints will 
not be performed. 
 
3.4.2 Safety Endpoints 
• All TEAEs 
• Treatment related adverse events 
• Serious Adverse Events (SAEs) 
• TEAEs leading to drug discontinuation 
• Routine laboratory test parameters (hematology, chemistry) 
• Deaths 
4 
STATISTICAL CONSIDERATIONS 
4.1 General Analysis Considerations 
The statistical analyses will be reported using summary tables, figures, and data listings. All 
analyses and tabulations will be performed using SAS® Version 9.4 or higher. All tables, 
listings, and figures will be validated and reviewed before being finalized. Tables will be 
reviewed for accuracy, consistency with this plan, consistency within tables, and consistency 
with corresponding output. 
For the continuous variables, number of non-missing values and mean, standard deviation, 
median, minimum, and maximum will be tabulated by treatment arm. For the categorical 
variables, the counts and percent for each possible value will be tabulated by treatment arm. 
 
4.2 Sample Size 
The sample size calculation assumes a hazard ratio (HR) of 0.65 based on the results from 
previous Phase 3 studies (SPI-611 and SPI-612) of Qapzola and placebo comparisons overall 
and in the drug instillation time window 31-90 minutes post-TURBT. The enrolled patients will 
be randomized in a 2:1 ratio to either Qapzola or placebo. 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
Approximately 500 patients will be enrolled and treated in this study. Accrual time is estimated 
as 24 months and follow-up time as approximately 24 months. For the sample size calculation, a 
hazard ratio (HR) of 0.65 is assumed for the improvement in Time to Recurrence in favor of 
Qapzola as compared to the placebo with a hazard rate of 0.3 in placebo arm. In a 2:1 
randomization of Qapzola and placebo, sample sizes of 284 in APZ and 141 in PBO Target 
disease patients (total of 425) will provide 85% power. This sample size is estimated to provide a 
total of 208 recurrence events during the follow-up duration of at least 24 months. 
The study was terminated early due to business reason and patient recruitment was incomplete. 
 
4.3 Randomization 
The randomization plan will use a permuted block design and will not be stratified. Study drug 
kits will contain either vials of Qapzola or placebo. Patients will be randomized within a center. 
Patient numbers will be assigned sequentially at each site. 
Patients who meet all eligibility criteria may be considered for randomization. Eligibility of all 
patients will be reviewed and approved for randomization by the Sponsor’s Medical Monitor, or 
designee. Patients approved for randomization will be randomized 2:1 to receive either one 
instillation of 8 mg Qapzola (Day 1) or one dose of placebo. 
 
4.4 Baseline Measurements 
Baseline measurement of any variable for each patient will be the last available value of the 
variable on or before the date of Visit 1, Day 1, which is the day on which the patient undergoes 
TURBT and first study drug instillation. 
 
4.5 Handling of Missing Data 
Except for partial dates, missing data will not be imputed. That is, the analyses will be performed 
considering all observed data. 
For the date of historical events prior to the study, if the month and day are missing, the date will 
be imputed as July 1. If the day is missing, it would be imputed as the 15th of the month. 
For start date of adverse events and concomitant medications, if the month is missing and the 
year is the same as the year of randomization, it is assumed that the event is treatment-emergent, 
and that the medication is taken during the study, unless the stop date occurs prior to the first 
dose date. In such cases, the start date is imputed as the date of first dose of study drug. 
If the year is missing, no imputation will be done for the year, and the entire date variable will be 
set to missing, and the AE is assumed to be treatment emergent, and concomitant medication is 
assumed to be started during the study. 
The imputed date value will only be used for the calculation of derived variables. The originally 
collected date value will be presented in the data listings. 
For the dates of events which occurred during the study, a missing day is set to the 15th of the 
month. No imputation will be performed if month or year is missing, however missing values 
will be queried. 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
4.6 Analysis Population 
• Safety Population: including all patients who have had a TURBT and have received 
treatment of study drug. The patients in safety population will be classified according to 
the actual treatment received, regardless of random assignment. 
 
4.7 Final Analysis 
The study was terminated early due to business reason and the final analysis will be performed 
for safety endpoints only. 
 
5 
STUDY PATIENTS 
 
5.1 Disposition of Patients 
Patients in defined populations as shown in Section 4.6 and reasons for discontinuation will be 
summarized by randomized treatment arms. 
 
5.2 Pretreatment Characteristics 
Demographics, including gender, age, race, and smoking status will be summarized by actual 
treatment arms for patients in Safety Population. 
 
6 
EFFICACY EVALUATION 
The study was terminated early due to business reason and analysis for efficacy endpoints will 
not be performed. 
 
7 
SAFETY EVALUATION 
Safety endpoints will be evaluated for Safety Population and patients will be classified 
according to actual treatment received. 
 
7.1 Extent of Exposure 
Summary table and listing will be provided for instillation time from TURBT, volume of 
instillation, and duration of retention. 
 
7.2 Concomitant Medications 
Concomitant medications will be classified by WHO Drug Dictionary and be reported in listing. 
 
7.3 Adverse Events 
An overall summary table of treatment emergent adverse events (TEAE) will be provided. The 
summary will include any TEAE, TEAE by severity, SAE, TEAE and SAE leading to study drug 
discontinuation, any treatment-related AE, treatment-related AE by severity, treatment-related 
SAE, and treatment-related AE leading to study drug discontinuation. 
 
7.3.1 Treatment Emergent Adverse Events 
A TEAE is any AE that occurs from the first dose of study treatment until 35 days after the last 
dose of study drug administration. TEAEs will be graded according to National Cancer Institute 


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Statistical Analysis Plan 
Apaziquone 
Study SPI-EOQ-13-306 
 
 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, and grouped by 
the MedDRA preferred term, and summarized by worst grade severity per patient by treatment 
arms. 
The incidences of treatment emergent AEs will be presented by MedDRA SOC and PT with any 
grade and with Grade 3 or 4. Patients who experience more than one type of AE will be counted 
under each of the corresponding PT. Patients who experience different episodes of the same AE 
will be counted only once under the corresponding PT. Similarly, for determination of MedDRA 
SOC incidences, patients who experience multiple AEs under the same SOC will be counted 
only once for that SOC. Listing of all TEAEs will also be provided. 
 
7.3.2 Treatment-Related Adverse Events 
Assessment of relatedness to study drug for all AEs will be classified by investigators and reported. 
“Definitely related”, “probably related” and “possibly related” AEs will be considered as treatment 
related. An AE will be assigned as treatment-related if the relationship to study drug is missing. 
The incidences of treatment-related AEs will be presented by MedDRA SOC and PT with any 
grade and with Grade 3 or 4. 
 
7.3.3 Serious Adverse Events 
Serious adverse events are those events that result in death, are life-threatening, require or 
prolong inpatient hospitalization, result in persistent or significant disability/incapacity, or cause 
congenital anomaly/birth defect. 
All SAEs will be provided in listing and the incidence will be summarized in the overall 
summary of TEAE table. 
 
7.3.4 Other Important Adverse Events 
TEAEs leading to death and study drug discontinuation will be presented in separate listings and 
the incidence will be summarized in the overall summary of TEAE table. 
 
7.4 Clinical Laboratory Evaluations 
Clinical laboratory samples are collected pretreatment and throughout study. Where applicable, 
all laboratory results will be classified according to the NCI CTCAE version 4.03. Results will 
be provided in listing. 
 
8 REFERENCES 
None.