CYCLONE 3: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Abemaciclib in Combination With Abiraterone Plus Prednisone in Men With High-Risk Metastatic Hormone-Sensitive Prostate Cancer
Phase: PHASE3
Conditions: Prostatic Neoplasms, Neoplasm Metastasis, Urogenital Neoplasms, Physiological Effects of Drugs, Antineoplastic Agents, Antineoplastic Agents, Hormonal, Androgens, Hormones, Hormones, Hormone Substitutes, and Hormone Antagonists, Abiraterone Acetate, Steroid Synthesis Inhibitors, Cytochrome P-450, Enzyme Inhibitors, Prednisone, Prednisolone, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6
Sponsor: Eli Lilly and Company

Pr ot oc ol I 3 Y- M C-J P E G (e)
C Y C L O N E 3: A P hase 3, Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d St u d y of A be macicli b 
i n C o m bi nati o n Wit h A birater o ne Pl us Pre d nis o ne i n Me n Wit h Hi g h- Ris k Metastatic 
H or m o ne- Se nsiti ve Pr ostate Ca ncer
N C T 0 5 2 8 8 1 6 6
A p pr o val Date: 0 6-J U N- 2 0 2 4 

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1  
Title P a ge  
C o nfi d e nti al I nf or m ati o n  
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d i s i nt e n d e d f or t h e u s e of cli ni c al i n v e sti g at or s. It i s t h e 
pr o p ert y of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s a n d s h o ul d n ot b e c o pi e d b y or di stri b ut e d t o p er s o n s n ot i n v ol v e d i n 
t h e cli ni c al i n v e sti g ati o n of a b e m a ci cli b ( L Y 2 8 3 5 2 1 9) , u nl e s s s u c h p er s o n s ar e b o u n d b y a c o nfi d e nti alit y agr e e m e nt wit h 
Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.  
N ot e t o R e g ul at or y A ut h oriti e s:  T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a a n d/ or c o m m er ci all y c o nfi d e nti al 
i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or 
t o a n y p u bli c r el e a s e. I n t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) E x e m pti o n 4 
a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n a p pr o v al of Eli Lill y a n d C o m p a n y or it s 
s u b si di ari e s . 
Pr ot oc ol Title:  
C Y C L O N E 3: A P hase 3, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y of A be macicli b 
i n C o m bi nati o n wit h A birater o n e pl us Pre d nis o ne i n Me n wit h Hi g h-Ris k Metastatic H or m o ne -
Se nsiti ve Pr ostate Ca ncer  
Pr ot oc o l N u m ber: I 3 Y-M C -J P E G 
A me n d me nt N u m ber:  e 
C o m p o u n d : A be macicli b ( L Y 2 8 3 5 2 1 9)  
Brief Title: 
C Y C L O N E 3: A St u d y of A be maci cli b wit h A birater o ne i n Me n wit h Hi g h -Ris k Metastatic 
H or m o ne -Se nsiti ve Pr ostate Ca ncer  
St u d y P h ase: P hase  3  
Acr o n y m : C Y C L O N E  3  
S p o ns or N a me: Eli Lill y a n d C o m pa n y  
Le g al Re gistere d A d dress: Eli Lill y a n d C o m pa n y, I n dia na p olis, I n dia na, U S A 4 6 2 8 5  
Re g ul at or y A ge nc y I de ntifier N u m ber(s)  
I N D: 1 3 9 6 9 4  
E U trial n u m ber:  2 0 2 2 -5 0 0 4 6 1 -2 8 -0 6  
D oc u me nt I D:  V V -C LI N -1 1 7 5 9 2  
A p pr o v al D ate:  Pr ot oc ol A me n d me nt (e) Electr o nicall y  Si g ne d a n d  A p pr o ve d  b y Lill y  o n  date 
pr o vi de d bel o w.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
2  
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y . 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
3  
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges T a ble   
D O C U M E N T HI S T O R Y  
D oc u m e nt  
D ate  
A m e n d m e nt ( d)  
1 8 -J ul -2 0 2 3  
A m e n d m e nt ( c)  
2 0 -O ct -2 0 2 2  
A m e n d m e nt ( b)  
0 5 -A u g -2 0 2 2  
A m e n d m e nt ( a)  
2 5 -M ar -2 0 2 2  
Ori gi n al Pr ot o c ol  
0 1 -F e b -2 0 2 2  
A me n d me nt [e]  
T his a me n d me nt is c o nsi dere d t o be n o ns u bsta ntial.  
O ver all rati o n ale f or t h e a me n d me nt:  
T he p ur p ose of t his a me n d me nt is t o clarif y t he dr u g distri b uti o n ti mi n g d uri n g t he c o nti n ue d -
access peri o d of t his st u d y.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3. 2 C o nti n ue d Access 
S o A  
A d de d f o ot n ote clarif yi n g h o w ofte n 
i n vesti gati o nal pr o d ucts ma y be dis pe nse d 
d uri n g c o nti n ue d access peri o d.  
Clarificati o n  
A d mi nister a be maci cli b –  A d diti o n t o 
I nstr u cti o ns t o sa y “A be macicli b  ca n be 
a d mi nistere d e ver y 2 8 ± 3 , 5 6 ± 3 , or 8 4 ± 3  
da ys at i n vesti gat or discreti o n.   U p t o 3 
c ycles of a be macicli b d osa ge ma y be 
dis pe nse d at a ti me. ” 
Clarificati o n  
A d mi nister a birater o n e –  A d diti o n t o 
I nstr u cti o ns t o sa y “A birater o ne s u p plie d b y 
s p o nsor ca n be a d mi nistere d e ver y 2 8 ± 3 , 
5 6  ± 3 , or 8 4 ± 3  da ys at i n vesti gat or 
discreti o n.  I n cas es of site s o urce d 
a birater o n e, f re q ue n c y of dis pe nsi n g is left t o 
t he j u d g me nt of t he i n vesti gat or base d o n 
sta n dar d of care” 
Clarificati o n  
A d mi nister pre d nis o ne –  A d diti o n t o 
I nstr u cti o ns t o sa y “Pre d nis o ne  s u p plie d b y 
s p o ns or ca n be a d mi nistere d e ver y 2 8 ± 3 , 5 6 
± 3 , or 8 4 ± 3  da ys at i n vesti gat or discreti o n.  
I n cases of site s o urce d pre d nis o ne, 
fre q ue n c y of dis pe nsi n g is left t o t he 
j u d g me nt of t he i n vesti gat or base d o n 
sta n dar d of care.” 
Clarificati o n  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
4  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 6 C o nti n ue d Access t o 
t he St u d y I nter v e nti o n 
after t he E n d of t he St u d y  
A d de d 6 b ullets defi ni n g w he n partici pa nts 
will be disc o nti n ue d fr o m st u d y i nter ve nti o n.  
Re m o ve d 1 st se nte nce i n 4t h para gra p h 
re gar di n g e n di n g of parti ci pa nt’s c o nti n ue d-
access peri o d.  
Clarificati o n  
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
5  
 
T a ble of C o nte nts  
  
1.  
Pr ot oc ol S u m m ar y  ..........................................................................................................9  
1. 1.  
S y n o psis  ............................................................................................................................9  
1. 2.  
Sc he ma  ............................................................................................................................1 3  
1. 3.  
Sc he d ule of A cti vities ( S o A)  ..........................................................................................1 4  
1. 3. 1.  
Sa m pli n g Sc he d ule f or Bi o mar kers, Ge netics a n d 
P har mac o ki netics  ............................................................................................................2 1  
1. 3. 2.  
C o nti n ue d Access S o A  ...................................................................................................2 4  
2.  
I ntr o d ucti o n ...................................................................................................................2 5  
2. 1.  
St u d y Rati o nale  ...............................................................................................................2 5  
2. 2.  
Bac k gr o u n d  .....................................................................................................................2 6  
2. 2. 1.  
Metastatic H or m o ne -Se nsiti ve Pr ostate Ca ncer ..............................................................2 6  
2. 2. 2.  
A be macicli b  ....................................................................................................................2 8  
2. 2. 3.  
A birater o n e  .....................................................................................................................3 0  
2. 3.  
Be nefit/ Ris k Assess me nt  ................................................................................................3 0  
2. 3. 1.  
Ris k Assess me nt  .............................................................................................................3 0  
2. 3. 2.  
Be nefit Assess me nt  .........................................................................................................3 1  
2. 3. 3.  
O verall Be nefit Ris k C o ncl usi o n  ....................................................................................3 1  
3.  
O bjecti ves, E n d p oi nts, a n d Esti m a n ds  .......................................................................3 2  
4.  
St u d y Desi g n  ..................................................................................................................3 5  
4. 1.  
O verall  Desi g n  ................................................................................................................3 5  
4. 2.  
Scie ntific Rati o nale f or St u d y Desi g n  ............................................................................3 6  
4. 3.  
J ustificati o n f or D ose ......................................................................................................3 7  
4. 4.  
E n d of St u d y Defi niti o n  ..................................................................................................3 8  
5.  
St u d y P o p ul ati o n  ...........................................................................................................3 9  
5. 1.  
I n cl usi o n Criteria ............................................................................................................3 9  
5. 2.  
E xcl usi o n Criteria  ...........................................................................................................4 0  
5. 3.  
Lifest yle C o nsi derati o ns  .................................................................................................4 2  
5. 4.  
Scree n Fail ures  ................................................................................................................4 2  
5. 5.  
Criteria f or T e m p oraril y Dela yi n g 
E nr oll me nt/ Ra n d o mizati o n/ A d mi nistrati o n of St u d y I nter ve nti o n 
of a Partici pa nt  ................................................................................................................4 3  
6.  
St u d y I nter ve nti o n(s) a n d C o nc o mit a nt T her a p y  .....................................................4 4  
6. 1.  
St u d y I nter v e nti o n(s) A d mi nistere d ................................................................................4 4  
6. 1. 1.  
Pac ka gi n g a n d La b eli n g  ..................................................................................................4 5  
6. 1. 2.  
Bac k gr o u n d T hera p y or Sta n dar d -of -C are  ......................................................................4 5  
6. 2.  
Pre parati o n, H a n dli n g, St ora ge, a n d Acc o u nta bilit y  ......................................................4 5  
6. 2. 1.  
Selecti o n a n d  Ti mi n g of D oses  .......................................................................................4 6  
6. 3.  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  ............................................4 6  
6. 3. 1.  
Bli n di n g ...........................................................................................................................4 6  
6. 3. 2.  
U n bli n di n g at I nteri m A nal yses  ......................................................................................4 7  
6. 3. 3.  
E mer ge nc y U n bli n di n g  ...................................................................................................4 7  
6. 3. 4.  
I n a d vert e nt U n bli n di n g ...................................................................................................4 7  
6. 4.  
St u d y I nter v e nti o n C o m plia nce  ......................................................................................4 8  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
6  
6. 5.  
D ose M o dificati o n  ..........................................................................................................4 8  
6. 5. 1.  
D ose Re d ucti o ns f or Bli n de d St u d y Dr u g ( A be macicli b/ Place b o)  .................................4 8  
6. 5. 2.  
D ose M o dificati o ns - A b e macicli b/ Place b o  ...................................................................4 9  
6. 5. 3.  
D ose M o dificati o ns f or I ncreas e d A L T or A S T - 
A be macicli b/ Place b o a n d A birater o n e  ...........................................................................5 1  
6. 6.  
C o nti n ue d Access t o St u d y I nter ve nti o n aft er t he E n d of t he 
St u d y  ...............................................................................................................................5 3  
6. 7.  
Treat me nt of O v er d ose  ...................................................................................................5 3  
6. 8.  
C o nc o mita nt T hera p y  .....................................................................................................5 4  
6. 8. 1.  
S u p p orti ve Care  ..............................................................................................................5 6  
6. 8. 2.  
S u p p orti ve Ma na ge me nt f or Diarr hea  ............................................................................5 6  
7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al ........................................................................................5 8  
7. 1.  
Disc o nti n uati o n of St u d y I nter ve nti o n  ............................................................................5 8  
7. 2.  
Partici pa nt Disc o nti n ua ti o n/ Wit h dra wal fr o m t he St u d y ................................................5 9  
7. 2. 1.  
Disc o nti n uati o n of I n a d v erte ntl y Ra n d o mize d Patie nts  .................................................5 9  
7. 3.  
L ost t o F oll o w u p  ............................................................................................................5 9  
8.  
St u d y Assess m e nts a n d Pr oce d ures .............................................................................6 1  
8. 1.  
Efficac y Assess me nts  .....................................................................................................6 1  
8. 2.  
Safet y Assess me nts  .........................................................................................................6 3  
8. 2. 1.  
Cli nical Safet y La b orat or y Tests  ....................................................................................6 3  
8. 2. 2.  
He patic Safet y M o nit ori n g  ..............................................................................................6 4  
8. 2. 3.  
G ui da nce f or M o nit ori n g Re nal F u ncti o n  .......................................................................6 5  
8. 2. 4.  
G ui da nce f or I nterstitial L u n g Disease/ P ne u m o nitis  ......................................................6 5  
8. 2. 5.  
G ui da nce f or Ve n o us T hr o m b oe m b olic E ve nts ( V T Es)  .................................................6 6  
8. 2. 6.  
G ui da nce f or H y perte nsi o n, H y p o ka le mia, Fl ui d Rete nti o n, a n d 
Car di o vasc ular A d vers e Reacti o ns D ue t o Mi neral oc ortic oi d 
E xcess  .............................................................................................................................6 6  
8. 2. 7.  
G ui da nce f or A dre n oc ortical  I ns uffici e nc y ....................................................................6 6  
8. 2. 8.  
G ui da nce f or H y p o gl yc e mia  ...........................................................................................6 7  
8. 3.  
A d verse E v e nts, Seri o us A d verse E v e nts, a n d Pr o d uct 
C o m plai nts  ......................................................................................................................6 7  
8. 3. 1.  
Ti mi n g a n d Mec ha nis m f or C ollecti n g E ve nts  ...............................................................6 8  
8. 3. 2.  
Met h o d of Dete cti n g A E a n d S A Es  ................................................................................6 9  
8. 3. 3.  
F oll o w -u p of A Es a n d S A Es  ...........................................................................................6 9  
8. 3. 4.  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es  ...............................................................7 0  
8. 3. 5.  
Pre g na nc y  ........................................................................................................................7 0  
8. 3. 6.  
A d verse E v e nts of S peci al I nt erest  .................................................................................7 1  
8. 4.  
P har mac o ki netics  ............................................................................................................7 1  
8. 5.  
P har mac o d y na mics  .........................................................................................................7 1  
8. 6.  
Ge netics  ..........................................................................................................................7 1  
8. 7.  
Bi o mar kers  ......................................................................................................................7 2  
8. 7. 1.  
Plas ma Sa m ples f or Bi o mar ker Res e arc h  .......................................................................7 3  
8. 7. 2.  
Tiss ue Sa m ples f or Bi o mar ker Res earc h  ........................................................................7 4  
8. 7. 3.  
W h ole -Bl o o d Sa m ple f or Bi o mar ker Researc h  ..............................................................7 5  
8. 8.  
I m m u n o ge nicit y Assess me nts.........................................................................................7 5  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
7  
8. 9.  
Me dical Res o urce Utilizati o n a n d Healt h Ec o n o mi cs  ....................................................7 5  
8. 9. 1.  
Patie nt -Re p orte d O utc o mes  ............................................................................................7 5  
8. 9. 2.  
Healt h Care Res o urce Utilizati o n  ...................................................................................7 7  
9.  
St atistic al C o nsi der ati o ns  .............................................................................................7 8  
9. 1.  
Statistical H y p ot heses  .....................................................................................................7 8  
9. 2.  
Sa m ple Size Deter mi nati o n  ............................................................................................7 8  
9. 3.  
A nal yses Sets  ..................................................................................................................7 8  
9. 4.  
Statistical A nal yses  .........................................................................................................7 9  
9. 4. 1.  
Ge neral C o nsi derati o ns  ...................................................................................................7 9  
9. 4. 2.  
Pri mar y E n d p oi nt/ Esti ma n d A nal ysis  .............................................................................7 9  
9. 4. 3.  
Sec o n dar y E n d p oi nts A n al yses  .......................................................................................8 0  
9. 4. 4.  
E x pl orat or y E n d p oi nts A nal yses  .....................................................................................8 1  
9. 4. 5.  
Safet y A nal yses  ...............................................................................................................8 2  
9. 4. 6.  
Ot her A nal yses  ................................................................................................................8 2  
9. 5.  
I nteri m A nal ysis ..............................................................................................................8 3  
9. 5. 1.  
Safet y I nteri m A nal ysis ...................................................................................................8 3  
9. 5. 2.  
Efficac y I nteri m A n al ysis  ...............................................................................................8 3  
1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns  ..................................8 5  
1 0. 1.  
A p pe n di x 1: Re g ulat or y, Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns  ................................................................................................................8 5  
1 0. 1. 1.  Re g ulat or y a n d Et hical C o nsi derati o ns  ...........................................................................8 5  
1 0. 1. 2.  Fi na ncial Discl os ur e ........................................................................................................8 6  
1 0. 1. 3.  I nf or me d C o nse nt Pr ocess ..............................................................................................8 6  
1 0. 1. 4.  Data Pr otecti o n ................................................................................................................8 6  
1 0. 1. 5.  C o m mittees Str uct ure ......................................................................................................8 7  
1 0. 1. 6.  Disse mi nati o n of Cli nical St u d y Data .............................................................................8 7  
1 0. 1. 7.  Data Q ualit y Ass ur a nce  ..................................................................................................8 8  
1 0. 1. 8.  S o urce D oc u m e nts  ..........................................................................................................8 9  
1 0. 1. 9.  St u d y a n d Site Start a n d Cl os ure  ....................................................................................8 9  
1 0. 1. 1 0.  P u blicati o n P olic y  ...........................................................................................................9 0  
1 0. 1. 1 1.  I n v esti gat or I nf or mati o n .................................................................................................9 0  
1 0. 1. 1 2.  L o n g -Ter m Sa m ple Rete nti o n .........................................................................................9 0  
1 0. 2.  
A p pe n di x 2: Cli nical La b orat or y Tests  ...........................................................................9 1  
1 0. 3.  
A p pe n di x 3: A d verse E v e nts a n d Seri o us A d verse E ve nts: 
Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w -
u p, a n d Re p orti n g  ............................................................................................................9 3  
1 0. 3. 1.  Defi niti o n of A E  .............................................................................................................9 3  
1 0. 3. 2.  Defi niti o n of S A E  ...........................................................................................................9 4  
1 0. 3. 3.  Defi niti o n of Pr o d uct C o m plai nts  ...................................................................................9 5  
1 0. 3. 4.  Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E a n d Pr o d uct 
C o m plai nts  ......................................................................................................................9 5  
1 0. 3. 5.  Re p orti n g of S A Es  ..........................................................................................................9 7  
1 0. 3. 6.  Re g ulat or y Re p orti n g Re q uire me nts  ...............................................................................9 7  
1 0. 4.  
A p pe n di x 4: C o ntrace pti ve a n d Barri er G ui da nce  ..........................................................9 9  
1 0. 4. 1.  Defi niti o ns .......................................................................................................................9 9  
1 0. 4. 2.  C o ntrace pti o n G ui da nce ................................................................................................1 0 0  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
8  
1 0. 5.  
A p pe n di x 5: Li ver Safet y: S u g geste d Acti o ns a n d F oll o w -u p 
Assess me nts  ..................................................................................................................1 0 1  
1 0. 6.  
A p pe n di x 6: Ti mi n g a n d Mec ha nis m f or C ollecti n g E ve nts  ........................................1 0 3  
1 0. 7.  
A p pe n di x 7: I n d ucers a n d Str o n g I n hi bit ors of C Y P 3 A 4  .............................................1 0 5  
1 0. 8.  
A p pe n di x 8: C o u ntr y -s pecific Re q uire me nts ...............................................................1 0 7  
1 0. 8. 1.  Re m o val of t he Le gall y A ut h orize d Re prese ntati ve, Le gal 
G uar dia n, a n d Pare nts i n Ger ma n y  ...............................................................................1 0 7  
1 0. 8. 2.  Disc o nti n uati o n of St u d y Dr u g i n I na d verte ntl y E nr olle d 
Partici pa nts i n Ca na da ...................................................................................................1 1 0  
1 0. 9.  
A p pe n di x 9: Pr ot oc ol J P E G R E CI S T Criteria 1. 1 f or S oft Tiss ue  ...............................1 1 1  
1 0. 1 0.  
A p pe n di x 1 0: Pr ot oc ol J P E G C T C A E 5. 0 
Diarr hea/ P ne u m o nitis/ A L T a n d A S T I ncreas e d Defi niti o ns  ........................................1 1 7  
1 0. 1 1.  
A p pe n di x 1 1: Pr o visi o ns f or C ha n ges i n St u d y C o n d uct D uri n g 
E xce pti o nal Circ u msta nces  ...........................................................................................1 1 9  
1 0. 1 2.  
A p pe n di x 1 2: A b bre viati o ns a n d Defi niti o ns  ...............................................................1 2 3  
1 0. 1 3.  
A p pe n di x 1 3: Pr ot oc ol A me n d me nt Hist or y  ................................................................1 3 0  
1 1.  
Refere nces  ....................................................................................................................1 3 7  
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
9  
1.  
Pr ot oc ol S u m m ar y   
1. 1.  
S y n o psis   
Pr ot oc ol Title:   
C Y C L O N E 3: A P hase 3, Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y of A be macicli b 
i n C o m bi nati o n wit h A birater o n e pl us Pre d nis o ne i n Me n wit h Hi g h-Ris k Metastatic H or m o ne -
Se nsiti ve Pr ostate Ca ncer  
Brief Title:   
C Y C L O N E 3: A St u d y of A be maci cli b wit h A birater o ne i n Me n wit h Hi g h -Ris k Metastatic 
H or m o ne -Se nsiti ve Pr ostate Ca ncer  
Re g ul at or y A ge nc y I de ntifier N u m ber(s):   
I N D: 1 3 9 6 9 4  
E U trial n u m ber:  2 0 2 2 -5 0 0 4 6 1 -2 8 -0 6  
R ati o n ale : 
Pr ostate ca ncer  is a lea di n g ca use of m ortalit y a n d m or bi dit y gl o ball y a n d re prese nts a s u bst a ntial 
p u blic healt h b ur de n. Wit h nearl y  1. 4 milli o n ne w cases a n d 3 7 5,0 0 0  d eat hs  w orl d wi de , pr ostate 
ca ncer is t he sec o n d m ost fre q ue nt ca ncer a n d t h e fift h lea di n g ca use of ca n cer deat h a m o n g me n 
i n 2 0 2 0 ( S u n g et al. 2 0 2 1).  
Me n wit h m H S P C ha ve  eit her pri mar y pr o gressi ve disease or prese nt wit h metasta ses at i nitial 
dia g n osis  ( de n o v o m H S P C). W hile A D T  al o ne or i n c o m bi nati o n wit h first-ge nerati o n a nti -
a n dr o ge ns has b ee n t he mai nsta y of treat me nt f or m H S P C, t he treat me nt la n dsca pe h as c h a n ge d 
ra dicall y i n rece nt ye ars. Life -pr ol o n gi n g  treatme nt s n o w i ncl u de d oceta xel c he m ot hera p y a n d 
n o vel h or m o nal a ge nts , s uc h as a bir ater o ne, a pal ut a mi de, a n d e n zal uta mi de . Des pite t hese 
si g nifica nt rece nt i m pr o ve me nts, t here is still a pressi n g me dical  nee d f or tail ore d treat me nt 
a p pr oac h es, partic ul arl y f or patie nts wit h hi g h -ris k disease w h o e x p erie n ce s h orter s ur vi val 
o utc o mes wit h c urre nt a p pr o ve d treat me nts.  F or t h ese hi g h -ris k patie nts, e arl y treat me nt 
i nte nsificati o n wit h n o vel c o m bi nati o n t hera p y has t he p ote ntia l t o mea ni n gf ull y i m pr o ve cli nical 
o utc o me s. 
A be macicli b  is a p ote nt a n d selecti ve oral  i n hi bit or of C D K 4 & 6 t hat is a p pr o ve d  f or t he 
treat me nt of earl y a n d a d va nce d / metastatic H R + / H E R 2- breast ca ncer  (Verze ni o pac ka ge i ns ert, 
2 0 2 1 ). 
 
 
 
 
 
  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0  
O bjecti ves  a n d  E n d p oi nt s: 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
 
T o deter mi ne w het her a d di n g 
a b e macicli b t o a birater o ne pl us 
pre d nis o ne
a i m pr o ves ra di o gra p hic 
pr o gressi o n -free s ur vi val (r P F S). 
 
r P F S assesse d b y t he i n vesti gat or. 
Sec o n dar y  
 
 
T o e v al uate i m pr o ve me nts i n ot her 
cli nicall y rele v a nt efficac y e n d p oi nts 
wit h t he a d diti o n of a b e macicli b t o 
a birater o ne pl us pre d nis o ne. 
 
r P F S b y bli n de d, i n de pe n de nt, ce ntral re vie w ( BI C R)  
 
Cli nical P F S (c P F S)  
 
C astrati o n -resista nt pr ostate c a ncer ( C R P C)-free 
s ur vi val 
 
Ti me t o s y m pt o matic pr o gressi o n  
 
Ti me t o P S A pr o gressi o n  
 
Ti me t o i nitiati o n of ne w a ntica ncer t hera p y  
 
O verall sur vi val ( O S) . 
 
T o c h aracterize t he safet y of a d di n g 
a b e macicli b  t o a birater o ne pl us 
pre d nis o ne.   
 
T he safet y e n d p oi nts e val uate d will i ncl u de, b ut are 
n ot li mite d t o, t he f oll o wi n g: A E s, T E A Es, S A Es, 
cli nical la b orat or y tests, E C Gs, vital si g ns, a n d 
p h ysical e xa mi nati o ns.   
 
T o c h aracterize t he P K 
of  a b e macicli b  w he n a d mi nistere d i n 
c o m bi nati o n wit h a birater o ne.   
 
C o nce ntrati o ns of  a be macicli b.   
 
T o assess patie nt -re p orte d pai n a n d 
H R Q o L . 
 
Ti me t o p ai n p r o gressi o n  
 
Ti me t o deteri orati o n i n  H R Q o L  meas ure d b y t he 
F A C T -P ( P h ysical Well -Bei n g a n d P C S sc ores) a n d 
E Q -5 D -5 L.    
A b bre viati o ns: A E = a d verse e v e nt; E C G  = electr o car di o gra m ; E Q-5 D -5 L  = E ur o pea n Q ualit y of Life –  5 
di me nsi o ns –  5 le vel ; F A C T -P = F u ncti o nal Assess me nt of Ca ncer T hera p y –  Pr ostate;  H R Q o L  - healt h -relate d 
q ualit y of life ; P K = p har mac o ki netics; P S A = pr ostate-s pecific a nti ge n; P C S = p h ysical c o m p o ne nt s u m mar y ; 
r P F S = ra di o gra p hic pr o gressi o n-free s ur vi val; S A E = seri o us a d verse e ve nt; T E A E = treat me nt -e mer ge nt 
a d verse e ve nt. 
a P re d nis o ne i m plies pre d nis o ne or pre d nis ol o ne.  
 
O ver all Desi g n : 
C Y C L O N E  3  is a m ulti nati o nal, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d , P hase 3 st u d y t o 
assess t he safet y a n d effi cac y of  a d di n g a be m acicli b t o a birater o ne pl us pre d nis o ne i n patie nts 
wit h hi g h -ris k m H S P C. Hi g h-ris k is defi ne d as t h e prese n ce of ≥4 b o n e m etastases a n d/ or ≥1 
visceral metastas es.   
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 1  
P artici pa nts will be ra n d o mize d i n a 1: 1 rati o t o recei ve a birater o ne pl us pre d n is o ne a n d 
a be maci cli b ( e x peri me nt al ar m)  or mat c hi n g place b o (c o ntr ol ar m). Ra n d o mizati o n will be 
stratifie d acc or di n g t o t he f oll o wi n g fact ors: 
 de n o v o metastatic pr ostate ca ncer ( m etastatic d ise ase at i nitial dia g n osis)  (Y es vs . N o) . 
 visceral metastas es  (Y es vs . N o ). 
A dia gra m of t he st u d y d esi g n is pr o vi de d bel o w i n Secti o n 1. 2 . 
 
Brief S u m m ar y:  
T his P hase 3, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y is de si g ne d t o assess t he safet y 
a n d effi cac y of a be m acicli b i n c o m bi nati o n  wit h a birater o ne pl us pre d nis o ne f or t he tr eat me nt of 
patie nts wit h hi g h -ris k metastatic h or m o ne -s e nsiti ve pr ostate ca ncer  (m H S P C ). T he pri mar y 
o bjecti ve is t o deter mi ne  w het her  a b e maci cli b , a n oral selecti ve i n hi bit or of C D K 4 & 6 , a d de d t o 
sta n dar d a n dr o ge n de pri vati o n  t hera p y a n d a birater o ne pl us  pre d nis o ne d ela ys ra di o gra p hic 
disease pr o gressi o n . 
St u d y P o p ul ati o n:  
T his st u d y will e nr oll partici pa nts wit h pr ostate ca ncer t hat has s prea d t o ot her parts of t h e b o d y  
a n d still res p o n ds t o treat me nts t o l o wer test oster o ne, a c o n diti o n referre d t o as metastatic  
h or m o ne -se nsiti ve pr ostate ca ncer ( m H S P C). I n a d diti o n, partici pa nts m ust ha ve at least 1  of t he 
2  f oll o wi n g hi g h-ris k feat ures:  
 D isease t hat has s prea d t o t he b o nes wit h e vi de nce of 4 or m ore lesi o ns. 
 Disease t hat has s prea d t o t he viscera , w hic h are t he s oft i nter nal or g a ns of t he b o d y (f or 
e xa m ple, t he l u n gs , li ver, a n d t he or ga ns of t he di gesti ve s yste m).  
Partici pa nts s h o ul d n ot ha ve pre vi o usl y r ecei v e d s yste mic treat me nt f or metastatic pr ostate 
ca ncer e x ce pt f or u p t o 3 m o nt hs of A D T (L H R H a g o nist/a nta g o nist or bilateral orc hi ect o m y) , 
wit h or wit h o ut first -ge nerati o n a nti -a n dr o ge n, pri or t o  ra n d o mizati o n. 
Partici pa nts w h o ha ve n ot u n der g o ne bilateral orc hiect o m y are re q uire d t o c o nti n ue bac k gr o u n d 
A D T  wit h a n  L H R H a g o nist/a nta g o nist  t hr o u g h o ut t he st u d y. 
Me dical c o n diti o ns , i ncl u di n g b ut n ot li mite d t o, i nfla m mati o n a n d scarri n g of t he l u n gs, se vere 
s h ort ness of breat h, car diac arrh yt h mia,  heart disease , u nc o ntr olle d h y p erte nsi o n, c hr o nic li ver 
disease,  a dre nal d ysf u n cti o n, or  acti ve s yste mic i nfecti o ns ma y precl u de partici pati o n i n t he 
st u d y.  
T he c o m plete list of eli gi bilit y criteria is pr o vi de d i n  t he S ecti o n 5  of  t his pr ot oc ol. 
N u m ber of P artici p a nt s: 
A p pr o xi matel y 9 0 0  parti ci pa nts will be ra n d o mize d. 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2  
Tre at me nt Ar ms  a n d D ur ati o n : 
A bir ater o ne a n d pre d nis o ne ( or pre d nis ol o ne):  
All partici pa nts will recei ve t hera p y wit h a birater o ne 
 o nce d ail y pl us pre d nis o ne 
 
Pre d nis ol o ne ma y be use d i n lie u of pre d nis o ne per l ocal a birater o ne prescri bi n g i nf or mati o n or 
w here pre d nis o ne is n ot c o m merciall y a vaila ble ; t h eref ore, hereafter  i n t his pr ot oc ol  pre d nis o ne 
i m plies pre d nis o ne or pre d nis ol o ne. 
Bli n de d st u dy d r u g: 
 E x peri me ntal ar m: A b e macicli b  
orall y  
 (see Secti o n 4. 3 ).  
 C o ntr ol  ar m: Place b o  
 orall y 
 
N ote: Partici pa nts w h o h a ve n ot u n der g o n e bilateral orc hiect o m y are re q uir e d t o c o nti n ue 
bac k gr o u n d A D T  wit h a n  L H R H a g o nist/a nta g o nist  t hr o u g h o ut t he st u d y. 
T he st u d y i ncl u des a scree ni n g peri o d of u p t o 2 8 da ys pri or ra n d o mizati o n t o esta blis h 
eli gi bilit y. A birater o ne pl us pre d nis o ne a n d a be macicli b/ place b o  will be i nitiate d ≤7 da ys 
f oll o wi n g ra n d o mizati o n, a d mi nistere d i n 2 8-da y treat me nt c y cles, a n d c o nti n u e d u ntil 
ra di o gra p hic pr o gressi o n, u nacce pta ble  t o xicit y, or u ntil ot her disc o nti n uati o n criteria are met 
(see Secti o n 7. 1 ). All partici pa nts  disc o nti n ui n g st u d y treat me nt will e nter t he s h ort - a n d l o n g -
ter m f oll o w-u p peri o ds a n d ha ve pr oce d ures perf or me d as s h o w n i n t he S o A  ( Secti o n 1. 3 ), 
e xce pt t h ose l ost t o f oll o w-u p, t h ose w h o wit h dra w i nf or me d  c o ns e nt  or  dea t h. 
Et hic al C o nsi der ati o ns of Be nefit/ Ris k:  
T he p ote ntial ris ks of a be macicli b i n c o mbi nati o n wit h  a birater o n e pl us pre d nis o ne  are j ustifie d 
i n c o nsi derati o n of t he m eas ures t o mi ni mize t hes e ris ks a n d t he a ntici pat e d be nefit of i m pr o ve d 
disease c o ntr ol, as m eas ure d b y ra di o gr a p hic pr o gressi o n -free s ur vi val i n p artici pa nts wit h hi g h -
ris k metastatic h or m o ne -se nsiti ve pr ostate ca n cer. F or t hese hi g h-ris k patie nts, t his n o vel 
c o m bi nati o n t hera p y has t he p ote ntial t o mea ni n gf ull y i m pr o ve cli nical o utc o mes .  
D at a M o nit ori n g C o m mittee: Yes  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3  
1. 2.  
Sc he m a    
 
 
A b bre viati o ns: 
C T = c o m p ute d t o m o gra p h y; L H R H = l utei nizi n g h or m o ne -releasi n g h or m o ne; m H S P C = metastatic h or m o ne -se nsiti ve 
pr ostate ca ncer; M RI = ma g netic res o na n ce i ma gi n g; N = n u m ber of partici pa nts; Q D = o nce dail y.  
* Pre d nis ol o ne ma y be use d i n lie u of pre d nis o ne per l ocal a birater o ne prescri bi n g i nf or mati o n or w here pre d nis o ne is n ot c o m merciall y a v aila ble.  
Partici pa nts w h o ha v e n ot u n der g o ne bilateral orc hiect o m y are re q uire d t o c o nti n ue bac k gr o u n d a n dr o ge n de pri vati o n t hera p y wi t h a n L H R H a g o nist/a nta g o nist 
t hr o u g h o ut t he st u d y. 
Partici pa nts w h o are still o n st u d y i nter ve nti o n at t he ti me of st u d y c o m pleti o n ma y c o nti n ue t o recei ve st u d y i nter ve nti o n if t he y are e x perie nci n g cli nical b e n efit  
a n d n o u n d ue ris ks  (see Secti o n 6. 6 , C o n ti n ue d Access) .
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI
C CI
C CI
C CI
C CI
C CI
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 4  
1. 3.  
Sc he d ule of Acti vities  ( S o A)  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
Ge ner al  
I nf or me d 
c o nse nt  
X  
  
  
  
  
  
Writte n i nf or me d c o nse nt m ust b e o btai ne d wit hi n 2 8 da ys pri or t o 
ra n d o mizati o n A N D pri or t o c o n d ucti n g a n y pr ot oc ol-s pecific 
tests/ pr oce d ures. 
I ncl usi o n / 
e xcl usi o n 
criteria  
X  
 
  
  
  
  
Re vie w a n d c o nfir m i ncl usi o n a n d e x cl usi o n criteria pri or t o 
ra n d o mizati o n.  
De m o gra p hics  
X  
 
 
 
 
 
I ncl u de race, et h nicit y, ge n der , a n d birt h date per l ocal re g ulati o ns . 
Pree xisti n g 
c o n diti o ns a n d 
me dical hist or y  
X  
  
  
  
  
  
I ncl u di n g assess me nt of pree xisti n g c o n diti o ns, hist orical ill nesses t hat 
res ol ve d, rele v a nt s ur gical hist or y a n d ha bits (s uc h as t o bacc o a n d alc o h ol 
use).  
Pri or 
treat me nts f or 
pr ostate ca ncer  
X  
 
 
 
 
 
Rec or d all  pri or a ntica n cer t hera p y f or pr ostate ca ncer (f or e xa m ple, 
s yste mic t hera p y, s ur ger y, ra di o p har mace uticals, a n d ra di ot hera p y).  
Pri or a n d 
c o nc o mita nt 
me dic ati o n 
C o nti n u o us fr o m ti me of I nf or me d C o nse nt F or m si g nat ure u ntil 3 0 
da ys after t he last d ose of st u d y treat me nt.  
  
C ollect c o nc o mita nt me dicati o ns at scree ni n g a n d t hr o u g h o ut t he st u d y 
i ncl u di n g s h ort-ter m f oll o w-u p. I ncl u des o ver -t he-c o u nter prescri pti o ns a n d 
a nal gesics use.  
P h ysical 
e xa mi nati o n  
  
X  
X  
  
 
X  
 
- C o m plete p h ysical e x a mi nati o n wit h hei g ht, wei g ht, a n d vital si g ns 
(te m perat ure, bl o o d press ure, p ulse rate, p ulse o xi metr y) will be 
perf or me d at scree ni n g .  
- S y m pt o m -directe d p h ysical e xa mi nati o n, meas ure me nt of wei g ht, a n d 
vital si g ns will be perf or me d  d uri n g cli nic visits  at t he start of eac h c y cle 
a n d V 8 0 1. D oes n ot n ee d t o be re p eate d o n C 1 D 1 if assesse d ≤7 da ys at 
scree ni n g, u nless cli nicall y i n dicate d.  
- A d diti o nal e x a mi nati o ns s h o ul d be perf or me d as cli nicall y i n dicate d.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 5  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
E C O G P S  
  
X  
X  
  
 
X  
 
D oes n ot nee d t o be re p eate d o n C ycle 1 Da y 1 if assesse d at scree ni n g ≤7 
da ys.  
Re m ote 
Tele h ealt h 
Visit  
 
 
E ver y 
ot her 
c y cle  
st arti n g 
o n  C ycle  
1 4  
(C ycles 
1 4, 1 6, 
1 8 , etc.) 
 
 
X  
 
- Starti n g at C ycle 1 4, if dee me d a p pr o priate b y t he i n vesti gat or, 
partici pa nts ma y ha ve re m ote tele h ealt h (tele me dici ne/tele p h o ne) visits 
e ver y ot her c ycle ( C ycles 1 4, 1 6, 1 8 , etc.). La b orat or y assess me nts a n d 
ot her cli nic  pr oce d ures  (f or e xa m ple, p h ysical e x a mi nati o n , vitals, a n d  
P R Os ) are n ot re q uire d o n c ycles w he n  re m ote tele h ealt h visits are 
perf or me d . D uri n g tele h ealt h visits , A L T , A S T  a n d bilir u bi n m o nit ori n g 
ma y be perf or me d l ocall y per i n vesti gat or discreti o n i n acc or da n ce wit h 
t he a birater o ne prescri bi n g i nf or mati o n . If cli nicall y i n dicate d or at a n y 
ti me, partici pa nts ca n ret ur n t o t he sta n dar d cli nic visit sc he d ule (i n-pers o n 
cli nic visits o n Da y 1 of eac h c y cle).  
- Detecti o n of ne w or w orse ni n g A E s, c h a n ge i n c o nc o mita nt me dicati o ns, 
a n d s y m pt o ms s us pici o us of disease pr o gressi o n are hi g hl y i m p orta nt. T he 
i n vesti gat or or a n ot her me dicall y q ualifie d i n di vi d ual is e x pecte d t o 
c o n d uct a c o m pre h e nsi ve a n d s yste matic assess me nt of t hese s y m pt o ms 
d uri n g t he re m ote visit.  
- U nsc he d ule d cli nic visits a n d a n y c orres p o n di n g pr oce d ures dee me d 
necessar y are at t he discreti o n of t he i n vesti gat or. U nsc h e d ule d visits ma y 
i ncl u de p h ysical e xa mi nati o ns, vital si g ns, E C O G perf or ma nce stat us, 
t u m or a n d/ or s y m pt o matic pr o gressi o n assess ment(s), ce ntral c h e mistr y 
a n d he mat ol o g y, ret ur n of st u d y i nter ve nti o n, or res u me d d osi n g, if 
pre vi o usl y i nterr u pte d.  
- Partici pa nts  w h o e x perie nce ≥ Gra d e 3 la b orat or y a b n or malit y c o nsi dere d 
p ossi bl y relate d a n d cli nicall y si g nifica nt b y t he i n vesti gat or, at a n y ti me 
d uri n g t he o n -treat me nt peri o d, will c o nti n ue t o ha v e i n-pers o n cli nic 
visits wit h st u d y pr oce d ures as o utli ne d i n t he S o A.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 6  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
L a b or at or y Assess m e nts  
C oa g ulati o n  
 
X  
 
 
 
X  
 
- See Secti o n 1 0. 2 . Re p eat if cli nicall y i n dicate d. 
Uri nal ysis  
 
X  
 
 
 
X  
 
- See Secti o n 1 0. 2 . Re p eat if cli nicall y i n dicate d. 
P S A  
 
X  
X  
 
 
X  
 
- See Secti o n 1 0. 2 . Re p eat if cli nicall y i n dicate d. 
 
- P S A, test oster o ne, he mat ol o g y, a n d cli nical c h e mistr y d o n ot n ee d t o be 
re peate d o n C ycle 1 Da y 1 if assesse d ≤7  da ys at scree ni n g  u nless 
cli nicall y i n dicate d . 
 
 
- Refer t o Secti o n 8. 2. 2  f or m ore fre q ue nt h e p atic m o nit ori n g. 
Test oster o ne  
 
X  
X  
 
 
X  
 
He mat ol o g y  
 
X  
X  
X  
 
X  
 
Cli nical 
c he mistr y  
 
X  
X  
X  
X  
X  
 
Ot her Cli nic al Assess m e nts  
1 2 -lea d E C G 
X  
D a y 1 of C ycle s 4, 7, 1 0, 1 3 , a n d  as 
cli nic all y i n dic ate d  t here after. 
 
X  
 
Sta n dar d 1 2 -lea d E C G perf or me d l ocall y. H y p o kale mia s h o ul d be c orrecte d 
(a n d n or malizati o n c o nfir me d) pri or t o E C G c ollecti o n. P artici pa nts m ust 
be s u pi ne f or a p pr o xi matel y 5 t o 1 0 mi n utes bef ore E C G c ollecti o n a n d 
re mai n s u pi ne b ut a wa k e d uri n g E C G c ollecti o n. Re p eat if cli nicall y 
i n dicate d.   
Car diac E C H O 
or M U G A sca n  
X  
  
  
  
  
  
Re peat if cli nicall y i n dicate d.  
A d verse e v e nt 
assess me nt  
C o nti n u o us fr o m ti me of I nf or me d C o nse nt F or m si g nat ure u ntil 3 0 
da ys after t he last d ose of st u d y treat me nt.  
 
X  
- Gra di n g via C T C A E versi o n 5. 0 ( N CI 2 0 1 7).  
- After V 8 0 1, o nl y S A Es t hat are relate d t o st u d y re gi me n or pr ot oc ol 
pr oce d ure will be c ollecte d.  
- All dr u g - or pr oce d ure -relate d A Es  a n d S A Es s h o ul d be f oll o we d u ntil 
t he y res ol ve, are n o l o n ger c o nsi dere d t o be dr u g- or pr oce d ure -relate d, 
bec o me sta ble or ret ur n t o baseli ne, t he patie nt  starts a ne w t hera p y, t he 
patie nt dies, or t he patie nt bec o mes l ost t o f oll o w -u p. I n L T F U, fre q ue n c y 
of e val uati o n is left t o t he j u d g me nt of t he i n vesti gat or.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 7  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
P ost -
disc o nti n uati o n 
a ntica n cer 
t hera pies 
 
 
 
 
 
X  
X  
C ollect u ntil deat h, wit h dra wal of c o nse nt, or st u d y c o m pleti o n.  
S ur vi val 
assess me nt  
 
 
 
 
 
X  
X  
Alt h o u g h prefera ble t o c ollect d uri n g a cli nic visit, s ur vi val i nf or mati o n 
ma y be c ollecte d b y c o ntacti n g t he patie nt or fa mil y directl y (f or e xa m ple, 
via tele p h o ne) if n o pr oce d ures are re q uire d. T his s h o ul d be c ollecte d at 
mi ni m u m e ver y 9 0 ( ± 1 4) da ys if n o ot her pr oce d ures are perf or me d.  
T u m or Assess m e nt a n d S y m pt o m atic Pr o gressi o n
 
Brai n M RI  or 
C T  
X  
E ver y 1 2 wee ks f or t he first 2 4 
wee ks a n d e ver y 1 6 wee ks 
t here after. 
 
Sc he d ule d base d o n C 1 D 1, i ma gi n g 
s h o ul d be perf or me d acc or di n g t o 
X  
X  
Scree ni n g  b rai n M RI or C T is o nl y  re q uire d f or partici pa nts  wit h s us pecte d 
C N S metastases  or hist or y of treate d C N S metastases.  
Scree ni n g is n ot re q uired  f or as y m pt o matic patie nts.  
- O nl y patie nts wit h a hist or y of pretreate d C N S metastases re q uire 
s u bse q ue nt o n st u d y brai n i ma gi n g 
- U nsc he d ule d a n d m ore fre q ue nt assess me nts if cli nicall y i n dicate d . 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 8  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
C T or M RI of 
c hest, 
a b d o me n , a n d 
pel vis  
 
A N D  
 
W h ole -b o d y 
b o ne sca n  
X  
cale n dar da ys, i n de pe n de nt of c ycle 
del a ys  (t hat is, Wee k 1 3, Wee k 2 5, 
t he n Wee k 4 1, Wee k 5 7...) 
 
I ma gi n g s h o ul d be perf or me d wit hi n 
1 4 da ys of disc o nti n uati o n  fr o m 
st u d y i nter ve nti o n d ue t o  
s y m pt o matic pr o gressi o n if n o 
ra di o gra p hic pr o gressi o n ( u nless 
pri or sca ns were perf or me d ≤ 1 4 
da ys)  
X  
X  
- Perf or m wit hi n 7 da ys pri or t o t he sc h e d ule d assess me nt (e xce pt i n 
scree ni n g peri o d). 
- B ot h C T/ M RI A N D b o ne sca ns are re q uire d at scree ni n g a n d all 
s u bse q ue nt t u m or assess me nts re g ar dless of l ocati o n of metastasis.  
- All C T / M RI a n d b o ne sca ns m ust b e s u b mitte d t o t he s p o ns or-desi g nate d 
facilit y f or BI C R. A n y  p re-baseli ne sca ns d oc u me nti n g metastatic disease 
(i ncl u di n g P S M A-P E T/ C T sca ns ) will be c ollecte d a n d st ore d f or ce ntral 
re vie w. See S ecti o n 8. 1  a n d r efer t o i ma gi n g ma n ual f or a d diti o nal details.  
- C T/ M RI a n d b o ne s ca ns perf or me d as part of r o uti ne care are acce pta ble 
as baseli ne assess me nts  if d o ne wit hi n 2 8 da ys pri or t o ra n d o mizati o n a n d 
a vaila ble f or BI C R as n ote d a b o ve. 
- U nsc he d ule d assess me nts if si g ns  a n d/or s y m pt o ms  of disease pr o gressi o n 
are o bser ve d.  
- Partici pa nts  disc o nti n ui n g treat me nt pri or t o d oc u me nte d ra di o gra p hic 
pr o gressi o n wi ll c o nti n ue t o ha ve sc h e d ule d disease assess m e nts (t hat is, 
e ver y 1 2 or 1 6 wee ks) u ntil d oc u me nte d ra di o gra p hic pr o gressi o n.  
S y m pt o matic 
pr o gressi o n  
  
  
X  
  
 
X  
X  
Assess:  
- S y m pt o matic S keletal E ve nt, defi ne d as ca n cer -relate d s y m pt o matic 
fract ure, s ur ger y or ra diati o n t o b o ne, or s pi nal c or d c o m pressi o n.  
- Pai n pr o gressi o n or w orse ni n g of disease -relate d s y m pt o ms re q uiri n g 
i nitiati o n of a ne w s yste mic a ntica n cer t hera p y. 
- De v el o p me nt of cli nicall y si g nifica nt s y m pt o ms d ue t o l oc ore gi o nal t u m or 
pr o gress i o n re q uiri n g s ur gical i nter ve nti o n or ra diati o n t hera p y. 
 
N ote: Partici pa nts  disc o nti n ui n g treat me nt f or reas o n ot her t ha n 
s y m pt o matic pr o gressi o n will c o nti n ue t o be f oll o we d f or t he de v el o p me nt 
of s y m pt o matic pr o gressi o n d uri n g S h ort -Ter m a n d L o n g -Ter m F oll o w -
U p.   
E x pl or at or y Bi o m ar k er a n d Ge netic S a m ples ( bl o o d a n d t u m or tiss ue). See Secti o n 1. 3. 1  f or s a m pli n g sc he d ule. 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 9  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
P h ar m ac o ki netics. See Secti o n 1. 3. 1  f or P K s a m pli n g sc he d ule a n d p atie nt di ar y. 
Patie nt d osi n g 
diar y  
 
 
C 1 D 1, C 2 D 1, a n d C 3 D 1  
 
 
- Re vie w diar y C 1 D 1 t hr o u g h C 3 D 1.  
- After C ycle 3 Da y 1, t he diar y is n o l o n ger re q uire d.  
P atie nt -Re p orte d O utc o m es  
W orst Pai n 
N R S  
 
 
D a y 1 of e ver y c ycle t hr o u g h 
C ycle 1 3;  
 t he n e ver y 4 c ycles t here after  
( C 1 7 D 1, C 2 1 D 1, C 2 5 D 1, C 2 9 D 1 
etc. ) 
X  
 
All P R O assess me nts will b e self -re p orte d b y partici pa nt a n d s h o ul d be 
c o m plete d bef ore si g nifica nt i nteracti o n wit h site pers o n nel a n d 
a d mi nistere d i n t he f oll o wi n g or der: W orst Pai n N R S, F A C T -P, E Q -5 D -
5 L, a n d P R O -C T C A E.   
F A C T -P  
 
 
X  
 
E Q -5 D -5 L  
 
 
X  
 
P R O -C T C A E  
 
 
X  
 
St u d y Tre a t m e nt 
Re gister visit 
wit h I W R S  
X  
 
 
 
 
 
St u d y patie nt n u m ber is assi g ne d at re gistrati o n.  
Assi g n 
treat me nt via 
I W R S 
X  
 
 
 
 
 
Treat me nt assi g ne d at ra n d o mizati o n ≤ 7 da ys pri or t o C ycle 1 Da y 1 after 
meeti n g eli gi bilit y.  
Dis pe nse 
a be macicli b/ 
place b o  
 
 
See 
i nstr ucti o ns 
 
 
 
 
- Dis pe nse d via I W R S . 
- C ycle 1 t hr o u g h C ycle 1 2: dis pe nse d  o n Da y 1 of e v er y c ycle . 
- C ycle 1 3 a n d be y o n d: dis pe nse d o n Da y 1 e v er y 2 c y cles ( C 1 3 D 1, C 1 5 D 1 
etc.) . 
- Partici pa nts will ret ur n use d b ottles o n Da y 1 of cli nic visits f or dr u g 
acc o u nta bilit y. 
- See Secti o n 6. 2. 1  f or details.    
A be macicli b/ 
place b o  
 
 
 o n Da ys 1 t hr o u g h 2 8 
of a 2 8 -da y c ycle.  
 
 
 
A birater o ne  
 
 
O nce dail y o n Da ys 1 t hr o u g h 2 8 of 
a 2 8 -da y c y cle.  
 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
2 0  
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
Pre d nis o ne  
  
  
 O nce dail y o n Da ys 1 t hr o u g h 2 8 of 
a 2 8 -da y c ycle.   
 
  
Pre d nis ol o ne ma y be use d i n lie u of pre d nis o ne per l ocal a birater o ne 
prescri bi n g i nf or mati o n or w here pre d nis o ne is n ot c o m merciall y 
a vaila ble.  
 
A b br e viati o ns: A E = a d verse e v e nt; A L T = ala ni ne a mi n otra nsferase ; A S T = as partate a mi n otra nsferase ; BI C R  = bli n de d i n de pe n de nt -ce ntral re vie w ; C 1 D 1 = 
C ycle 1 Da y 1 ; C N S = ce ntral ner v o us s yste m; C T = c o m p ute d t o m o gra p h y; C T C A E = C o m m o n Ter mi n ol o g y Criteria f o r A d verse E ve nts ( N CI 2 0 1 7); E C G 
= electr ocar di o gra m; E C H O =  ec h ocar di o gra m ; E C O G  P S  = Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce sc ore ( O ke n et al. 1 9 8 2); E Q-5 D -5 L = 
E ur o pea n Q ualit y of Life –  5 di me nsi o ns –  5 le vel; F A C T -P = F u ncti o nal Assess me nt of Ca ncer T hera p y –  Pr ostate Ca n cer; I W R S = i nteracti ve we b-res p o nse 
s yste m; L T F U = l o n g -ter m f oll o w-u p ; M RI = ma g netic res o na nce i ma g i n g; M U G A = m ulti -gate d ac q uisiti o n sca n; N CI = Nat i o nal Ca n cer I nstit ute; N R S = 
n u meric rati n g scale; P E T = p ositr o n e missi o n t o m o gra p h y ; P K = p har mac o ki netics ; P R O = patie nt-re p orte d o utc o me; P S A = pr ostate-s pecific a nti ge n; 
P S M A = pr ostate -s pecific me m bra n e a nti ge n; Q D = o nce dail y; S A E = seri o us a d verse e ve nt . 
a U ns c h e d ule d visits ma y be perf or me d at a n y ti me d uri n g t he st u d y w he ne ver necessar y t o assess f or o r f oll o w-u p o n a d verse  e v e nts at t he partici pa nt’s re q uest 
or if dee me d necessar y b y t he i n vesti gat or .  
b  S h ort -ter m f oll o w-u p be gi ns w he n t he patie nt a n d t he i n vesti gat or a gree t hat t he patie nt will n o l o n ger c o nti n ue st u d y treat me nt a n d lasts a p pr o xi matel y 3 0 
da ys ( ± 7 da ys), pri or t o start of a ne w a ntica ncer t hera p y.  
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
2 1  
1. 3. 1.  
S a m pli n g Sc he d ule f or Bi o m ar ker s, Ge netics a n d P h ar m ac o ki netics   
P h ar m ac o ki netics s a m ples  
P har mac o ki netic sa m ples will be c ollecte d as s p ecifie d i n t he ta ble bel o w. Sa m ples will be a nal yze d f or c o nce n trati o ns of a b e macicli b 
a n d its acti ve meta b olites, M 2 a n d M 2 0 . 
T he ti me a n d date of t he P K sa m ple dra w s h o ul d be rec or de d o n t he l a b orat or y re q uisiti o n f or m. De viati o n fr o m t he s pecifie d 
sa m pli n g sc he me is per mitte d w he n practical a n d l o gistical c o ncer ns arise.  
D uri n g t he P K sa m pli n g peri o d ( C ycle 1 Da y 1 u ntil  C ycle 3 Da y 1), partici pa nts will c o m plete a Patie nt D osi n g Diar y t o rec or d t he 
ti me a n d date of all bli n d e d st u d y dr u g d oses. D osi n g ti mes s h o ul d be e ntere d i nt o t he e C R F f or d os es ta ke n o n  
 t he m or ni n g of t he pla n n e d P K c ollecti o n, a n d  
 t he m or ni n g a n d e ve ni n g d oses ta ke n t he d a y bef ore t he pla n n e d P K c ollecti o n ( C ycles 2 a n d 3 ). 
Bi o m ar ker s a n d Ge netics s a m ples  
Bi o mar ker s a n d ge n etics sa m ples will be c ollecte d as s pecifie d i n t he ta bl e bel o w . 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
2 2  
 
Bi o m ar ker s, Ge netics  a n d P h ar m ac o ki netic s S a m pli n g Sc he d ule  
S a m pli n g D a y  
Bi o m ar ker s a n d Ge netics  
P h ar m ac o ki netics  
 
T u m or 
Tiss ue  
Pl as m a  
( Strec k) 
W h ole Bl o o d  
(Ge netics )  
Micr os a m ple P K  
Pl as m a P K  
Scree ni n g  
X a 
 
 
 
 
C ycle 1 Da y 1  
 
X  
X b 
P ost -d ose : A n yti me bet wee n  1  h o ur after t he 
i nitial d ose of bli n de d st u d y dr u g a n d pri or t o 
t he sec o n d d ose of t he da y 
Wit hi n ± 1 0 mi n utes of 
micr osa m ple  
C ycle 2 Da y 1  
 
 
 
Pre -d ose c 
 
P ost -d ose : A n yti me  bet wee n 4  h o urs after t he 
first dail y d ose of bli n de d st u d y dr u g a n d pri or 
t o t he sec o n d d ose of t he da y d 
C ycle 3 Da y 1  
 
 
 
Pre -d ose c 
Wit hi n ± 1 0 mi n utes of 
micr osa m ple  
C ycle 4  Da y 1  
 
X  
 
 
 
C ycle 7 Da y 1  
 
X  
 
 
 
E n d of Treat me nt or 
S h ort -Ter m F oll o w -
U p ( V 8 0 1)   
( pri or t o ne w 
a ntica n cer t hera p y)  
X e 
X  
 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
2 3  
a A rc hi val t u m or sa m ple will be c ollecte d, w here a vaila ble. T he m ost rece nt  sa m ple is desire d. M etastatic sa m ple w here a vaila ble is preferre d o ver pri mar y 
t u m or. S oft  tiss ue as well as b o n y metastatic lesi o ns are acce pta ble . T he t u m or sa m ples will prefera bl y be i n t he f or m of a f or mali n -fi xe d, paraffi n e m be d de d 
bl oc k . If t his is n ot p ossi ble, a p pr o xi matel y  2 0 sli des of fres hl y pre pare d u nstai ne d 5 -micr o n secti o ns fr o m t he arc hi val t u m or bl oc k ma y be pr o vi de d . 
Sa m ples ca n be c ollecte d at a n y ti me d uri n g st u d y if n ot c ollecte d at scree ni n g . 
b  W h ole bl o o d : c ollect o nce. Sa m ple ca n be c ollecte d at a s u bse q ue nt ti me p oi nt if n ot c ollecte d at C ycle 1 Da y 1. 
c  Partici pa nts s h o ul d refrai n fr o m ta ki n g bli n de d st u d y dr u g u ntil arri val at t he cli nic. Bli n de d st u d y dr u g a d mi nistrati o n ma y  res u me f oll o wi n g t he P K sa m ple 
dra w.  
d  S a m ple ma y be c ollecte d b y t he partici pa nt or care gi ver , as m ut uall y a gree d u p o n b y t he i n vesti gat or a n d partici pa nt. 
e T u m or tiss ue c ollecti o n at t he ti me of o n -st u d y ra di o gra p hic pr o gressi o n is o pti o nal. A fres h metastatic bi o ps y (f or mali n -fi xe d a n d paraffi n e m be d de d) ma y be 
ta ke n at t he ti me of o n-st u d y ra di o gra p hic pr o gressi o n, pri or t o start of ne w a ntica ncer t hera p y if t he i n vesti gat or dee ms t his t o be a p pr o priate a n d  safe. Bi o ps y 
of a pr o gressi n g metastatic lesi o n is preferre d w he ne ver p ossi ble. S oft tiss ue as well as b o n y metastatic lesi o ns will be c o nsi dere d acce pta ble. If patie nt 
disc o nti n ues st u d y f or reas o ns ot her t ha n ra di o gra p hic pr o gressi o n, t he bi o ps y s h o ul d be c o nsi dere d o nl y if t he patie nt has c o m plete d at least 4 c y cles of st u d y 
treat me nt. 
 
 
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C O N FI D E N TI A L  
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2 4  
1. 3. 2.  
C o nti n ue d Access  S o A   
C o nti n ue d -Acc ess Sc he d ule of Acti vities  
 
C o nti n ue d Access  
Tre at m e nt a  
F oll o w -U p b  
 
Visit  
5 0 1 -5 X X  
9 0 1  
 
Pr o ce d ure c 
 
 
I nstr ucti o ns 
A d verse eve nts collecti o n  
X  
X  
Gra di n g via C T C A E, Versi o n 5. 0. Fre q ue n c y of e val uati o n, i ncl u di n g efficac y 
assess me nts, is left t o t he j u d g me nt of t he i n vesti gat or base d o n sta n dar d of care . 
A d mi nister abe macicli b   
X  
 
Ta ke prescri be d d ose  
 o n Da ys 1 t hr o u g h 2 8 of a 2 8 -da y c y cle.  A be macicli b  
ca n be a d mi nistere d e ver y 2 8 ± 3 , 5 6 ± 3 , or 8 4 ± 3  da ys at i n vesti gat or discreti o n.   
U p t o 3 c ycles of a be macicli b d osa g e ma y be dis pe nse d at a ti me.  
A d mi nister abirater o ne   
X  
 
Ta ke prescri be d d ose Q D o n Da ys 1 t hr o u g h 2 8 of a 2 8 -da y c y cle.  A birater o ne  
s u p plie d b y s p o ns or ca n be a d mi nistere d e v er y 2 8 ± 3 , 5 6 ± 3 , or 8 4 ± 3  da ys at 
i n vesti gat or discreti o n. I n cases of site s o urce d a birater o ne, f re q ue n c y of 
dis pe ns i n g is left t o t he j u d g me nt of t he i n vesti gat or base d o n sta n dar d of care.  
A d mi nister p re d nis o ned  
X  
 
Ta ke prescri be d d ose Q D o n Da ys 1 t hr o u g h 2 8 of a 2 8 -da y c y cle.  Pre d nis o ne  
s u p plie d b y s p o ns or ca n be a d mi nistere d e v er y 2 8 ± 3 , 5 6 ± 3 , or 8 4 ± 3  da ys at 
i n vesti gat or discreti o n. I n cases of site s o urce d pre d nis o ne, f re q ue n c y of 
dis pe ns i n g is left t o t he j u d g me nt of t he i n vesti gat or base d o n sta n dar d of care. 
A b bre viati o ns: 
 C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; I P = i n vesti gati o nal pr o d uct; Q D = o nce dail y.  
a I P will be dis pe nse d at a ma xi m u m  of e v er y 3 c ycles ( 8 4 ± 3  da ys). A d diti o nal visits ma y be perf or me d as cli nicall y i n dicate d.  
b  C o nti n ue d -access f oll o w -u p be gi ns w he n t he patie nt a n d t he i n vesti gat or a gree t hat t he patie nt will n o l o n ger c o nti n ue treat me nt i n t he c o nti n ue d  access 
peri o d a n d lasts a p pr o xi matel y 3 0 da ys.  
c Efficac y assess me nts will be d o ne at t he i n vesti gat or’s discreti o n base d o n t he sta n dar d of care.  
d  I n t his pr ot oc ol pre d nis o ne i m plies pre d nis o ne or pre d nis ol o ne.
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C CI
C CI

C O N FI D E N TI A L  
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2 5  
2.  
I ntr o d ucti o n  
2. 1.  
St u d y R ati o n ale   
A be macicli b is a n oral selecti ve i n hi bit or of  C D K 4 & 6 t hat is a d mi nistere d o n a c o nti n u o us 
sc he d ule. A be m acicli b is a p pr o ve d gl o ball y f or t h e treat me nt of H R + , H E R 2 -, a d va nce d  or 
metastatic breast ca ncer  base d o n i m pr o ve me nts i n P F S w he n a d de d t o e n d ocri ne t hera p y 
(Sle d ge et al. 2 0 1 7 ; J o h nst o n et al. 2 0 1 9). A be macicli b is als o a p pr o ve d i n s electe d ge o gra p hies 
i ncl u di n g t he U S as si n gle-a ge nt t hera p y f or t he tr eat me nt of H R +, H E R 2 - metastatic breast 
ca ncer ( Di c kler et al. 2 0 1 7). O S be nefit has b ee n c o nfir me d f or a be macicli b i n c o m bi nati o n wit h 
f ul vestra nt ( Sle d ge et al. 2 0 2 0) i n e n d ocri ne -resist a nt metastatic breast ca n cer . Rece ntl y, t he 
a d diti o n of a be maci cli b t o a dj u va nt e n d ocri n e t hera p y i n patie nts wit h  hi g h -ris k n o de p ositi ve 
H R + , H E R 2 - earl y-sta ge breast c a ncer de m o nstrat e d si g nifica nt re d u cti o n i n t he ris k of 
rec urre nce, i ncl u di n g r o b ust i m pr o ve me nts i n I D F S a n d D R F S (J o h nst o n et al. 2 0 2 0; Har bec k et 
al. 2 0 2 1 ). T hese d ata are t he basis f or se v eral r e g ulat or y a p pr o vals, i ncl u di n g i n t he U S. 
T he acti vit y of a b e macicli b i n pr ostate ca ncer is c urre ntl y bei n g i n vesti gate d i n se veral cli nical 
st u dies i ncl u di n g: 
 I 3 Y-M C -J P C M ( C Y C L O N E 2), a P has e 2/ 3,  ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d st u d y of a birat er o ne acetat e pl us pre d nis o ne wit h or wit h o ut 
a be maci cli b i n patie nts wit h metastatic castrati o n -resista nt pr ostate ca n cer 
[ N C T 0 3 7 0 6 3 6 5].  
 I 3 Y-M C -J P C Y (C Y C L O N E 1 ), A P hase 2 st u d y of a be macicli b i n metastatic 
castrati o n -resista nt pr ostate ca n cer patie nts pre vi o usl y treate d wit h a n o vel 
h or m o nal a ge nt a n d ta x a ne -base d c he m ot hera p y  [N C T 0 4 4 0 8 9 2 4].  
T he treat me nt la n ds ca pe of m H S P C has e v ol ve d i n rece nt y ears. T h e a d diti o n of d oceta xel 
c he m ot hera p y, a b irater o ne, e nzal uta mi de, or a p al uta mi de t o A D T si g nifica ntl y i m pr o ves 
o utc o mes  of  patie nts wit h m H S P C (S wee ne y et al . 2 0 1 5; Ja mes et al. 2 0 1 6; Fi zazi  et al. 2 0 1 7; 
Ja mes et al. 2 0 1 7; Ar mstr o n g et al. 2 0 1 9; C hi et al. 2 0 1 9 ; Da vis  et al. 2 0 1 9). H o we ver, des pite  
si g nifica nt a d va nces i n t hera p y , patie nts wit h hi g h -ris k/ hi g h-v ol u me  disease ha ve a p o or er 
pr o g n osis  wit h s h orter ti me t o pr o gressi o n a n d s ur vi val (K yria k o p o ul os et al. 2 0 1 8; Clar ke et al. 
2 0 1 9; Fizazi et al. 2 0 1 9; H o yle et a l. 2 0 1 9 ; C h o w d h ur y et al. 2 0 2 1) . T h us , t here is a pressi n g 
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2 6  
me dical nee d f or n o vel  tr eat me nt a p pr o ac hes i n t his s u b gr o u p of patie nts w h o ma y be nefit fr o m 
earl y treat me nt i nte nsificati o n wit h ne w c o m bi nati o n t hera p y . 
C Y C L O N E 3  is a, m ultice nter, m ulti nati o nal, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d 
P hase 3 st u d y t o assess t he safet y a n d efficac y of a d di n g a be macicli b t o a birater o ne pl us 
pre d nis o ne i n me n wit h hi g h -ris k m H S P C. Hi g h-ris k is defi ne d as t he prese nce of ≥4 b o n e 
metastases a n d/ or ≥1 vis ceral met astases.  
2. 2.  
B ac k gr o u n d   
2. 2. 1.  
Met ast atic H or m o ne -Se nsiti ve Pr ost ate C a ncer   
Pr ostate ca ncer  is a lea di n g ca use of m ortalit y a n d m or bi dit y gl o ball y a n d re prese nts a s u bst a ntial 
p u blic healt h b ur de n. Wit h nearl y  1. 4 milli o n ne w cases a n d 3 7 5,0 0 0  d eat hs  w orl d wi de , pr ostate 
ca ncer is t he sec o n d m ost fre q ue nt ca ncer a n d t h e fift h lea di n g ca use of ca n cer deat h a m o n g me n 
i n 2 0 2 0 ( S u n g et al. 2 0 2 1). T he i nci de n ce a n d sta g e at dia g n osis var y s u bsta ntiall y acr oss t he 
w orl d a n d is str o n gl y c orrelate d t o l ocal P S A scree ni n g pr o gra ms.  
Metastatic h or m o ne -s e nsiti ve pr ostate ca ncer is i n c ura ble a n d descri bes t he cli nical sit uati o n, 
w here b y, a patie nt wit h me tastatic pr ostate ca ncer  has eit her ne ver recei ve d treat me nt wit h A D T 
or e x hi bits o n g oi n g se nsiti vit y t o A D T.  Me n wit h m H S P C ha ve  eit her pri mar y pr o gressi ve 
metastatic disease or pres e nt wit h metastases at dia g n osis ( de n o v o m H S P C).  A p pr o xi matel y 
3 0 % of me n dia g n ose d wit h l ocalize d pr ostate ca n cer will de ve l o p met astas es  ( Ha h n et al. 2 0 1 7). 
D e n o v o metastatic dise ase  acc o u nt s f or 7 % of di a g n ose d cases i n t he U S, ~ 2 0 % i n Fra nce a n d 
U K  a n d u p t o 6 0 % i n Asi a (S E E R Ca ncer Stat Facts: pr ostate [ W W W] ; I N Ca pr ostate ca n cer 
pa ge [ W W W] ; C he n et al. 2 0 1 4 ; NI C E 2 0 2 0 ). 
W hile A D T  al o ne h as bee n t he sta n dar d of care f or m H S P C f or deca des, th e treat me nt la n dsca pe 
has ra pi dl y e v ol ve d i n rece nt years . Se veral treat me nts, i ncl u di n g d oceta xel, a birater o ne, 
e nzal uta mi de, a n d a pal ut a mi de, ha ve eac h d e m o nstrate d s ur vi val be n efit w he n use d u pfr o nt wit h 
A D T .  
D ocet a xel  
T he be nefit of a d di n g d o ceta xel t o A D T f or m H S P C was esta blis he d b y t he C H A A R T E D a n d  
S T A M P E D E ( Ar m C) trials ( S wee ne y et al. 2 0 1 5; Ja mes et al. 2 0 1 6).  
T he C H A A R T E D  st u d y was t he first st u d y t o de m o nstrate t hat a d di n g d o ceta xel t o A D T  i n me n 
i nitiati n g treat me nt f or m H S P C pr ol o n gs s ur vi val ( S wee ne y et al. 2 0 1 5). T he me dia n O S  was 
1 3. 6  m o nt hs  l o n ger wit h A D T pl us d oceta xel t ha n wit h A D T al o ne ( 5 7. 6  m o nt hs vs. 4 4. 0 
m o nt hs; H R : 0. 6 1 ). T his s ur vi val be nefit o nl y reac he d si g nifica nce i n patie nts wit h hi g h -v ol u me 
de fi ne d as t he prese n ce of visceral met astases or ≥4 b o ne lesi o ns wit h ≥1 be y o n d t he ve rte bral 
b o dies a n d pel vis  (H R: 0. 6 0; CI: 0. 4 5 – 0. 8 1; p  <  0. 0 0 1) , b ut n ot i n l o w -v ol u me disease ( H R: 
0. 6 0; CI: 0. 3 2 – 1. 1 3) .  T h e a d diti o n of d oceta xel als o le d t o si g nifica nt i m pr o ve me nts i n 
sec o n dar y e n d p oi nts, s uc h as t he ti me t o de vel o p me nt of castrati o n -resista nt pr ostate ca n cer a n d 
ti me t o cli nical pr o gressi o n, wit h t he be nefit m ore pr o n o u nce d i n all cases a m o n g patie nts wit h 
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2 7  
hi g h - rat her t ha n l o w-v ol u me disease ( S w ee ne y et al. 2 0 1 5).  I n a l o n g-ter m s ur vi val a nal ysis of 
t he C H A A R T E D st u d y, after a me dia n f oll o w -u p of 5 3. 7  m o nt hs,  t he me dia n O S was 5 7. 6 
m o nt hs f or A D T pl us d oceta xel  vs. 4 7. 2 m o nt hs f or A D T al o ne ( H R : 0. 7 2) ( K yria k o p o ul os  et al. 
2 0 1 8).  T he s ur vi val be n efit was c o nfir me d f or hi g h-v ol u me disease (5 1. 2 vs. 3 4. 4 m o nt hs, H R : 
0. 6 3)  b ut  t here w as still n o  e vi de nce of a n  O S  be n efit i n l o w -v ol u me diseas e (6 3. 5 m o nt hs vs. 
N R, H R : 1. 0 4 ). 
T he m ulti -ar m S T A M P E D E trial als o s h o we d a s ur vi val be nefit i n t he M 1 s u b gr o u p ( Ar m C), 
wit h t he a d diti o n of  d oceta xel t o sta n dar d of care  ( H R: 0. 7 6) (Ja mes et al. 2 0 1 6 ). A  retr os p ecti ve 
a nal ysis acc or di n g t o disease v ol u me  bas e d o n  t he C H A A R T E D defi niti o n c o nfir m e d t he b e nefit 
i n s ur vi val f or u pfr o nt d o ceta xel at l o n ger f oll o w -u p , h o we ver, t h ere was n o e vi de nce of 
heter o ge n eit y of treat me nt effect o n s ur vi val o ver metastatic b ur de n s u b -gr o u ps  (hi g h v ol u me: 
H R : 0. 8 1, p = 0. 0 6 4; l o w v ol u me: H R : 0. 7 6, p = 0. 1 0 7 ; i nteracti o n p =  0. 8 2 7 ) ( Clar ke et al. 2 0 1 9). 
S T A M P E D E als o recr uit e d m ore patie nts wit h de n o v o metastatic di sease ( ~ 9 5 % vs.  7 3 %), 
re pres e nti n g a differe nt n at ural hist or y of t he disease a n d t here b y, p ossi bl y e x plai ni n g t he 
differe ntial res p o nse t o t hera p y.  
 
A bir ater o ne  
T w o se parate trials ( L A TI T U D E a n d S T A M P E D E Ar m G) de m o nstrat e d t he a d diti o n of 
a birater o n e acetate t o A D T si g nifica ntl y i m pr o ve d O S i n t he m H S P C setti n g.  
L A TI T U D E  e nr olle d all ne wl y dia g n ose d patie nts wit h  at least 2 of 3  ris k fact ors: a Gleas o n 
sc ore of ≥8 , ≥3 b o n e metast ases, or t he prese n ce of meas ura bl e visceral metastasis . T he me dia n 
r P F S was 3 3. 0 m o nt hs i n t he a birater o ne gr o u p a n d 1 4. 8 m o nt hs i n t he place b o gr o u p ( H R: 0. 4 7) 
( Fizazi et al. 2 0 1 7). After a me dia n f oll o w -u p of 5 1. 8  m o nt hs,  t he me dia n O S was si g nifica ntl y 
l o n ger i n t he a birat er o ne gr o u p t ha n i n t he place b o gr o u p  ( 5 3. 3 vs. 3 6. 5 m o nt hs; H R : 0. 6 6) 
(Fizazi et al. 2 0 1 9 ). I n a p ost h oc a nal ysis  patie nts were  str atifie d base d o n disease v ol u me, 
defi ne d usi n g t he C H A A R T E D criteria. I n patie nts wit h hi g h -v ol u me disease, a birater o ne 
i m pr o ved r P F S b y 1 9 m o nt hs ( 3 3. 1 vs. 1 4. 7 m o nt hs; H R : 0. 4 6) a n d O S b y 1 6  m o nt hs ( 4 9. 7 vs. 
3 3. 3  m o nt hs; H R : 0. 6 2).  I n t he l o w-v ol u me s u b gr o u p, a birater o n e i m pr o ve d r P F S ( 4 9. 8 vs. 
2 2. 4  m o nt hs; H R : 0. 5 9) b ut n ot O S ( n ot reac he d i n eit her ar m; H R: 0. 7 2,  p = 0. 1 2 4 2) ( Fizazi et al. 
2 0 1 9). H o we v er, t he pr o p orti o n of l o w -v ol u me disease patie nts w as relati v el y s mall ( ~ 2 0 %, 2 4 3 
of 1 1 9 9 patie nts) a n d, i m p orta ntl y, t he st u d y was n ot p o were d f or t his s u b gr o u p a nal ysis . 
Data fr o m S T A M P E D E  (Ar m G)  c o nfir m s t he s ur vi val a d va nta ge of a d di n g a birater o n e t o 
sta n dar d A D T (H R : 0. 6 1 ) (Ja mes et al. 2 0 1 7). N ot a bl y, t his be nefit was  als o o bser ve d w he n  
stratifie d b y L A TI T U D E l o w- or hi g h -ris k criteria ( H R: 0. 6 6 a n d H R : 0. 5 4; p -i nteracti o n = 0. 3 9), 
or C H A A R T E D l o w - or hi g h -v ol u me disease ( H R: 0. 6 4 a n d H R : 0. 6 0; p -i nteracti o n = 0. 7 7) 
( H o yle et al. 2 0 1 9). 
M ore rece ntl y, P E A C E 1 , a P hase 3 ra n d o mize d st u d y wit h  a 2 x 2 fact ori al desi g n , e val uate d t he 
a d diti o n of a birater o n e pl us pre d nis o ne a n d/ or l ocal R T t o sta n dar d t hera p y wit h A D T ± 
d oceta xel i n me n wit h de n o v o m H S P C. I n t he o verall p o p ulati o n, r P F S a n d O S w ere 
si g nifica ntl y i m pr o ve d wit h a birater o ne (r P F S: 4. 5  vs. 2. 2  years , H R : 0. 5 4  a n d O S: 5. 7 vs. 4. 7 
ye ars, H R : 0. 8 2 ) (Fi z azi et al. 2 0 2 1a , 2 0 2 1 b ). Si milarl y, i n t he s u b gr o u p of patie nts w h o recei ve d 
d oceta xel  (6 0 %, n = 7 1 0 , a m o n g w h o m 6 4 % ha d hi g h disease v ol u me ), Fi zazi et al re p orte d t he 
a d diti o n of a b irater o n e i m pr o ve d b ot h r P F S a n d O S r P F S: 4. 5 vs. 2. 0 years , H R : 0. 5 0  a n d O S: 
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N E  vs. 4. 4  years, H R : 0. 7 5 ). S ur vi val be nefits were c o nsiste nt acr oss s u b gr o u ps a nal yze d , 
i ncl u di n g t he hi g h-v ol u me gr o u p (r P F S: 4. 1 vs. 1. 6 years, H R : 0. 4 7 a n d O S: 5. 1 vs. 3. 5 years , 
H R : 0. 7 2).  T he r P F S i n l o w-v ol u me was i m pr o ve d r P F S: N E vs. 2. 7 years, H R : 0. 5 8), h o we ver, 
s ur vi val data are c urre ntl y i m mat ure f or t his gr o u p. 
E nz al ut a mi de a n d a p al ut a mi de  
T hree  ra n d o mize d P has e 3 trials, E N Z A M E T, A R C H E S, a n d TI T A N de m o nstrate d t hat earl y 
treat me nt i nte nsificati o n wit h t he a d diti o n of n o vel a n dr o ge n rece pt or anta g o nists, e nzal uta mi de 
or a pal uta mi de, t o A D T dela ye d ti me t o pr o gressi o n a n d i m pr o ve d O S i n m H S P C patie nts wit h 
rela pse d or de n o v o disease ( Ar mstr o n g et al. 2 0 1 9; C hi et al. 2 0 1 9; Da vis et al. 2 0 1 9).  
H o we ver, it is u nclear if t he o bser ve d O S be nefit is mai ntai ne d irres pecti ve of disease v ol u me or 
ris k, a n d n o ne of t hes e st u dies was p o were d f or detecti n g a heter o g e neit y of effect. T he 
E N Z A M E T a n al ysis fa v ore d a s ur vi val b e nefit of e nzal uta mi de i n l o w -v o l u me disease gr o u p  
w hile  A R C H E S fa v ore d  t he hi g h -v ol u me ( Da vis et al. 2 0 1 9; Ar mstr o n g et al. 2 0 2 1). I n TI T A N, 
s u b gr o u p a nal yses fa v ore d a  s ur vi val be nefit of a p al uta mi de i n t he hi g h -v ol u me a n d hi g h -ris k 
gr o u ps ( C hi et al. 2 0 1 9 ; Oz g ur o gl u et al. 2 0 2 0).  
E N Z A M E T  all o we d t he use of c o nc urre nt d o ceta xel , w hile  A R C H E S a n d TI T A N per mitte d 
pri or treat me nt wit h u p t o 6 c ycles of d o ceta xel , re prese nti n g 4 5 %, 1 8 %, a n d 1 1 % of t he 
res pecti ve tri al p o p ulati o n s. Data fr o m  su b gr o u p a nal ys es are y et u nclear o n t he  be nefit o f a d di n g 
d oceta xel t o e n zal uta mi d e or a pal uta mi de , warra nt i n g f urt her f oll o w-u p . M ore mat ure d ata fr o m 
t he E N Z A M E T st u d y a n d i nitial data fr o m t he A R A S E N S st u d y (dar ol uta mi de wit h d oceta xel; 
N C T 0 2 7 9 9 6 0 2) are a wait e d t o hel p  clarif y t h e r ole of a n dr o ge n rece pt or i n hi bit ors  w he n 
c o m bi ne d wit h d oceta x el.  
Me dic al nee d  
H i g h disease b ur de n is c o nsi dere d a n i n de pe n de nt pr o g n ostic fact or f or m H S P C ( Fra nci ni et al. 
2 0 1 8)  a n d pla ys a n i m p orta nt r ole w he n sel ecti n g a p pr o priate treat me nts. Base d o n m ost c urre nt 
g ui deli nes,  A D T wit h a birater o n e, a pa l uta mi de, e n zal uta mi de or d oceta xel are acce pta ble 
treat me nt o pti o ns f or t he i nte n de d st u d y p o p ulati o n.  W hile o utc o mes of patie nts prese nti n g wit h 
de n o v o or rec urre nt  hi g h -ris k/v ol u me  m H S P C  were i m pr o ve d wit h  c o m bi n ati o n t hera p y, t his 
gr o u p  of patie nts  still e x perie nces sh orter  ti me t o pr o gressi o n t o castr ati o n -resista nt disease a n d 
dis mal s ur vi val c o m pare d t o t he l o w -ris k/v ol u me gr o u p . T h us, t here is a pressi n g u n met nee d f or 
n o vel treat me nt a p pr oac h es, partic ularl y i n t his p o or pr o g n osis gr o u p of patie nts f or w h o m earl y 
treat me nt i nte nsificati o n has t he p ote ntial t o de m o nstrate cli nicall y mea ni n gf u l i m pr o ve me nts.  
T his  P hase 3, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y will  e val uate t he safet y a n d 
effic ac y of a d di n g  a be ma cicli b t o a birater o n e pl us pre d nis o ne i n patie nts wit h hi g h-ris k m H S P C. 
2. 2. 2.  
A be m acicli b   
D uri n g t he cell c y cle, t he G 1 restricti o n p oi nt c o ntr ols e ntr y i nt o S p hase a n d is esse ntial f or 
mai ntai ni n g c o ntr ol of cell di visi o n ( S herr 1 9 9 6; Orte ga et al. 2 0 0 2). T he C D Ks 4 a n d 6 
partici pate i n a c o m ple x wit h D -t y pe c ycli ns t o i nitiate t he tra nsiti o n t hr o u g h t he G 1 restricti o n 
p oi nt b y p h os p h or ylati n g a n d i nacti vati n g t he R b t u m or -s u p press or pr ot ei n. 
Alterati o ns i n t his pat h wa y occ ur fre q u e ntl y i n h u ma n ca ncers a n d i n v ol ve ( 1) l oss of C D K 
i n hi bit ors b y m utati o n or e pi ge netic sile nci n g, ( 2) m utati o n/ o vere x pressi o n of eit her C D K 4 a n d 
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C D K 6 or c ycli n D, or ( 3) i nacti vati o n of R b. T hes e alterati o ns re n der cells less de pe n de nt o n 
mit o ge nic si g nali n g f or pr oliferati o n. A part fr o m  th ose t u m ors wit h c o m plete i nacti vati o n of R b, 
w hic h f u ncti o ns d o w nstr ea m of t he C D K 4 a n d C D K 6 – c ycli n D c o m ple x, all of t hese ca ncers are 
p ote ntiall y se nsiti ve t o p har mac ol o gic i n hi biti o n of C D K 4 a n d C D K 6. Fr o m a t hera pe utic 
sta n d p oi nt, t he g oal of i n hi bitin g C D K 4 a n d C D K 6 wit h a s mall -m olec ule i n hi bit or is t o pre ve nt 
cell c ycle pr o gressi o n t hr o u g h t he G 1 restricti o n p oi nt, t h us arresti n g t u m or gr o wt h.  
A be macicli b is a n oral, selecti ve, a n d p ote nt A T P -c o m petiti ve i n hi bit or of C D K 4 &  6  t hat is 
a d mi nistere d o n  a c o nti n u o us d osi n g sc he d ule. T h e cli nical acti vit y of a b e macicli b has bee n 
e xte nsi vel y st u die d i n H R + , H E R 2- a d va n ce d a n d M B C , a n d m ost rece ntl y as a dj u va nt t hera p y 
i n hi g h -ris k n o de p ositi ve H R + H E R 2 - earl y-sta g e breast ca ncer . 
A be macicli b m o n ot hera p y de m o nstrate d mea ni n gf ul a ntit u m or acti vit y i n hea vil y pretreate d 
h or m o ne refract or y H R +, H E R 2 - metastatic breast ca ncer wit h res p o ns e rates of 1 9. 7 % a n d 
2 8. 6 % o bser ve d i n t he P hase 2 si n gle -ar m st u d y M O N A R C H 1 ( N C T 0 2 1 0 2 4 9 0) a n d i n t he 
P hase 2 r a n d o mize d st u d y ne xt M O N A R C H ( N C T 0 2 7 4 7 0 0 4), res pecti vel y ( Dic kler et al. 2 0 1 7; 
Ha milt o n et al. 2 0 1 9).  
I n M O N A R C H 2, a  P has e 3  ra n d o mize d, pl ace b o-c o ntr olle d st u d y  ( N C T 0 2 1 0 7 7 0 3), the  a d diti o n 
of a be ma cicli b t o f ul vestra nt si g nifica nt l y i m pr o ved  P F S c o m pare d t o f ul vestra nt al o ne ( 1 6.4  
m o nt hs vs. 9. 3 m o nt hs, H R : 0. 5 5 3 ; 9 5 % CI: 0.4 4 9 , 0.6 8 1 ). I n patie nts wit h meas ura ble disease, 
a be maci cli b pl us f ul vestra nt ac hie v e d a n O R R of 4 8. 1 % ( 9 5 % CI, 4 2. 6 % t o 5 3. 6 %) c o m pare d 
wit h 2 1. 3 % ( 9 5 % CI, 1 5. 1 % t o 2 7. 6 %) i n t he c o ntr ol ar m ( Sle d ge et al. 2 0 1 7). I m p orta ntl y, O S  
was si g nifica ntl y i m pr o ve d i n t he a be macicli b ar m c o m pare d t o t he c o ntr ol ar m ( 4 6. 7 m o nt hs vs. 
3 7. 3 m o nt hs, H R : 0. 7 6 ; 9 5 % CI, 0. 61 -0. 9 5 ), a n d t his  s ur vi val be nefit was c o nsiste nt acr oss 
s u b gr o u ps, i ncl u di n g patie nts wit h visceral metast ases ( Sle d ge et al. 2 0 2 0). 
I n t he P h ase 3 ra n d o mize d, place b o-c o ntr olle d M O N A R C H 3 st u d y  ( N C T0 2 2 4 6 6 2 1 ), t he 
a d diti o n of a be maci cli b t o a n o nster oi dal AI as i nitial treat me nt of H R +, H E R 2 − a d va nce d breast 
ca ncer pr o vi de d a si g nifica nt i m pr o ve me nt i n P F S ( 2 8. 2 m o nt hs vs . 1 4. 8 m o nt hs; H R : 0. 5 4; 9 5 % 
CI:  0. 4 2  t o 0.7 0 ) a n d O R R ( meas ura ble disease: 6 1. 0 % vs. 4 5. 5 %) c o m pare d t o place b o pl us AI 
(J o h nst o n et al. 2 0 1 9). T he O S data fr o m t his st u d y c o nti n ue t o mat ure.  
I n m o narc h E, a  P hase 3 ra n d o mize d, o pe n -l a bel st u d y (N C T 0 3 1 5 5 9 9 7), a b e macicli b was st u die d 
i n c o m bi nati o n wit h a dj u va nt e n d ocri ne t h era p y i n patie nts wit h hi g h -ris k, n o de p ositi ve H R + 
H E R 2 - earl y-st a ge breast ca ncer.  At t he ti me of pri mar y a nal ysis  (J o h nst o n et al. 2 0 2 0), aft er a 
me dia n f oll o w u p of 1 9 m o nt hs , pa tie nts treate d wit h a be macicli b pl us a dj u va nt  e n d ocri ne 
t hera py de m o nstrat e d a 2 9 % re d ucti o n i n t he ris k of rec urre n ce (H R : 0. 7 1, 9 5 % CI: 0. 5 8 t o 0. 8 7; 
p =. 0 0 0 9 ) Li ke wise , after 2 7 m o nt hs of f oll o w -u p , i m pr o ve d rates of I D F S a n d D R F S were 
mai ntai ne d  (Har bec k et al . 2 0 2 1 ). 
T he m ost c o m m o n a d verse reacti o ns  f or a b e macicli b (i nci de nce ≥2 0 %) are diarr hea, 
ne utr o pe nia, na us ea, a b d o mi nal pai n, i nfecti o ns, fati g ue, a ne mia, le u k o pe nia, decrease d a p petite, 
v o miti n g, hea dac he, al o pecia, a n d t hr o m b o c yt o pe nia  (Verze ni o  pac ka g e i nsert, 2 0 2 1 ). 
A be macicli b ( V E R Z E NI O [S ]) is c urre ntl y a p pr o ve d f or t he treat me nt of H R + H E R 2 − brea st 
ca ncer. F or details see l ocal pres cri bi n g i nf or mati o n. 
Details o n t he safet y pr ofile of m o n ot hera p y a b e m acicli b as well i n c o m bi n ati o n wit h ot her 
a ge nts are a vaila ble i n t h e I B.  
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2. 2. 3.  
A bir ater o ne   
A birater o n e, t he acti ve meta b olite of a bira t er o ne acetate, irre versi bl y i n hi bits c yt oc hr o me P 4 5 0 
( C Y P) 1 7 ( 1 7 α-h y dr o x ylase/ C 1 7, 2 0 -l yase), a n ess e ntial e nz y me i n a n dr o ge n bi os y nt hesis t hat is 
e x presse d i n testic ular, a dre nal a n d pr ostatic t u m or tiss ues. A birater o n e acetate is a p pr o ve d i n 
c o m bi nati o n  wit h pre d nis o ne f or t he treat me nt of p atie nts wit h hi g h -ris k m H S P C a n d m C R P C 
(a birater o ne acetat e pac k a ge i nsert , 2 0 2 0 ). 
F or m ore i nf or mati o n, refer t o t he a bir ater o n e prescri bi n g i nf or mati o n.   
2. 3.  
Be nefit/ Ris k Assess me nt   
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits, ris ks, S A Es, a n d reas o na bl y 
a ntici pated  A Es of a be m acicli b ca n b e f o u n d i n t h e I B. I nf or mati o n o n  A Es e x pecte d t o b e 
relate d t o a b e macicli b ca n be f o u n d i n I B. I nf or m ati o n o n S A Es e x pecte d i n t he st u d y p o p ulati o n 
i n de pe n de nt of dr u g e x p os ure will be assesse d b y t he s p o ns or i n a g gre g ate peri o dicall y d uri n g 
t he c o urse of t h e st u d y a n d ma y be f o u n d i n t he I B. 
M ore deta ile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d ris ks of a birater o ne, 
pre d nis o ne  (or pre d nis ol o ne) , a n d bac k gr o u n d t hera p y wit h L H R H a g o nists/a nta g o nists  ma y be 
f o u n d i n t he f oll o wi n g: Patie nt I nf or mati o n Leaflet, Pac ka ge I ns ert, or S u m mar y of Pr o d uct 
C haracteristics . 
2. 3. 1.  
Ris k Assess m e nt   
St u d y I nter ve nti o n  
T his st u d y ai ms t o c o m pare t he effic ac y a n d safet y of a be macicli b a n d a bir ater o ne pl us 
pre d nis o ne (e x peri me ntal ar m) vers us pl ace b o a n d a birater o n e pl us pre d nis o ne  (c o ntr ol ar m) i n 
partici pa nts wit h hi g h -ris k m H S P C. All partici pa nts will recei ve a n esta blis he d acti ve tr eat me nt 
wit h a birater o n e pl us pre d nis o ne a n d will c o nti n ue A D T  t hr o u g h o ut t he st u d y. A birater o n e pl us 
pre d nis o ne  as t he c o ntr ol ar m refl ects a n acce pta bl e treat me nt o pti o n f or hi g h -ris k m H S P C per 
E S M O a n d N C C N g ui deli nes ( Par ker et al. 2 0 2 0; N C C N 2 0 2 2 ).  
He mat ol o g y, he patic, a n d re nal f u n cti o n tests will be re g ularl y m o nit ore d t hr o u g h o ut t he st u d y i n 
acc or da nce wit h a be ma ci cli b a n d a birater o ne pres cri bi n g i nf or mati o n. I ncrease d s usce pti bilit y t o 
i nfecti o n will be m o nit ore d wit h re g ular he mat ol o g y m o nit ori n g. T hese acti vities  e na ble 
a p pr o priate i n v esti gat or o versi g ht  f or i de ntificati o n a n d ma na ge m e nt of A Es .  
A p pr o priate s afet y ass ess me nts, o n -st u d y m o nit ori n g, a n d A E ma na g e me nt are det aile d i n 
Secti o n 8. 3  a n d i n t he S o A i n Secti o n 1. 3 . 
St u d y Pr oce d ures  
Detaile d sc he d ul e of st u d y pr oce d ures is i n Secti o n 1. 3 .  
Partic i pa nts will u n der g o re g ularl y sc h e d ule d bl o o d dra ws b y ve ni p u nct ure, w hic h is c o m m o n i n 
cli nical practice wit h l o w ris ks of c o m plicati o ns . 
T o e ns ure o pti mal ma na g e me nt o f A Es a n d ma xi mize s u p p orti ve care, d os e a dj ust me nt f o r A Es 
of a be ma cicli b/ place b o a n d a birater o n e, al o n g wit h s pecific g ui deli nes o n ma na ge me nt f or A D Rs 
( he mat ol o gic t o xicities, diarr hea, A L T/ A S T i ncrease d, I L D/ p ne u m o nitis, V T E, h y perte nsi o n, 
a dre nal i ns ufficie nc y, a n d h y p o gl yce mia) are pr o vi de d i n t he pr ot oc ol.   
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Partici pa nts will u n der g o re g ular ra di ol o gical i ma gi n g t o assess f or cli nical be nefit as per 
i nter nati o nal g ui deli nes (M ottet et al. 2 0 2 1 ; N C C N 2 0 2 2). T he 1 2- a n d 1 6-wee ks  i ma gi n g 
i nter vals use d i n t his st u d y a p pear reas o na ble a n d are c o nsiste nt wit h P C W G 3 rec o m me n d ati o ns 
i n metastatic pr ostate ca n cer cli nic al trials. T he i n vesti gat or i n c o nj u ncti o n wit h g ui da nce 
pr o vi de d i n Secti o n 1. 3  a n d Secti o n 1 0. 9 , A p pe n di x 9 will select a p pr o priat e i ma gi n g st u d y.  
A n i n de pe n de nt D M C will be c o m missi o ne d t o re vie w t he safet y a n d efficac y of t he tr eat me nt 
c o m bi nati o n a n d ma ke rec o m me n dati o ns as t o t he f ut ure c o n d u ct of t he st u d y. T he s p o ns or will 
m o nit or bli n de d data o n a n o n g oi n g basis wit h t he i nte nt of earl y safet y si g nal i de ntificati o n a n d 
ris k mi ni mizati o n. 
2. 3. 2.  
Be nefit Assess m e nt   
Des pite t hera p e utic a d v a nces i n m H S P C, t here is still a pressi n g u n met me dical  nee d f or tail ore d 
treat me nt a p pr o ac hes, p artic ularl y f or p atie nts wit h hi g h-ris k disease w h o e x perie nce s h orter 
s ur vi val o utc o mes wit h c urre nt a p pr o v e d treat me nts. F or t hese hi g h -ris k patie nts, earl y treat me nt 
i nte nsificati o n wit h n o vel c o m bi nati o n t hera p y has t he p ote ntial t o mea ni n gf ull y i m pr o ve cli nical 
o utc o mes.  
A be macicli b is a p ote nt a n d selecti ve oral i n hi bit or t hat has de m o nstrate d si g nifica nt cli nical 
be nefit a n d i m pr o ve d o v erall s ur vi val i n H R +, H E R 2 - metastatic breast ca ncer , i ncl u di n g 
s ub gr o u ps wit h a d verse pr o g n ostic fact ors . 
 
 
 
 
 
  
All partici pa nts will recei ve acti ve b ac k gr o u n d t hera p y wit h a birat er o ne pl us pre d nis o ne a n d will 
c o nti n ue A D T  t hr o u g h o ut t he st u d y. 
 
 
 
  
2. 3. 3.  
O ver all Be nefit Ris k C o ncl usi o n   
T he p ote ntial ris ks of a be macicli b i n c o m bi nati o n wit h a birater o n e pl us pre d nis o ne are j ustifie d 
i n c o nsi derati o n of t he m eas ures t o mi ni mize t hes e ris ks a n d t he a ntici pat e d be nefit of i m pr o ve d 
disease c o ntr ol, as m eas ure d b y i m pr o ve d rP F S i n partici pa nts wit h hi g h -ris k m H S P C, a n 
i nc ura ble disease wit h a p o or pr o g n osis. F or t hes e hi g h-ris k patie nts, earl y i nte nsificati o n wit h 
t his n o vel c o m bi nati o n t hera p y has t h e p ote ntial t o mea ni n gf ull y i m pr o ve cli nical o utc o mes.  
Ta ki n g i nt o acc o u nt t he a b o ve meas ur es, it is deter mi ne d t hat t he p ote ntial ris ks t o t he 
partici pa nts are reas o na bl e i n relati o n t o t he a ntici pate d  be nefits f or partici pati n g i n t he st u d y . 
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C CI

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3.  
O bjecti ves , E n d p oi nts , a n d Esti m a n ds  
 
O bjecti ves  
E n d p oi nts  
Pri mar y  
 
 T o deter mi ne w het her  a d di n g a b e macicli b t o  
a birater o ne pl us pre d nis o ne
a i m pr o ves 
ra di o gra p hic pr o gressi o n-free s ur vi val (r P F S).  
 r P F S assesse d b y t he i n vesti gat or . 
Sec o n dar y  
 
 T o e v al uate i m pr o ve me nts i n ot her cli nicall y 
rele v a nt efficac y  e n d p oi nts wit h t he a d diti o n of 
a b e macicli b t o a birater o ne pl us pre d nis o ne.  
 r P F S b y bli n de d, i n de pe n de nt, ce ntral re vie w ( BI C R)  
 Cli nical P F S  (c P F S) 
 C astrati o n -resista nt pr ostate c a ncer ( C R P C)-free 
s ur vi val 
 Ti me t o s y m pt o matic pr o gressi o n  
 Ti me t o P S A  pr o gressi o n   
 Ti me t o i nitiati o n of ne w a ntica ncer t hera p y  
 O verall sur vi val ( O S) . 
 T o c h aracterize t he safet y of a d di n g 
a b e macicli b  t o a birater o ne pl us pre d nis o ne.   
 T he safet y e n d p oi nts e val uate d will i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: A Es, T E A Es, S A Es, cli nical 
la b orat or y tests, E C Gs, vital si g ns, a n d p h ysical 
e xa mi nati o ns.   
 T o c h aracterize t he P K of  a b e macicli b  w he n 
a d mi nistere d i n c o m bi nati o n wit h a birater o ne.   
 C o nce ntrat i o ns of a be macicli b. 
 T o assess patie nt -re p orte d pai n a n d H R Q o L .   
 Ti me t o p ai n p r o gressi o n 
 Ti me t o deteri orati o n i n  H R Q o L  meas ure d b y t he 
F A C T -P ( P h ysical Well -Bei n g a n d P C S sc ores) a n d 
E Q -5 D -5 L.  
E x pl orat or y  
 
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A b bre viati o ns:  A E = a d verse e v e nt; E C G = electr ocar di o gra m;  E Q -5 D -5 L  = E ur o pea n Q ualit y of Life –  5 
di me nsi o ns –  5 le vel ; H R Q o L = Healt h -relate d q ualit y of life; F A C T-P = F u ncti o nal Assess me nt of Ca ncer 
T hera p y -Pr ostate; P K = p har mac o ki netics; P R O -C T C A E = Patie nt -Re p orte d O utc o mes -C o m m o n Ter mi n ol o g y 
Cr iteria f or A d verse E ve nts; P S A = pr ostate -s pecific a nti ge n; R E CI S T = Res p o nse E val uati o n Criteria i n S oli d 
T u m ors; S A E = seri o us a d verse e v e nt ; T E A E = treat me nt-e mer ge nt a d verse e ve nt.  
a P re d nis o ne i m plies pred nis o ne or pre d nis ol o ne.   
 
Pri m ar y esti m a n d  
T he pri mar y researc h q u esti o n is: W hat is t he differe nce i n r P F S w he n a d di n g a be macicli b or 
place b o  t o a birater o ne pl us pre d nis o ne i n patie nts wit h hi g h -ris k m H S P C? 
T he esti ma n d f or t he pri mar y o bjecti ve is descri b e d b y t he f oll o wi n g attri b utes:  
 P o p ulati o n: a d ult me n  wit h hi g h -ris k m H S P C  ra n d o mize d t o st u d y ar ms ( pri mar y 
a nal ysis p o p ulati o n). F urt her details ca n b e f o u n d i n Secti o n 5 . 
 E n d p oi nt: i n vesti gat or -assesse d r P F S i n t he pri mar y a nal ysis p o p ulati o n, w hic h is defi ne d 
as t he ti me fr o m ra n d o mi zati o n u ntil  
o  first occ urre nce of d oc u me nte d ra di o gr a p hic dise ase pr o gressi o n , or 
o  deat h fr o m a n y ca use . 
 Treat me nt c o n diti o n: A b e macicli b 
 a n d a birater o n e 
 pl us 
pre d nis o ne 
 will be c o m pare d t o  place b o  
 a n d  a birater o ne 1 
 
 pl us pre d nis o ne 
. S t u d y i nter ve nti o n will be a d mi nistere d u ntil ra di o gra p hic 
pr o gressi o n, u nacce pta bl e t o xicit y, or u ntil ot her  disc o nti n uati o n criteria are met (see 
Secti o n 7. 1 ). F urt her details o n st u d y i nter ve nti o n, c o nc o mita nt t hera p y, a n d d ose 
m o dificati o n, ca n be f o u n d i n Secti o n 6 . 
 I nterc urre nt-e ve nt strate gies (I E S):  
o  St u d y i nter ve nti o n disc o nti n uati o n pri or t o ra di o gra p hic pr o gressi o n  or deat h 
wit h o ut pri or pr o gressi o n  is ha n dle d  wit h 
 
 
o  T he i nitiati o n of ne w a ntica ncer t hera p y pri or t o d oc u me nte d diseas e pr o gressi o n 
or deat h wit h o ut pri or  pr o gressi o n  is ha n dle d wit h  
 
 
 
o  E xte n de d ti me wit h o ut a de q uate ass ess me nt pri or t o d oc u me nte d disease 
pr o gressi o n or deat h  wit h o ut pri or pr o gressi o n  is h a n dle d wit h 
 
 
  
 P o p ulati o n -le vel s u m mar y meas ure: H azar d rati o of rP F S i n t he e x peri me ntal ar m v ersus  
t he c o ntr ol ar m esti mate d usi n g a stratifie d C o x re gressi o n m o del ( C o x 1 9 7 2) . 
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 Rati o nale f or  I E S: T he i nterest lies i n t he  treat me nt effect re gar dless of st u d y i nter ve nti o n 
disc o nti n uati o n  a n d wit h o ut t he c o nf o u n di n g effect of  t he start of a ne w a ntica ncer 
t hera p y or e xten de d ti me wit h o ut a de q uate ass ess me nt.    
o  St u d y i nter ve nti o n disc o nti n uati o n d ue t o reas o ns ot her t ha n d oc u me nte d 
ra di o gra p hic dise ase pr o gressi o n or deat h wit h o ut pri or pr o gressi o n  is ha n dle d 
wit h 
 Ti me fr o m ra n d o mizati o n 
u ntil d oc u me nte d disease pr o gressi o n or deat h wit h o ut pri or pr o gressi o n  
re gar dl ess of st u d y i nter v e nti o n disc o nti n uati o n will be c o nsi dere d i n t he 
a nal ysis.   
o  T he  initiati o n of ne w  a ntica ncer t hera p y  c o ul d ha p pe n  pri or t o o bser vi n g a n r P F S 
e ve nt a n d p ote ntiall y c o nf o u n d t he assess me nt of t he pri mar y e n d p oi nt . 
 
  
o  Disease pr o gressi o n o bser ve d aft er a n e xte n de d ti me wit h o ut  a de q uate  t u m or 
assess me nt ma y ha ve o cc urre d m uc h earlier b ut is n ot re p orte d beca use t h e 
sc he d ule d ass ess me nt was n ot d o ne. T his i na de q uate o bser vati o n ma y  i ntr o d uce 
bias t o  r P F S esti mates. If e xte n de d ti me wit h o ut  a de q uate ass ess me nt occ urs,  
 
 
 
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4.  
St u d y Desi g n   
4. 1.  
O ver all  Desi g n   
C Y C L O N E 3  is a m ultice nter, m ulti nati o nal, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d , 
P hase 3 st u d y t o assess t he safet y a n d efficac y of a d di n g a be macicli b t o a birater o ne pl us 
pre d nis o ne i n patie nts wit h hi g h -ris k m H SP C. Hi g h -ris k is defi ne d as t he prese nce of ≥4 b o ne 
metastases a n d/ or ≥1 vis ceral met astases.  
A p pr o xi matel y 9 0 0  parti ci pa nts (see Secti o n 5  f or st u d y p o p ulati o n) will be ra n d o mize d  i n a 1: 1 
rati o. 
Tre at me nt Ar ms:  
A bir ater o ne a n d pre d nis o ne ( or pre d nis ol o ne):  
All partici pa nts will recei ve t hera p y wit h a birater o ne 
 pl us pre d nis o ne 
 
Pre d nis ol o ne ma y be use d i n lie u of pre d nis o ne per l ocal a birater o ne prescri bi n g i nf or mati o n or 
w here pre d nis o ne is n ot c o m merciall y a vaila ble.  
Bli n de d st u dy dr u g : 
 E x peri me ntal ar m: A b e macicli b  
orall y 
 T he d os e has bee n 
deter mi ne d i n t he P hase 2/ 3 St u d y C Y C L O N E 2 (see Secti o n 4. 3 ).  
 C o ntr ol ar m: Place b o  
 orall y 
 
A birater o n e, pre d nis o ne , a n d a be ma cicli b/ place b o, will be i nitiate d ≤7 da ys f oll o wi n g 
ra n d o mizati o n a n d a d mi nistere d o n Da ys 1 t hr o u g h 2 8 of a 2 8 -da y c ycle u ntil disease 
pr o gressi o n, u nacce pta bl e t o xicit y, or ot her disc o nti n uati o n criteria are met (see Secti o n 7. 1 ). 
Details o n treat me nt a d mi nistrati o n ar e descri be d i n Secti o n 6. 1 . 
N ote: Partici pa nts w h o h a ve n ot u n der g o n e bilateral orc hiect o m y are re q uir e d t o c o nti n ue 
bac k gr o u n d A D T  wit h a n  L H R H a g o nist/a nta g o nist  t hr o u g h o ut t he st u d y. 
Str atific ati o n:  
Ra n d o mizati o n will be  stratifie d acc or di n g t o t he f oll o wi n g fact ors:  
 de n o v o metastatic pr ostate ca ncer (m etastatic dise ase  at i nitial dia g n osis)  ( Yes vs. N o ). 
 visceral metastas es ( Yes vs. N o) . 
T hese stratificati o n criteria were s elect e d beca use t he y re prese nt i m p orta nt pr o g n ostic fact ors 
a n d/ or a n i m bala nce t hat ma y bias st u d y res ults.  
Pri m ar y e n d p oi nt:  
T he pri mar y e n d p oi nt of t he st u d y is i n vesti gat or-assesse d  r P F S or deat h fr o m a n y ca use, 
w hic he ver occ urs first.  Ot her  st u d y e n d p oi nts are liste d i n Secti o n 3 . 
Pla n ne d a nal yses wit h detaile d descri pti o ns are liste d i n Secti o ns 9. 4. 2  a n d 9. 4. 3 . 
Partici pa nt s will be m o nit ore d  t hr o u g h o ut t he st u d y f or safet y a n d ha v e pr oce d ures p erf or me d  as 
o utli ne d i n t he S o A  (see Secti o n  1. 3 ). 
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All partici pa nts disc o nti n ui n g st u d y treat me nt will e nter t he s h ort - a n d l o n g -ter m f oll o w-u p 
peri o ds a n d ha v e pr oce d ures perf or me d as s h o w n i n t he S o A  ( Secti o n 1. 3 ), e xce pt t h ose l ost t o 
f oll o w-u p, t he partici pa nt wit h dre w c o nse nt or die d.  
I n a d diti o n, partici pa nts  disc o nti n ui n g treat me nt pri or t o d oc u me nte d ra di o gra p hic pr o gressi o n 
will c o nti n ue t o ha ve sc h e d ule d disease assess me nts u ntil d oc u me nte d ra di o gra p hic pr o gressi o n 
a n d will be f oll o we d f or t he de vel o p me nt of s y m pt o matic pr o gressi o n.  
Partici pa nts  disc o nti n u i n g treat me nt d ue t o d oc u m e nte d ra di o gr a p hic pr o gressi o n will be 
f oll o we d f or t he d e vel o p me nt of s y m pt o matic pr o gressi o n.  
All patie nts will be f oll o we d f or s ur vi v al.  
Ill ustrati o n of t he st u d y d esi g n is i n Secti o n 1. 2 . 
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n   
T he o verall rati o nale f or t he st u d y is descri be d i n S ecti o n 2. 1 . S pecific desi g n as pects are 
disc usse d bel o w:  
A ra n d o mize d, c o ntr olle d desi g n is bei n g use d i n t his st u d y. Ra n d o mizati o n mi ni mizes 
s yste matic bias i n t he selecti o n a n d assi g n me nt of patie nts t o st u d y t hera p y a n d pr o vi des 
j ustificati o n f or i nfere ntial statistical met h o ds t o be use d o n data fr o m t his st u d y. Usi n g a n 
a p pr o priate c o nc urre nt c o ntr ol ar m e na bles direct statistical esti mati o n of be nefits a n d har ms d ue 
t o st u d y t hera p y a n d mi ni mizes bias i n t he assess m e nt a n d i nter pretati o n of o bser ve d treat me nt 
effects. T he eli gi bilit y criteria  w ere caref ull y c o nsi dere d t o e ns ure t he e nr olle d partici pa nts  are 
re pres e ntati ve of p atie nts wit h hi g h -ris k m H S P C, mi ni mizi n g hete r o ge neit y w hile mai ntai ni n g 
cli nical rele v a nce a n d ali g n me nt wit h  c urre nt treat me nt g ui deli nes. T heref ore, p atie nts will be 
stratifie d f or ke y  fact ors ass ociate d wit h cli nical o utc o mes t o f urt her re d uce t he p ote ntial f or bias 
a n d i m pr o ve t he p o wer of t he a nal yses.  
I n v esti gati o nal dr u g  a d mi nistrati o n i n t his st u d y is d o u ble -bli n d  a n d is place b o c o ntr olle d. T his 
i m plies t hat patie nts are bli n de d t o t heir treat me nt assi g n me nt a n d t hat i n vesti gati o nal sites a n d 
t he s p o ns or st u d y tea m d o n ot ha ve i m me diate access t o treat me nt assi g n me nts f or a n y p atie nts. 
T h ese desi g n f eat ure s f urt her mi ni mize p ote ntial bias d ue t o k n o wle d ge of patie nt’s treat me nt 
d ur i n g e val uati o n of st u d y e n d p oi nts, at t he patie nt le vel or a g gre gate d acr oss patie nts. 
Dela yi n g t he e mer ge nce or t he pr o gressi o n of ra di o gra p hicall y detecta ble dista nt metastases is a 
cli nicall y rele va nt e n d p oi nt f or t he deter mi nati o n of t he be nefit of t he  st u d y treat me nt t hat is n ot 
i m pacte d b y p ost-treat me nt a ntica ncer t hera pi es. T heref ore, t he s electe d pri mar y e n d p oi nt of t he 
st u d y is i n vesti gat or-assesse d r P F S , w hic h ta kes i nt o acc o u nt s pecificities of  m etastatic pr ostate 
ca ncer w hic h  is a h eter o g e ne o us diseas e t hat pr o gresses t hr o u g h m ulti ple cli nical ste ps wit h a 
hi g h pre vale nce of b o n e metastases. Pr o gressi o n of metastatic b o ne dise as e is of para m o u nt 
cli nical i m p orta nce si nc e it is res p o nsi ble f or t he se vere m or bi dit y of s kelet al -relat e d e ve nts s uc h 
as s y m pt o matic fract ur es, pai n, s ur ger y or p alliati ve ra diati o n t o b o ne, a n d s pi nal c or d 
c o m pressi o n.  
Res p o nse E val uati o n Criteria i n S oli d T u m ors, Versi o n 1. 1 desi g nates n u mer o us lesi o ns as 
n o n meas ura ble. T h ese i n cl u de b o ne metastas es w it h o ut a s oft tiss ue c o m p o ne nt meas uri n g ≥1 0 
m m (t he lar ge maj orit y of b o ne metastases). C o n ve nti o nal R E CI S T als o lac ks pr o visi o ns t o 
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differe ntiat e tr ue pr o gressi o n of b o ne metastasis fr o m t he flare, a para d o xical w orse ni n g of t he 
b o ne sca n attri b ute d t o b o ne heali n g as a res ult of a fa v ora ble a ntit u m or effect.  
T o e ns ure c o nsiste nt a n d re pr o d uci ble assess me nt of r P F S a n d c o ntr ol f or t u m or flare, c riteria f or 
defi ni n g pr o gress i o n of disease b y b o ne s ca ns ha v e bee n d e vel o pe d b y t he Pr ostate Ca ncer 
Cli nical T rials W or ki n g Gr o u p  ( P C W G) a n d us e d wi del y i n  metastatic pr ostate ca ncer  
ran d o mize d trials .  
I n t his st u d y, t he c o nse ns us g ui deli nes of t he R E CI S T 1. 1 f or s oft tiss ue a n d t he P C W G f or b o ne 
are ta k e n i nt o c o nsi derati o n a n d a da pte d f or t his hi g h-ris k m H S P C patie nt p o p ulati o n f or t he 
deter mi nati o n of r P F S. T he r P F S ( w hic h als o i ncl u des deat h fr o m a n y  ca us e) will be assess e d b y 
t he i n vesti gat or/l ocal ra di ol o gist f or t he pri mar y e n d p oi nt, a n d r P F S b y BI C R will be e val uate d 
as a sec o n d ar y e n d p oi nt.  
T o c o m ple me nt t he pri mar y e n d p oi nt of r P F S, ot her cli nicall y rel e va nt as p ects of diseas e 
pr o gressi o n s uc h as s y m pt o matic pr o gressi o n, P S A pr o gressi o n, a n d t he i nitiati o n of ne w 
a ntica ncer t hera p y are assesse d i n sec o n dar y e n d p oi nts. I m p orta nt ly, O S  will als o be assesse d as 
a sec o n dar y e n d p oi nt. At t he ti me of t he r P F S pri mar y o utc o me, it  is li kel y t hat O S  will be 
i m mat ure. H o we ver, gi ve n t he p ositi ve c orrelati o n bet wee n dise ase pr o gressi o n a n d O S f or 
patie nts wit h metastatic p r ostate ca n cer ( Rat h k o pf et al. 2 0 1 8 ; Mae da et al . 2 0 2 1 , W o o et al. 
2 0 2 1), it is a ntici pate d t hat a cli nicall y rel e va nt be nefit i n r P F S is e x pecte d t o tra nslate i nt o a 
s ur vi val be nefit wit h l o n ger f oll o w-u p.  
I n t his st u d y, c ollecti o n of de m o gra p hic i nf or mati o n i ncl u des race a n d et h nicit y . T he scie ntific 
rati o nale is base d o n t he nee d t o assess varia ble res p o nse i n safet y a n d/ or efficac y b ase d o n race  
a n d/or et h nicit y . 
4. 3.  
J ustific ati o n f or D ose   
I n C Y C L O N E 3, a be m acicli b ( or matc he d place b o) will be at a d mi nistere d at a d ose of 
 
 i n c o m bi nati o n wit h a birater o n e 
 pl us pre d nis o ne  
 o n a 2 8-da y  
c o nti n u o us d osi n g sc he d ule. 
A be m acicli b  
T he a p pr o ve d starti n g d ose of a be m acicli b i n breast ca ncer is: 
 1 5 0 m g BI D i n c o m bi nati o n wit h  e n d ocri ne t hera p y , a n d 
 2 0 0 m g BI D w h e n gi ve n as a m o n ot hera p y.  
H o we ver, data fr o m pre vi o us cli nical st u dies c o n d ucte d i n me n a n d w o me n s u g geste d t hat me n 
t olerate a hi g her d ose of a be maci cli b t ha n w o me n. I n t he P h ase 1 m o n ot hera p y d ose escalati o n 
St u d y I 3 Y -M C -J P B A, me n re p ort e d l o wer GI t o xicit y rates  t ha n w o me n: di arr hea ( 5 6. 0 % vs. 
7 1. 0 %), na usea ( 4 1. 3 % vs . 5 1. 1 %), v o miti n g ( 2 2. 7 % vs . 3 5. 9 %), a n d a b d o mi nal pai n ( 1 2. 0 % vs . 
1 9. 1 %).  Si milar l y, l o wer rates of GI t o xicities i n me n vers us w o me n were als o o bser ve d i n a 
P hase 3  St u d y I 3 Y -M C -J P B K i n patie nts wit h Sta ge I V n o n-s mall c ell l u n g ca ncer. As a res ult, 
C Y C L O N E 2, a P hase 2/ 3 st u d y e val uati n g a be macicli b/ place b o i n c o m bi n ati o n wit h a birater o n e 
 pl us pre d nis o ne / pre d nis ol o ne 
 i n patie nts wit h m C R P C 
( N C T 0 3 7 0 6 3 6 5) i ncl u de d a n i nitial safet y lea d i n peri o d w here patie nts were ra n d o mize d t o 
a be maci cli b/ place b o  
 or  
 t o deter mi ne t he R P 2 D of a be maci cli b  f or t his 
st u d y dr u g c o m bi nati o n i n pr ostate ca n cer patie nts . 
 
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I n a pla n ne d s afet y a n al ysis of
 
 
 
 
I n p atie nts wit h M B C, i ncl u di n g t h ose i n M O N A R C H 2, a p ositi ve e x p os ure-efficac y 
relati o ns hi p was pre vi o usl y o bser ve d ( T ur ner et al.  2 0 1 8), w hic h i n dicates p atie nts wit h hi g her 
P K e x p os ures are m ore li kel y t o e x perie n ce greater treat me nt be nefit t ha n t h ose  wit h l o wer 
e x p os ures.
 
 
 
T heref ore, i n C Y C L O N E 3 , 
 was selecte d as t he starti n g d ose f or 
a be maci cli b/ place b o i n c o m bi nati o n wit h a birater o ne pl us  pre d nis o ne  i n hi g h-ris k m H S P C. 
A bir ater o ne/ Pre d nis o ne  
T he d oses of a birater o n e
 a n d pre dnis o ne  
 were s electe d base d o n 
prescri bi n g i nf or mati o n f or m H S P C .  
4. 4.  
E n d of St u d y  Defi niti o n   
T his st u d y will be c o nsi d ere d c o m plete (t h at is, t he scie ntific e val uati o n will be c o m plete [st u d y 
c o m pleti o n]) f oll o wi n g t he e val uati o n of fi nal O S data as det er mi ne d b y t he sp o ns or. I n vesti gat ors 
will c o nti n ue t o f oll o w t he st u d y sc he d ule f or all partici pa nts u ntil n otifie d b y t he sp o ns or t hat 
st u d y c o m pleti o n has occ urre d. 
“ E n d of st u d y” refers t o t he date of t he l ast visit or last sc he d ule d pr oce d ure f or t he last 
partici pa nt . T he e n d of trial occ urs after st u d y c o m pleti o n a n d after t he last partici pa nt has 
disc o nti n ue d st u d y treat me nt a n d c o m plete d c o nti n ue d -access peri o d f oll o w -u p ( see Secti o n 6. 6 ).  
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5.  
St u d y P o p ul ati o n   
Partici pa nts m ust meet all incl usi o n criteria a n d n o ne of t he e x cl usi o n criteri a. Pr os pecti ve 
a p pr o val of pr ot oc ol de vi ati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as pr ot oc ol 
wai vers or e xe m pti o ns, is n ot per mitte d.  
5. 1.  
I ncl usi o n Criteri a  
1.  A d ult me n (≥1 8 years or a ge of maj orit y per l ocal re g ulati o n ) willi n g a n d a ble t o pr o vi de 
writte n i nf or me d c o ns e nt a n d c o m pl y wit h st u d y pr oce d ures (see i n Secti o n 1 0. 1. 3 , 
A p pe n di x 1).  
2.  Hist ol o gicall y  c o nfir me d pre d o mi na nt a de n o carci n o ma of t he pr ostate . Well -
differe ntiat e d  ne ur oe n d o cri ne carci n o ma, s mall  cell  or lar ge cell ne ur oe n d o cri ne 
carci n o ma,  s arc o m at oi d, a n d carci n oi d t u m ors are e xcl u de d.  
3.  Hi g h -ris k metastatic h or m o ne -se nsiti ve pr ostate ca ncer d oc u me nte d o n c o n ve nti o nal 
i ma gi n g. Hi g h -ris k is defi ne d as:  
 ≥4 b o ne metastases b y b o ne sca n   
a n d/ or 
 ≥1  visceral metastas es  (f or e xa m ple, li ver, l u n g, a n d a dre nal) b y C T or M RI.  
- L ocal i n vasi o n (f or e x a m ple,  bla d der) or l y m p h n o de i n v ol ve me nt 
d o es n ot  q ualif y as visceral metastases . A p re vi o usl y irra diate d v isceral lesi o n 
as t he s ole site of diseas e ca n meet hi g h -ris k metastatic disease criteria 
pr o vi de d t here h as bee n s u bse q ue nt ra di o gr a p hic pr o gressi o n at t hat site.  
4.  Partici pa nts m ust ha ve i nitiated  A D T  wit h L H R H a g o nist/a nta g o nist or bilateral 
orc hiect o m y  p ri or t o ra n d o mizati o n.  
 U p t o 3 m o nt hs of A D T pri or t o ra n d o mizati o n is per mitte d  wit h or wit h o ut first -
ge nerati o n a nti -a n dr o ge n (f or e x a m ple, bical uta mi de). T he start of A D T is t he 
earliest date a n L H R H a g o nist/a nta g o nist was a d mi nistere d, or date of s ur gi cal 
castrati o n.  
 F or par tici pa nts recei vi n g a n L H R H a g o nist, first ge nerati o n a nti-a n dr o ge ns are 
all o we d t o c o nti n ue f or u p t o  2 wee ks aft er C ycle 1 D a y 1, all ot her use 
s u bse q ue nt t o Cycle 1  D a y 1  is pr o hi bite d. 
 Partici pa nts w h o ha ve n ot u n der g o ne a bilateral or c hiect o m y m ust  c o nti n ue t he 
L H R H a g o nist/a nta g o nist t hr o u g h o ut t he st u d y. 
5.  F or patie nts r ecei vi n g b o ne -m o dif yi n g a ge nts ( f or e xa m ple, bis p h os p h o nat es or 
de n os u ma b) f or t h e ma na ge me nt of b o ne metast asis, d ose  m ust be sta ble f or at least  4 
wee ks pri or t o  ra n d o mizati o n. T his d oes n ot a p pl y t o patie nts o n oste o p or osis d osi n g.  
 
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6.  Ha ve a d e q uate or ga n f u ncti o n, as defi ne d b el o w:  
  
S yste m   
L a b or at or y V al ue   
C ar di ac   
L V E F   
≥5 0 %   
Cli nic al C he mistr y   
Ser u m al b u mi n  
≥3 g/ d L   
Ser u m p otassi u m   
≥3. 5 m m ol / L  
He m at ol o gic   
A bs ol ute n e utr o p hil 
co u nt ( A N C )  
≥1. 5 × 1 0 9/ L 
G -C S F s h o ul d n ot be a d mi nistere d t o meet criteria .  
Platelets   
≥1 0 0 × 1 0 9/ L   
T ra nsf usi o n s h o ul d n ot be a d mi nistere d t o meet criteria.  
He m o gl o bi n   
≥9 g/ d L ( ≥9 0 g/ L)  
Tra nsf usi o n s h o ul d n ot be a d mi nistere d t o meet criteria .  
He p atic   
T otal bilir u bi n   
≤1. 5 × U L N    
A L T a n d A S T   
≤2. 5 × U L N   
Re n al   
e G F R (calc ulate d per 
l ocal cli nical practice 
g ui deli nes)  
≥3 0 m L/ mi n  
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; G -C S F = gra n ul oc yte c ol o n y -
sti m ulati n g fact or; L V E F = left v e ntric ular ejecti o n fracti o n; U L N = u p per li mit of n or mal.  
 
7.  Easter n  C o o perati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce stat us of 0 or 1 at scree ni n g.  
8.  P artici pa nts  wit h fe male part ners of c hil d beari n g  p ote ntial m ust a gree t o use a c o n d o m 
al o n g wit h  a n ot her effecti ve c o ntrace pti o n met h o d d uri n g t he st u d y a n d f or at least 3 
wee ks f oll o wi n g t he last d ose of st u d y treat me nt.  
5. 2.  
E xcl usi o n Criteri a   
Partici pa nts are e xcl u de d fr o m t he st u d y if A N Y of t he f oll o wi n g criteri a a p pl y:  
9.  K n o w n  or s us pect e d c o ntrai n dicati o ns or h y perse nsiti vit y t o a birater o ne, 
pre d nis o ne / pre d nis ol o ne, or a be macicli b or t o a n y of t he e xci pie nts; i na bilit y t o s wall o w 
oral me dicati o ns  or gastr oi ntesti nal  dis or der affecti n g a bs or pti o n.  
1 0.  Pri or  treat me nt wit h a be macicli b or a n y ot her C D K 4 & 6 i n hi bit or . 
1 1.  De vel o p me nt of meta st atic pr ostate ca ncer i n t he c o nte xt of castrat e le vels of 
test oster o ne. 
1 2.  Recei ve d  a n y pri or s yste mic t hera p y f or m etastatic pr ostate ca ncer (i ncl u di n g 
i n vesti gati o nal a ge nts), e xce pt f or A D T  a n d first-ge nerati o n a nti -a n dr o ge n  (see i ncl usi o n 
criteri o n [4 ]). 
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1 3.  Ra diati o n  t hera p y t o treat t he pri mar y pr ostate  t u m or i n t he c o nte xt of metastatic disease  
a n d/ or ra diati o n or s ur g er y t o all metastatic lesi o ns. O ne c o urse of palliati ve ra diati o n or 
s ur gical t hera p y is p er mitte d if it was a d mi nistere d at least 2 wee ks pri or t o 
ra n d o mizati o n. 
1 4.  U ntreate d  s pi nal c or d c o m pressi o n, s pi nal metastases wit h e mer g e nt ris k of s pi nal c or d 
c o m pressi o n , or  str uct ur all y u nsta ble b o ne lesi o ns at hi g h-ris k f or i m pe n di n g fract ur e.  
1 5.  K n o w n u ntreat e d C N S metasta ses or a n y hist or y  of le pt o me ni n geal diseas e. S cree ni n g  of 
as y m pt o matic  patie nts f or C N S metastases is n ot re q uire d. N ote: Patie nts wit h a hist or y 
of treate d brai n metastas es b y eit her s ur g er y or ra diati o n t hera p y  are eli gi ble  pr o vi de d  
t hat disease is sta ble f oll o wi n g treat me nt f or at least 8 wee ks  pri or t o ra n d o mizati o n  a n d 
wit h n o  re q uire me nt f or c ortic oster oi ds f or at least 2 wee ks pri or t o r a n d o mizati o n .  
1 6.  Seri o us  pree xisti n g me dical c o n diti o n(s) t hat, i n t he j u d g me nt of t he i n vesti gat or, w o ul d 
precl u de p artici pati o n i n t his st u d y (f or e xa m ple, i nterstitial l u n g disease, se vere d ys p n ea 
at rest or re q uiri n g o x y ge n t hera p y, hist or y of maj or s ur gical r esecti o n i n v ol vi n g t he 
st o mac h or s mall b o wel, or pree xisti n g Cr o h n’s disease or ulcerati ve c olitis or a 
pree xisti n g c hr o nic c o n diti o n res ulti n g i n baseli ne Gra de 2 or hi g her diarr hea).  
1 7.  Cli nicall y  si g nifica nt car di o vasc ular diseas e as e vi de nce d b y m y ocar dial i nfarcti o n , 
arterial t hr o m b otic e v e nts, or se vere/u nsta ble a n gi na  i n t he past 6 m o nt hs, or Ne w Y or k 
Heart Ass o ciati o n Class II t o I V heart fail ure.   
1 8.  Hist or y  of a n y of t he f oll o wi n g c o n diti o ns: s y nc o pe of car di o vasc ular eti ol o g y, 
ve ntric ular arr h yt h mia of pat h ol o gical ori gi n (i ncl u di n g, b ut n ot li mite d t o, 
ve ntric ular  ta c h ycar dia a n d ve ntric ular fi brillati o n), or s u d de n car diac arrest. C hr o nic a n d 
he m o d y na micall y sta ble atrial arr h yt h mia well -c o ntr olle d o n me dical t hera p y is 
per mitte d .  
1 9.  U nc o ntr olle d  h y pert e nsi o n (s yst olic bl o o d press ur e [ B P] ≥1 6 0 m m H g or diast olic B P ≥9 5 
m m H g). Patie nts wit h a hist or y of h y perte nsi o n are all o we d pr o vi de d B P is c o ntr olle d  b y 
a nti-h y perte nsi ve tr eat me nt.   
2 0.  Cli nicall y  acti ve or c hr o nic li ver disease, m o derate/se vere h e patic i m pair me nt ( C hil d -
P u g h Class B a n d C), ascites, or blee di n g dis or ders sec o n dar y t o h e patic d ysf u ncti o n.   
2 1.  Hist or y of a dre n al d ysf u ncti o n.  
2 2.  Ha d  a maj or s ur ger y wit hi n 2  wee ks pri or t o r a n d o mizati o n. All i ncisi o ns m ust be heale d 
or heali n g, ase ptic a n d wit h o ut si g ns or s y m pt o ms of i nfecti o n.  
2 3.  Pri or or acti ve c o n c urre nt mali g na nc y ( wit h t he e x ce pti o n of n o n -mela n o m at o us s ki n 
ca ncer). Patie nts wit h carci n o ma i n si t u of a n y ori gi n a n d patie nts wit h pri or mali g na ncies 
w h o are i n r e missi o n a n d / or w h ose li keli h o o d of rec urre nce is ver y l o w per i n vesti gat or’s 
j u d g me nt are eli gi ble f or t his st u d y. T he Lill y C R P/ C R S will a p pr o ve e nr oll me nt of 
patie nts wit h pri or mali g na nc ies i n re missi o n bef ore t hese p atie nts are e nr olle d. 
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2 4.  Acti ve  s yste mic i nfecti o ns (f or e x a m ple, bact erial i nfecti o n re q uiri n g i ntra v e n o us [I V] 
a nti bi otics at ti me of i nitiati n g st u d y treat me nt, f u n gal i nfecti o n, or det ecta ble viral 
i nfecti o n re q uiri n g s yste mic t hera p y) or viral l oa d (s uc h as k n o w n h u ma n 
i m m u n o deficie nc y vir us p ositi vit y or wit h k n o w n acti ve he p atitis B or C [f or e xa m ple, 
he patitis B s urface a nti ge n p ositi ve]). Scree ni n g is n ot re q uire d f or e nr oll m e nt.   
2 5.  Ha ve  recei v e d li ve vacci nati o n ≤ 4 wee ks pri or t o ra n d o mizati o n. I nacti vate d vacci nes 
are per mitte d.   
2 6.  C urre nt e nr oll me nt i n a cli nical st u d y i n v ol vi n g a n i n vesti gati o nal pr o d uct or a n y ot her 
t y pe of me dical r esearc h j u d ge d n ot t o be scie ntificall y or me dicall y c o m p ati ble with t his 
st u d y. Ha ve partici p ate d i n a n y cli nical trial f or w hic h treat me nt assi g n me nt is still 
bli n de d. If patie nt has partici pate d i n a cli nical st u d y i n v ol vi n g a n i n vesti gati o nal pr o d uct, 
3 m o nt hs or 5 half -li ves ( w hic he ver is s h ort er) s h o ul d ha ve passe d pri or t o 
ra n d o mizati o n. If a patie nt is c urre ntl y e nr olle d i n a cli nical trial i n v ol vi n g n o n-a p pr o ve d 
use of a de vi ce, t he n a gree me nt wit h t he i n vesti gat or a n d t he Lill y C R P/ C R S is re q uire d 
t o esta blis h eli gi bilit y. 
5. 3.  
Lifest yle C o nsi der ati o ns   
T he f oll o wi n g lifest yle restricti o ns are a p plica ble t o all ra n d o mize d patie nts:   
 
W hile o n st u d y, patie nts s h o ul d refrai n fr o m c o ns u mi n g gra pefr uit a n d p o me gra nate 
fr uits a n d/ or j uice, sa w p al mett o a n d ot her her bal/ n o n -her bal  pr o d ucts k n o w n t o be str o n g 
i n hi bit ors of C Y P 3 A, ha ve pr ostate ca ncer acti vit y, or affect P S A le vels.  
 
P artici pa nts wit h fe male part ner s of c hil d beari n g p ote ntial  m ust  a gree t o use a c o n d o m 
al o n g wit h a n ot her effecti ve c o ntrace pti o n met h o d d uri n g t he st u d y a n d f or at least 3 
wee ks f oll o wi n g t he last d ose of st u d y treat me nt  (see Secti o n 1 0. 4 , A p pe n di x 4).  
 
Partici pa nts s h o ul d  n ot  d o nate bl o o d or s per m d uri n g t he st u d y a n d f or 3 m o nt hs after 
t he last d ose  of st u d y treat me nt .  
5. 4.  
Scree n F ail ures   
S cree n fail ures are defi ne d as partici pa nt s w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are  
n ot s u bse q ue ntl y e nr olle d  i n t he st u d y. A mi ni mal set of scree n fail ure i nf or mati o n is re q uire d t o 
e ns ure tra ns p are nt re p orti n g of scree n fail ure parti ci pa nt s t o meet t he C o ns oli date d Sta n dar ds of 
Re p orti n g Trials  p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities. 
Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, s cree n fail ure det ails, eli gi bilit y criteria, a n d a n y 
S A E . 
T he f oll o wi n g partici pa nts ma y be eli gi ble f or rescree ni n g:  
 Partici pa nts w h o bec o me eli gi ble t o e nr oll i n t he st u d y beca use of  a pr ot oc ol a me n d me nt.  
 Partici pa nts w h ose stat us has c ha n ge d s u c h t hat t h e eli gi bilit y criteri o n t hat ca use d t he 
partici pa nt t o scree n fail w o ul d n o l o n ger ca us e t he partici pa nt t o fail scree ni n g a gai n ( f or 
e xa m ple, u ne x p ecte d s ur ger y d uri n g t he scree ni n g peri o d t hat is n o l o n ger rele va nt 
f oll o wi n g rec o ver y fr o m s ur ger y). 
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 A patie nt w h o c o m pletes scree ni n g a n d meets a ll i ncl usi o n a n d e xcl usi o n re q uire me nts 
b ut is u na ble t o be e nr oll e d d ue t o e xte n u ati n g cir c u msta nces (s u c h as se vere weat her, 
deat h i n fa mil y, c hil d ill ness) .  
T he i nter val bet w ee n res cree ni n g s h o ul d be ≥2 wee ks. I n di vi d uals ma y be rescree ne d a 
ma xi m u m of  2 ti mes. Rescree n e d partici p a nts m ust si g n a ne w I C F a n d will be assi g ne d a ne w 
i de ntificati o n n u m ber.  
Re peati n g la b orat or y t esti n g d uri n g t he scree ni n g peri o d or re p eati n g scree ni n g tests t o c o m pl y 
wit h t he pr ot oc ol -desi g nate d scree ni n g peri o d d oes n ot c o nstit ute rescree ni n g.  
5. 5.  
Criteri a f or Te m p or aril y Del a yi n g 
E nr oll me nt/ R a n d o miz ati o n/ A d mi nistr ati o n of St u d y I nter ve nti o n of 
a P artici p a nt   
N ot a p plica ble.  
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6.  
St u d y I nter ve nti o n (s) a n d C o nc o mit a nt T her a p y   
St u d y i nter ve nti o n is defi ne d as a ny i n vesti gati o nal i nter ve nti o n(s), mar ket e d pr o d uct(s), 
place b o , or me di cal de vi ce (s) i nte n d e d t o be a d mi nistere d t o/ use d b y a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol.  H erei n, st u d y i nter ve nti o n is defi ne d as a birater o n e pl us 
pre d nis o ne /pre d nis ol o ne a n d bli n de d st u d y dr u g  a be macicli b/ place b o.  
6. 1.  
St u d y I nter ve nti o n(s) A d mi nistere d   
All partici pa nts will recei ve t hera p y wit h a birater o ne 
 pl us pre d nis o ne 
 
 Pre d nis ol o ne ma y be use d i n lie u of pre d nis o ne per l ocal a birater o ne prescri bi n g 
i nf or mati o n or w here pre d nis o ne is n ot c o m merciall y a vaila ble. I n t his pr ot oc ol, pre d nis o ne 
i m plies pre d nis o ne or pre d nis ol o ne. 
Bli n de d st u d y dr u g (a be macicli b  or place b o)  will be a d mi nistere d at a starti n g d ose of  
 
 at a p pr o xi m atel y t he sa me ti me 
e ver y da y . Pla ce b o will b e pr o vi de d as a ta blet f or m ulati o n a n d will be matc he d i n size, c ol or, 
a n d s ha pe t o a b e macicli b ta blets t o mai ntai n t he st u d y bli n d.  
Bli n de d st u d y dr u g  s h o ul d be s wall o we d w h ol e wit h a glass of water ( d o n ot c he w, cr us h, s plit, 
diss ol ve i n water, or alter i n a n y wa y pri or t o s w all o wi n g). Bli n de d st u d y dr u g ma y be ta ke n wit h 
or wit h o ut f o o d.  
If a partici pa nt misses a d ose at t he sc he d ul e d ti me f or n o n me dical reas o ns, t he d ose s h o ul d be 
ta ke n as s o o n as p ossi ble o n t he sa me da y 
 
If a partici p a nt v o mits after ta ki n g a d ose, t h e n 
t he d ose s h o ul d n ot be reta ke n, a n d t he ne xt d ose s h o ul d be ta ke n at t he us ual sc he d ule d ti me. 
I nstr u ct patie nts n ot t o i n gest ta blets if br o ke n, crac ke d or ot her wise n ot i ntact.  
T he i n vesti gat or or his/ her desi g ne e is res p o nsi ble f or t he f oll o wi n g:  
 F oll o wi n g t he pr ot oc ol at all ti mes . 
 E x plai ni n g t he c orrect us e of t he dr u g s a n d pla n ne d d urati o n of eac h i n di vi d ual’s 
treat me nt t o t he partici pa nt/st u d y-site pers o n nel/le gal re prese ntati ve. 
 Verif yi n g i nstr ucti o ns are f oll o we d pr o p erl y.  
 Mai ntai ni n g acc urate rec or ds of bli n de d st u d y dr u g  dis pe nsi n g a n d c ollecti o n.  
 At t he e n d of t he  st u d y, ret ur ni n g all u n use d bli n de d st u d y dr u g t o Lill y, or its 
desi g nee, u nless t he site  a grees a n d  is a ut h orize d b y Lill y or its desi g nee t o 
destr o y u n use d me dicati o n, as o utli ne d i n t he P har mac y Ma n ual . 
 
 
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T his ta ble pr o vi des details o n t he i nter ve nti o ns use d i n t his cli nical st u d y. 
I nter v e nti o n N a m e 
A be macicli b  
Matc hi n g Place b o  
A birater o ne  
Pre d nis o ne  
A ut h orize d as defi ne d 
b y E U Cli nic al Tri al 
Re g ul ati o n  
D os a ge Le vel(s)  
R o ute of 
A d mi nistr ati o n  
Oral  
Oral  
Oral  
Oral   
A b bre viati o n: N A = n ot ap plica ble .  
6. 1. 1.  
P ac k a gi n g a n d L a beli n g   
A be macicli b  a n d m atc hi n g place b o will be s u p plie d b y Lill y as ta blets f or oral a d mi nistrati o n. 
A birater o n e a n d pre d nis o ne  will be s o urce d i n acc or da nce t o l ocal re g ulati o n a n d c o u ntr y 
re q uire me nts. Sites s h o ul d c o nfir m a birat er o ne a n d pre d nis o ne s o urce t o e ns ure a de q u ate s u p pl y. 
All s t u d y i nter ve nti o n will be s u p plie d i n acc or da nce wit h c urre nt G o o d M a n ufact uri n g Practice 
a n d la bele d acc or di n g t o t he  c o u ntr y’s re g ulat or y re q uire me nts.  
6. 1. 2.  
B ac k gr o u n d T her a p y or St a n d ar d -of -C are   
Partici pa nts w h o ha ve n ot u n der g o ne bilateral orc hiect o m y are re q uire d t o c o nti n ue bac k gr o u n d 
A D T  wit h a n L H R H a g o nist/a nta g o nist  t hr o u g h o ut t he st u d y. T he c h oice of L H R H 
a g o nist/a nta g o nist  will be p h ysicia n’s c h oice . L H R H a g o nist/a nta g o nis t d osi n g  a n d 
a d mi nistrati o n will be i n acc or da nce wit h t he pres cri bi n g i nf or mati o n.  
 
6. 2.  
Pre p ar ati o n , H a n dli n g , St or a ge , a n d Acc o u nt a bilit y   
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate st ora ge c o n diti o ns ha ve bee n mai ntai ne d 
f or bli n de d  st u d y dr u g  a n d a n y discre p a ncies are re p orte d a n d res ol ve d pri or t o dis pe nsi n g .  
O nl y partici pa nts ra n d o mize d i n t he st u d y ma y recei ve st u d y i nter ve nti o n. All st u d y i nter ve nti o n 
s h o ul d be st ore d acc or di n g t o t heir ass ociate d pr o d uct la bel a n d ta k e n as i n dicate d. B li n de d st u d y 
dr u g  m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or 
a ut o mate d) area i n a cc or da nce wit h t he la bele d st ora ge c o n diti o ns wit h access li mite d t o t he 
i n vesti gat or a n d a ut h orize d st u d y pers o n nel. 
O nl y a ut h orize d st u d y pers o n nel ma y s u p pl y bli n de d st u d y dr u g . T he i n v esti gat or or a ut h orize d 
st u d y pers o n nel are res p o nsi ble f or bli n de d st u d y dr u g  acc o u nt a bilit y, rec o n ciliati o n, a n d rec or d 
mai nte na nce ( t hat is, recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
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F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d bli n de d st u d y dr u g  are 
pr o vi de d i n t he P har mac y Ma n ual . 
6. 2. 1.  
Selecti o n a n d Ti mi n g of D oses   
T he first d ose  of  a birater o ne pl us pre d nis o ne a n d a be maci cli b/ place b o s h o ul d be i nitiate d wit hi n 
7 da ys f oll o wi n g ra n d o mizati o n. A treat me nt c ycl e is defi ne d as a n i nter val of 2 8 da ys  ( ± 3 da ys). 
A birater o n e a n d pre d nis o ne s h o ul d be a d mi nistere d orall y o nce dail y , acc or di n g t o t h e res pecti ve 
prescri bi n g i nf or mati o n.  
A be macicli b / place b o will be a d mi nistere d orall y 
 at a p pr o xi matel y t he sa me ti mes 
eac h d a y. Details o n treat me nt a d mi nistrati o n are descri be d i n Secti o n 6. 1 . I n t he e ve nt of a d ose 
s us pe nsi o n d ue t o t o xicit y i m me diatel y pri or t o t he be gi n ni n g of a c y cle, t h e P K sa m pli n g 
sc he d ule o utli ne d i n Secti o n 1. 3. 1  ma y re q uire a dj ust me nt a n d t he s p o ns or s h o ul d be n otifie d.  
A dela y or a n earlier start  of a  c ycl e d ue t o l o gistical reas o ns (f or e x a m ple, d ue t o h oli da y  or  
vacati o n , wee ke n d, i ncl e me nt weat her, or ot her u nf oresee n cir c u msta nces), will be per mitte d f or 
u p t o a ma xi m u m of 7 da ys (a n d n ot be c o nsi der e d a pr ot oc ol vi olati o n). D uri n g t his peri o d , if 
t he partici pa nt has a de q u ate dr u g s u p pl y, he  ma y c o nti n ue st u d y i nter ve nti o n per i n vesti gat or’s 
discreti o n ; a d diti o nal bli n de d st u d y dr u g  ma y be dis pe nse d at t he i n vesti gat or’s discreti o n . 
Reas o ns f or a d diti o nal dis pe nsi n g m ust be d oc u me nte d . 
Partici pa nts ma y c o nti n ue t o recei ve st u d y i nter ve nti o n wit h a birater o ne , pre d nis o ne a n d 
a be maci cli b/ place b o  u ntil e vi de nce of dis ease pr o gressi o n, or a n y disc o nti n uati o n criteria are met  
( See Secti o n 7 ).  
6. 3.  
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g   
P artici pa nts  w h o m eet all eli gi bilit y  criteria ( Secti o n 5 ) will be ran d o ml y assi g ne d t o recei ve 
a birater o n e pl us pre d nis o ne i n c o m bi nati o n wit h a be macicli b or place b o.  
T he I W R S will use ra n d o mizati o n stratificati o n fact ors  ( Secti o n 4. 1 ) t o assi g n d o u ble-bli n d st u d y 
dr u g (a be m acicli b or place b o)  t o e ac h patie nt. Bef ore t he st u d y is i nitiate d, l o g i n i nf or mati o n 
a n d i nstr ucti o ns f or t he I W R S will be pr o vi de d t o eac h site. 
St u d y i nter ve nti o n will be dis pe nse d at t he st u d y visits s u m marize d i n S o A ( Secti o n 1. 3 ).  
6. 3. 1.  
Bli n di n g   
T his is a d o u ble -bli n d st u d y.  
T o preser ve t he bli n di n g of t he st u d y, a mi ni m u m n u m ber of Lill y pers o n nel will see t he 
ra n d o mizati o n ta ble a n d treat me nt assi g n me nts bef ore t he st u d y is c o m plete d. Access t o 
u n bli n de d data/ d oc u me nts will be c o ntr olle d b y restricti n g ac cess t o t he data/ d oc u me nts i n 
Lill y’s data a n d statistical ware h o use. A n y c ha n g es t o t his u n bli n di n g pla n ma y be descri be d i n a 
pr ot oc ol a me n d me nt, t he S A P, a n d/ or a se parate u n bli n di n g pla n d oc u me nt.  
Efficac y i nf or mati o n will n ot be s hare d wit h  sites u ntil t he st u d y is c o m plete d. U p o n st u d y 
c o m pleti o n (see Secti o n 4. 4 ), i n vesti gat ors ma y u n bli n d patie nts t o st u d y treat me nt assi g n me nt. 
U n bli n di n g of t he i n vesti gat or a n d t he patie nt at t he ti me of d oc u me nte d o bj ecti ve diseas e 
pr o gressi o n is per mitte d t o e ns ure o pti mal patie nt ma na ge me nt  a n d/ or facilitate selecti o n of 
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s u bse q ue nt treat me nt. T h e i n vesti gat or m ust c o ns ult wit h t he Lill y C R P/ C R S pri or t o u n bli n di n g.  
U n bli n di n g m ust be perf or me d t hr o u g h t he I W R S.  
If a n i n vesti gat or or p arti ci pa nt is u n bli n de d, t he partici pa nt m ust be disc o nti n ue d fr o m t he st u d y 
i nter ve nti o n a n d will u n der g o p ost -disc o nti n uati o n f oll o w -u p . L o n g -ter m f oll o w-u p pr o ce d ures 
will be f oll o we d u ntil deat h, l oss of f oll o w -u p, wit h dra wal of c o nse nt, or st u d y c o m pleti o n.  
6. 3. 2.  
U n bli n di n g at I nteri m A n al yses   
See Secti o n  9. 5  f or det ails o n t he c o n d uct of i nteri m a nal yses. O nl y t he i n d e pe n de nt D M C is 
a ut h orize d t o e v al uate u n bli n de d f utilit y a n d i nteri m efficac y a n al yses. T he D M C will be 
i n de pe n de nt a n d c o nsist of at least 3 me m bers e xt er nal t o Lill y, n o ne of w h o m are i n v ol ve d as 
st u d y i n vesti gat ors, i ncl u di n g at least 1 cli nicia n a n d 1 statisticia n. T he D M C will c o m m u nicate 
a n y rec o m me n d ati o ns base d o n t he i nteri m a nal y s es t o t he Lill y Se ni or Ma na ge me nt Desi g ne e. 
F urt her details are i ncl u d e d i n t he D M C C harter. F or t h ose a n al yses assi g n e d t o t he D M C, o nl y 
t he desi g nate d Statistical A nal ysis Ce nter, w hic h is i n de pe n de nt of t he s p o ns or, will perf or m 
a nal yses o n u n bli n de d d ata. St u d y sites will recei ve i nf or mati o n a b o ut i nteri m res ults o nl y if t he y 
nee d t o k n o w f or t h e safet y of t heir patie nts . F urt h er details are i ncl u de d i n t he st u d y u n bli n di n g 
pla n.  
6. 3. 3.  
E mer ge nc y U n bli n di n g   
I n case of a n e m er ge n c y, t he i n vesti gat or has t he s ole res p o nsi bilit y f or deter mi ni n g if u n bli n di n g 
of a partici p a nt’s  treat me nt assi g n me nt is warra nte d. Partici pa nt  safet y m ust al wa ys be t he first 
c o nsi derati o n i n ma ki n g s uc h a d eter mi nati o n. If t he i n vesti gat or deci d es t hat u n bli n di n g is 
warra nte d, t he i n vesti gat or s h o ul d c o ntact t he Lill y  C R P/ C R S pri or t o u n bli n di n g a partici pa nt ’s 
treat me nt assi g n me nt u nless t his c o ul d dela y e mer ge nc y treat me nt of t he patie nt. If a 
partici pa nt ’s treat me nt assi g n me nt is u n bli n de d, Lill y  m ust be n otifie d i m me diatel y.  
E mer ge nc y u n bli n di n g f or A Es m ust be perf or me d t hr o u g h t he I W R S. T his o pti o n m ust be use d 
w he n  t he partici p a nt ’s ac ute well-bei n g r e q uires k n o wle d ge of t he p artici pa nt ’s treat me nt 
assi g n me nt.  
All calls res ulti n g i n a n u n bli n di n g e ve nt are rec or de d a n d re p orte d b y t he I W R S. If t h e 
i n vesti gat or or partici pa nt  bec o mes u n bli n de d, t hat partici pa nt  will be disc o nti n ue d fr o m st u d y 
i nter ve nti o n a n d will u n der g o p ost -disc o nti n uati o n f oll o w -u p . L o n g-ter m f oll o w-u p pr oce d ures 
will be f oll o we d u ntil deat h, l oss of f oll o w -u p, or wit h dra wal of c o nse nt, or st u d y c o m pleti o n.  
6. 3. 4.  
I n a d verte nt U n bli n di n g  
E ver y eff ort will be ma d e t o bli n d b ot h t he partici pa nt  a n d t he i n vesti gat or t o t he i de ntit y of t he 
bli n de d st u d y dr u g , b ut t he i na d verte nt u n bli n di n g of a partici p a nt  ma y occ ur. If a n i n vesti gat or, 
site pers o n nel, or partici pa nt  is i na d verte ntl y u n bli n de d, t he u n bli n di n g will n ot be s ufficie nt 
ca use f or t he partici pa nt  t o be disc o nti n ue d fr o m st u d y i nter ve nti o n or e xcl u de d fr o m st u d y 
a nal yses.  
I n cases i n w hi c h t here are et hical r eas o ns f or t h e partici pa nt  t o re mai n o n t he st u d y i nter ve nti o n 
i n t he e ve nt of u n bli n di n g, t he i n vesti gat or m ust o btai n s pecific a p pr o val fr o m a Lill y C R P/ C R S 
f or t he partici p a nt  t o c o nti n ue i n t he st u d y. 
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6. 4.  
St u d y I nter ve nti o n C o m pli a nce   
Parti ci pa nt c o m plia nce wit h st u d y i nter ve nti o n will be assesse d at eac h c ycl e.  
C o m plia nce wit h  bli n de d st u d y dr u g will be assesse d b y c o u nti n g ret ur n e d ta blets.  C o m plia nce 
wit h a birater o n e a n d pre d nis o ne will be assesse d b y partici pa nt’s i nter vie w.  St u d y i nterve nti o n  
a d mi nistrati o n data will be rec or de d i n t he p artici pa nt’s me dical r ec or d a n d C R F. De viati o n(s) 
fr o m t he pres cri be d d osa ge re gi me n s h o ul d be rec or de d i n t he C R F. 
Partici pa nts w h o are si g nifica ntl y n o nc o m plia nt ma y be c o nsi dere d f or disc o nti n uati o n  fr o m 
st u d y i nter ve nti o n after disc ussi o n wit h Lill y C R P/ C R S. A partici pa nt ma y be c o nsi dere d 
si g nifica ntl y n o nc o m plia nt if he misses m ore t ha n 2 5 % of t he prescri be d d osa ge i n a gi ve n c y cle . 
Si milarl y, a partici pa nt ma y be c o nsi dere d si g nifica ntl y n o nc o m plia nt if he is j u d ge d b y t he 
i n vesti gat or t o ha ve i nte nti o nall y or re peate dl y ta ke n m ore t ha n (≥1 2 5 %) of t he prescri b e d 
a m o u nt of me dicati o n. D ose  s us pe nsi o ns or dela ys relate d t o t o xicit y ma y occ ur a n d will n ot 
res ult i n a partici pa nt bei n g c o nsi dere d n o n c o m plia nt. 
6. 5.  
D ose M o dific ati o n   
D ose a dj ust me nts (s us pe nsi o ns a n d re d ucti o ns) will be ma de base d o n t he cli nical as sess me nt of 
he mat ol o gic a n d n o n he m at ol o gic t o xicities ( defi ne d as a n A E p ossi bl y relat e d t o st u d y 
i nter ve nti o n per i n vesti gat or j u d g me nt). T he C T C A E v 5. 0 w ill be use d t o assess A Es. St u d y 
i nter ve nti o n ma y be s us p e n de d f or a ma xi m u m of 2 8 da ys t o all o w a pa tie nt s ufficie nt ti me f or 
rec o ver y fro m tr eat me nt-e mer ge nt A Es . If a p artici pa nt  d oes n ot rec o v er fr o m t he t o xicit y wit hi n 
2 8 da ys fr o m t he date of d ose s us pe nsi o n, t he partici pa nt  s h o ul d be c o nsi dere d f or p er ma n e nt 
disc o nti n uati o n fr o m st u d y i nter ve nti o n. I n e xce pti o nal circ u msta nces, a d ela y > 2 8 da ys is 
per mitte d u p o n a gree me nt bet wee n t he i n vesti gat or a n d t he Lill y C R P/ C R S.  
If eit her a birater o ne/pre d nis o ne or a be macicli b/ place b o h a s bee n disc o nti n ue d or ma xi mall y d ose 
re d uce d d u e t o t o xicit y a n d t he t o xicit y has n ot res ol ve d, patie nts ma y c o nti n ue t o recei v e t he 
ot her i nter ve nti o ns at t he c urre nt d ose if it is a p pare nt t hat t he t o xicit y is n ot relate d t o t hese ot h er 
i nter ve nti o ns a n d t he pati e nt c o nti n ues t o recei ve cli nical be nefit.  
D ose re d u cti o ns f or bli n de d st u d y dr u g s h o ul d be perf or me d as s h o w n i n t h e ta ble bel o w. 
A be macicli b/ place b o  m ust be re d uce d se q ue ntiall y b y 1 d ose le vel u nless a n e xce pti o n is gra nte d 
i n c o ns ultati o n wit h t he Lill y C R P/ C R S. Mi d -c ycle d ose re d u cti o ns f or a b e macicli b/ place b o m a y 
be i m ple me nte d b y i nf or mi n g patie nts t o re d uce t he n u m ber
 
 
6. 5. 1.  
D ose Re d ucti o ns f or Bli n de d St u d y Dr u g ( A be m acicli b / Pl ace b o  
St u d y Dr u g  
St arti n g 
d ose  
D ose Re d ucti o n  
First  
Sec o n d  
T hir d  
F o urt h  
A be macicli b /
Place b o  
A b bre viati o n s: 
 m g =  milli gra ms . 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI
C CI
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4 9  
D ose a dj ust me nts f or a birater o n e a n d pre d nis o ne s h o ul d f oll o w prescri bi n g i nf or mati o n. See 
Secti o n  6. 5. 3  f or g ui da nce o n d ose m o dificati o n f or a b n or mal li ver f u ncti o n test. 
F or partici pa nts re q uiri n g a d ose re d u cti o n of a n y st u d y i nter ve nti o n, re-es calati o n t o a pri or d ose 
le vel is per mitte d o nl y after c o ns ultati o n wit h a n d a p pr o val b y t he Lill y C R P/ C RS .  
 
6. 5. 2.  
D ose M o dific ati o ns  - A be m acicli b / Pl ace b o  
T he t a ble bel o w  pr o vi des  a g ui da nce f or t he ma n a ge me nt of treat me nt -e mer ge nt, relat e d, a n d 
cli nicall y si g nifica nt A Es of  a be ma cicli b / place b o. A n i n vesti gat or ma y s us pe n d or re d u ce d os es 
wit h o ut meeti n g o ne of t he criteri a bel o w a n d w o ul d n ot be c o nsi dere d a pr ot oc ol de viati o n.  
Partici pa nts u n der g oi n g s ur gical pr oce d ures s h o ul d f oll o w t he g ui deli nes bel o w:  
 F or mi n or s ur geries a n d pr oce d ures (f or e xa m ple, a m b ulat or y), i n vesti g at ors s h o ul d treat 
as cli nicall y i n dicate d a n d cl osel y m o nit or a n y si g ns of i nfecti o n or heali n g 
c o m plicati o ns.  
 F or maj or s ur g eries, t he rec o m me n dati o n is t o s us pe n d d osi n g of a be macicli b/ place b o f or 
at least 7 da ys bef ore s ur ger y a n d ma y be res u me d as cli nicall y i n dicate d.  
 C o nsi der m o nit ori n g ne utr o p hils a n d platelets bef ore s ur ger y a n d bef ore res u mi n g 
a be maci cli b/ place b o. T h e scars s h o ul d be ase ptic a n d heali n g pr ocess be reas o na ble 
bef ore res u mi n g a be m aci cli b/ place b o.  
 
T o xicit y D ose M o dific ati o ns of A be m acicli b / Pl ace b o 
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A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase; A S C O = A merica n S ociet y of Cli nical O nc ol o g y; A S T = as partate 
a mi n otra nsferase; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( N CI 2 0 1 7).  
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N ote: Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or. Re c urre nt t o xicit y refers t o t he 
sa me e v e nt o cc urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m t he st o p date of t he first e ve nt. As a ge neral 
g ui da n ce, base d o n t he ris k/ be nefit bala n ce assess me nt per t he i n vesti gat or, f or a partici pa nt w h o e x perie nces a ne w 
e pis o de of Gra de 3 he mat ol o gical t o xicit y after m ore t ha n 8 wee ks f oll o wi n g t he last e pis o de of t he sa me Gra d e 3 
he mat ol o gical t o xicit y, t he i n vesti gat or ma y c o nsi der res u mi n g t he partici pa nt o n t he sa me d ose s h o ul d t he 
partici pa nt satisf y t he f oll o wi n g c o n diti o ns:  
 
T he partici pa nt s h o we d sta ble he mat ol o gical c o u nts ( ≤Gra de 2) d uri n g t hat ti mefra me  
 
I n t he a bse n ce of a n y i nfecti o us si g n or ris k fact or 
 
T he partici pa nt is be nefiti n g fr o m st u d y i nter ve nti o n.  
6. 5. 3.  
D ose M o dific ati o n s f or I ncre ase d A L T or A S T - A be m ac icli b/ Pl ace b o a n d 
A bir ater o ne   
Meas ure s er u m a mi n otra nsferas es ( A L T a n d A S T) a n d bilir u bi n le vels pri or t o starti n g st u d y 
i nter ve nti o n a n d e ver y 2 wee ks f or t he first 3 m o nt hs , a n d m o nt hl y t hereaft er .  
A fter C ycle 1 4, p atie nts eli gi ble f or  re m ote tel e healt h visits will ha ve la b orat or y assess me nts 
e ver y 2 m o nt hs, u nless m ore fre q ue nt assess m e nt is dee me d necessar y per i nvesti gat or  j u d g me nt. 
D uri n g tele healt h visits , A L T , A S T  a n d bilir u bi n  m o nit ori n g ma y be perf or me d l ocall y per 
i n vesti gat or discreti o n i n acc ord a nce wit h t he a bir ater o ne prescri bi n g i nf or mati o n . See S o A 
(Secti o n 1. 3 ) f or d etails.  
Pr o m ptl y meas ure A L T, A S T, A L P, T B L, D B L, G G T, a n d C K if cli nical s y m pt o ms or si g ns 
s u g gesti ve of he pat ot o xicit y de vel o p. 
Re vie w c o nc o mita nt me dicati o ns t hat are p ote ntiall y he pat ot o xic if patie nts de vel o p li ver 
f u ncti o n test a b n or malities. 
T he ta ble bel o w pr o vi des g ui da nce f or ma na g e me nt of ele vati o n of A L T or A S T. A n i n vesti gat or 
ma y s us pe n d or re d u ce d oses wit h o ut 1 of t he bel o w criteria b ei n g met. T his w o ul d n ot be 
c o nsi dered a pr ot oc ol de viati o n.  
 
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5 2  
T o xicit y D ose M o dific ati o ns f or I ncre ase d A L T or A S T - A be m acicli b/ Pl ace b o a n d 
A bir ater o ne  
C T C A E Gr a de  
( See Secti o n 1 0. 1 0  [A p pe n di x 1 0 ] f or C T C A E 
5. 0 gr a di n g of A L T/ A S T)  
 
D ose M o dific ati o n  
Gra d e 1 or Gra d e 2  
N o d ose m o dificati o n is re q uire d . 
Persiste nt or rec urre nt Gra de 2  
 
 
S us pe n d a be macicli b/ place b o a n d a birater o ne u ntil t o xicit y 
res ol ves t o baseli ne or Gra de 1. 
 
Res u me a be macicli b/ place b o at ne xt l o wer d ose . 
Res u me a birater o ne at c urre nt d os e. 
Gra d e 3  
 
S us pe n d a be macicli b/ place b o a n d a birater o ne u ntil t o xicit y 
res ol ves t o baseli ne or Gra de 1 . 
 
Res u me a be macicli b/ place b o at ne xt l o wer d ose . 
Res u me a birater o ne at ne xt l o wer d ose a.  
≥Gra d e 2 wit h t otal bilir u bi n > 2 × U L N, i n t he 
a bse n ce of c h olestasis  
 
or rec urre nt Gra de 3 b  
 
or Gra d e 4  
 
Per ma ne ntl y disc o nti n ue a be macicli b/ place b o a n d 
a birater o ne . 
A b bre viati o ns:  A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C R P/ C R S  =  Cli nical Researc h 
P h ysicia n/ Cli nical Researc h S cie ntist;  C T C A E  =  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  ( N CI 2 0 1 7); 
U L N = u p per li mit of n or mal.  
 
Deter mi nati o n of persiste nt e ve nts will be at t he discreti o n of t he i n vesti gat or.   
 
Rec urre nt t o xicit y refers t o t he sa me e ve nt occ urri n g wit hi n t he ne xt 8 wee ks (as meas ure d fr o m 
t he restarti n g date of t he st u d y dr u g). 
a If at a n y ti me, a p atie nt de vel o ps a Gra de ≥3 el e vati o n of A L T or A S T at t he re d uce d d ose of 
5 0 0  m g o nce dail y, per m a ne ntl y disc o nti n ue a birater o ne.  
b  If rec urre nt Gra d e 3 (t hat is, wit hi n 8 wee ks as me as ure d fr o m t he restarti n g date of t he st u d y 
d r u g) is o nl y o bser ve d f or A S T, t he i n vesti gat or ma y c o ns ult wit h t he Lill y C R P/ C R S pri or t o 
per ma ne ntl y disc o nti n ui n g st u d y i nter ve nti o n.  
He patic m o nit ori n g s h o ul d be i nitiate d f or patie nts w h o de vel o p li ver f u ncti o n test a b n or malities.  
Refer t o Secti o n 8. 2. 2  f or He patic Safet y M o nit ori n g.  
 
 
 
A d diti o nal safet y data s h o ul d be c ollecte d  f or pati e nts w h o de vel o p li ver f u ncti o n test 
a b n or malities.  Refer t o S ecti o n 8. 2. 2. 1  f or A d diti o nal  He patic Safet y Data C ollecti o n.   
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6. 6.  
C o nti n ue d Access t o St u d y I nter ve nti o n after t he E n d of t he St u d y  
Partici pa nts w h o are still o n st u d y i nter ve nti o n at t he ti me of st u d y c o m pleti o n ma y c o nti n ue t o 
recei v e st u d y i nter ve nti o n if t he y are e x peri e nci n g cli nical be nefit a n d n o u n d ue ris ks. Place b o 
will n o l o n ger be a d mi nistere d.  
T he c o nti n ue d access p eri o d will a p pl y t o t his st u d y o nl y if at least 1 partici pa nt is still o n st u d y 
i nter ve nti o n w he n st u d y c o m pleti o n occ urs. Lill y will n otif y i n vesti gat ors w he n t he c o nti n ue d 
access peri o d be gi n s. 
Partici pa nts are n ot r e q uire d t o si g n a ne w I C F bef ore treat me nt is pr o vi de d d uri n g t he c o nti n ue d 
access peri o d; t he i nitial I C F f or t his st u d y i ncl u des c o nti n ue d access u n der t his pr ot oc ol. 
Partici pa nts will be disc o nti n ue d fr o m st u d y i nter ve nti o n i n t he f oll o wi n g circ u msta nces: 
 
cli nical  or ra di o gr a p hic  disease pr o gressi o n  
 
t he i n vesti gat or deter mi n es it is i n t he partici pa nt’s best i nterest t o disc o nti n ue t he st u d y 
i nter ve nti o n  
 
t he partici pa nt re q uests t o disc o nti n ue t he st u d y i nter ve nti o n 
 
u nacce pta ble t o xicit y  
 
i nitiati o n of a ne w a ntica ncer t hera p y;  d isc o nti n uati o n of t he st u d y i nter ve nti o n 
will occ ur pri or t o t he i ntr o d ucti o n of t he ne w t h era p y , a n d 
 
t he partici pa nt is e nr olle d i n a n y ot her cli nical st u d y i n v ol vi n g a n i n vestigati o nal 
pr o d uct or a n y ot her t y pe of me dical r esearc h j u d g e d n ot t o be scie ntificall y or 
me dicall y c o m pati ble wit h t his st u d y.  
C o nti n ue d access f oll o w -u p will be gi n w he n t he partici pa nt a n d t he i n vesti gat or a gree t o 
disc o nti n ue st u d y i nter ve nti o n a n d last s a p pr o xi matel y 3 0 da ys. F oll o w -u p pr oce d ures will be 
perf or me d as s h o w n i n t h e C o nti n ue d Access S o A  ( Secti o n 1. 3. 2 ). 
Partici pa nts w h o are i n s h ort -ter m f oll o w-u p w he n t he c o nti n ue d access peri o d be gi ns will 
c o nti n ue i n s h ort -ter m f oll o w-u p u ntil t he 3 0 -da y s h ort -ter m f oll o w-u p visit is c o m plete d. L o n g -
ter m f oll o w-u p d oes n ot a p pl y.  
Partici pa nts w h o are i n l o n g -ter m f oll o w-u p w he n t he c o nti n ue d access p eri o d be gi ns will be 
disc o nti n ue d fr o m l o n g -ter m f oll o w-u p.  
I n all cases, n o f oll o w-u p pr oce d ures will be perf or me d f or a p artici pa nt w h o wit h dra ws 
i nf or me d c o nse nt u nless he or s he has e x plicitl y pr o vi de d per missi o n a n d c o nse nt. 
6. 7.  
Tre at me nt of O ver d ose   
I n case of o ver d os e, use s u p p orti ve t hera p y. T h ere is n o k n o w n a nti d ote f or a be maci cli b 
o ver d ose.  I n case of o ver d ose, t he patie nt s h o ul d r ecei ve s u p p orti ve meas ures. Refer t o t he 
s pecific I B a n d/ or Pr o d u ct La bel f or t h e a p plica bl e tar gete d a ge nt(s) wit h mar kete d a p pr o val.  
I n t he e ve nt of a n o ver d ose, t he i n vesti gat or s h o ul d: 
● C o ntact t he Lill y C R P/ C R S  i m me diatel y. 
● Cl osel y m o nit or t he partici pa nt f or a n y A E / S A E a n d la b orat or y a b n or malities. 
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● O btai n a plas ma sa m ple f or P K a nal ysis as s o o n as p ossi ble after t he o v er d ose has 
bee n i de ntifie d, u nless t h e Lill y C R P/ C R S s pecifies ot her wise.  
● D oc u me nt t he q ua ntit y of t he e xcess d ose as w ell as t he d urati o n of t he o ver d ose . 
Decisi o ns re g ar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he i n vesti gat or i n 
c o ns ultati o n wit h t he Lill y C R P/ C R S base d o n t he cli nical e val uati o n of t he partic i pa nt. 
6. 8.  
C o nc o mit a nt T her a p y   
A p pr o priate d o c u me ntati o n f or all f or ms of pre me dicati o ns, s u p p orti ve care, a n d c o n c o mita nt 
me dicati o ns i ncl u di n g o ver -t he-c o u nter a n d a n al gesics use m ust be rec or de d i n t he C R F. 
C o nc o mita nt me dicati o ns a n d s u p p orti ve care t hera pies m ust als o be d oc u me nte d at ti me of 
disc o nti n uati o ns a n d at t he s h ort -ter m 3 0-d a y f oll o w -u p visit. T he Lill y C R P/ C R S s h o ul d be 
c o ntacte d if t here are a n y q uesti o ns re gar di n g c o n c o mita nt or pri or t hera p y.  
Per mitte d:  
B o ne l oss pre ve nti o n treat me nt s (f or e xa m ple, bis p h os p h o nates or de n os u m a b ) per t h eir 
res pecti ve a p pr o ve d l a bels. I nitiati o n of a n d switc hi n g bet wee n  b o ne l oss pre ve nti o n treat me nts 
is per mitte d d uri n g st u d y if it is i n t he a bse nce of disease pr o gressi o n, a n d d ue t o reas o ns 
i ncl u di n g, b ut n ot li mite d t o, t olera bilit y.  
I n t he a bse n ce of ra di o gr a p hic pr o gressi o n:  
 o ne c o urse of palliati ve  ra di ot hera p y at a si n gle site of b o n e metast ases  pres e nt at 
baseli ne is per mitte d  pr o vi de d me dical ma na g e me nt , s uc h as wit h  a nal gesics , is 
i ns ufficie nt. 
 o ne s ur gical i nter v e nti o n f or s y m pt o matic b o ne metastases or t he pre ve nti o n of a s keletal-
relate d e v e nt , s uc h as a n i m pe di n g fract ur e, is permitte d  at a si n gle site of b o ne 
metastases pres e nt at bas eli ne . 
 sur g er y/palliati ve ra di ot hera p y  f or uri nar y tract s y m pt o ms are per mitte d . 
A be macicli b/ place b o  s h o ul d be s us pe n de d t o all o w f or c orrecti o n of p ossi ble o n g oi n g rele va nt 
st u d y dr u g relate d a d v ers e e ve nts ( n e utr o pe nia/t hr o m b oc yt o pe nia/a ne mia), bef ore a partici p a nt  
u n der g oes palliati ve ra di ati o n treat me nt , a n d ma y be restart e d aft er 2  wee ks as l o n g as a n y b o ne 
marr o w t o xic it y has r ec o vere d.  
A be macicli b/ place b o s h o ul d be s us pe n de d bef ore electi ve s ur ger y  t o all o w f or c orrecti o n of 
p ossi ble o n g oi n g  rele va nt st u d y dr u g relate d a d v erse e ve nts  ( ne utr o pe nia/t hr o m b oc yt o pe nia/ 
a ne mia), a n d pri or t o ur ge nt i nter ve nti o n s. A be macicli b/ place b o ma y  be res u me d as cli nicall y 
i n dicate d. C l osel y m o nit or a n y si g ns of i nfecti o n or heali n g c o m plicati o ns. T he i ncisi o ns s h o ul d 
be ase ptic a n d h eali n g pr ocess reas o na ble bef ore res u mi n g a be macicli b/ place b o.  
R efer t o t he prescri bi n g i nf or mati o n  f or a bir ater o n e a n d pre d nis o n e. 
All palliati ve ra di ot hera p y a n d s ur ger y pr oce d ures m ust be d oc u me nte d i n t he C R F.  
Pr o hi bite d:  
N o ot her a ntica n cer t hera p y  e xce pt t hat r e q uire d b y t he pr ot oc ol  wi ll be per mitte d w hile 
partici pa nts are o n st u d y i nter ve nti o n (i ncl u di n g, b ut n ot li mite d t o a nti -h or m o nal a ge nts, ot her 
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C D K 4 a n d/ or C D K 6 i n hi bit ors, bi ol o gics, ot her a nti ne o plastic a n d i n vesti gati o nal a ge nts, 
c he m ot hera p y, ra di o p har mace uticals, i m m u n ot hera p y, a ntica n cer vacci n es, ket oc o naz ol e).  
Dr u gs, or her bal/ n o n -her bal pr o d ucts ( f or e xa m pl e, sa w pal mett o or p o me gra nate) t hat ha ve 
k n o w n  pr ostate ca ncer acti vit y a n d/ or are k n o w n t o affect P S A le vels, are n ot per mitte d w hile o n 
st u d y i nter ve nti o n. S pir o n ola ct o ne is n ot per mitte d. Me gestr ol acetate as a n a p petite sti m ula nt is 
n ot per mitte d.  
Dr u g -Dr u g I nter acti o n:  
A be macicli b is e xte nsi vel y meta b olize d t hr o u g h o xi dati o n b y C Y P 3 A. I n cli nical dr u g 
i nteracti o n st u dies: 
 c oa d mi nistrati o n of clarit hr o m yci n, a str o n g C Y P 3 A i n hi bit or, i ncrease d e x p os ure (area 
u n der t he c o n ce ntr ati o n -vers us -ti me c ur ve [ A U C]) t o a be maci cli b b y 3. 4-f ol d ( St u d y I 3 Y-
M C -J P B E), a n d 
 c oa d mi nistrati o n of rifa m pi n, a str o n g C Y P 3 A i n d ucer, decrease d e x p os ure t o 
a be maci cli b b y 9 5 % ( St u d y I 3 Y-M C -J P B F).  
Str o n g i n hi bit ors of C Y P 3 A ( gi ve n via n o n -t o pical r o utes of a d mi nistrati o n) s h o ul d be 
s u bstit ute d or a v oi de d if p ossi ble (Secti o n 1 0. 7 , A p pe n di x 7 ). T his i ncl u des gra pefr uit or 
gra pefr uit j uice. A v oi d  oral a d mi nistrati o n of t he ver y str o n g C Y P 3 A i n hi bit or, ket oc o naz ol e.  
If c oa d mi nistrati o n wit h a str o n g C Y P 3 A i n hi bit or is u na v oi da ble, i n vesti gat ors s h o ul d re d uce 
t he d ose of a b e macicli b/ place b o b y  
 at t he start of C Y P 3 A i n hi bit or treat me nt. T hat is, f or 
patie nts recei vi n g 
 re d u ce t he d ose t o 
 F or patie nts w h o 
ha ve alr ea d y d ose re d uce d t o 
 f or t olera bilit y, re d uce t h e d ose 
f urt her t o 
 res pecti vel y. Alter nati vel y, t he i n vesti gat or ma y c o nsi der 
s us pe n di n g a be maci cli b/ place b o f or t he d urati o n of t he C Y P 3 A i n hi bit or me dicati o n.  D ose 
s us pe nsi o ns ≥2 8 da ys m ust be disc usse d wit h Lill y C R P/ C R S. 
U p o n dis c o nti n uati o n of t he str o n g C Y P 3 A i n hi bit or, a be maci cli b/ place b o ma y be res u me d at 
t he sa me d ose le v el or re-escal ate d t o t he d ose t hat was use d bef ore starti n g t he str o n g 
i n hi bit or after a s ufficie nt was h o ut peri o d (at least 3 half-li ves of t he str o n g i n hibit or). Re -
escalati o n of t he a be ma cicli b/ place b o d ose re q uires re vie w a n d a p pr o val fr o m Lill y C R P/ C R S.  
I n d u cers of C Y P 3 A s h o ul d be s u bstit ute d or a v oi de d if p ossi ble (Secti o n 1 0. 7 , A p pe n di x 7 ). 
C oa d mi nistrati o n wit h a C Y P 3 A i n d ucer ≥2 8 da ys m ust be disc usse d wit h Lill y C R P/ C R S.  
A birater o n e is a s u bstrate of C Y P 3 A 4, a n d as s uc h it is rec o m me n de d t o a v oi d c o nc o mita nt 
str on g C Y P 3 A 4 i n d ucers. A birater o n e is a n i n hi bit or of t he he patic dr u g -m eta b olizi n g e nz y mes 
C Y P 2 D 6 a n d C Y P 2 C 8. F or f urt her i nf or m ati o n re gar di n g t he p ote ntial f or a birater o n e a n d/ or 
pre d nis o ne t o affect t he e x p os ures of ot her m e dici nal pr o d ucts, or f or t he p o te ntial f or me dici nal 
pr o d ucts t o affect t he e x p os ures of a bir ater o n e a n d/ or pre d nis o ne refer t o prescri bi n g 
i nf or mati o n. 
Tr a ns p orter S u bstr ates : 
At cli nicall y rele va nt c o n ce ntrati o ns, a b e macicli b i n hi bits t he tra ns p orters P -gl yc o pr otei n, breast 
ca ncer resista nce pr ot ei n, or ga nic cati o n tra ns p orter 2 ( O C T 2), m ulti dr u g a n d t o xi n e xtr usi o n 
pr otei n 1 ( M A T E 1), a n d M A T E 2 -K. T he o bs er ve d ser u m creati ni ne i ncrease i n cli nical st u dies 
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C CI
C CI
C CI
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wit h a be macicli b is li kel y d ue t o i n hi biti o n of t u b ular secreti o n of cr eati ni ne via O C T 2, M A T E 1, 
a n d M A T E 2 -K. I n vi v o i nteracti o ns of a b e maci cli b wit h narr o w t hera pe uti c i n de x s u bstrates of  
t hese tra ns p orters, s uc h as di g o xi n a n d da bi gatra n, ma y occ ur. 
V acci nes:  
Li ve vacci n es s h o ul d be a v oi de d d uri n g , a n d u p t o 9 0 da ys after t he last d ose of st u d y treat me nt. 
6. 8. 1.  
S u p p orti ve C are   
Patie nts s h o ul d recei ve s u p p orti ve care t o ma xi mize q ualit y of life as j u d g e d a p pr o priate d b y t h e 
treati n g p h ysicia n. If it is u nclear w h et her a t hera p y s h o ul d be re gar de d as s u p p orti ve care, t he 
i n vesti gat or s h o ul d c o ns ult t he Lill y C R P/ C R S. Use of all s u p p orti ve care t h era p y a n d 
c o nc o mita nt me dicati o ns s h o ul d be ca pt ure d i n t h e C R Fs.  
Gr o wt h fact ors s h o ul d n ot be a d mi nistere d t o e na ble a patie nt t o satisf y st u d y i ncl usi o n criteria. 
Gra n ul oc yte c ol o n y -sti m ulati n g fact or ( G-C S F) or si milar a ge nts are n ot p er mitte d as pri mar y 
pr o p h yla xis.  
T he use of G -C S F is per mitte d at t he discreti o n of t he i n vesti gat or base d o n A merica n S ociet y of  
Cli nical O nc ol o g y ( A S C O; S mit h et al. 2 0 1 5) a n d E ur o pea n S ociet y f or Me dical O nc ol o g y 
( Cra wf or d et al. 2 0 0 9) g ui deli nes. If t he a d mi nistrati o n of gr o wt h fact ors is cli nicall y i n dicate d, 
d osi n g of a be maci cli b/ place b o m ust be s us pe n d e d a n d m ust n ot be rec o m m e nce d wit hi n 4 8 
h o urs of t he last d ose of gr o wt h fact ors b ei n g a d mi nistere d. T he d ose of a be macicli b/ place b o 
m ust be re d uce d b y 1 d os e le vel f oll o wi n g t he a d mi nistrati o n of gr o wt h fact ors.  
Tra nsf usi o n t hera p y is per mitte d d uri n g t he st u d y if cli nicall y i n dicate d at a n y ti me d uri n g t he 
st u d y b ut s h o ul d n ot be a d mi nistere d t o e na ble a p atie nt t o satisf y st u d y i ncl usi o n criteria.  
Er yt hr o p oiesis -sti m ulati n g a ge nts ( E S As; i ncl u di n g er yt hr o p oieti n a n d dar be p oeti n) ma y be us e d 
i n acc or da nce wit h t he A S C O/ A S H g ui deli nes ( Rizz o et al. 2 0 1 0).  
6. 8. 2.  
S u p p orti ve M a n a ge me nt f or Di arr he a   
W he n st u d y i nter ve nti o n is i nitiate d, t he partici pa nt s s h o ul d recei ve i nstr ucti o ns f or t he 
ma na ge me nt of diarr hea. I n t he e ve nt of di arr h ea, s u p p orti ve meas ures s h o ul d be i nitiate d as 
e arl y as p ossi ble . T hese i ncl u de: 
 At t he first si g n of l o ose st o ols, t he patie nt s h o ul d i nitiate a nti diarr heal t hera p y ( f or 
e xa m ple, l o pera mi de) a n d n otif y t he i n vesti gat or/site f or f urt her i nstr ucti o ns a n d 
a p pr o priate f oll o w-u p.  
 Patie nts s h o ul d als o be e nc o ura ge d t o dri n k fl ui ds (f or e x a m ple, 8 t o 1 0 glasses of clear 
fl ui ds per da y ). 
 Site pers o n nel s h o ul d assess res p o nse wit hi n 2 4 h o urs.  
 If diarr hea do es n ot res ol ve wit h a nti diarr heal t hera p y wit hi n 2 4 h o urs t o eit her baseli ne 
or Gra d e 1, bli n de d st u d y dr u g s h o ul d be s us pe n de d u ntil diarr hea is res ol ve d t o baseli ne 
or Gra d e 1.  
 W he n bli n de d st u d y dr u g rec o m me nces, d osi n g s h o ul d be a dj uste d as o utli ne d i n Secti o n 
6. 5. 2 . 
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I n s e vere cas es of diarr hea, t he meas uri n g of n e utr o p hil c o u nts a n d b o d y te m perat ure a n d 
pr oacti ve ma n a ge me nt of diarr hea wit h a nti diarr heal a ge nts s h o ul d be c o nsi dere d.  
If diarr hea is se v ere (re q uiri n g I V re h y drati o n) a n d/ or ass ociate d wit h fe ver or se vere 
ne utr o pe nia, a nti bi otics s h o ul d be c o nsi dere d . 
Patie nts wit h se vere diarr hea or a n y gra d e of diarr hea ass oci ate d wit h se vere na usea or v o miti n g  
s h o ul d be caref ull y m o nit ore d a n d gi ve n I V fl ui d (I V h y drati o n) a n d electr ol yte re place me nt.  
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7.  
Disc o nti n u ati o n of St u d y I nter ve nti o n a n d P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al   
Disc o nti n uati o n of s pecific sites or of t he st u d y are ha n dle d as p art of Secti o n 1 0. 1. 9 , 
A p pe n di x  1.  
7. 1.  
Disc o nti n u ati o n of St u d y I nter ve nti o n  
Disc o nti n uati o n of st u d y i nter ve nti o n  (a birat er o ne, pre d nis o ne/ pre d nis ol o ne , a n d bli n de d st u d y 
dr u g a be ma cicli b/ place b o)  d oes n ot c o nstit ute  wit h dra wal fr o m t he st u d y . 
Partici pa nts  w h o disc o nti n ue st u d y i nter ve nti o n  s h o ul d remai n in t he st u d y a n d be f oll o we d f or 
pri mar y, sec o n d ar y , a n d e x pl orat or y e n d p oi nts .  
F oll o wi n g disc o nti n uati o n of st u d y i nter ve nti o n , p artici pa nts will e nter t he s h ort - a n d l o n g -ter m 
f oll o w-u p peri o ds a n d s c he d ule d assess me nts s h o ul d c o nti n ue acc or di n g t o t he S o A (see 
Secti o n  1. 3 ) u ntil  deat h, l oss of f oll o w -u p , or wit h dra wal of c o nse nt .  
Partici pa nts  wit h P S A -o nl y pr o gressi o n s h o ul d c o nti n ue st u d y i nter ve nti o n w here p ar tici pa nt 
safet y is n ot c o m pr o mise d. Alt h o u g h P S A meas ure me nts will be perf or me d i n t his st u d y, 
pr o gressi o n or c h a n ge i n P S A val ues s h o ul d n ot be use d as t he s ole criteri o n f or deter mi ni n g  
disease pr o gressi o n or  disc o nti n uati o n  of st u d y i nter ve nti o n . 
Partici pa nts will be disc o nti n ue d fr o m st u d y i nter ve nti o n i n t he f oll o wi n g circ u msta nces:  
 u nacce pta ble t o xicit y   
 ra di o gra p hic pr o gressi o n  as descri be d i n Secti o n 8. 1  
 i nitiati o n of a ne w  a ntica ncer t hera p y.  Disc o nti n u ati o n of t he  st u d y 
i nter ve nti o n will occ ur pri or t o t he i ntr o d ucti o n of t he ne w t hera p y . 
 t he partici pa nt is si g nifica ntl y n o nc o m plia nt wit h st u d y pr oce d ures a n d/ or 
i nter ve nti o n 
 t he i n vesti gat or deter mi n es it is i n t he partici pa nt ’s best i nterest t o 
disc o nti n ue t he st u d y i nter ve nti o n t he partici pa nt  re q uests t o disc o nti n ue 
t he st u d y i nter ve nti o n 
 t he partici pa nt’s  desi g n ee (le gal re prese nt ati ve) re q uests t hat t he 
partici pa nt  disc o nti n ue s t he st u d y i nter ve nti o n 
 t he partici pa nt is e nr olle d i n a n y ot her cli nical st u d y i n v ol vi n g a n 
i n vesti gati o nal pr o d uct or a n y ot her t y pe of me dical researc h j u d ge d n ot t o 
be scie ntifi call y or me di call y c o m pati ble wit h t his st u d y . 
T he reas o n a n d date of disc o nti n uati o n will be c ollecte d f or all partici pa nts.   
In t he a bse n ce of ra di o gr a p hic pr o gressi o n , ima gi n g ( C T/ M RI a n d b o n e sca ns) m ust be 
perf or me d wit hi n 1 4 da ys of disc o nti n uati o n d ue t o s y m pt o matic pr o gressi o n  u nless pri or sca ns 
were p erf or me d ≤1 4 da ys  pri or  t o s y m pt o matic pr o gressi o n. 
I n e xce pti o nal circ u msta nces, a partici pa nt ma y c o nti n ue st u d y i nter ve nti o n be y o n d ra di o gr a p hic 
pr o gressi o n if t here is n o effecti ve alter nati ve t hera p y a n d / or t he partici p a nt, i n t he o pi ni o n of t he 
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i n vesti gat or, is recei vi n g cli nical be nefit fr o m t he st u dy dr u g. I n t h ese rare cases, t he i n vesti gat or 
m ust o btai n d oc u me nte d a p pr o val fr o m t he Lill y C R P/ C R S t o all o w t he partici pa nt  t o c o nti n ue 
st u d y i nter ve nti o n. A d diti o nall y, t he partici pa nt  m ust rec o nse nt pri or t o c o nti n ui n g t o recei ve 
st u d y i nter ve nti o n. 
 
7. 2.  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y   
A partici pa nt  will be disc o nti n ue d fr o m t he st u d y i n t he f oll o wi n g circ u msta nces:  
● at a n y ti me at t he partici p a nt’s  o w n re q u est . 
● at t he re q uest of t h e parti ci pa nt’s desi g nee (f or e x a m ple, pare nts or l e gal 
g uar dia n) . 
● at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral, c o m plia nce, or 
a d mi nistrati ve reas o ns . 
● partici pati o n i n t he st u d y nee ds t o  be st o p pe d f or me dical, safet y, re g ulat or y, or 
ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G C P . 
At t he ti me of disc o nti n ui n g fr o m t he st u d y , a f oll o w-u p safet y  visit s h o ul d be c o n d ucte d, as 
s h o w n i n t he S o A ( Secti o n 1. 3 ). See S o A f or data t o be c ollecte d at t he ti me of st u d y 
disc o nti n uati o n a n d f oll o w -u p a n d f or a n y f urt her e val uati o ns t hat nee d t o b e c o m plete d.  T he 
partici pa nt will be per ma ne ntl y disc o nti n ue d fr o m b ot h t he st u d y i nter ve nti o n a n d t he st u d y at 
t hat ti me. 
If t he partici p a nt  wit h dra ws c o nse nt  f or discl osure of f ut ure i nf or mati o n, t he s p o ns or ma y ret ai n 
a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s u c h a wit h dra wal of c o nse nt . If a partici pa nt  
wit h dra ws fr o m t he st u d y, he/s he ma y re q u est destr ucti o n of a n y sa m ples ta ke n a n d n ot teste d , 
a n d t he i n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds . 
7. 2. 1.  
Disc o nti n u ati o n of I n a d verte ntl y R a n d o mize d P atie n ts  
T he criteri a f or e nr oll me nt m ust be f oll o we d e x plicitl y. If t h e i n vesti gat or or site i de ntifies a 
patie nt w h o di d n ot meet e nr oll me nt criteria a n d w h o was i na d vert e ntl y ra n d o mize d, t he s p o ns or 
m ust be n otifie d. If t he s p o ns or i de ntifies a patie nt w h o di d n ot meet e nr oll me nt criteria a n d w h o 
was i na d vert e ntl y ra n d o mize d, t he i n vesti gat or site will be n otifie d. Patie nts w h o are 
i na d verte ntl y ra n d o mize d s h o ul d be disc o nti n ue d fr o m  t he st u d y a n d will ha ve f oll o w -u p 
pr oce d ures perf or me d as s h o w n i n t he S o A  ( Secti o n 1. 3 ). 
 
7. 3.  
L ost t o F oll o w  u p   
A partici pa nt will be c o nsi dere d l ost t o f oll o w -u p if he re p eate dl y fails t o ret ur n f or sc h e d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e. Site pers o n nel or desi g nee are e x p ecte d t o 
ma ke dili ge nt atte m pts t o c o ntact partici p a nts w h o fail t o ret ur n f or a sc h e d ule d visit or were 
ot her wise u na ble t o b e f oll o we d u p b y t he site.   
Site p ers o n nel, or a n i n de pe n de nt t hir d part y, will atte m pt t o c ollect t he vital stat us of t he 
partici pa nt wit hi n le gal a n d et hical b o u n daries f or all partici pa nts ra n d o mize d, i ncl u di n g t h ose 
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w h o di d n ot get i n vesti gati o nal pr o d uct. P u blic s o urces ma y b e searc he d f or vital stat us 
i nf or mati o n. If vital stat us is deter mi ne d t o be decease d, t his will be d oc u m e nte d, a n d t he 
partici pa nt will n ot be c o nsi dere d l ost t o f oll o w -u p. Lill y  pers o n nel will n ot be i n v ol ve d i n a n y 
atte m pts t o c ollect vital stat us i nf or mati o n . 
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8.  
St u d y Assess me nts a n d Pr oce d ures   
St u d y pr oce d ures a n d t heir ti mi n g are o utli ne d  i n t he S o A ( Secti o n 1. 3 ).  
I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h t he sp o ns or i m me diatel y u p o n occ urre nce or 
a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y i nter ve nti o n. 
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial 
a n d re q uir e d f or st u d y c o n d uct.  
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat  p ote ntial partici pa nt s 
meet all eli gi bilit y criteria. T he i n vesti gat or will mai ntai n a scree ni n g l o g t o rec or d details of all 
partici pa nt s scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or sc ree ni n g fail ure, as 
a p plica ble.  
A p pe n di x 2 ( Secti o n 1 0. 2 ) pr o vi des a list of la b orat or y tests t hat will be perf or me d f or t his st u d y.  
U nless ot her wise state d i n t he f oll o wi n g s u bsecti o ns, all sa m ples c ollecte d f or s pecifi e d 
la b orat or y tests will be d estr o ye d wit hi n 6 0 da ys after recei pt of c o nfir me d test res ults. Certai n 
sa m ples ma y be ret ai ne d f or a l o n ger p eri o d, if necessar y, t o c o m pl y wit h a p plica ble la ws, 
re g ulati o ns, or la b orat or y certificati o n sta n dar ds. 
8. 1.  
Effic ac y Assess me nts   
T u m or a n d s y m pt o matic pr o gressi o n  will be assesse d f or eac h partici pa nt acc or di n g t o t he S o A 
( Secti o n 1. 3 ). D uri n g st u d y, u nsc he d ule d t u m or assess me nt a n d a p pr o priate i ma gi n g s h o ul d be 
c o nsi dere d if t here are si g ns or s y m pt o ms s u g gesti ve of disease pr o gressi o n.  
F or all patie nts, i ma gi n g ( C T  or M RI of t he c h est, a b d o me n, a n d pel vis a n d  ra di o n ucli de b o ne 
sca n) will be perf or me d at scree ni n g a n d re peate d e ver y 1 2 wee ks f or t he first 2 4 wee ks a n d 
e ver y 1 6 w ee ks t hereafter, acc or di n g t o cale n dar da ys  fr o m start of st u d y t h era p y ( C 1 D 1), 
re gar dl ess of treat me nt dela ys per t he S o A ( Secti o n 1. 3 ). I ma gi n g s h o ul d be perf or me d wit hi n 7 
da ys pri or t o t he sc he d ul e d  assess me nt . 
I ma gi n g s ho ul d be p erf or me d wit hi n 1 4 da ys of disc o nti n uati o n fr o m st u d y i nter ve nti o n d ue  t o 
s y m pt o matic pr o gressi o n i n t he a bse nce of d oc u m e nte d ra di o gr a p hic pr o gressi o n ( u nless pri or 
sca ns were perf or me d ≤1 4 da ys).  
T he met h o d of assess me nt use d at baseli ne m ust b e use d c o nsiste ntl y f or s erial t u m or assess me nt 
t hr o u g h o ut t he st u d y.  
All C T/ M RI a n d b o ne sca ns will be c ollecte d a n d st ore d ce ntr all y  f or BI C R . A n y p re-b aseli ne  
sca ns d oc u me nti n g metastatic disease  (i ncl u di n g P S M A-P E T/ C T sca ns) will be c ollecte d a n d 
st ore d ce ntr all y  f or BI C R. I n e xce pti o nal cases, w he n pre -b aseli ne sca ns are n ot a ble t o be 
c ollecte d fr o m a n o utsi de i nstit uti o n, t he c orres p o n di n g ra di ol o g y re p orts are acce pta ble a n d will 
n ot be  c o nsi dere d a pr ot o c ol vi olati o n.  Refer t o i ma gi n g ma n ual f or a d diti o nal details . 
T he pri mar y effic ac y e n d p oi nt is r P F S assesse d b y t he i n vesti gat or. 
Ra di o gra p hic pr o gressi o n -free s ur vi val (r P F S) will be assesse d b y se q u e ntial i ma gi n g st u dies 
a n d is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he earliest dat e of i n vesti gat or-
assesse d  ra di o gra p hic dis ease pr o gressi o n i n s oft tiss ue ( per R E CI S T 1. 1) A N D/ O R b o ne disease 
( per t he b el o w criteria a d a pte d fr o m P C W G 3) , or deat h fr o m a n y ca use, w hic he ver occ urs first.  
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S oft tiss ue disease will be assesse d p er R E CI S T 1. 1, see Secti o n 1 0. 9 , A p pe n di x 9. Ra di o gra p hic 
disease pr o gressi o n i n s oft tiss ue d oes n ot re q uire a c o nfir mat or y s ca n .  
B o ne lesi o ns will be assesse d b y b o ne sci nti gra p h y ( b o ne sca ns). P ositi ve h ot s p ots o n t he b o ne 
sca n s h o ul d be c o nsi dere d u ne q ui v ocal sites of mali g na nt disease t o be rec or de d as metastatic 
b o ne lesi o ns. C ha n ges i n i nte nsit y of u pta ke al o ne d o n ot c o nstit ute eit her pr o gressi o n or 
re gressi o n. 
B o ne pr o gressi o n is defi ne d as:  
 Pr o gressi o n at t he W ee k 1 3 sc a n:  
A p peara nce of ≥2 ne w lesi o ns o n t he Wee k  1 3 sca n c o m p are d t o b aseli ne sc a n A N D ≥2 
a d diti o nal ne w lesi o ns o n a  c o nfir mat or y  s ca n p erf or me d ≥6 wee ks lat er or o n t he ne xt 
sc he d ule d sca n ( Wee k 2 5 sca n) .  
A t otal of ≥4 ne w lesi o ns c o m pare d t o bas eli ne; t his is t he “ 2 + 2 r ule”.  
T he date of pr o gressi o n is t he da te of t he sca n t hat d oc u me nts t he first 2 ne w lesi o ns. 
 
 Pr o gressi o n at t he W ee k  2 5 sc a n or l ater:  
 
Pr ot oc ol -s pecifie d d oc u me nt ati o n f or r a di o gr a p hic pr o gressi o n 
D ate Pr o gressi o n 
Detecte d  
Criteri a f or Pr o gressi o n  
Criteri a f or C o nfir m ati o n of 
Pr o gressi o n ( Re q uire m e nt 
a n d Ti mi n g)  
Criteri a f or 
D oc u m e nt ati o n of 
Dise ase Pr o gressi o n o n 
C o nfir m at or y Sc a n  
B o ne Pr o gressi o n  
Wee k 1 3  
 
≥2 ne w lesi o ns c o m pare d 
t o baseli ne b o ne sca n. 
Re q uires c o nfir mati o n o n a 
sca n perf or me d ≥6 wee ks later 
or o n t he ne xt sc he d ule d sca n 
( Wee k 2 5 sca n). 
C o nfir mat or y sca n m ust 
s h o w ≥2 a d diti o nal ne w 
lesi o ns c o m pare d t o t he 
Wee k 1 3 sca n.  
Wee k 2 5 or l ater  
N ote: Pr o gressi o n detecte d at a n u nsc h e d ule d b o ne  sca n pri or t o Wee k 2 5 will re q uire t he sa me criteria f or 
d oc u me ntati o n of disease  pr o gressi o n as Wee k 1 3 wit h a c o nfir mat or y sca n ≥6 wee ks later or at t he ne xt 
sc h e d ule d sca n. 
S oft T iss ue Pr o gressi o n 
A n y p ost -b aseli ne 
sc a n 
 
Pr o gressi ve disease o n C T 
or M RI per R E CI S T v 1. 1 . 
N o c o nfir mat or y sca n 
re q uire d.  
N ot a p plica ble . 
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I n a d diti o n t o t he pri mar y e n d p oi nt of r P F S b y i n vesti gat or-assess e d ra di o gra p hic diseas e 
pr o gressi o n or deat h, r P F S b y BI C R will be assesse d. A ce ntr al ra di ol o g y v e n d or will c ollect a n d 
st ore i ma ges f or BI C R  re vie w. Sec o n dar y efficac y e n d p oi nts i ncl u de cli nical pr o gressi o n -free 
s urvi val (c P F S),  castrati o n -resista nt pr ostate ca ncer ( C R P C)-free s ur vi val, ti me t o P S A 
pr o gressi o n, ti me t o i nitiati o n of ne w a ntica ncer t hera p y,  ti me t o s y m pt o matic pr o gressi o n a n d 
O S . 
See Se cti o ns 9. 4. 3  a n d 9. 4. 4  f or defi niti o ns of all s ec o n dar y a n d e x pl or at or y efficac y e n d p oi nts.  
 
8. 2.  
S afet y Assess me nts   
Pla n ne d ti me p oi nts f or all safet y assess me nts (f or e xa m ple, vital si g ns a n d la b orat or y tests) are 
pr o vi de d i n t he S o A  ( Secti o n 1. 3 ). 
Res ults fr o m a n y cli nical la b orat or y test a n al yze d b y a ce ntr al la b orat or y (refer t o Secti o n  1 0. 2 , 
A p pe n di x  2 ) will be pr o vi de d t o i n vesti gati ve sites b y Lill y or its desi g nee.  
8. 2. 1.  
Cli nic al S afet y L a b or at or y Tests   
S ee Secti o n 1 0. 2 , A p pe n di x 2 f or t he list of cli nical la b orat or y tests t o be p erf or me d a n d 
t he S oA ( Secti o n 1. 3 ) f or t he ti mi n g a n d fre q ue n c y. 
T he i n vesti gat or m ust re vie w t he la b orat or y res ults, d oc u me nt t his re vie w, a n d re p ort a n y 
cli nicall y rele va nt c ha n g es occ urri n g d uri n g t he st u d y as a n A E. T h e la b orat or y res ults 
m ust be retai ne d wit h s o urce d oc u m e nts u nless a S o urce D oc u m e n t A gree me nt or 
c o m para ble d o c u me nt cit es a n ele ctr o nic l ocati o n t hat acc o m m o dates t h e e x pecte d 
rete ntio n d urati o n. Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose w hic h are 
n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he i n vesti gat or t o be 
w orse ne d b y st u d y i nter ve nti o n. 
All la b orat or y tests wit h a b n or mal val ues c o nsi dere d cl i nicall y si g nifica nt a n d p ossi bl y 
relate d t o st u d y i nter ve nti o n d uri n g st u d y i nter ve nti o n u ntil t he c o m pleti o n of V 8 0 1  
s h o ul d be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or o r Lill y C R P/ C R S . 
○ If s uc h val ues d o n ot ret ur n t o n or mal/ baseli ne wit hi n a peri o d of ti me j u d g e d 
reas o na bl e b y t he i n vesti gat or, t he eti ol o g y s h o ul d be i de ntifie d, a n d t he 
s p o ns or n otifie d. 
○ All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n Secti o n 1 0. 2 , 
A p pe n di x 2, m ust be c o n d ucte d i n acc or da n ce wit h t he S o A ( Secti o n 1. 3 ), 
sta n dar d c ollecti o n re q uir e me nts, a n d t he la b orat or y ma n ual. 
o  If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifi e d la b orat or y assess me nts 
perf or me d at a n i n vesti gat or -desi g nate d l ocal la b orat or y or are c o nsi dere d 
cli nicall y si g nifica nt b y t he i n vesti gat or ( f or e xa m ple, S A E or A E or d ose 
m o dificati o n), t he n  re p ort t he i nf or mati o n as a n A E. 
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8. 2. 2.  
He p atic S afet y M o nit ori n g   
Cl ose he p atic m o nit ori n g a n d e v al u ati o n  
Li ver testi n g ( Secti o n 1 0. 5 , A p pe n di x 5 ), i ncl u di n g A L T, A S T, A L P, T B L, D. Bil, G G T, a n d 
C K, s h o ul d be re peate d wit hi n 2 t o 4 da ys t o c o n fir m t he a b n or malit y a n d t o deter mi ne if it is 
i ncreasi n g or decreasi n g, if 1 or m ore of t hes e c o n diti o ns occ ur:  
If a p artici p a nt wit h b aseli ne 
res ults of...  
de vel o ps t he f oll o wi n g ele v ati o ns:  
A L T or A S T < 1. 5 ×  U L N  
A L T or A S T ≥5 ×  U L N or  
A L T or A S T ≥3 ×  U L N c o nc urre nt wit h T B L ≥2 ×  
U L N  
A L T or A S T ≥1. 5 ×  U L N  
A L T or A S T ≥3 ×  bas eli ne or  
A L T or A S T ≥2 ×  bas eli ne c o nc urre nt wit h T B L ≥2 ×  
U L N  
If t he a b n or m alit y persists or w orse ns, cli nical a n d la b orat or y m o nit ori n g a n d e val uati o n f or 
p ossi ble ca uses of a b n or mal li ver tests s h o ul d be i nitiate d b y t he i n vesti gat or i n c o ns ultati o n wit h 
t he Lill y  C R P/ C R S . At a mi ni m u m, e val uati o n s h o ul d i ncl u de p hysical e xa mi nati o n, a t h or o u g h 
me dical hist or y t hat i ncl u des s y m pt o ms, rece nt ill nesses (f or e xa m ple, h eart fail ure, s yste mic 
i nfecti o n, h y p ote nsi o n, or seiz ures), hist or y of c o n c o mita nt me dicati o ns (i ncl u di n g o ver-t he-
c o u nter, her bal, a n d diet ar y s u p ple me nts), a n d hist or y of alc o h ol dri n ki n g a n d/ or ot her s u bsta nce 
a b use. I n a d diti o n, t he e v al uati o n s h o ul d i ncl u de a bl o o d test f or P T -I N R; ser ol o gical tests f or 
viral he patitis A, B, C, E, a ut oi m m u ne he patitis; a n d a n a b d o mi nal i ma gi n g st u d y (f or e xa m ple, 
ult ras o u n d or C T sca n). 
Base d o n t he partici pa nt ’s hist or y a n d i nitial e val uati o n res ults, f urt her testi n g s h o ul d be 
c o nsi dere d, i n c o ns ultati o n wit h t he Lill y C R P/ C R S, i ncl u di n g tests f or he patitis D vir us, 
c yt o me gal o vir us, E pstei n -Barr vir us, aceta mi n o p h e n le vels, aceta mi n o p he n pr otei n a d d ucts, 
uri ne t o xic ol o g y scree n, Wils o n’s disease, bl o o d alc o h ol le vels, uri nar y et h yl gl uc ur o ni de, a n d 
bl o o d p h os p hati d ylet ha n ol. Base d o n t he circ u mst a nces a n d t h e i n vesti gat or’s assess me nt of t he 
partici pa nt’s cli nical c o n diti o n, t he i n vesti gat or s h o ul d c o nsi der referri n g t he partici pa nt f or a 
he pat ol o gist or gastr oe nt er ol o gist c o ns ultati o n, ma g netic res o n a nce c h ola n gi o pa ncreat o gra p h y, 
e n d osc o pic retr o gra d e c h ola n gi o pa ncreat o gra p h y, car diac ec h o car di o gra m, a n d/ or a li ver bi o ps y.  
F or patie nts w h o e x perie nce d he p at o xicit y a n d res u me d treat me nt, A S T, A L T , a n d bilir u bi n 
s h o ul d be m o nit ori n g e ver y wee k f or t he first m o nt h, e ver y 2 wee ks f or t h e f oll o wi n g 2 m o nt hs 
a n d m o nt hl y t hereaft er.  
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8. 2. 2. 1.  
A d diti o n al He p atic S afet y D at a C ollecti o n   
A d diti o nal safet y data s h o ul d be c ollecte d via t he C R F if 1 or m ore of t he f oll o wi n g c o n diti o ns 
occ ur:  
I n p artici p a nts e nr olle d wit h b aseli ne A L T or A S T < 1. 5×  U L N  
 Ele vati o n of ser u m A L T or A S T t o ≥5 ×  U L N o n 2 or m ore c o ns ec uti ve bl o o d  
tests. 
 T he c o m bi nati o n of ele v ate d A L T or A S T ≥3 ×  U L N a n d ele vate d T B L ≥2 ×  
U L N . 
I n p artici p a nts e nr olle d wit h b aseli ne A L T or A S T ≥1. 5×  U L N  
 Ele vate d A L T or A S T ≥3 ×  baseli ne o n 2 or m or e c o nsec uti ve tests . 
 T he c o m bi nati o n of ele v ate d A L T or A S T ≥2 ×  baseli ne a n d ele vate d T B L 
≥2 ×  U L N . 
I n all st u dy p artici p a nts 
 Disc o nti n uati o n fr o m st u d y treat me nt d ue t o a h e p atic e ve nt or a b n or malit y of 
li ver tests. 
 Occ urre nce of a h e patic e ve nt c o nsi dere d t o b e a n S A E . 
8. 2. 3.  
G ui d a nce f or M o nit ori n g Re n al F u ncti o n   
A be macicli b has b ee n s h o w n t o i ncreas e ser u m creati ni ne d ue t o i n hi biti o n of re nal t u b ular 
tra ns p orters wit h o ut affecti n g gl o mer ular f u ncti o n (as meas ure d b y i o he x ol cleara nce). I n cli nical 
st u dies, i ncreases i n ser u m creati ni ne occ urre d wit hi n t he first m o nt h of a be macicli b d osi n g, 
re mai ne d el e vate d b ut sta ble t hr o u g h t he treat me nt peri o d, were re v ersi ble u p o n treat me nt 
disc o nti n uati o n, a n d were n ot acc o m p a nie d b y c h a n ges i n mar kers of re nal f u ncti o n, s uc h as 
bl o o d urea nitr o ge n, c ystati n C, or calc ulate d gl o mer ular filtrati o n rate bas e d o n c ystati n C.  
D ose a dj ust me nt ( o missi o n, re d ucti o n, or disc o nti n uati o n) s h o ul d n ot s olel y be base d o n 
i nter pretati o n of ser u m creati ni ne val ues beca us e t hese ma y n ot reflect r e nal f u ncti o n. Ot her 
meas ures of re nal f u ncti o n, s uc h as c ystati n  C , or G F R, s h o ul d be use d as a n alter nati ve t o eit her 
creati ni ne or creati ni ne calc ulati o ns  of G F R. A s er u m c ystati n C is c ollecte d wit h ce ntral 
c he mistr y la b orat or y s a m ple. If deteri orati o n of re nal f u ncti o n is s us pecte d per t he i n vesti gat or’s 
cli nical assess me nt, a n d c o nsi dere d p oss i bl y relat e d t o bli n de d st u d y dr u g, d ose alterati o n s h o ul d 
f oll o w t he pr ot oc ol g ui da nce f or n o n-he mat ol o gical  t o xicities i n Secti o n 6. 5. 2 .  
8. 2. 4.  
G ui d a nce f or I nterstiti al L u n g Dise ase/ P ne u m o nitis  
I nterstitial l u n g disease/ p ne u m o nitis has bee n i de ntifie d as a n A D R f or a be macicli b. T he 
maj orit y of e ve nts o bser ve d i n cli nical trials were Gra de 1 or Gra de 2, wit h seri o us cases a n d 
fatal e ve nts r e p orte d. A d diti o nal i nf or mati o n is a vaila ble i n t he I B. 
M o nit or patie nts f or p ul m o nar y s y m pt o ms i n dicati ve of I L D/ p ne u m o nitis  s uc h as h y p o xia,  
d ys p nea, c o u g h, a n d fe v er, a n d i n vesti gate a n d tr eat as per l ocal cli nical pr actice (i n cl u di n g 
c ortic oster oi ds as a p pr o priate). If I L D/ p ne u m o nitis is s us pecte d, i n vesti gati o ns ma y i ncl u de 
i ma gi n g, s uc h as hi g h-res ol uti o n C T, br o nc h oal ve olar la va ge, a n d bi o ps y as cli nicall y i n dicate d.  
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Refer t o Secti o n  6. 5  f or g ui da nce o n d ose a dj ust me nts of a be macicli b/ place b o  f or partici pa nts  
wit h I L D/ p n e u m o nitis . Disc o nti n ue a be maci cli b/ place b o i n cases of se v ere ( Gra d e 3 or Gra de 4) 
I L D/ p ne u m o nitis.  
8. 2. 5.  
G ui d a nce f or V e n o us T hr o m b oe m b olic E ve nts  ( V T Es)  
I n breast c a ncer, V T E h as bee n i de ntifie d as a n A D R f or a be macicli b i n c o m bi nati o n wit h E T. I n 
t he ra n d o mize d P has e 3 st u dies i n partici pa nts wit h breast c a ncer w h o recei ve d a bemacicli b i n 
c o m bi nati o n wit h E T,  a greater n u m ber of p artici p a nts e x perie n ce d V T Es i n t he a be macicli b pl us 
E T ar ms t ha n i n t he place b o pl us E T ar m or E T al o ne ar m. T he m aj orit y of partici pa nts w h o 
e x perie n ce d V T Es were treate d wit h a ntic o a g ula nts.  
I n st u dies wit h si n gle-a g e nt a be ma cicli b use i n t he metastatic breast ca n cer p o p ulati o n or ot her 
t u m or t y pes, i ncl u di n g no n -small  cell lu n g ca ncer, n o i ncreas e d rates of V T Es were o bs er ve d as 
c o m pare d t o t he i nci d e nce of V T Es f or t hese p atie nt p o p ulati o ns w h o were  treate d wit h ot her 
a ntica ncer a g e nts. At t his ti me, t he mec ha nis m u n derl yi n g t he ass ociati o n bet wee n a be macicli b 
a n d t he occ urre n ce of V T Es is n ot k n o w n.  
M o nit or partici pa nts f or si g ns a n d s y m pt o ms of dee p vei n t hr o m b osis a n d p ul m o nar y e m b olis m 
a n d treat as m e dicall y a p pr o priate. D os e m o dificati o ns a n d ma na ge me nt of a be maci cli b/ place b o 
s h o ul d f oll o w t he pr ot oc ol g ui da nce f or V T E  i n Secti o n  6. 5. 2 .  
8. 2. 6.  
G ui d a nce f or H y perte nsi o n, H y p o k ale mi a, Fl ui d Rete nti o n, a n d C ar di o v asc ul ar 
A d verse R e acti o ns D ue t o Mi ner al oc ortic oi d E xces s  
A birater o n e ma y ca use h y perte nsi o n, h y p o kale mi a, a n d fl ui d ret e nti o n as a c o nse q ue nce of 
i ncreas e d mi neral oc ortic oi d le vels res ulti n g fr o m C Y P 1 7 i n hi biti o n. 
M o nit or patie nts f or h y perte nsi o n, h y p o kale mia, a n d s y m pt o ms of fl ui d rete nti o n at least o nce a 
m o nt h. Patie nts wit h l o w p otassi u m w hile o n st u d y or a hist or y of h y p o kal e mia fr o m a 
pree xisti n g or c o nc urre nt me dical c o n diti o n s h o ul d be c o nsi dere d f or m or e f re q ue nt la b orat or y 
electr ol yte e v al uati o n per i n vesti gat or’s discreti o n. C o ntr ol h y perte nsi o n a n d c orrect 
h y p o kale mia bef ore a n d d uri n g treat me nt.   
Cl osel y m o nit or patie nts w h ose u n derl yi n g me dical c o n diti o ns mi g ht be c o m pr o mise d b y 
i ncreas es i n bl o o d press ure, h y p o kale mia, or fl ui d rete nti o n s uc h as t h ose wit h heart fail ure, 
rece nt m y ocar dial i nfarcti o n, car di o vasc ul ar disease, or ve ntric ular arr h yt h mia. Q T pr ol o n gati o n 
a n d T orsa des d e P oi ntes ha ve bee n o bser ve d i n patie nts w h o de vel o p h y p o kale mia w hile t a ki n g 
a birater o n e. T he s afet y of a birater o ne i n patie nts wit h left ve ntric ular ejecti o n fracti o n < 5 0 % h as 
n ot bee n esta blis he d.  
Refer t o a bir ater o n e pres cri bi n g i nf or mati o n.  
8. 2. 7.  
G ui d a nce f or A dr e n oc o rtic al I ns ufficie nc y   
A dre n oc ortical i ns ufficie nc y was r e p orte d i n patie nts recei vi n g a bir ater o n e i n c o m bi nati o n wit h 
pre d nis o ne, f oll o wi n g i nterr u pti o n of dail y ster oi ds a n d/ or wit h c o nc urre nt i nfecti o n or stress.  
M o nit or patie nts f or s y m pt o ms a n d si g ns of a dre n oc ortical i ns u ffici e nc y, p artic ularl y if patie nts 
are wit h dr a w n fr o m pre d nis o ne, ha ve pre d nis o ne d ose re d ucti o ns, or e x perie nce u n us ual stress. 
S y m pt o ms a n d si g ns of a dre n oc ortical i ns ufficie n c y ma y be mas ke d b y a d verse reacti o ns 
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ass ociate d wit h mi neral o c ortic oi d e xcess  see n i n p atie nts treate d wit h a bir at er o ne. If cli nicall y 
i n dicate d, perf or m a p pr o priate tests t o c o nfir m t he dia g n osis of a dre n o c ortical i ns ufficie n c y. 
I n crease d d osa g e of c ortic oster oi ds ma y be i n dicat e d bef ore, d uri n g a n d aft er stressf ul sit uati o ns. 
Ref er t o a bir ater o n e pres cri bi n g i nf or mati o n.  
8. 2. 8.  
G ui d a nce f or H y p o gl yc e mi a   
Se vere h y p o gl yc e mia has bee n re p orte d w he n a bir ater o ne was a d mi nistere d t o patie nts wit h 
pree xisti n g dia betes  recei vi n g me dicati o ns c o ntai ni n g t hiaz oli di ne di o nes (i ncl u di n g pi o glitaz o ne) 
or re pa gli ni de. M o nit or bl o o d gl uc ose i n patie nts wit h dia betes d uri n g a n d after disc o nti n uati o n 
of treat me nt wit h a bir ater o ne. Assess if a nti dia beti c dr u g d osa ge n ee ds t o b e a dj uste d t o 
mi ni mize t he ris k of h y p o gl yce mia.  
Refer t o a bir ater o n e pres cri bi n g i nf or mati o n.  
8. 3.  
A d verse E ve nts , Seri o us A d verse E ve nts , a n d Pr o d uct C o m pl ai nts  
Lill y sta n dar ds f or re p or ti n g A Es are t o be f oll o we d re gar dless of c o u ntr y re g ulat or y 
re q uire me nts are less stri n ge nt. A cli nical st u d y A E is a n y u nt o war d me dical e ve nt ass oci ate d 
wit h t he use of a dr u g i n h u ma ns, irres pecti ve if t he A E is relate d t o st u d y i nter ve nti o n.  
T he defi n iti o ns of t he f oll o wi n g e ve nts ca n be f o u n d i n S ecti o n 1 0. 3 , A p pe n di x 3:  
 A d verse e ve nts ( A Es)  
 Seri o us a d verse e ve nts ( S A Es)  
 Pr o d uct c o m plai nts ( P Cs)  
A d verse  e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt’s le gall y a ut h orize d re prese nt ati ve). 
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t hese defi niti o ns a n d re mai n res p o nsi ble f or f oll o wi n g u p e ve nts t hat 
are seri o us, c o nsi dere d relate d t o t he st u d y i nter ve nti o n or st u d y  pr oce d ures, or t hat ca use d t h e 
partici pa nt t o disc o nti n ue t he st u d y i nter ve nti o n (see Secti o n 7 ). 
T he i n vesti gat or will use C T C A E versi o n 5. 0 ( N CI 2 0 1 7) t o assi g n A E se v erit y gra des.  
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g e ve nts. O pe n -e n de d a n d n o n -lea di n g 
ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut e ve nt occ urre n ces.  
After t he i nitial re p ort, t he i n vesti gat or is re q uir ed t o pr oacti vel y f oll o w eac h partici pa nt at 
s u bse q ue nt visits/c o ntacts. All S A Es a n d A Es will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he 
e ve nt is ot her wise e x pl ai ne d, or t he partici pa nt is l ost t o f oll o w -u p (as defi n e d i n Secti o n  7. 3 ). 
F or pr o d u ct c o m plai nts, t he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w -u p i ncl u des a n y 
s u p ple me ntal i n vesti gati o ns as i n dicate d t o el uci d ate t he nat ur e a n d/ or ca us alit y. F urt her 
i nf or mati o n o n f oll o w-u p pr oce d ures is pr o vi de d i n Secti o n  1 0. 3 , A p pe n di x 3. 
Lac k of dr u g effect is n ot a n A E i n cli nical st u dies, beca use t h e p ur p ose of t he cli nical st u d y is t o  
esta blis h treat me nt effect.  
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After t he I C F is si g ne d, st u d y site pers o n nel will rec or d via C R F/el ectr o nic data e ntr y/ desi g nat e d 
data tra ns missi o n met h o ds t he occ urre nce a n d nat ure of eac h p atie nt’s pree xisti n g c o n diti o ns, 
i ncl u di n g cli nicall y si g nifica nt si g ns a n d s y m pt o ms of t he disease u n der treat me nt i n t he st u d y. 
I n a d diti o n, st u d y site pers o n nel will rec or d via C R F/electr o nic d ata e ntr y/ desi g nate d data 
trans missi o n met h o ds a n y c ha n ge i n t he pree xisti n g c o n diti o ns a n d a n y ne w c o n diti o ns as A Es. 
I n v esti gat ors s h o ul d rec or d t heir assess me nt of t he p ote ntial relate d ness of eac h A E t o st u d y 
i nter ve nti o n via C R F/electr o nic data e ntr y/ desi g n ate d data tra ns missi o n met h o ds.  
T he i n vesti gat or will i nter pret a n d d o c u me nt w het her or n ot a n A E has a reas o na ble p ossi bilit y 
of bei n g relat e d t o st u d y i nter ve nti o n or a st u d y pr oce d ure , t a ki n g i nt o acc o u nt t he disease, 
c o nc o mita nt treat me nts, or pat h ol o gies. A “reas o n a ble p ossi bilit y” mea ns t hat t here is a ca use -
a n d-effect relati o ns hi p bet wee n t he st u d y i nter ve nti o n a n d/ or st u d y pr oce d ure an d t he A E.  
Pla n ne d s ur geries a n d n o ns ur gical i n ter ve nti o ns s h o ul d n ot be re p orte d as A Es u nless t he 
u n derl yi n g me dical c o n diti o n has w orse ne d d uri n g t he c o urse of t h e st u d y.  
St u d y site pers o n n el m ust re p ort a n y d ose m o dificati o ns or treat me nt disc o nti n uati o ns t hat res ult 
fr o m A Es t o Lill y or its desi g nee via C R F/electr o nic data e ntr y/ desi g n ate d data tra ns missi o n 
met h o ds, clarif yi n g, if p ossi ble, t he circ u msta nces lea di n g t o t he d ose m o dificati o n or  
disc o nti n uati o n of treat me nt.  
8. 3. 1.  
Ti mi n g a n d Mec h a nis m f or C ollecti n g E ve nts   
All S A Es will  be c ollecte d fr o m t he si g ni n g of t he I C F u ntil partici pati o n i n st u d y has e n de d.  
All A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he s h ort -ter m 3 0-da y f oll o w -u p visit.  
A d verse e ve nts t hat be gi n bef ore t h e start of st u d y i nter ve nti o n  b ut after si g ni n g of t he I C F 
will be rec or de d o n t he A d verse E ve nt C R F. Alt h o u g h all A Es after si g ni n g t he I C F are 
rec or de d b y t he site i n t he C R F/electr o nic d ata e ntr y, S A E re p orti n g t o t he s p o ns or be gi ns 
after t he p artici pa nt has si g ne d t he I C F a n d h as recei ve d st u d y dr u g. H o we ver, if a n S A E 
occ urs after si g ni n g t he I C F, b ut pri or t o recei vi n g a be maci cli b, it nee ds t o be re p ort e d O N L Y 
if it is c o nsi dere d reas o na bl y p ossi bl y relate d t o st u d y pr oce d ures.  
All S A Es will be rec or de d a n d re p ort e d t o t he s p o ns or or desi g nee i m me di atel y a n d u n der n o 
circ u msta nce s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n Secti o n 1 0. 3 , A p pe n di x 3. T he 
i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g 
a vaila ble. Seri o us a d v ers e e ve nts, i ncl u di n g deat h, ca use d b y disease pr o gressi o n s h o ul d n ot 
be re p ort e d u nless t he i n vesti gat or de e ms t he m t o be p os si bl y relate d t o st u d y i nter ve nti o n. 
I n v esti gat ors are n ot o bli gate d t o acti vel y se e k A Es or S A Es after c o ncl usi o n of t he st u d y 
partici pati o n (t he partici pa nt s u m mar y C R F has bee n c o m plete d). H o we ver, if t he i n vesti gat or 
lear ns of a n y S A E, i n cl u di n g a deat h, at a n y ti me after a partici pa nt h as bee n disc har ge d fr o m 
t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be reas o na bl y relate d t o t he st u d y i nter ve nti o n or 
st u d y partici pati o n, t he i n vesti gat or m ust pr o m ptl y n otif y t he s p o ns or. 
Als o s ee T i mi n g a n d Mec ha nis m f or C ollecti n g E ve nts  ta ble i n Secti o n 1 0. 6 , A p pe n di x 6. 
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8. 3. 2.  
Met h o d of Detecti n g A E a n d S A Es   
T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of A E a n d S A E a n d t he pr oce d ures 
f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n Secti o n 1 0. 3 , A p pe n di x 3.  
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d n o n -
lea di n g ver bal q u esti o ni n g of t he partici pa nt is t he preferre d m et h o d t o i n q uire a b o ut A E 
occ urre nces.  
Seri o us A d verse E ve nts   
A n S A E is a n y A E fr o m t his st u d y t hat res ults i n 1 of t he f oll o wi n g o utc o mes:  
 deat h  
 i nitial or pr ol o n ge d i n patie nt h os pitalizati o n  
 a life-t hreate ni n g e x p erie nce (t hat is, i m me diate ris k of d yi n g)  
 persiste nt or si g nifica nt  disa bilit y/i nca pacit y  
 c o n ge nital a n o mal y/ birt h  defect  
 i m p orta nt me dical  e ve nts  t hat ma y  n ot  be  i m me diatel y life-t hreate ni n g or  res ult i n deat h 
or re q uire h os pitaliz ati o n ma y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, t he y ma y je o par dize t he partici pa nt a n d ma y re q uir e i nter ve nti o n t o 
pre ve nt  o ne  of  t h e ot her  o utc o mes  liste d i n t he defi niti o n  a b o ve.  
Pla n ne d h os p italizati o ns or pr oce d ures f or pree xisti n g c o n diti o ns t hat were rec or de d i n t he 
partici pa nt’s me dical hist or y at t he ti me of e nr oll me nt s h o ul d n ot be c o nsi dere d S A Es.  
H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n wit h o ut a preci pitati n g cli nical A E (f or 
e xa m ple, f or t h e a d mi nistrati o n of st u d y i nter ve nti o n or ot her pr ot oc ol -re q uire d pr oce d ure) 
s h o ul d n ot be c o nsi dere d S A Es. 
Pre g na nc y ( d uri n g mater nal or pater n al e x p os ure t o st u d y i nter ve nti o n) d oes n ot meet t he 
defi niti o n of a n A E b ut s h o ul d be re p orte d. H o we ver, t o f ulfill re g ulat or y re q uire me nts a n y 
pre g na nc y s h o ul d b e re p orte d f oll o wi n g t he S A E pr ocess t o c ollect d ata o n t he o utc o me f or b ot h 
m ot her a n d fet us. See Secti o n 8. 3. 5  f or details.  
S us pecte d U ne x pecte d Seri o us A d verse Re a cti o ns  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns are seri o us e ve nts t hat are n ot liste d i n t he I B 
a n d t hat t he i n vesti gat or i de ntifies as rel ate d t o st u d y i nter ve nti o n or st u d y pr oce d ure. U nite d 
States 2 1 C F R 3 1 2. 3 2 a n d Re g ulati o n ( E U) N o 5 3 6/ 2 0 1 4 a n d t he ass ociate d detaile d g ui da nce or 
nati o nal re g ulat or y re q uir e me nts i n partici pati n g c o u ntries re q uire t h e re p orti n g of S U S A Rs. 
Lill y has pr oce d ures t hat will be f oll o w e d f or t he rec or di n g a n d e x pe dite d re p orti n g of S U S A Rs 
t hat are c o nsiste nt wit h gl o bal re g ulati o ns a n d ass ociate d detaile d g ui da n ce.  
8. 3. 3.  
F oll o w -u p of A Es a n d S A Es   
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es  will be f oll o we d u ntil res ol uti o n t o baseli ne, sta bilizati o n, 
t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt dies or is l ost t o f oll o w-u p (as defi ne d i n 
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Secti o n 7. 3 ). F urt her i nf or mati o n o n f oll o w-u p pr o ce d ures is pr o vi d e d i n Secti o n 1 0. 3 , A p pe n di x 
3.  
8. 3. 4.  
Re g ul at or y Re p orti n g Re q uire me nts f or S A Es   
Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or of a n  S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of partici pa nts a n d t he safet y of a st u d y 
i nter ve nti o n u n der cli nic al i n vesti gati o n are met. 
T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a g e ncies a b o ut t he safet y of a st u d y i nt er ve nti o n u n der cli nical i n vesti gati o n. T he 
s p o ns or will c o m pl y wit h c o u ntr y-s pecific re g ul at or y re q uire m e nts relati n g t o safet y re p orti n g t o 
t he re g ulat or y a ut h orit y, I R Bs/I E Cs, a n d i n vesti gat ors. 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n  S A E or ot her s pecific 
safet y i nf or mati o n (f or e xa m ple, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w a n d 
t he n file it al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts. 
8. 3. 5.  
Pre g n a nc y   
C ollecti o n of pre g n a nc y i nf or m ati o n  
M ale p artici p a nts wit h p art ners w h o bec o me pre g n a nt  
● T he i n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male 
partici pa nt’s f e male part ner w h o bec o mes pre g na nt w hile t he male partici p a nt is 
i n t his st u d y. T his a p plies o nl y t o male partici pa nts w h o recei ve st u d y 
i nter ve nti o n. 
● After le ar ni n g of a pre g n a nc y i n t he fe m ale part n er of a st u d y partici p a nt, t he 
i n vesti gat or will 
o  Atte m pt t o o btai n a c o nse nt  t o releas e i nf or mati o n fr o m t he pre g n a nt fe male 
part ner directl y, a n d  
o  If c o nse nt is gr a nte d, wit hi n 2 4 h o urs after o btai ni n g t his c o nse nt wil l rec or d 
pre g na nc y i nf or mati o n o n t he a p pr o priat e f or m a n d s u b mit it t o t he s p o ns or.  
If c o nse nt is n ot o btai ne d , t he i n vesti gat or will d oc u me nt ref usal of c o nse nt  or t he reas o n 
t hat t he c o nse nt was n ot o btai ne d. 
If c o nse nt is o btai ne d, t h e fe male p art ner will be f oll o we d t o deter mi ne t he 
o utc o me of t he pre g na nc y. I nf or mati o n o n t he stat us of t he m ot her a n d c hil d will 
be f or w ar de d t o t he s p o ns or. Ge nerall y, t he f oll o w -u p will be n o l o n ger t h a n 6 t o 
8 wee ks f oll o wi n g t he esti mate d deli ver y da te. A n y ter mi nati o n of t he pre g na nc y 
will be re p orte d re gar dless of gestati o nal a ge,  fetal stat us ( prese nce or a bs e nce of 
a n o malies) or i n dicati o n f or t he pr oce d ure.  
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8. 3. 6.  
A d verse E ve nts of S peci al I nterest   
A d verse e ve nts of s pecial i nterest f or a b e macicli b i ncl u de  ne utr o pe nia , i nfecti o ns, d iarr hea, 
he patic e v e nts i ncl u di n g i ncreas es i n A S T/ A L T , V T E, a n d I L D/ p n e u m o nitis. N o A Es nee d t o be 
a dj u dicate d. Secti o n 6. 5  prese nts  t he d ose m o dificati o n g ui deli nes. 
8. 4.  
P h ar m ac o ki netics   
P har mac o ki netic sa m ples will be c ollecte d fr o m st u d y partici pa nts  at t he visits a n d ti mes 
s pecifie d i n t he S o A ( Secti o n 1. 3. 1 ). At all P K ti me p oi nts, a v ol u metric a bs or pti ve 
micr osa m pli n g de vice  will be use d t o c ollect a bl o o d sa m ple b y ca pillar y p u nct ure . I n a d diti o n, 
o n C ycle  1 Da y 1 a n d C y cle 3 Da y 1, a P K sa m ple will als o be c ollecte d at a p pr o xi matel y t he 
sa me ti me ( wit hi n [ +/-] 1 0 mi n utes) as t he bl o o d micr osa m ple via ve n o us p u nct ure c ollecti o n 
i nt o a vac utai ner. It is i m p orta nt t o c ollect acc urat e i nf or mati o n f or t he ti m e a n d date of eac h P K 
sa m ple o n t he la b re q uisiti o n f or m. 
It is als o i m p orta nt t o c ollecti o n acc urate i nf or mati o n f or t he ti me a n d date of d oses of bli n de d 
st u d y dr u g ar o u n d t he P K sa m pli n g c ollecti o n ti mes. Acc or di n gl y, d uri n g t he P K sa m pli n g 
peri o d ( C ycle 1 Da y 1 t o C ycle 3 Da y 1), p artici pa nts will c o m plete a Patie nt D osi n g Diar y t o 
rec or d t h e ti me a n d date of bli n de d st u d y dr u g d oses, w hic h will be utilize d i n P K assess me nts. 
T he i nf or mati o n i n t his diar y s h o ul d be c ollect e d a n d re vie we d o n Da y 1 of C ycle 2 a n d C ycle 3 
f or eac h pri or c ycle a n d be d oc u me nte d i n t he C R F. T his  diar y is n ot i nte n de d t o m o nit or 
c o m plia nce.  
P har mac o ki netic sa m ples will be a nal yze d at a la b orat or y a p pr o ve d b y t he sp o ns or a n d st ore d at 
a facilit y desi g nate d b y t he sp o ns or. C o nce ntr ati o ns of a be macicli b a n d its meta b olites, M 2 a n d 
M 2 0, will be deter mi ne d usi n g vali date d li q ui d c hr o mat o gra p h y wit h ta n de m mass s pectr o metr y 
met h o ds.  
P har mac o ki netic sa m ples ma y be retai n e d f or a ma xi m u m of 1 year f oll o wi n g last partici pa nt  
visit f or t he st u d y.  
A d diti o nal  sa m ples ma y be c ollecte d duri n g t he st u d y if warra nte d a n d a gree d u p o n bet w ee n 
b ot h t he i n vesti gat or a n d sp o ns or. I nstr u cti o ns f or t he c ollecti o n a n d ha n dli n g of bl o o d sa m ples 
will be pr o vi de d b y t he sp o ns or . T he act ual date a n d ti me ( 2 4-h o ur cl oc k ti me) of eac h sa m ple 
will be rec o r de d. 
8. 5.  
P h ar m ac o d y n a mics   
P har mac o d y na mic p ara m eters a re n ot e val u ate d i n t his st u d y. 
8. 6.  
Ge netics   
A ger mli ne D N A s a m ple t hat ca n be use d f or ge n etic researc h will ori gi nate fr o m t he w h ole -
bl o o d  sa m ple c ollecte d i n Secti o n 8. 7. 3  f or bi o mar ker researc h. Ge netic res earc h m a y i ncl u de  
a nal ysis of ger mli ne p ol y m or p his ms t hat are rele va nt t o st u d y i nter ve nti o n, mec ha nis m of ac ti o n, 
t he varia ble p h ar mac o ki netics a n d res p o ns e t o st u d y dr u g(s) (i ncl u di n g e v al uati o n of A Es or 
differe n ces i n effic ac y), cell c ycle, i m m u ne f u ncti o n, a n d pat h wa ys ass ociat e d wit h pr ostate  
ca ncer. E xa m ples of ge n etic researc h i n cl u de ger mli ne p ol y m or p his ms i n ge nes lea di n g t o  
h o m ol o g o us rec o m bi nati o n deficie nc y re p air ( f or e xa m ple, B R C A 1, B R C A 2, C H E K 2, A T M, 
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M U T Y H, A P C, H O X B 1 3, M S H 2, T P 5 3, P A L B 2, P M S 2, M L H 1, M S H 2, M S H 6 ), c o m m o n 
ger mli ne p ol y m or p his ms i n ge nes i n v ol ve d i n t he cell  c ycle (f or e xa m ple, C D K N 1 A, C D K N 1 B, 
a n d A U R K A), c o m m o n ger mli ne p ol y m or p his ms ass ociate d  wit h i m m u ne variati o ns i n i m m u ne 
rejecti o n of t u m ors (f or e xa m ple, C D 2 8, I C O S, P D C D 1, T N F S F 4, C D 2 2 6, H A V C R 2, C T L A 4, 
a n d L A G 3), c o m m o n ger mli ne p ol y m or p his ms i n ge nes ass ociat e d  wit h i ncrease i n ris k of 
pr ostate  ca n cer (f or e xa m ple, M T H F R, s o me varia nts of H S D 1 7, S L C O 2 , C Y P 1 7 , C Y P 1 9, 
S R D 5 A 2  a n d H S D 3 B 1 ), a n d c o m m o n ger mli ne p ol y m or p his ms i n ge nes relate d t o t he 
mec ha nis m of acti o n of a be macicli b or  a nti-a n dr o ge n  t hera p y. Ge netic a nal ysis res ults ma y 
occ ur after t he cli nical st u d y re p ort is  writte n a n d t heref ore a s e parate ge n etic Data A nal ysis Pla n 
will be de vel o pe d.  
Ge netic sa m ples ma y b e assesse d b y vari o us met h o ds, i ncl u di n g w h ole -ge n o me a n d e x o me  
se q ue nci n g, ge n e pa nel s e q ue nci n g, ge n o m e-wi de ass ociati o n st u dies, a n d D N A ca n di d ate ge n e  
st u dies. Re gar dless of t he tec h n ol o g y utilize d, data ge nerat e d will be use d o nl y f or t he s pecifi c 
ge netic res earc h sc o p e descri be d i n t his secti o n, a n d wit hi n t he li mits of t his pr ot oc ol.  
Ge netic researc h ma y lea d t o t he i de ntificati o n of ge netic i nci de ntal fi n di n gs. Ge netic i nci de ntal  
fi n di n gs are variati o ns pr ese nt i n ger mli ne D N A t hat are disc o v ere d u ni nte nti o nall y a n d t hat ma y  
n o net heless be of me di cal val ue or utilit y t o t he p h ysicia n a n d t he patie nt. T he met h o ds use d i n  
t his st u d y t o perf or m ge netic researc h are n ot cli nicall y vali date d t o detect ger mli ne varia nts, a n d 
t heref ore, n o cli nical c o n cl usi o ns ca n be deri ve d fr o m t he m. As s uc h, s u bject t o l ocal re g ulati o ns, 
n o i nci de ntal fi n di n gs will be re p orte d t o t he p atie nts partici pati n g i n ge netic researc h.  
Sa m ples will n ot be use d t o c o n d uct u ns pecifie d disease or p o p ulati o n ge netic researc h eit her  
n o w or i n t he f ut ure. A d diti o nal a nal yses wit hi n t he researc h s c o pe d escri be d i n t his secti o n ma y  
be c o n d ucte d if it is h y p ot hesize d t hat t his ma y hel p f urt her u n dersta n d t he cli nical data. Sa m ples  
ma y als o be use d t o de v el o p relate d researc h met h o ds or t o vali date dia g n ostic t o ols or assa ys,  
b ut o nl y wit hi n t he s pecific researc h s c o pe des cri b e d i n t his pr ot oc ol. T he sa m ples ma y be  
a nal yze d as part of a m ulti -st u d y assess me nt of ge netic fact ors i n v ol ve d i n t he res p o nse t o t he 
st u d y i nter ve nti o n or st u d y i nter ve nti o ns of t his class, a n d/ or t o u n dersta n d st u d y disease or  
relate d c o n diti o ns, wit hi n t he sc o pe des cri be d i n t his pr ot oc ol. 
Ge netic sa m ples will be c o de d wit h t he partici p a nt n u m ber. T h ese sa m ples a n d a n y data  
ge nerat e d ca n b e li n ke d b ac k t o t he partici p a nt o nl y b y t he st u d y site pers o n nel. L o n g -ter m 
sa m ple rete nti o n is o utli ne d i n Secti o n 1 0. 1. 1 2  ( A p pe n di x 1). Tec h n ol o gies are e x p ecte d t o 
i m pr o ve d uri n g t he st ora ge peri o d a n d, t heref ore, ca n n ot be s pecificall y na me d. Re gar dless of t he 
tec h n ol o g y utilize d, data ge nerat e d will be use d o nl y f or t he s pecifi c ge netic researc h sc o p e 
descr i be d i n t his secti o n, a n d wit hi n t he li mits of t his pr ot oc ol.  
8. 7.  
Bi o m ar kers   
T his st u d y will a nal yze bi o mar kers rele va nt t o st u d y i nter ve nti o n,  mec ha nis m of acti o n, t he  
varia ble res p o nse t o st u d y dr u g(s) (i ncl u di n g e v al uati o n of A Es or differe n ces i n effi cac y), cell  
c ycle, i m m u ne f u ncti o n, or pat h wa ys ass o ciate d wit h pr ostate  ca ncer. Sa m ples c ollecte d will  
e na ble e x a mi nati o n of t hese q uesti o ns t hr o u g h t he meas ure me nt of b i o m olec ules, i ncl u di n g 
D N A, R N A, pr otei ns, li pi ds, a n d ot her circ ul ati n g or cell ular ele me nts. Deri vati ves of sa m ples  
(f or e x a m ple t u m or i ma g es) ca n als o be use d t o i d e ntif y bi o mar kers of p atie nt res p o nse or 
resista nce. E x ce pt f or t he cases  det aile d i n Sec ti o ns 8. 7. 1  (ct D N A se q u e nci n g wit h o ut patie nt-
matc he d ger mli ne s u btracti o n) a n d  8. 7. 2  (t u m or D N A se q ue n ci n g wit h o ut patie nt-matc he d 
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ger mli ne s u btracti o n), bi o mar ker  a nal yses will n ot pr o d uce i nter preta ble res ults o n ger mli ne 
D N A a n d t heref ore will n ot lea d t o  t he i de ntificati o n of ge netic i nci de ntal fi n di n gs as descri be d 
i n Secti o n 8. 6 . Bi o mar ker a nal yses usi n g D N A as a s u bstrate will ge nerate i nter preta bl e 
i nf or mati o n o n t u m or s o matic varia nts, t u m or s o matic c o p y n u m ber c h a n ges a n d t u m or s o matic 
rearra n ge m e nts. Bi o mar ker a nal ys es usi n g R N A as s u bstrate will a v oi d t he i de ntificati o n of 
ge netic vari a nts a n d will f oc us o n  q ua ntif yi n g ge n e e x pressi o n a n d re p orti n g t u m or s o matic ge ne 
f usi o ns a n d ot her t u m or s o matic rearra n g e me nts. Bi o mar ker a nal ysis res ults ma y occ ur after t h e 
cli nical st u d y re p ort  is writte n a n d t heref ore a s e parate bi o mar k er Dat a A nal ysis Pla n will be 
de vel o pe d.  
Sa m ples f or  bi o mar ker researc h will be c ollecte d fr o m all partici pa nts as s p ecifie d i n t he 
sa m pli n g sc he d ule ( Secti o n 1. 3. 1 ), w here l ocal re g ulati o ns all o w. It is p ossi ble t hat bi o mar ker 
data f or partici pa nts i n t he st u d y ha ve  alr ea d y b ee n ge nerat e d fr o m sa m ples t hat were c ollecte d 
a n d a nal yz e d pri or t o e nr olli n g i n t his  trial. T his ma y i ncl u de data ge nerate d fr o m ge netic 
a nal yses. If a vaila ble, t h ese data ma y be  re q u este d fr o m me dical r ec or ds f or use i n t he researc h 
descri be d i n Secti o ns 8. 7. 1  a n d 8. 7. 2 . 
A d diti o nal a nal yses wit hi n t he s pecific researc h s c o pe descri b e d i n t his secti o n ma y be  
c o n d ucte d if it is h y p ot hesize d t hat t his ma y hel p f urt her u n derst a n d t he cli nical data. Sa m ples  
ma y be use d t o de vel o p relate d res earc h met h o ds or t o vali date dia g n ostic t o ols or assa ys, b ut  
o nl y wit hi n t he s pecific researc h sc o pe d escri b e d i n t his pr ot oc ol. T he sa m ples ma y be a nal y ze d  
as part of a m ulti -st u d y assess me nt of n o n-ge netic fact or s i n v ol ve d i n t he res p o nse t o st u d y 
i nter ve nti o n or st u d y i nter ve nti o ns of t his class, a n d/ or t o u n dersta n d st u d y disease or relate d 
c o n diti o ns, wit hi n t he sc o pe descri b e d i n t his pr ot oc ol.  
All sa m ples will be c o de d wit h t he partici pa nt n u m ber. T hese s a m pl es a n d a n y data ge n erat e d  
ca n be li n ke d b ac k t o t he partici pa nt o nl y b y t he st u d y site pers o n nel. L o n g -ter m sa m ple 
rete nti o n is o utli ne d i n Secti o n 1 0. 1. 1 2  ( A p pe n di x 1). Tec h n ol o gies are e x p ecte d t o i m pr o ve 
d uri n g t he st ora ge peri o d,  a n d t heref ore, ca n n ot be s pecificall y na me d. Re g ar dless of t he 
tec h n ol o g y utilize d, data ge nerat e d will be use d o nl y f or t he s pecifi c bi o mar ker res earc h sc o pe 
descri be d i n t his secti o n, a n d wit hi n t he li mits of t his pr ot oc ol.   
8. 7. 1.  
Pl as m a S a m ples f or Bi o m ar ker Rese arc h   
P las ma sa m ples ma y be assesse d b y E LI S A, micr o R N A pr ofili n g, meta b ol o mics, a n d/ or ot her 
rele va nt si n gle-ple x or m ulti ple x -base d assa y met h o ds f or n o n ge netic  fact ors t hat ma y pre dict f or 
cli nical be nefit or c orrelate wit h treat me nt -relate d a d verse e ve nts. P ote ntial ser u m a n d plas ma -
base d bi o mar kers t o be i n vesti gate d  i ncl u de, b ut are n ot li mite d t o, a ntit u m or a nti b o dies, 
c yt o ki nes, c he m o ki nes, i nfla m mat or y fact ors, a n gi o ge nic  bi o mar kers, a n d micr o R N As.   
Plas ma sa m ples ma y als o be use d f or circ ulati n g t u m or D N A (ct D N A) a nal yses. ct D N A a n al ysis 
ma y be perf or me d wit h p at ie nt-matc he d g er mli ne D N A s u btracti o n. Ger mli ne D N A f or eac h 
s u bject will ori gi nate fr o m D N A e xtracte d fr o m w h ole bl o o d as descri be d i n Secti o n 8. 7. 3 . 
Re vie w of ger mli ne D N A se q ue nci n g r es ults ma y be c o n d ucte d, b ut o nl y f or data q ualit y c o ntr ol 
p ur p oses. At n o p oi nt i n t his pr ocess will ger mli ne D N A vari a nts be a nal y ze d a n d i nter prete d b y 
t he researc h p ers o n nel. As s uc h, ct D N A a n al ysis wit h ger mli ne D NA s u btracti o n will n ot 
pr o d uce i nter preta ble res ults o n ger mli ne D N A, is n ot c o nsi dere d ge n etic researc h, a n d t heref ore, 
will n ot lea d t o t he i de ntificati o n of ge n etic i nci de ntal fi n di n gs as descri be d i n Secti o n 8. 6 . 
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ct D N A a n al ysis ma y als o be perf or me d wit h o ut ger mli ne D N A s u btracti o n. I n t his case, it ma y 
be c o nsi dere d ge netic res earc h a n d t he i de ntificati o n of ge netic i nci de nt al fi n di n gs is p ossi ble.  
Re gar dless of w h et her p atie nt -matc he d ger mli ne D N A s u btracti o n is use d or n ot d uri n g ct D N A 
a nal ysis, t he met h o ds use d i n t his st u d y f or bi o mar ker a nal ys es are n ot cli nicall y vali date d t o 
detect ger mli ne v aria nts, a n d t heref ore, n o cli nical c o ncl usi o ns ca n  be d eri v e d fr o m t he m. As 
s uc h, n o i nci de ntal fi n di n gs will be re p orte d t o t he patie nts partici pati n g i n bi o mar ker researc h, 
s u bject t o l ocal re g ulati o ns. 
8. 7. 2.  
Tiss ue S a m ples f or Bi o m ar ker Rese arc h   
Arc hi val t u m or sa m ple , o btai ne d pri or t o i nitiati n g st u d y treat me nt , will be c ollecte d, w h ere 
a vaila ble. T he m ost rece nt sa m ple is desire d. Met astatic sa m ple w here a v aila ble is preferre d o v er 
pri mar y t u m or. S oft tiss ue as well as b o n y met astatic lesi o ns are acce pt a ble. T he t u m or sa m ples 
will prefera bl y be i n t he f or m of a f or m ali n-fi xe d, paraffi n e m be d de d bl o c k. If t his is n ot 
p ossi ble, a p pr o xi matel y  2 0 sli des of fres hl y pre pare d u nstai ne d 5 -micr o n  secti o ns fr o m t he 
arc hi val t u m or bl oc k ma y be pr o vi de d.  Sa m ples ca n be c ollecte d at a n y ti me d uri n g st u d y if n ot 
c ollecte d at s cree ni n g. D ue dili ge nce s h o ul d be us e d t o ma ke s ure t h at t u m or sa m ple ( n ot a 
n or mal a djace nt or a t u m or mar gi n sa m ple) is pr o vi de d.  
Pat h ol o g y re p ort s acc o m pa n yi n g t u m or tiss ue will be re q uest e d w here a v aila ble. Pat h ol o g y 
re p orts m ust be c o de d wit h t he partici pa nt n u m ber. Pers o nal i de ntifiers, i ncl u di n g t he 
partici pa nt’s na me a n d i nitials, m ust be re m o ve d fr o m t he i nstit uti o nal pat h ol o g y re p ort pri or t o 
s u b missi o n. Arc hi val bl oc ks will be secti o ne d b y t he s p o ns or. T he s p o ns or has a ri g ht t o retai n a 
p orti o n  of t he s u b mitte d tiss ue, a n d arc hi val bl oc ks ma y be ret ur n e d t o t he st u d y site, u p o n 
re q uest. 
A n o pti o nal fres h metast atic bi o ps y (f or mali n fi xe d a n d paraffi n e m be d d e d) ma y be ta ke n at t he 
ti me of o n-st u d y ra di o gra p hic pr o gressi o n, pri or t o start of ne w antica ncer t hera p y if t he 
i n vesti gat or dee ms t his t o be a p pr o pri ate a n d safe. Bi o ps y of a pr o gressi n g metastatic lesi o n is 
preferre d w he ne v er p ossi ble. S oft tiss ue  as well as b o n y metastatic lesi o ns will be c o nsi dere d 
acce pta ble. If patie nt disc o nti n ues st u d y f or reas o ns ot her t ha n ra di o gr a p hic pr o gressi o n, t he 
bi o ps y s h o ul d be c o nsi dere d o nl y if t he patie nt has c o m plete d at least 4 c y cl es of st u d y 
treat me nt. 
Vari o us n o n -ge n etic bi o mar kers wit h p ote ntial pr o g n ostic or pre dicti ve val ue f or t he treat me nt of 
pr ostate  ca n cer wit h st u d y i nter ve nti o n are c urre ntl y u n der i n vesti gati o n a n d ma y be assesse d i n 
t his st u d y. T hese t u m or tiss ue n o n-ge netic bi o mar kers i ncl u de, b ut are n ot li mite d t o, cell -c ycle 
pat h wa y ge n es/ pr otei ns ( f or e xa m ple, D-c y cli n alterati o ns, C C N E 1/ 2, C D K N 2 A/ B, R B 1 l oss of 
f u ncti o n, E 2 F 1, C D K 4, C D K 6, C D K 2, F O X M 1), PI 3 K pat h wa y (f or e x a m ple, P T E N l oss, 
PI K 3 C A, A K T 1), M A P K pat h wa y ( f or e x a m ple, K R A S, N R A S, N F 1), F G F R pat h wa y (f or 
e xa m ple, F G F g e nes, F G F R 1/ 2/ 3), a n d M Y C, R B 1 a n d ot her tar g et ge ne si g nat ures. I n a d diti o n, 
s u b p o p ulati o ns of t u m or, str o mal, a n d i m m u ne cells a n d se veral m R N A e x pressi o n si g nat ures 
relate d t o a b e macicli b a n d E T mec ha nis m of acti o n or hall mar ks of ca ncer ma y be st u die d. 
T u m or sa m ples ma y als o be use d t o f urt h er c haracterize t he t u m or -i m m u ne micr oe n vir o n me nt, 
i ncl u di n g, b ut n ot li mite d t o, cell-c ycle pr otei ns, T -cell c hec k p oi nt rece pt ors a n d li ga n ds, a n d 
i ntrat u m oral i m m u ne cell s u bsets, i ncl u di n g T-re g ulat or y cells, m yel oi d-deri ve d s u p press or cells, 
macr o p ha g e s, nat ural kill er ( N K) cells, a n d B cells.  
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T u m or sa m ples ma y be retr os pecti vel y ass esse d f or t he e x pressi o n of t he bi o mar kers i n dicate d 
a b o ve usi n g a variet y of met h o d ol o gies i ncl usi ve of, b ut n ot li mite d t o, I H C, t u m or i ma gi n g, 
R N A Sc o pe, mass s pectr o met r y, q R T-P C R, m R N A e x pressi o n b y R N A se q ue nci n g or 
h y bri dizati o n, a n d s o matic D N A m utati o ns b y t u m or w h ole -e x o m e or pa n el D N A se q ue n ci n g.  
T u m or D N A a n al ysis ( w h ole -e x o me or p a nel D N A se q ue nci n g) m a y be perf or me d wit h patie nt  
matc he d ger mli ne D N A s u btracti o n . Ger mli ne D N A f or eac h s u bject will ori gi nate fr o m D N A 
e xtracte d fr o m w h ole bl o o d as descri be d i n Secti o n 8. 7. 3 . Re vie w of ger mli ne D N A se q u e nci n g 
res ults ma y be c o n d uct e d, b ut o nl y f or data q ualit y c o ntr ol p ur p oses. At n o p oi nt i n t his pr ocess 
will ger mli ne D N A vari a nts be a nal yze d a n d i nter prete d b y t he researc h p ers o n nel. As s uc h, 
t u m or D N A a nal ysis wit h ger mli ne D N A s u btracti o n will n ot pr o d uce i nter preta ble res ults o n 
ger mli ne D N A, is n ot c o nsi dere d ge n etic res earc h, a n d t heref ore, will n ot lea d t o t he 
i de ntificati o n of ge netic i nci de ntal fi n di n gs as des cri be d i n Secti o n 8. 6 . 
T u m or D N A a n al ysis ma y als o be perf or me d wit h o ut ger mli ne D N A s u btracti o n. I n t his case, it 
ma y be c o nsi dere d ge n etic researc h a n d t he i de ntificati o n of ge netic i nci d e ntal fi n di n gs is 
p ossi ble. Re gar dless of w het her patie nt -mat c he d g er mli ne D N A s u btracti o n is use d or n ot d uri n g 
t he t u m or D N A a n al ysis, t he met h o ds use d i n t his st u d y f or bi o mar ker a nal yses are n ot cli nicall y 
vali date d t o detect ger mli ne varia nts, a n d t h eref ore, n o cli nical c o ncl usi o ns ca n be d er i ve d fr o m 
t he m. As s uc h, n o i nci de ntal fi n di n gs will be re p orte d t o t he patie nts partici pati n g i n bi o mar ker 
researc h, s u bject t o l ocal re g ulati o ns. 
T u m or R N A se q ue nci n g a nal yses q ua ntitate tiss ue m R N A e x pressi o n le vels, re p ort ge ne f usi o ns,  
s plice varia nts, a n d ot her s o matic rearra n g e me nts, a n d d o n ot detect ger mli ne varia nts. 
T heref ore, t hes e a nal ys es are n ot c o nsi dere d ge n etic researc h a n d n o ge neti c i nci de ntal fi n di n gs  
as descri be d i n Secti o n 8. 6  will be i de ntifie d.   
8. 7. 3.  
W h ole -Bl o o d S a m ple f or Bi o m ar ker Rese arc h   
T his sa m ple ma y als o be use d f or t he  e xtracti o n of D N A t hat all o ws patie nt -matc he d ger mli ne 
D N A s u btracti o n d uri n g ct D N A  ( Secti o n 8. 7. 1 ), a n d t u m or D N A a nal ysis fr o m tiss ue ( Secti o n 
8. 7. 2 ). 
T his w h ole -bl o o d D N A s a m ple will be use d t o o btai n ger mli ne D N A t hat m a y als o be utilize d 
f or ge netic researc h as descri be d i n Secti o n 8. 6 . 
8. 8.  
I m m u n o ge nicit y Assess me nts  
N ot a p plica ble.  
8. 9.  
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mic s  
8. 9. 1.  
P atie nt -Re p orte d O utc o mes   
P atie nt-re p orte d o utc o m e meas ures will be a d mi nistere d b y pa p er q uesti o n naires  t o assess pai n, 
H R Q o L, a n d patie nt -re p orte d a d verse e v e nts/t o xicit y. T here are 4  P R O q uesti o n naires i ncl u de d 
i n t his st u d y. T he y s h o ul d be c o m plete d bef ore si g nifica nt i nteracti o n wit h site pers o n nel  a n d 
a d mi nistere d i n t he f oll o wi n g or der: 
1.  Brief Pai n I n ve nt or y –  S h ort F or m ( B PI -S F) W orst Pai n N u meric Rati n g Scale ( N R S)  
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2.  F u ncti o nal Assess me nt of Ca ncer T hera p y –  Pr ostate ( F A C T -P)  
3.  E ur o Q ol 5 Di me nsi o n 5 Le vel ( E Q -5 D -5 L)  
4.  Patie nt -Re p orte d O utc o me –  C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( P R O -
C T C A E ™)  
T he P R O  q uesti o n naires will be a d mi nistere d i n t he la n g ua ge i n w hi c h t he patie nt is fl ue nt or 
literate a n d a d mi nistere d acc or di n g t o t he S o A ( Secti o n 1. 3 ) i n c o u ntries w here t he 
q uesti o n naires ha ve b ee n tra nslate d i nt o t he nati ve la n g u a ge of t he re gi o n . 
8. 9. 1. 1.  
B PI -S F W orst P ai n  N R S   
T he W orst Pai n  N R S  ite m e xtracte d fr o m t he B PI-S F  is a si n gle-ite m, pati e nt -re p ort e d, 1 1-p oi nt 
h oriz o ntal scale  ( At ki ns o n et al. 2 0 1 0).  T he si n gle  q uesti o n of t his scale  is o btai ne d 
fr o m q uesti o n # 3 of t he  B PI -S F  ( C h a p ma n a n d L oeser  1 9 8 9)  a n d assess es t he partici pa n t’s pai n 
i n t he last 2 4 h o urs . T his scale is a nc h ore d at 0 t o 1 0, w it h 0 re pres e nti n g “n o pai n ” a n d 1 0 
re pres e nti n g “pai n as b a d as y o u ca n i ma gi ne ”. 
T o deter mi ne ti me t o pai n pr o gressi o n, a nal g esic me dicati o n use  will be assesse d  al o n g wit h t he 
data fr o m t he W orst Pai n N R S. Data o n a nal gesic me dicati o n use will be rec or de d o n t he 
c o nc o mita nt me dicati o n C R F . T he use of pai n me dicati o ns fr o m t he pre vi o us visit s h o ul d be 
re vie we d wit h t he patie nt at eac h s u bs e q ue nt visit. I nf or mati o n o n ne w or st o p pe d a nal gesics 
s h o ul d be rec or de d. T his i nf or mati o n s h o ul d be c ollecte d d uri n g t he st u d y a n d at t he 3 0 -da y 
f oll o w-u p visit. A nal gesics/ o pi oi ds c o ns u me d b y patie nts will be classifie d i nt o cate g ories 
acc or di n g t o t he A Q A. A Q A will  t he n be use d t o deter mi ne if c h a n ges i n t he w orst pai n 
assess me nt are attri b uta ble t o i ncreas e d or decreas e d a nal gesia ( C h u n g et al. 2 0 1 4).  
8. 9. 1. 2.  
F A C T -P   
T he F A C T -P is a n esta blis he d a n d vali date d  p atie nt -re p orte d mea s ure f or assessi n g q ualit y of 
life a n d ca n cer -s pecific s y m pt o ms i n partici pa nts  wit h pr ostate ca n cer ( Es p er et al. 1 9 9 7;  Cella  et 
al. 2 0 0 9). T he F A C T -P  i ncl u des 2 7 c ore ite ms fr o m t he F A C T -G  a n d 1 2 ite ms o n pr ostate ca n cer 
relate d s y m pt o ms. T his 3 9 -ite m q uesti o n naire assesses t he  partici pa nts’ q ualit y of life a n d ca n cer 
s y m pt o ms o ver t he past 7 da ys a n d c o nsists of 5 s u bscales (p h ysical, s ocial/fa mil y, e m oti o nal, 
f u ncti o nal well-bei n g , a n d pr ostate ca n cer s u bs cal e).  Eac h ite m is rate d o n a 5 -p oi nt Li kert s cal e 
ra n gi n g fr o m 0 ( n ot at all) t o 4 ( ver y m uc h). Eac h ite m is t he n c o m bi ne d t o pr o d uce s u bscale 
sc ores, as w ell as t otal sc ores f or t he F A C T-G (ra n gi n g fr o m 0 t o 1 0 8) a n d F A C T -P (ra n gi n g 
fr o m 0 t o 1 5 6). Hi g her s c ores re prese nt better q ualit y of life ( Cella et al. 1 9 9 3; Cella et al. 2 0 0 9). 
T he F A C T -G P 5 , ite m n o. 5 o n t he F A C T -P, assesses  o verall si de effect b ot her o ver t h e past 7 
da ys ( Pear ma n et al. 2 0 1 8)  in ass ociati o n wit h re p orte d P R O -C T C A E  ite ms. 
8. 9. 1. 3.  
E Q -5 D -5 L   
T he E Q -5 D -5 L  ( E ur o Q ol Researc h F o u n d ati o n  2 0 1 9)  is a sta n dar dize d 5-it e m self-
a d mi nistere d  i nstr u me nt f or use as a meas ure of healt h o utc o me. It pr o vi des a si m ple descri pti ve 
pr ofile a n d a si n gle i n de x val ue f or healt h stat us t hat ca n be us e d i n t he cli nical a n d ec o n o mic 
e val uati o n of healt h care as well as p o p ulati o n healt h s ur ve ys. T he E Q -5 D -5 L  assesses  5 
di me nsi o ns of healt h:  m o bilit y, self -care, us u al acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n, usi n g  a 5 -le vel of s e verit y ( n o pr o ble m, sli g ht, m o derate, se vere, or e xtre me 
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pr o ble m). I n a d diti o n,  t he E Q  Vis ual  A nal o g  Scale  rec or ds c urre nt self-rat e d healt h state  fr o m 0 
(t he w orst i ma gi na ble healt h) t o 1 0 0 (t he best i ma gi na ble healt h ). T h e recall peri o d is “t o da y ”.  
8. 9. 1. 4.  
P R O -C T C A E   
T he P R O -C T C A E is a pa tie nt-re p orte d o utc o m e meas ure m e nt s yste m de vel o pe d b y t he N CI t o 
c ollect s y m pt o matic A Es fr o m ca n cer partici pa nts e nr olle d i n cli nical trials ( Basc h  et al. 2 0 1 4; 
D uec k et al. 2 0 1 5; Be n nett et al. 2 0 1 6). T he i nte nt of usi n g t he P R O -C T C A E is t o pr o vi de 
partici pa nts’ pers pecti ves of t heir A E e x p erie n ce  a n d will n ot be use d f or A E re p orti n g . T he 
i nf or mati o n fr o m P R O-C T C A E  are o nl y use d strictl y t o t he st u d y’s e x pl orat or y o bjecti ve.  In 
a d diti o n, t his i nf or mati o n will n ot be re vie we d b y t he sites t o mi ni m ize bias.  
T he P R O -C T C A E ite m li brar y ( Versi o n 1. 0; N CI 2 0 2 0) i ncl u des 7 8 s y m pt o matic A Es a n d a 
t otal of 1 2 4 t otal ite ms dra w n fr o m t he C T C A E t h at meas ure p artici pa nts’ s y m pt o matic t o xicities 
o ver t he past 7 da ys. P R O -C T C A E  res p o nses are sc ore d fr o m 0  t o 4  ( or 0/ 1  f or a bse nt/ prese nt).  
Fr o m t his ite m li brar y, 6 s p ecific A Es ( 1 3 t otal ite ms) were s electe d base d o n t he m ost fre q ue nt 
partici pa nt -felt A Es re p orte d i n a be macicli b a n d/ or a birater o ne: 
- 
na usea ( F S)  
- 
diarr hea ( F)  
- 
a b d o mi nal pai n ( F SI)  
- 
s welli n g ( F SI)  
- 
fati g ue ( SI), a n d  
- 
h ot  flas hes ( FS ) 
( F =fre q u e nc y; S =se v erit y; I =i nterferen ce ) 
8. 9. 2.  
He alt h C are R es o urce Utiliz ati o n   
Healt h care res o urce utilizati o n will be c ollecte d i n t he C R F b y t he i n vesti gat or a n d st u d y site 
pers o n nel f or all partici p a nts t hr o u g h o ut t he st u d y. Pr ot oc ol -ma n date d pr o ce d ures, tests, a n d 
e nc o u nters are e xcl u de d.  
T he data c ollecte d will i ncl u de:  
• 
h os pitalizati o n ( yes or n o) a n d d urati o n of h os pitalizat i o n (a d missi o n a n d disc har ge 
dates) . 
• 
e mer ge n c y r o o m visits ( yes a n d n u m ber of e ve nts, or n o) . 
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9.  
St atistic al C o nsi der ati o ns   
T he S A P  will be fi nalize d pri or t o u n bli n di n g,  a n d it will i ncl u de a m ore tec h nical a n d detaile d 
descri pti o n of t he statistical a nal yses d escri b e d i n t his secti o n. T his secti o n is a s u m mar y of t he 
pla n ne d statistical a nal ysis f oc usi n g o n t he pri mar y e n d p oi nt . 
9. 1.  
St atistic al H y p ot heses   
Treat me nt of p artici pa nts wit h hi g h -ris k m H S P C wit h a be macicli b i n c o m bi nati o n wit h 
a birater o n e pl us pre d nis o ne will pr o vi de a cli nicall y mea ni n gf ul i ncrease i n r P F S o ver treat m e nt 
wit h place b o a n d a birater o ne pl us pre d nis o ne.  
9. 2.  
S a m ple Size Deter mi n ati o n   
A p pr o xi matel y 9 0 0  parti ci pa nts will be ra n d o mize d i nt o t he st u d y usi n g a 1: 1 rati o. T he pri mar y 
e n d p oint is r P F S. 
 
 
 
Acc o u nti n g f or t he pla n ne d f utilit y a n d i nteri m 
a nal yses, t he desir e d p o w er is ac hie v e d u n der t h es e ass u m pti o ns w he n t he pri mar y a nal ysis is 
c o n d ucte d after a p pr o xi matel y  
 r P F S e ve nts ha ve occ u rre d i n t he I T T p o p ulati o n. 
9. 3.  
A n al yses  Sets   
P o p ul ati o n  
Descri pti o n  
I nte nt-t o-Treat (I T T)  
All ra n d o mize d partici pa nts, re gar dless of w het her t he y t o o k a n y d oses of 
st u d y i nter ve nti o n, or if t he y t o o k t he c orrect treat me nt. Partici pa nts will be 
a n al yze d acc or di n g t o t he treat me nt gr o u p as ra n d o mize d a n d n ot b y act ual 
treat me nt recei ve d. 
Safet y  
All ra n d o mize d partici pa nts w h o recei ve d at least 1 d ose of a n y st u d y 
i nter ve ntio n. Partici pa nts will be a nal yze d acc or di n g t o t he first d ose of 
st u d y i nter ve nti o n t he y act uall y recei ve d, re gar dless of t he ar m t o w hic h 
t he y were ra n d o mize d. 
Meas ura ble disease p o p ulati o n  
All ra n d o mize d patie nts w h o ha ve meas ura ble disease i n s oft tiss ue at 
baseli ne acc or di n g t o R E CI S T v 1. 1. T his p o p ulati o n will be use d f or 
efficac y a nal yses base d o n s oft  tiss ue t u m or res p o nse relate d e n d p oi nts s uc h 
as best o verall res p o nse.  
P har mac o ki netic ( P K) anal ysis  
All ra n d o mize d partici pa nts w h o recei ve d at least 1 d ose of st u d y 
i nter ve nti o n a n d at least 1 p ost baseli ne e val ua ble P K sa m ple. 
Bi o mar ker p o p ulati o n  
T he s u bset of patie nts fr o m t he I T T p o p ulati o n fr o m w h o m a vali d assa y 
res ult has bee n o btai ne d. 
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C O N FI D E N TI A L  
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7 9  
9. 4.  
St atistic al A n al yses   
9. 4. 1.  
Ge ner al C o nsi der ati o ns   
Statistical a nal ysis of t his st u d y will be t he res p o nsi bilit y of s p o ns or or its desi g nee.  
All tests of treat me nt effects  will be c o n d ucte d at a 1 -si de d al p ha le v el of . 0 2 5, u nless ot her wise 
state d, a n d all CIs will be gi ve n at a 2-si de d 9 5 % l e vel.  
F ull details of t he pla n ne d a nal yses will be d oc u m e nte d i n t he S A P. A n y c h a n ge t o t he data 
a nal ysis met h o ds descri b e d i n t he pr o t oc ol will re q uire a n a me n d m e nt o nl y if it c ha n ges a 
pri nci pal feat ure of t he pr ot oc ol. Bef ore u n bli n di n g of t he a g gre gate data base, mi n or 
m o dificati o ns or clarificati o ns t o t he data a nal ysis met h o ds ma y be descri b e d a n d j ustifie d i n t he 
S A P. A n y ot her c ha n ge t o t he data a n al ysis met h o ds descri be d i n t he pr ot o c ol, a n d t he 
j ustificati o n f or ma ki n g t he c ha n g e, will be descri be d i n t he S A P a n d t he cli nical st u d y re p ort. 
A d diti o nal e x pl orat or y a nal yses of t he data will be c o n d ucte d as dee m e d a p pr o priate.  
Ha n dli n g of missi n g, u n use d, a n d s p uri o us data are a d dress e d pr os pecti vel y i n t he o verall 
statistical met h o ds descri be d i n t he pr ot oc ol a n d i n t he S A P, w here a p pr o priate. A dj ust me nts t o 
t he pla n ne d a n al yses are descri be d i n t he fi n al C S R. 
9. 4. 2.  
Pri m ar y E n d p oi nt / Esti m an d  A n al ysis   
T he pri mar y e n d p oi nt of C Y C L O N E 3 will be i n vesti gat or -assess e d r P F S. Ra di o gra p hic 
pr o gressi o n -free s ur vi val is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he earliest 
date of i n vesti gat or -assesse d ra di o gra p hic disease pr o gressi o n i n s oft tiss ue ( per R E CI S T 1. 1) 
A N D/ O R b o ne diseas e ( per a da pt e d P C W G 3 , as descri be d i n Secti o n 8. 1 ), or deat h fr o m a n y 
ca use, w hic h e ver occ urs first.  Patie nts w h o ha ve n eit her pr o gresse d n or die d will be ce ns ore d at 
t he date of t heir last ra di o gra p hic t u m or assess me nt (if a vaila ble) or t he dat e of ra n d o mizati o n (if 
n o p ost -baseli ne ra di o gr a p hic assess me nt is a vaila ble). T he det aile d ce ns ori n g r ules are  d escri b e d 
i n t he S A P. 
T he o verall t y pe I err or will be c o ntr olle d at a 1 -si de d al p ha le vel of 0. 0 2 5. T he pri mar y a n al ysis 
of r P F S will be perf or me d o n t he I T T p o p ulati o n a n d will use t he l o g -ra n k test stratifie d b y t he 
ra n d o mizati o n fact ors. T here is 1  pl a n ne d f utilit y a nal ysis, 1 pla n ne d efficac y i nteri m a nal ysis, 
a n d t he pri mar y o utc o m e a nal ysis of r P F S.  
Wit hi n t he a nal yses of r P F S
 
 T he f utilit y a nal ysis is pla n ne d t o ta ke place after 
 
 T here are 2 pla n ne d efficac y a nal yses of 
r P F S. A n i nteri m a nal ysis will be perf or me d afte
 
T he 
c u m ulati ve 1 -si de d t y pe I err or rate of 0. 0 2 5 will be mai ntai ne d 
 
 
 
 
 
 
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C O N FI D E N TI A L  
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8 0  
St atistic al A n al ysis Milest o nes  
Milest o ne  
r P F S 
O ne -si de d B o u n d ar y p-v al ue 
f or r P F S Effic ac y 
A b bre viati o ns: 
 
a 
 
b 
 
9. 4. 3.  
Sec o n d ar y E n d p oi n ts A n al ys es  
9. 4. 3. 1.  
r P F S b y Bli n de d, I n de pe n de nt, Ce ntr al Re vie w   
A n  rP F S a nal ysis base d o n bli n de d i n de pe n de nt ce ntral re vie w d ata will be c o n d ucte d. A ce ntral 
ra di ol o g y ve n d or will c ollect a n d st ore i ma g es f or BI C R  re vie w.   
9. 4. 3. 2.  
Cli nic al P F S  (c P F S)  
Cli nical P F S is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he earliest date of 
i n vesti gat or-assesse d ra di o gra p hic disease pr o gressi o n, s y m pt o matic pr o gressi o n , or deat h fr o m 
a n y ca use, w hic he v er occ urs first.  
9. 4. 3. 3.  
C astr ati o n -Resist a nt Pr ost ate C a nce r ( C R P C)-free S ur vi v al  
C R P C -free s ur vi val is defi ne d as  t he ti me fr o m t h e date of ra n d o mizati o n t o t he earliest date of 
castrati o n  resista n ce, as d e m o nstrate d b y a n y of t h e f oll o wi n g ( w hic he v er occ urs earliest):  
 C o nfir me d P S A  pr o gressi o n (as descri b e d i n Secti o n 9. 4. 3. 5 ) wit h  ser u m test oster o ne 
≤5 0 n g/ d L ( ≤1. 7 3 n m ol/ L)  
 In v esti gat or -ass esse d ra di o gra p hic pr o gressi o n  wit h ser u m test oster o ne ≤5 0 n g/ d L 
( ≤1. 7 3 n m ol/ L)  
 D eat h fr o m a n y ca us e.  
9. 4. 3. 4.  
Ti m e t o S y m pt o m atic Pr o gressi o n   
Ti me t o s y m pt o matic pr o gressi o n is defi ne d as t he ti me fr o m ra n d o mizati o n t o a n y of t he 
f oll o wi n g ( w hic he ver occ urs earlier): 
 S y m pt o matic skeletal eve nt ( S S E), defi ne d as  ca n cer-relate d s y m pt o matic fract ur e, 
s ur ger y or ra diati o n t o b o ne, or s pi nal c or d c o m pressi o n. 
 Pai n pr o gressi o n or w ors e ni n g of disease -relat e d s y m pt o ms re q uiri n g i nitiati o n of a ne w 
s yste mic a ntica ncer t hera p y. 
 De vel o p me nt of cli nic all y si g nifi ca nt s y m pt o ms d ue t o l oc o -re gi o n al t u m or pr o gressi o n 
re q uiri n g s ur gical i nter v e nti o n or ra diati o n t hera p y. 
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9. 4. 3. 5.  
Ti m e t o P S A Pr o gressi o n  
Ti me t o P S A pr o gressi o n is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of first 
o bser vati o n of P S A pr o gressi o n. T he P S A pr o gressi o n is defi ne d as a ≥2 5 % i ncrease a n d a n 
a bs ol ute i ncrease of ≥2 n g/ m L a b o ve t he na dir ( or baseli ne val ue if b aseli n e is t he l o west o n 
st u d y), w hic h is c o nfir me d b y a sec o n d v al ue o btai ne d 3 or m ore wee ks later. A n y p ost-baseli ne 
P S A meas ure me nts wit hi n 1 2 wee ks si nce b aseli n e will be i g n ore d i n deter mi ni n g P S A  
pr o gressi o n.   
9. 4. 3. 6.  
Ti m e t o I niti ati o n of Ne w A ntic a ncer T her a p y   
Ti me t o i nitiati o n of ne w a ntica ncer t hera p y is defi ne d as t he ti me fr o m ra n d o mizati o n u ntil t he 
first i nitiati o n of a ne w a ntica ncer t h era p y.  
9. 4. 3. 7.  
O ver all S ur vi v al   
O verall s ur vi val is defi n e d as t he ti me fr o m ra n d o mizati o n u ntil deat h fr o m a n y ca use.  
9. 4. 3. 8.  
Ti m e t o P ai n Pr o gressi o n   
Ti me t o pai n pr o gressi o n ( usi n g t he B PI -S F W orst Pai n N R S sc ore a n d A Q A sc ore) is defi ne d as 
t he ti me fr o m ra n d o mizati o n t o a n y of t he f oll o wi n g ( w hic he ver occ urs earlier): 
 a n i ncrease fr o m baseli ne of at least 2 p oi nts i n W orst Pai n N R S sc ore at 2 c o nsec uti ve 
assess me nts at least 3 wee ks a part, wit h n o decrease fr o m baseli ne i n o pi oi d use  
 i nitiati o n of o pi oi d use or i ncreas e fr o m bas eli ne i n o pi oi d use. 
Partici pa nts  w h o d o n ot satisf y a n y of t he criteria a b o ve will be ce ns ore d at t he ti me  of t he last 
k n o w n assess me nt t hat s h o we d a n a bs e nce of pai n pr o gressi o n.  
F u rt her d etails c o ncer ni n g a nal yses o n sec o n dar y e n d p oi nts ca n be f o u n d i n t he S A P.  
9. 4. 4.  
E x pl or at or y E n d p oi nt s A n al ys es  
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9. 4. 5.  
S afet y A n al yse s  
All partici pa nts i n t he safet y a nal ysis set defi ne d i n Secti o n 9. 4  will be e val uate d f or safe ty 
a n d t o xicit y.   
T he m ost c urre nt v ersi o n of t he  Me d D R A
®  will be use d w he n re p orti n g A Es b y Me d D R A ter ms.  
T he Me d D R A L o wer Le vel Ter m ( L L T) will be use d i n t he tre at me nt-e mer ge nt c o m p utati o n.  
Treat me nt -e mer ge nt a d v erse e v e nts will be s u m marize d b y S yste m Or g a n Class ( S O C) a n d b y 
decreasi n g fre q ue nc y of Preferre d Ter m ( P T) wit hi n S O C.    
Safet y a nal yses will i ncl u de s u m maries of t he f oll o wi n g:   
 
a d verse e ve nts, i ncl u d i n g se verit y a n d p ossi ble rel ati o ns hi p t o st u d y dr u g. 
 
seri o us a d vers e e v e nts, i ncl u di n g p ossi ble relati o ns hi p t o st u d y dr u g. 
 
a d verse e ve nts lea di n g t o d ose a dj ust me nts . 
 
disc o nti n uati o ns fr o m st u d y treat me nt d ue t o a d v erse e ve nts or d eat h . 
 
treat me nt-e mer ge nt a b n or mal c ha n ges i n la b orat or y val ues . 
 
treat me nt-e mer ge nt a b n or mal c ha n ges i n vital si g ns a n d E C Gs . 
F ull safet y a n al ysis descri pti o ns ca n be f o u n d i n t he S A P.  
9. 4. 6.  
Ot her A n al yses   
9. 4. 6. 1.  
P atie nt -Re p orte d O utc o mes a n d He alt h C are Res o urce Utiliz ati o n   
F or eac h P R O i nstr u me nt, perce nt a ge c o m plia nce will be calc ulate d as t he n u m ber of c o m plete d 
assess m e nts di vi de d b y t he n u m ber of e x pect e d assess me nts. Data will be s e parat el y s u m marize d 
usi n g descri pti ve statistics. F urt her details will be pr o vi de d i n t he S A P f or eac h P R O i nstr u me nt, 
res pecti vel y. 
Fre q u e nc y c o u nts of h os pitalizati o ns a n d e mer ge nc y r o o m visits will be re p orte d descri pti vel y 
f or eac h treat me nt ar m b y c ycle. 
9. 4. 6. 2.  
P h ar m ac o ki netic a n d E x p os ure -Res p o nse A n al yses   
P har mac o ki netic a n al yses will be c o n d ucte d o n all partici pa n ts w h o ha ve recei ve d at least 1 d ose 
of st u d y i nter ve nti o n a n d ha ve at least 1 e val ua ble P K sa m ple.  
A be macicli b P K a n al yses ma y i ncl u de, b ut are n ot li mite d t o:  
( 1) S u m mar y a nal yses of i n di vi d ual a n d/ or mea n c o n ce ntrati o ns of a be m acicli b, M 2, a n d 
M 2 0, gr o u pe d  b y a nal yte, d ose le vel, ti me p oi nt, etc.  
( 2) C o m paris o n of ti me -matc he d plas ma a n d micr osa m pli n g P K sa m ples .  
( 3) P o p ulati o n P K m o deli n g a nal ysis t o e val uate p o p ulati o n P K para meters a n d 
i nter-i n di vi d ual P K varia bilit y. 
Relati o ns hi ps bet wee n  e x p os ure a n d meas ures  of efficac y a n d safet y ma y b e e x pl ore d.  
 
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C O N FI D E N TI A L  
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9. 5.  
I nteri m A n al ysis  
O nl y t he D M C is a ut h orize d t o e val u ate u n bli n de d i nteri m efficac y a n d s afet y a nal yses. St u d y 
sites will recei ve i nf or m ati o n a b o ut i nteri m res ults o nl y if t he y nee d t o k n o w f or t he safet y of 
t heir partici pa nts. U n bli n di n g details are s pecifie d i n a se parate bli n di n g a n d u n bli n di n g pla n 
d oc u me nt.  
9. 5. 1.  
S afet y I nteri m A n al ysis   
T he D M C will m o nit or t he o verall safet y of t he st u d y. T he D M C me m bers will re vie w u n bli n de d  
safet y data at eac h i nteri m a nal ysis. If a si g nifica nt safet y si g nal is i de ntifie d, the D M C ma y  
rec o m me n d a pr ot oc ol a me n d me nt, ter mi nati o n of e nr oll me nt, a n d/ or ter mi nati o n of st u d y 
treat me nt. T he rec o m me n dati o ns of t he D M C will be c o m m u nicate d t o t he sp o ns or S M D.   
I n t he e ve nt t hat bli n de d safet y m o nit ori n g b y t he st u d y tea m u nc o vers a n iss ue t hat nee ds t o be 
a d dresse d b y u n bli n di n g at t he treat me nt gr o u p le vel, me m bers of t he D M C ca n c o n d uct 
a d diti o nal a nal yses of t he safet y data. A d diti o nall y, u n bli n di n g of a li mite d n u m ber of t he 
sp o ns or re prese ntati ves e xter nal t o t he st u d y tea m ma y b e re q uir e d f or e val uati o n of selecte d 
S A Es f or deter mi nati o n of re g ulat or y re p orti n g.  
T here will be n o pres pecifie d r ules f or st o p pi n g t h e trial d ue t o safet y c o ncer ns.  T he D M C will 
meet a n d re vi e w t he o verall data a p pr o xi matel y e v er y 6 m o nt hs t hereafter w hile  patie nts re mai n 
i n t he o n-st u d y i nter ve nti o n peri o ds. At t he rec o m me n dati o n of t he D M C, t he fre q u e nc y of safet y 
i nteri m a nal yses ma y be m o difie d. See Secti o n 1 0. 1. 5. 1  f or f urt her details. 
9. 5. 2.  
Effic ac y I nteri m A n al ysis   
O ne f utilit y a nal ysis a n d o ne  effi cac y i nteri m a nal ysis are pla n ne d , as descri be d i n Secti o n 9. 4. 2 . 
If t he f utilit y b o u n dar y is met at t he f utilit y a nal ysis, t he D M C s h o ul d rec o m me n d t hat t he st u d y 
be st o p pe d f or f utilit y.  
T he effi cac y i nteri m a nal ysis will be c o n d ucte d  t o pr o vi de earl y effi cac y i nf or mati o n a n d c o ul d 
p ote ntiall y res ult i n earl y c o m m u nicati o n wit h re g ulat or y a ge nci es. T he D M C will be i nstr ucte d 
t o rec o m me n d t o t he S M D t hat t he s p o ns or be u n bli n de d if t he a nal ysis of r P F S reac hes 
statistical si g nifica nce as descri be d i n Secti o n 9. 4. 2  a n d a n y a d diti o nal criteria s pecifie d i n t he 
D M C c harter are m et. See t he se parate u n bli n di n g pla n f or details.  
T he sp o ns or d oes n ot i nte n d  t o st o p t he st u d y base d o n t he i nteri m a nal ysis of efficac y a n d all 
patie nts will c o nti n ue t o f oll o w -u p f or all st u d y o bjecti ves u ntil st u d y cl ose. Partici pa nts 
ra n d o mize d t o t he c o ntr ol gr o u p will n ot be per mitte d t o cr oss o ver t o t he e x peri me ntal gr o u p, as 
t his will c o nf ou n d t he assess me nt of O S.  If t he D M C ma kes a rec o m me n d ati o n c o u nter t o t his at 
a n i nteri m a nal ysis, f or e xa m ple, t he D M C  rec o m me n ds cr ossi n g all partici pa nts o ver t o t he 
e x peri me ntal treat me nt, re g ulat or y a ge n cies ma y b e c o ns ulte d  bef ore a n y acti o n is ta ke n. 
A d diti o nall y, patie nts will re mai n bli n de d f or t he d urati o n of t he st u d y u nless s pecific u n bli n di n g 
criteria are met.  
O nl y t he  D M C  is a ut h orize d t o e val u ate u n bli n de d i nteri m efficac y a n d s afet y a nal yses. St u d y 
sites will recei ve i nf or m ati o n a b o ut i nteri m res ults o nl y if t he y nee d t o k n o w f or t he safet y of 
t heir partici pa nts . 
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U n bli n di n g details are s p ecifie d i n t he u n bli n di n g pla n sec ti o n of t he S A P or i n a se parate 
u n bli n di n g pla n d oc u me nt.  
T he S A P  will descri be t he pla n ne d i nteri m a n al yses i n greater detail . 
T he ti mi n g of disse mi nati o n of data s u m maries base d o n i nteri m a nal yses is a d dresse d i n Secti o n 
1 0. 1. 6 , A p pe n di x 1 . 
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1 0.  
S u p p orti n g D oc u me nt ati o n a n d O per ati o n al C o nsi der ati o ns   
1 0. 1.  
A p pe n di x 1: Re g ul at or y, Et h ic al, a n d St u d y O versi g ht 
C o nsi der ati o ns   
1 0. 1. 1.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns   
 T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d wit h t he 
f oll o wi n g: 
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes 
i ncl u di n g t he Declarati o n of Helsi n ki a n d C o u ncil f or I nter n ati o nal 
Or ga nizati o ns of M e dical Scie nces I nter nati o nal Et hical G ui deli nes . 
o  A p plica ble I C H G C P G ui deli nes . 
o  A p plica ble la ws a n d re g ulati o ns . 
 T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I B, a n d ot her rele va nt d oc u me nts 
(f or e x a m ple, a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he 
i n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he I R B/I E C  bef ore t he st u d y is 
i nitiate d. 
 A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a p pr o val bef ore 
i m ple me ntati o n of c ha n g es ma de t o t he st u d y desi g n, e xce pt f or c ha n g es 
necessar y t o eli mi nate a n i m me diate hazar d t o st u d y partici pa n ts. 
 Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc ol will re q uire healt h 
a ut h orit y a p pr o val pri or t o i nitiati o n e xce pt f or c h a n ges necessar y t o eli mi nate 
a n i m me diate hazar d t o st u d y partici pa nts . 
 T he i n vesti gat or will be res p o nsi ble f or t he f oll o w i n g: 
o  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C 
a n n uall y or m ore fre q u e ntl y i n acc or da n ce wit h t h e re q uir e me nts, 
p olicies, a n d pr oce d ures esta blis he d b y t he I R B/I E C . 
o  N otif yi n g t he I R B/I E C of S A Es  or ot her si g nifica nt safet y fi n di n gs as 
re q uire d b y I R B/I E C pr o ce d ures. 
o  Pr o vi di n g o versi g ht of st u d y c o n d uct f or p artici pa nts u n der t heir 
res p o nsi bilit y a n d a d here nce t o re q uir e me nts of 2 1 C o de of Fe d eral 
Re g ulati o ns ( C F R ), I C H g ui deli nes, t he I R B/I E C, E ur o pea n re g ulati o n 
5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), a n d all ot her a p plica ble 
l ocal re g ulati o ns. 
o  Re p orti n g t o t he s p o ns or or desi g nee si g nifica nt iss ues relate d t o partici pa nt 
safet y, partici p a nt ri g hts, or data i nte grit y.  
 I n v esti gat or sites are c o m pe nsate d f or partici pati o n i n t he st u d y as detaile d i n 
t he cli nical trial a gree me nt . 
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C O N FI D E N TI A L  
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8 6  
1 0. 1. 2.  
Fi n a nci al Discl os ure   
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n as re q u este d t o all o w t he s p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y.  
1 0. 1. 3.  
I nf or me d C o nse nt Pr ocess  
● T he i n vesti gat or or t he i n vesti gat or’s re prese ntati v e will e x plai n t he nat ure of t he 
st u d y, i ncl u di n g t he ris ks a n d be nefits, t o t he partici pa nt or t he partici pa nt’s 
le gall y a ut h orize d re pres e ntati ve, a n d a ns w er all  q uesti o ns re gar di n g t he st u d y.  
● Partici pa nts m ust be i nf or me d t hat t heir part ici p ati o n is v ol u ntar y. Partici pa nts or 
t heir le gall y a ut h orize d re prese nt ati ves will be re q uire d t o si g n a state me nt of 
i nf or me d c o nse nt t hat meets t he re q uire m e nts of 2 1 C F R 5 0, l ocal re g ulati o ns, 
I C H g ui deli nes, pri vac y a n d data pr otecti o n re q uire me nts, w here a p plica ble, a n d 
t he IR B/I E C or st u d y c e nter.  
● T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore t he partici pa nt was e ntere d i n t he st u d y a n d t he date t he writte n 
c o nse nt was o btai ne d. T h e a ut h orize d p ers o n o btai ni n g t he i nf or me d c o nse nt m ust 
als o si g n t he I C F.  
● Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g 
t heir partici pati o n i n t he st u d y.  
● A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s 
le gall y a ut h orize d re pres e ntati ve  a n d is ke pt o n fil e . 
Partici pa nts w h o are rescree ne d are re q uir e d t o si g n a ne w I C F.  
1 0. 1. 4.  
D at a Pr otecti o n   
● Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt 
rec or ds, d atasets  or tiss ue sa m ples  t hat are tr a nsferre d t o t he s p o ns or will c o ntai n 
t he i de ntifier o nl y; partici pa nt na mes or an y i nf or mati o n w hic h w o ul d ma ke t he 
partici pa nt i de nti fia ble will n ot be tra nsferre d. 
● T he partici pa nt m ust be i nf or me d t hat t he partici pa nt’s pers o nal st u d y -relat e d data 
will be use d b y t he s p o ns or i n acc or da nce wit h l o cal data pr otecti o n la w. T he 
le vel of discl os ure m ust als o be e x plai ne d t o t he partici pa nt  w h o will be re q uire d 
t o gi ve c o nse nt f or t heir data t o be use d as d escri b e d i n t he i nf or me d c o ns e nt .  
● T he partici pa nt m ust be i nf or me d t hat t heir me dical rec or ds m a y be e x a mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y 
t he s p o ns or, b y a p pr o pri ate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut h orities.  
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● T he sp o ns or  a n d researc h sites  ha ve  pr ocesses i n place t o e ns ure data pr otecti o n, 
i nf or mati o n sec urit y a n d data i nte grit y. T hese pr ocesses i ncl u de a p pr o priate 
c o nti n ge nc y pla n(s) f or a p pr o priate a n d ti mel y res p o nse i n t he e ve nt of a data 
sec urit y breac h a n d are c o m plia nt wit h Ge neral D ata P r otecti o n Re g ulati o n 
( G D P R) data pri va c y re g ulati o ns a n d t he E ur o pea n Cli nical Trial Re g ulati o n 
( C T R) ( Articles 5 6, 5 7, 5 8). 
1 0. 1. 5.  
C o m mittees Str uct ure   
1 0. 1. 5. 1.  I n de pe n de nt D at a M o nit ori n g C o m mittee   
I nteri m a nal yses f or safet y a n d effi cac y will be c o n d ucte d, usi n g u n bli n de d data, u n der t he 
g ui da nce of a n i n de pe n d e nt D M C . T he D M C will c o nsist of at least 3 me m bers, i ncl u di n g a 
c hair, a p h ysici a n, a n d a statisticia n. T he D M C will c o m m u nicate a n y rec o m me n dati o ns base d 
o n i nteri m a nal ysis t o t he sp o ns or. If necessar y, t h e sp o ns or ma y f or m a n I n de pe n de nt Re vie w 
C o m mittee t o re vie w a n d act u p o n t he rec o m me n d atio ns of t he D M C. Details will be s pecifie d i n 
a se parate D M C c h arter.  
1 0. 1. 5. 2.  E arl y S afet y D at a Re vie w   
Case u n bli n di n g ma y be perf or me d f or a b o ve re vie ws if necessar y.  
1 0. 1. 6.  
Disse mi n ati o n of Cl i nic al St u d y D at a  
Re p orts  
T he s p o ns or will discl ose a s u m mar y of st u d y i nf or mati o n, i ncl u di n g ta b ular st u d y res ults, o n 
p u blicl y a vaila ble we bsit es w here re q uir e d b y l ocal la w or  re g ulati o n. 
T he s u m mar y of res ults will be p oste d wit hi n t he ti me fra me s pecifie d b y l ocal la w or re g ulati o n. 
If t he st u d y re mai ns o n g oi n g i n s o me c o u ntries a n d a statistical a nal ysis of a n i nc o m plete data s et 
w o ul d res ult i n a nal yses l ac ki n g scie ntific ri g or (f or e xa m ple, u n der p o were d) or c o m pr o mise t he 
i nte grit y of t he o verall a n al yses (f or e xa m ple, trial n ot yet u n bli n de d), t he s u m mar y of res ults 
will be s u b mitte d wit hi n 1 year after t he e n d of t h e st u d y gl o ball y or as s o o n as a vaila ble, 
w hi c he ver is earlier.  
D at a  
T he s p o ns or pr o vi des access t o all i n di vi d ual partici pa nt data c ollecte d d uri n g t he trial, after 
a n o n y mizati o n, wit h t he e xce pti o n of p har mac o ki netic  or p ha r m ac oge n etic data. Data are 
a vaila ble t o re q u est 6 m o nt hs after t he i n dicati o n st u die d has bee n a p pr o ve d i n t he U S a n d E U 
a n d after pri mar y p u blicati o n acce pta nce, w hic h e v er is later. N o e x pirati o n date of data re q u ests 
is c urre ntl y set o nc e data are ma d e a vaila bl e. 
Access is pr o vi de d after a pr o p osal has b ee n a p pr o ve d b y a n In d e p e n de nt R e vie w C o m mittee 
i de ntifie d f or t his p ur p os e a n d aft er recei pt of a si g ne d data s hari n g a gree me nt. Data a n d 
d oc u me nts, i ncl u di n g t he st u d y pr ot oc ol, S A P, cli nical st u d y re p ort, bla n k or a n n otate d C R Fs, 
will be pr o vi de d i n a sec ure data s h ari n g e n vir o n me nt f or u p t o 2 yea r per pro p osal.  
F or details o n s u b mitti n g a re q uest, see t he i nstr ucti o ns pr o vi de d at w w w. vi vli. or g.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

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8 8  
1 0. 1. 7.  
D at a Q u alit y Ass ur a nce   
● All partici pa nt data relati n g t o t he st u d y will be rec or de d o n pri nte d or electr o nic 
C R F s u nless tra ns mitte d t o t he s p o ns or or desi g ne e electr o ni call y ( f or e xa m ple, 
la b orat or y dat a). T he i n v esti gat or is res p o nsi ble f or verif yi n g t hat d ata e ntries are 
acc urate a n d c orrect b y p h ysicall y or electr o ni call y si g ni n g t he C R F.  
● T he i n vesti gat or m ust mai ntai n acc urate d oc u me nt ati o n (s o urce d ata) t hat 
s u p p orts t he i nf or mati o n e ntere d i n t he C R F. 
● T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, 
a n d re g ulat or y a ge n c y i ns pecti o ns a n d pr o vi de direct a ccess t o s o urce data 
d oc u me nts.  
● Q ualit y t olera nce li mits ( Q T Ls) will be pre -defi ne d t o i de ntif y s yste matic iss ues 
t hat ca n i m pact partici pa nt safet y a n d/ or relia bilit y of st u d y res ults. T hese pre-
defi ne d para meters will be m o nit ore d d uri n g t he st u d y a n d i m p orta nt e xc ursi o ns 
fr o m t he Q T Ls a n d re me dial acti o ns ta ke n will be s u m marize d i n t he cli nical 
st u d y re p ort. 
● M o nit ori n g details descri bi n g strate g y ( f or e xa m pl e, ris k-base d i nitiati ves i n 
o perati o ns a n d  q ualit y s u c h as ris k ma na g e me nt a n d miti gati o n strate gies a n d 
a nal ytical ris k -bas e d m o nit ori n g), met h o ds, res p o nsi bilities a n d re q uire me nts, 
i ncl u di n g ha n dli n g o f n o nc o m plia nce iss ues a n d m o nit ori n g tec h ni q ues are 
pr o vi de d i n t he M o nit ori n g Pla n.  
● T he s p o ns or or desi g ne e is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y 
i ncl u di ng q ualit y c hec ki n g of t he data.  
● T he s p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals ( f or 
e xa m ple, c o ntr act res earc h or ga nizati o ns ). 
● St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data 
e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d 
verifia ble fr o m s o urce d o c u me nts; t hat t he safet y a n d ri g hts of partici pa nts are 
bei n g pr otecte d; a n d t h at t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he 
c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her st u d y a gree me nts, I C H G C P, a n d all 
a p plica ble re g u lat or y re q uire me nts. 
● Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his 
st u d y m ust be retai ne d b y t he i n vesti gat or f or t he ti me peri o d o utli ne d i n t he 
cli nical trial agree me nt  u nless l ocal re g ulati o ns or i nstit uti o nal p olicies re q uire a 
l o n ger rete nti o n peri o d. N o rec or ds ma y be d estr o ye d d uri n g t he ret e nti o n peri o d 
wit h o ut t he writte n a p p r o val of t he sp o ns or. N o rec or ds ma y be tr a nsferre d t o 
a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o t he sp o ns or . 
● I n a d diti o n, sp o ns or  or its re pres e ntati ves will peri o dicall y c hec k a s a m ple of t he 
partici pa nt data rec or de d a gai nst s o urce d o c u me nts at t he st u d y site. T he st u d y 
ma y be a u dite d b y sp o ns or  or its re pres e ntati ves, a n d/ or re g ulat or y a ge n cies at 
a n y ti me. I n v esti gat ors will be gi ve n n otice bef ore a n a u dit occ urs.  
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D at a C a pt ure S yste m  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness 
of t he data re p orte d t o t h e sp o ns or.   
A n E D C  s yste m will be use d i n t his st u d y f or t he c ollecti o n of C R F data. T he i n vesti gat or 
mai ntai ns a se parate s o urce f or t h e data e ntere d b y t he i n vesti gat or or desi g nee i nt o t he 
sp o ns or -pr o vi de d E D C s yste m. T he i n vesti gat or is res p o nsi ble f or t he i de ntificati o n of a n y data 
t o be c o nsi dere d s o urce a n d f or t he c o nfir mati o n t hat data re p orte d are acc urate a n d c o m plete b y 
si g ni n g t he C R F. 
Data c ollecte d via t he s p o ns or -pr o vi de d dat a ca pt ure s yste m (s) will be  st or e d at t hir d-part y. T he 
i n vesti gat or will ha ve c o nti n u o us access t o t he dat a d uri n g t he st u d y a n d u ntil dec o m missi o ni n g 
of t he data ca pt ure s yste m (s). Pri or t o dec o m m issi o ni n g, t he i n vesti gat or will recei ve or access 
a n arc hi v al c o p y of p erti ne nt data f or rete nti o n.  
Data ma na g e d b y a ce ntr al ve n d or, s uc h as la b orat or y test data, will be st or e d electr o ni call y i n 
t he ce ntral v e n d or’s d ata base s yste m a n d re p orts/electr o nic tr a nsfers  will be pr o vi de d t o t he 
i n vesti gat or f or re vi e w a n d rete nti o n. Data will s u bse q ue ntl y be tra nsferre d fr o m t he ce ntr al 
ve n d or t o t he sp o ns or  dat a ware h o use.  
Data fr o m c o m plai nt f or ms s u b mitte d t o t he sp o ns or  will be e nc o de d a n d st ore d i n t he gl o bal P C  
ma na ge me nt s yste m.  
1 0. 1. 8.  
S o urce D oc u me nts   
● S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p artici pa nt a n d 
s u bsta ntiate t he i nte grit y of t he data c ollecte d. S o urce d oc u m e nts are file d at t he 
i n vesti gat or’s site. 
● Data re p orte d  o n  or e ntere d i n t he C R F a n d are tra nscri be d fr o m s o urce 
d oc u me nts m ust be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre p a ncies 
m ust be e x plai ne d. T he  i n vesti gat or ma y nee d t o r e q uest pre vi o us me dical rec or ds 
or tra nsfer rec or ds, de p e n di n g o n t he st u d y. Als o, c urre nt me di cal rec or ds m ust be 
a vaila ble.  
● Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n 1 0. 1. 7 . 
1 0. 1. 9.  
St u d y a n d Site St art a n d Cl os ure   
First Act of Rec ruit me nt  
T he st u d y start date is t he date o n w hic h t h e cli nical st u d y will be o pe n f or recr uit me nt of 
partici pa nts.  
T he first act of recr uit me nt is t he first site o pe n a n d will  be t he st u d y start date.  
St u d y or Site Ter mi n ati o n  
T he s p o ns or desi g ne e res er ves t he ri g ht t o cl ose t h e st u d y site or ter mi nate t h e st u d y at a n y ti me 
f or a n y reas o n at t he s ole discreti o n of t he sp o ns or. St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d o c u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y -site cl os ure visit has bee n perf or m e d.  
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9 0  
T he i n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or or i n ve sti gat or ma y i ncl u de b ut are 
n ot li mite d t o:  
F or st u d y ter mi nati o n:  
● Disc o nti n uati o n of f urt her st u d y i nter ve nti o n de vel o p me nt . 
F or site ter mi nati o n:  
● Fail ure of t he i n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he s p o ns or ’s pr oce d ures, or G C P g ui deli nes. 
● I n a de q uat e recr uit me nt (e val uate d after a reas o na ble a m o u nt of ti me) of 
partici pa nts b y t he i n vesti gat or . 
● T otal n u m ber of partici pa nts i ncl u de d earlier t ha n e x pecte d . 
If t he st u d y is pre mat ur el y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
in vesti gat ors, t he I E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y c o ntr act r esearc h or ga ni zati o n(s) 
use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble 
re g ulat or y re q uire me nts. T he in vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt  a n d s h o ul d ass ure 
a p pr o priate p artici pa nt  t h era p y a n d/ or f oll o w-u p . 
1 0. 1. 1 0.  
P u blic ati o n P olic y   
I n acc or da n ce wit h t he s p o ns or’s p u blicati o n p olic y, t he res ults of t his st u d y will be s u b mitte d 
f or p u blicati o n b y a peer-re vie we d j o ur nal. 
1 0. 1. 1 1.  
I n vesti g at or I nf or m ati o n  
Researc h ers wit h a p pr o priate e d ucati o n, trai ni n g, a n d e x perie n ce, as d eter mi ne d b y t he s p o ns or, 
will partici pate as i n vesti gat ors i n t his cli nical trial.  
1 0. 1. 1 2.  
L o n g -Ter m S a m ple Rete nti o n   
Sa m ple rete nti o n e na bles use of ne w tec h n ol o gies, res p o nse t o re g ul at or y q uesti o ns, a n d 
i n vesti gati o n of varia ble res p o nse t hat ma y n ot be o bser ve d u ntil later i n t he de vel o p me nt of 
a be maci cli b or after a be macicli b  bec o me(s) c o m merciall y a vaila bl e  f or tr eat me nt of m H S P C. 
 
S a m ple T y pe  
C ust o di a n  
Rete nti o n Peri o d After L ast 
P artici p a nt Visit a 
P har mac o ki netics  
S p o ns or or Desi g nee  
U p t o 1 year  
G e n etics  
S p o ns or or Desi g nee  
U p t o 7  years  
Bi o mar kers  
S p o ns or or Desi g nee  
U p t o 7  years  
a Rete nti o n peri o ds ma y differ l ocall y.  
T he s p o ns or has a ri g ht t o retai n a p orti o n of s u b mitte d bi o ps y tiss ue. Arc hi val bl oc ks will be 
ret ur ne d t o t he st u d y site. Sli des a n d tiss ue sa m ples c ollecte d o n st u d y will n ot be ret ur ne d.  
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9 1  
1 0. 2.  
A p pe n di x 2: Cli nic al L a b or at or y Tests   
● T he tests detaile d i n t he t a ble bel o w will be perf or me d b y t he ce ntr al la b orat or y  or 
b y t he l ocal la b orat or y as i n dicate d . 
● E nr oll me nt a n d treat me nt decisi o ns ma y be base d o n l ocal la b orat or y res ults. A 
d u plicate sa m ple m ust still be se nt t o t he ce ntral la b orat or y. Differe n ces b et wee n 
t hese sa m ples will n ot c o nstit ute a pr ot oc ol de viati o n. T he l ocal la b orat or y m ust 
be q ualifie d i n acc or da nce wit h a p plica ble l ocal re g ulati o ns.  
● A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d 
necessar y b y t he i n vesti g at or or re q uire d b y l ocal re g ulati o ns.  
● I n v esti gat ors m ust d oc u me nt t heir re vie w of t he l a b orat or y safet y res ults. 
 
Cli nic al L a b or at or y Tests  
C o m me nts  
He m at ol o g y  
Assa ye d b y S p o ns or -desi g nate d  la b orat or y. 
He m at ocrit  
He m o gl o bi n  
Er yt hr oc yte c o u nt ( R B Cs)  
Mea n cell v ol u me  
Mea n cell he m o gl o bi n c o nce ntrati o n  
Le u k oc ytes ( W B C)  
Differe ntial  ( Perce nt or  A bs ol ute C o u nts ) 
- 
Ne utr o p hils, se g me nte d  
- 
Ne utr o p hils, ba n ds (if detecte d , a n d 
re p orte d se p aratel y fr o m se g me nte d 
ne utr o p hils ) 
- 
L y m p h oc ytes  
- 
M o n oc ytes  
- 
E osi n o p hils  
- 
Bas o p hils  
 
A bs ol ute Ne utr o p hil C o u nt (se g me nte d a n d 
ba n ds) (calc ulati o n)  
Platelets  
Cli nic al C he mistr y  ( n o n-f asti n g) 
Assa ye d b y S p o ns or -desi g nate d la b orat or y . 
Ala ni ne a mi n otra nsferase ( A L T)  
Al b u mi n  
Al kali ne p h os p hatase ( A L P)  
As partate a mi n otra nsferase ( A S T)  
Bl o o d urea nitr o ge n ( B U N) or bl o o d urea  
Calci u m  
C h olester ol  
Creati ne ki nase ( C K)  
Creati ni ne  
C ystati n C  
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Cli nic al L a b or at or y Tests  
C o m me nts  
Direct bilir u bi n  
Gl uc ose  
Hi g h -de nsit y li p o pr otei n ( H D L)  
Lactate de h y dr o ge nase ( L D H)  
L o w -de nsit y li p o pr otei n ( L D L) 
Ma g nesi u m  
P h os p h or us  
P otassi u m  
S o di u m  
T otal bilir u bi n  
T otal pr otei n  
Tri gl yceri des  
Uric aci d  
A d diti o n al  Testi n g  
  
Assa ye d b y S p o ns or -desi g nate d la b orat or y . 
Test o ster o ne 
Pr ostate -specific anti ge n ( P S A)  
C o a g ul ati o n  
Assa ye d b y l ocal la b orat or y. 
Acti vate d partial t hr o m b o plasti n ti me (a P T T) 
or partial t hr o m b o plasti n ti me ( P T T)  
I nter nati o nal n or malize d rati o n (I N R) or 
Pr ot hr o m bi n ti me ( P T) 
Uri n al ysis  
Assa ye d b y l ocal la b orat or y. 
Bl o o d  
Gl uc ose  
Ket o nes  
Nitrate or Uri ne le u k oc yte esterase  
Pr otei n  
p H  
S pecific gra vit y  
A d diti o n al He p atic M o nit o ri n g  
See Secti o n 1 0. 5 , A p pe n di x 5. 
P h ar m ac o ki netic S a m ples  
L Y 2 8 3 5 2 1 9 c o nce ntrati o n  
Assa ye d b y S p o ns or -desi g nate d la b orat or y . 
 
Res ults will n ot be pr o vi de d t o t he i n vesti gati ve sites. 
P h ar m ac o g e no m ics S a m ple  
T his ge netic sa m ple  will  ori gi nate fr o m t he w h ole -bl o o d 
sa m ple c ollecte d i n Secti o n 8. 7  f or bi o mar ker researc h. 
Bi o m ar k er St or a ge S a m ples  
Assa ye d b y S p o ns or -desi g nate d la b orat or y . 
  
Arc hi val t u m or tiss ue 
O pti o nal tu m or bi o ps y  
Plas ma  (Strec k)  
W h ole bl o o d  
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1 0. 3.  
A p pe n di x 3: A d verse E ve nts  a n d Seri o us A d verse E ve nts : Defi niti o ns 
a n d Pr oce d ures f or Rec or di n g, E v al u ati n g, F oll o w -u p, a n d 
Re p orti n g   
1 0. 3. 1.  
Defi niti o n of A E   
A E Defi niti o n  
 A n A E is a n y u nt o war d me dical occ urre n ce i n a partici pa nt a d mi nistere d a 
p har mace utical pr o d uct a n d  w hic h d oes n ot necessaril y ha ve a ca usal r elati o ns hi p wit h 
t he st u d y i nter ve nti o n. A n A E ca n t heref ore be a n y u nfa v ora bl e  a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) 
te m p orall y ass ociate d wit h the use of a me di ci nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot relate d t o t he me dici n al (i n vesti gati o nal) pr o d u ct.  
 
E ve nts Meeti n g t he A E Defi niti o n  
 A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (f or e xa m ple, E C G, vital si g ns), i ncl u di n g t h ose t hat w orse n 
fr o m baseli ne, c o nsi d ere d cli nicall y si g nifica nt i n t he me dical a n d sci e ntific j u d g me nt 
of t he i n vesti gat or ( t hat is, n ot relate d t o pr o gressi o n of u n derl yi n g disease). 
 E xacer b ati 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 n detecte d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n 
t h o u g h it ma y ha ve bee n prese nt bef ore t he start of t he st u d y.  
 Si 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 -dr u g i nteracti o n.  
 Me dicati o n err or, mis use, or a b use of I M P, i ncl u di n g si g ns, s y m pt o ms, or cli nical 
se q uelae. 
 Lac k of effic ac y or fail ure of e x pecte d p har mac ol o gical acti o n per se will n ot be 
re p orte d as a n A E or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts. 
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of efficac y 
will be re p orte d as A E or S A E if t he y f ulfil l t he defi niti o n of a n A E or S A E.  
 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
 A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal s afet y 
assess me nts t hat are ass o ciate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
i n vesti gat or t o be m ore s e vere t h a n e x pecte d f or t he partici pa nt’s c o n diti o n. 
 T he disease/ dis or der bei n g st u die d or e x pect e d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he p artici pa nt’s 
c o n diti o n.  
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 Me dical or s ur gic al pr oce d ure ( f or e x a m ple, e n d osc o p y, a p pe n d ect o m y): t he c o n diti o n 
t hat lea ds t o t he pr oce d ure is t he A E. 
 Sit uati o ns i n w hic h a n u nt o war d me dical o cc urre n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
 A ntici pate d da y -t o-d a y fl uct uati o ns of p re-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 orse n.  
1 0. 3. 2.  
Defi niti o n of S A E   
A n S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose , meets o ne or 
m ore of t he criteri a list e d : 
a.  Res ults i n de at h  
b.  Is life-t hre ate ni n g 
T he ter m life-t hre ate ni n g i n t he defi niti o n of seri o us refers t o a n e ve nt i n w hic h t he partici pa nt 
was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y 
mi g ht ha ve ca use d d eat h, if it were m ore s e vere.  
c. 
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g  h os pit aliz ati o n  
 I n g e neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n a d mitte d t o  h os pital 
(i n v ol vi n g at least a n o ver ni g ht sta y) f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot 
ha ve bee n a p pr o priate i n t he p h ysicia n ’s office or o ut patie nt setti n g. C o m plicati o ns t hat 
occ ur d uri n g h os pitalizati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or 
f ulfills a n y ot her seri o us criteria, t he e ve nt is seri o us. Pla n ne d h os pitalizati o n or  f or 
electi ve treat me nt of a pree xi sti n g c o n diti o n t hat di d n ot w orse n fr o m bas eli ne is n ot 
c o nsi dere d a n A E.  
d.  Res ults i n persiste nt dis a bilit y/i nc a p acit y  
 T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal life f u ncti o ns.  
 T his defi niti o n is n ot i nte n d e d t o i ncl u de e x perie n ces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, n a usea, v o miti n g, diarr hea, i nfl ue nza, 
a n d acci de ntal tra u ma ( f or e xa m ple, s prai ne d a n kl e) w hic h ma y i nterfere wit h or 
pre ve nt e v er y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n. 
e. 
Is a c o n ge nit al a n o m al y/ birt h defect 
 A b n or mal pre g n a nc y o ut c o mes (e. g., s p o nta n e o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na n c y) are c o nsi dere d S A Es.  
f. 
Ot her sit u ati o n s: 
 Me dical or scie ntifi c j u d g me nt s h o ul d be e xercise d b y t he i n vesti gat or i n deci di n g 
w het her S A E re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical 
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e ve nts t hat ma y n ot be i m me diatel y life -t hreate ni n g or res ult i n deat h or h os pitalizatio n 
b ut ma y je o par dize t h e p artici pa nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts s h o ul d 
be c o nsi dere d seri o us.  
 
E xa m ples of s uc h e v e nts i ncl u de i n vasi ve or mali g na nt ca nc ers, i nte nsi ve treat me nt i n 
a n e mer g e nc y r o o m or at h o me f or aller gi c br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g d e pe n de nc y or 
dr u g a b use.   
1 0. 3. 3.  
Defi niti o n of Pr o d uct C o m pl ai nts   
Pr o d uct C o m pl ai nt  
 A pr o d uct c o m plai nt is a n y writte n, electr o ni c, or oral c o m m u nicati o n t hat alle ges 
deficie nci es relat e d t o t he i de ntit y, q ualit y, d ura bilit y, relia bilit y, saf et y, effecti ve ness 
or perf or ma nce of a st u d y i nter ve nti o n . W he n t he a bilit y t o use t he st u d y i nter ve nti o n 
safel y is i m pacte d, t he f oll o wi n g are als o pr o d uct c o m plai nts: 
o  Deficie n cies i n la beli n g i nf or mati o n, a n d  
o  Use err ors f or d e vice or dr u g -de vice c o m bi nati o n pr o d ucts d ue t o er g o n o mic 
desi g n ele me nts of t he pr o d uct.  
 Pr o d uct c o m plai nts relate d t o st u d y i nte rve nti o ns use d i n cli nical trials are c ollecte d i n 
or der t o e ns ur e t he safet y of partici pa nts, m o nit or q ualit y, a n d t o facilitate pr ocess a n d 
pr o d uct i m pr o ve me nts.  
 I n v esti gat ors will i nstr uct partici pa nts t o c o ntact t h e site as s o o n as p ossi ble if he or s he 
has a pr o d uct c o m plai nt or pr o ble m wit h t he st u d y i nte rve nti o n s o t hat t he sit uati o n ca n 
be assesse d.  
 A n e ve nt ma y me et t he d efi niti o n of b ot h a  pr o d uct c o m plai nt a n d a n A E/ S A E. I n s uc h 
cases, it s h o ul d be re p orte d as b ot h a pr o d u ct c o m plai nt a n d as a n A E/ S A E.  
 
1 0. 3. 4.  
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E  a n d Pr o d uct C o m pl ai nts   
A E , S A E , a n d Pr o d uct C o m pl ai nt  Rec or di n g  
 W he n a n A E/ S A E /pr o d uct c o m plai nt  occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or 
t o re vie w all d oc u me nt ati o n (f or e x a m ple, h os pital pr o gress n otes, la b orat or y re p orts, 
a n d dia g n ostics re p orts) relate d t o t he e ve nt.  
 T he i n vesti gat or will t he n rec or d all rele va nt A E/ S A E /pr o d uct c o m plai nt  i nf or mati o n 
i n t he partici pa nt’s me dical rec or ds, i n acc or da n ce wit h t he i n vesti gat or’s n or mal 
cli nical practice. A E/ S A E i nf or mati o n is re p orte d o n t he a p pr o priat e C R F pa ge a n d 
pr o d uct c o m plai nt  i nf or mati o n is re p orte d o n t he Pr o d uct C o m plai nt F or m. 
N ote: A n e ve nt ma y me et t he defi niti o n of b ot h a pr o d uct c o m plai nt a n d a n A E/ S A E. 
I n s u c h cas es, it s h o ul d be re p ort e d as b ot h a pr o d uct c o m plai nt  a n d as a n A E/ S A E.  
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 It is n ot  acce pta bl e f or t h e i n vesti gat or t o se n d p h ot oc o pies of t he partici p a nt’s me dical 
rec or ds t o S p o ns or or d esi g nee  i n lie u of c o m pleti o n of t he C R F pa ge f or A E/ S A E a n d 
t he Pr o d uct C o m plai nt F or m f or pr o d uct c o m plai nts . 
 T here ma y b e i nsta nces w he n c o pies of m e dical r ec or ds f or certai n cas es are re q u este d 
b y S p o ns or or desi g nee . I n t his case, all partici pa nt i de ntifiers, wit h t he e xce pti o n of 
t he partici pa nt n u m ber, will be re dact e d o n t he c o pies of t he me dical r ec or ds bef ore 
s u b missi o n t o S p o ns or or desi g nee . 
 T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns , 
s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot t he 
i n di vi d ual si g ns/s y m pt o ms) will be d oc u me nte d as t he A E/ S A E. 
Assess m e nt of I nte nsit y  
T he i n vesti gat or will use C T C A E versi o n 5. 0 ( N CI 2 0 1 7 ) t o assi g n A E se v erit y gra des.  
 
Assess m e nt of C a us alit y  
 T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y i nter ve nti o n a n d 
eac h o cc urre nce of eac h A E/ S A E.  T he i n vesti gat or will use cli nical j u d g me nt t o 
deter mi ne t he relati o ns hi p . 
 A “reas o na ble p ossi bilit y” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g g est a ca us al relati o ns hi p, rat her t ha n a rel ati o ns hi p ca n n ot be 
r ule d o ut. 
 Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t h e e ve nt t o st u d y i nter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.  
 T he i n vesti gat or will als o c o ns ult t he I B a n d/ or Pr o d uct I nf or mati o n, f or m ar kete d 
pr o d ucts, i n t heir assess me nt.  
 F or eac h A E/ S A E, t he i n vesti gat or m ust  d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t h e A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
 T here ma y b e sit uati o ns i n w hic h a n S A E has occ urre d a n d t h e i n vesti gat or has 
mi ni mal i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o S p o ns or or desi g nee . H o we ver, it 
is ver y i m p orta nt t hat t he i n vesti gat or al wa ys ma k e a n assess me nt of ca us alit y f or 
e ver y e v e nt bef ore t he i nitial tra ns missi o n of t he S A E data t o S p o ns or or desi g nee . 
 T he i n vesti gat or ma y c h a n ge t heir o pi ni o n of ca us alit y i n li g ht of f oll o w -u p 
i nf or mati o n a n d se n d an  S A E f oll o w -u p re p ort wit h t he u p date d ca us alit y assess me nt.  
 T he ca us alit y assess me nt is o ne of  t he criteria use d w he n deter mi ni n g r e g ulat or y 
re p orti n g re q uir e me nts. 
 
 
 
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F oll o w -u p of A Es a n d S A Es  
 T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d u ct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns as me dicall y i n dicate d or as re q uest e d b y S p o ns or or 
desi g nee  t o el uci dat e t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble. 
T his ma y i ncl u de a d diti o nal la b orat or y tests or i n v esti gati o ns, hist o pat h ol o gical 
e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.  
 If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p 
peri o d,  t he i n vesti gat or will pr o vi de S p o ns or or desi g nee  wit h a c o p y of a n y 
p ost -m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y.  
1 0. 3. 5.  
Re p orti n g of S A Es   
S A E Re p orti n g vi a a n Electr o nic D at a C ollecti o n T o ol  
 T he pri mar y mec ha nis m f or re p orti n g a n S A E will be t he electr o nic data c ollecti o n 
t o ol. 
 If t he ele ctr o nic s yste m is u na vaila ble, t he n t he sit e will use t he S A E pa per f or m (see 
ne xt secti o n) i n or der t o re p ort t he e ve nt wit hi n 2 4 h o urs.   
 T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes 
a vaila ble.  
 After t he st u d y is c o m plete d at a gi ve n site, t he el ectr o nic data c ollecti o n t o ol will be 
ta ke n off-li ne t o pre ve nt t he e ntr y of n e w data or c ha n ges t o e xisti n g data. 
 If a site recei v es a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei v es u p date d 
data o n a pre vi o usl y re p orte d S A E after t he electr o nic data c ollecti o n t o ol h as bee n 
ta ke n off-li ne, t h e n t he site ca n re p ort t his i nf or mati o n o n an  S A E pa per f or m (see ne xt 
secti o n) or t o t he Lill y C R P/ C R S b y tele p h o ne.  
 C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he S A E f or m. 
 
S A E Re p orti n g vi a P a per F or m  
 Facsi mile tra ns missi o n of t he S A E pa per f or m is t he preferre d met h o d t o tra ns mit t his 
i nf or mati o n t o t he Lill y C R P/ C R S . 
 I nitial n otificati o n via tel e p h o ne d oes n ot re place t he nee d f or t he i n vesti gat or t o 
c o m plete a n d si g n t he S A E C R F pa ges wit hi n t he desi g nate d re p orti n g ti me fra mes.  
 C o ntacts f or S A E re p orti n g ca n be f o u n d i n t he S A E f or m. 
1 0. 3. 6.  
Re g ul at or y Re p orti n g Re q uire me nts   
S A E Re g ul at or y Re p orti n g  
Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or of a n  S A E is esse ntial s o t hat 
le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of p artici pa nts 
a n d t he safet y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
9 8  
● T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ul at or y 
a ut h orit y a n d ot her re g ulat or y a ge n cies a b o ut t he safet y of a st u d y i nter ve nti o n 
u n der cli nical i n vesti gati o n. T he s p o ns or will c o m pl y wit h c o u ntr y -s pecific 
re g ulat or y re q uire me nts r elati n g t o safet y re p orti n g t o t he re g ulat or y a ut h orit y, 
I nstit uti o nal Re vie w B oar ds (I R B)/I n de pe n d e nt Et hics C o m mittees (I E C) , a n d 
i n vesti gat ors. 
● A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n  S A E or 
ot her s pecific s afet y i nf or mati o n (e. g., s u m mar y or listi n g of S A Es) fr o m t he 
s p o ns or will re vie w a n d t he n file it al o n g wit h t he  I B a n d will n otif y t he 
I R B/I E C, if a p pr o priate acc or di n g t o l ocal r e q uire me nts. 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
9 9  
1 0. 4.  
A p pe n di x 4: C o ntr ace pti ve a n d B arrier G ui d a nce   
1 0. 4. 1.  
Defi niti o ns   
 
 
W or d/ P hr ase  
Defi niti o n  
W o me n of 
c hil d beari n g  
p ote ntial  
Fe males are c o nsi dere d a w o ma n of c hil d beari n g  p ote ntial if  t he y ha ve ha d at least 
o ne c ycle of me nses . A n y a m o u nt of s p otti n g s h o ul d be c o nsi dere d me narc he.   
W o me n n ot of 
c hil d beari n g  
p ote ntial  
Fe males are c o nsi dere d w o me n n ot of c hil d beari n g  p ote ntial if  
 
t he y ha ve a c o n ge nital a n o mal y s uc h as M ulleria n a ge nesis,  
 
t he y are i nfertile d ue t o s ur gical sterilizati o n, or  
 
t he y are p ost-me n o pa usal.  
E xa m ples of s ur gical sterilizati o n i ncl u de:  h ysterect o m y, bilateral o o p h orect o m y,  
bilateral sal pi n gect o m y . 
 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 0  
1 0. 4. 2.  
C o ntr ace pti o n G ui d a nce   
T he ta ble bel o w descri bes c o ntrace pti o n g ui da nce f or male partici pa nts.  
T o pic  
G ui d a nce  
F or all me n   
s h o ul d refrai n fr o m s per m d o nati o n f or t he 
d urati o n of t he st u d y a n d f or at least 3 m o nt hs 
f oll o wi n g t he last d ose of st u d y treat me nt. 
C o ntrace pti o n f or me n wit h part ners of 
c hil d beari n g p ote ntial or pre g na nt  
eit her re mai n a bsti ne nt (if t his is t heir preferre d 
a n d us ual lifest yle), or  
 
m ust use c o n d o ms  wit h effecti ve 
c o ntrace pti o n  met h o d  d uri n g 
i nterc o urse f or t he d urati o n of t he 
st u d y, a n d f or at least 3 wee ks 
f oll o wi n g t he last d ose of st u d y 
treat me nt. 
E xa m ples of hi g hl y effecti ve, effecti ve a n d u nac ce pta ble met h o ds of c o ntrace pti o n ca n be f o u n d bel o w.  
Met h o ds  
E x a m ples  
Hi g hl y effecti ve c o ntrace pti o n  
 
c o m bi nati o n oral c o ntrace pti ve 
pill a n d mi ni -pill  
 
i m pla nte d c o ntrace pti ves 
 
i njecta ble c o ntrace pti ves 
 
c o ntrace pti ve patc h ( o nl y w o me n 
< 1 9 8 p o u n ds or 9 0 k g)  
 
t otal a bsti ne nce 
 
vasect o m y (if o nl y se x ual part ner)  
 
fall o pia n t u be i m pla nts (if 
c o nfir me d b y 
h yster osal pi n g o gra m)  
 
c o m bi ne d c o ntrace pti ve va gi nal 
ri n g, or  
 
i ntra uteri ne de vices 
Effecti ve c o ntrace pti o n  
 
male or fe male c o n d o ms wit h 
s per mici de  
 
dia p hra g ms  wit h s per mici de or 
cer vical s p o n ges  
 
barrier met h o d wit h use of a 
s per mici de 
o  c o n d o m wit h s per mici de  
o   dia p hra g m wit h s per mici de, or  
o  fe male c o n d o m wit h s per mici de 
N ote:  T he barrier met h o d m ust i ncl u de use of a 
s per mici de (i.e., c o n d o m wit h s per mici de, 
dia p hra g m wit h s per mici de, fe male c o n d o m wit h 
s per mici de) t o be c o nsi dere d effecti ve. 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 1  
1 0. 5.  
A p pe n di x  5 : Li ver S afet y: S u g geste d Acti o ns a n d F oll o w-u p 
Assess me nts   
He p atic E v al u ati o n Testi n g  
See Secti o n s 8. 2. 2  a n d 8. 2. 2. 1  f or g ui da nce o n a p pr o priate test selecti o n. 
T he Lill y -desi g nate d ce ntral la b orat or y m ust c o m plete t he a nal ysis of all s electe d testi n g e x ce pt 
f or micr o bi ol o g y testi n g.  
L ocal testi n g ma y be perf or me d i n a d diti o n t o ce ntral testi n g w he n necessar y f or i m me diate 
partici pa nt ma na g e me nt.  
Res ults will be re p orte d if a vali date d test or calc ulati o n is a vaila ble.  
He m at ol o g y  
Cli nic al C he mistr y  
He m o gl o bi n  
T otal bilir u bi n  
He mat ocrit  
Direct bilir u bi n  
Er yt hr oc ytes ( R B Cs –  re d bl o o d cells) 
Al kali ne p h os p hatase ( A L P)  
Le u k oc ytes ( W B Cs –  w hite bl o o d cells)  
Ala ni ne a mi n otra nsferas e ( A L T)  
Differe ntial:  
As partate a mi n otra nsferase ( A S T)  
    Ne utr o p hils , se g me nte d 
Ga m ma -gl uta m yl tra nsferase ( G G T)  
    L y m p h oc ytes  
Creati ne ki nase ( C K)  
    M o n oc ytes  
Ot her C he mistr y  
    Bas o p hils  
Aceta mi n o p he n  
    E osi n o p hils  
Aceta mi n o p he n pr ot ei n a d d ucts  
Platelets  
Al kali ne p h os p hatase is o e nz y mes  
Cell m or p h ol o g y ( R B C a n d W B C)  
Cer ul o plas mi n  
C o a g ul ati o n  
C o p per  
Et h yl alc o h ol ( Et O H)  
Pr ot hr o m bi n ti me, I N R ( P T -I N R) 
Ha pt o gl o bi n  
Ser ol o g y  
I m m u n o gl o b uli n I g A ( q u a ntitati ve) 
 
He patitis A vir us ( H A V) testi n g:  
I m m u n o gl o b uli n I g G ( q u a ntitati ve) 
    H A V t otal anti b o d y  
I m m u n o gl o b uli n I g M ( q ua ntitati ve) 
    H A V I g M a nti b o d y  
P h os p hati d ylet ha n ol ( P E th)  
He patis B vir us ( H B V) testi n g:  
Uri ne C he mistr y  
    He patitis B s urface a nti ge n ( H Bs A g)  
Dr u g scree n  
    He patitis B s urface a nti b o d y (a nti -H Bs)  
Et h yl gl uc ur o ni de ( Et G)  
    He patitis B c ore t otal a nti b o d y (a nti -H Bc)  
Ot her Ser ol o g y  
    He patitis B c ore I g M a nti b o d y  
A nti -n uclear a nti b o d y ( A N A)  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 2  
    He patitis B c ore I g G a nti b o d y  
A nti -s m o ot h m uscle a nti b o d y ( A S M A) a  
    H B V D N A  b  
A nti -acti n a nti b o d y c  
He patis C vir us ( H C V) testi n g:  
E pstei n -Barr vir us ( E B V) testi n g:  
    H C V a nti b o d y  
    E B V a nti b o d y  
    H C V R N A  b  
    E B V D N A  b  
He patitis D vir us ( H D V) testi n g:  
C yt o me gal o vir us ( C M V) testi n g:  
    H D V a nti b o d y  
    C M V a nti b o d y  
He patitis E vir us ( H E V) t esti n g:  
    C M V D N A  b  
    H E V I g G a nti b o d y  
Her pes si m ple x vir us ( H S V) testi n g:  
    H E V I g M a nti b o d y  
    H S V ( T y pe 1 a n d 2) a nti b o d y  
    H E V R N A b  
    H S V ( T y pe 1 a n d 2) D N A  b  
Micr o bi ol o g y 
d  
Li ver ki d ne y micr os o mal t y pe 1 ( L K M -1) 
a nti b o d y  
C ult ure:  
 
    Bl o o d  
 
    Uri ne  
 
a N ot re q uire d if a nti -acti n a nti b o d y is teste d.  
b  Refle x/c o nfir mati o n de p e n de nt o n re g ulat or y re q uire me nts, testi n g a vaila bilit y, or b ot h.  
c N ot re q uire d if a nti -s m o ot h m uscle a nti b o d y is teste d. 
d  Assa y e d O N L Y b y i n vesti gat or -desi g nate d l ocal la b orat or y; n o ce ntral testi n g a vaila ble.  
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 3  
1 0. 6.  
A p pe n di x 6 : Ti mi n g a n d Mec h a nis m f or C ollecti n g E ve nts   
T his ta ble descri bes t he ti mi n g, dea dli nes, a n d mec ha nis m f or c ollecti n g e v e nts.  
E ve nt  
C ollecti o n 
St a rt  
C ollecti o n 
St o p  
Ti mi n g f or Re p o rti n g 
t o S p o ns or or 
Desi g nee  
Mec h a nis m f or 
Re p orti n g  
B ac k -u p 
Met h o d of 
Re p orti n g  
A d verse E ve nt  
A E  
Si g ni n g of 
t he i nf or me d 
c o nse nt f or m 
(I C F) 
E n d of t he 
3 0 -da y s h ort -
ter m f oll o w-
u p visit  
As s o o n as p ossi ble 
u p o n site a ware ness  
A E C R F  
N/ A  
Seri o us A d verse E ve nt  
S A E a n d S A E 
u p dates –  pri or 
t o start of st u d y 
i nter ve nti o n a n d  
dee me d 
reas o na bl y 
p ossi bl y relate d 
wit h st u d y 
pr oce d ures  
Si g ni n g of 
t he I C F 
Start of 
i nter ve nti o n 
Wit hi n 2 4 h o urs of 
a ware ness  
S A E C R F  
S A E pa p er 
f or m 
S A E a a n d S A E 
u p dates –  after 
start of st u d y 
i nter ve nti o n 
Start of 
i nter ve nti o n 
Partici pati o n 
i n st u d y has 
e n de d 
Wit hi n 2 4 h o urs of 
a ware ness  
S A E C R F  
S A E pa p er 
f or m 
S A E b –  after 
partici pa nt’s 
st u d y 
partici pati o n has 
e n de d a n d  t he 
i n vesti gat or 
bec o mes a ware  
After 
partici pa nt’s 
st u d y 
partici pati o n 
has e n de d  
N/ A  
Wit hi n 2 4 h o urs of 
a ware ness  
S A E pa per f or m  
N/ A  
Pre g n a nc y  
Pre g na n c y i n 
fe male part ners 
of male 
partici pa nts  
After t he 
start of st u d y 
i nter ve nti o n 
1 wee k after 
last d ose  (see 
Secti o n 8. 3. 5  
f or pre g na nc y 
o utc o me 
f oll o w-u p 
g ui da n ce ) 
Wit hi n 2 4 h o urs (see 
Secti o n 8. 3. 5 ) 
Pre g na n c y pa per 
f or m 
N/ A  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 4  
E ve nt  
C ollecti o n 
St a rt  
C ollecti o n 
St o p  
Ti mi n g f or Re p o rti n g 
t o S p o ns or or 
Desi g nee  
Mec h a nis m f or 
Re p orti n g  
B ac k -u p 
Met h o d of 
Re p orti n g  
Pr o d uct C o m pl ai nts  
P C ass ociate d 
wit h a n S A E or 
mi g ht h a v e le d 
t o a n S A E 
Start of st u d y 
i nter ve nti o n 
E n d of st u d y 
i nter ve nti o n 
Wit hi n 2 4 h o urs of 
a ware ness  
Pr o d uct C o m plai nt 
f or m 
N/ A  
P C n ot 
ass ociate d wit h 
a n S A E  
Start of st u d y 
i nter ve nti o n 
E n d of st u d y 
i nter ve nti o n 
Wit hi n 1 b usi ness da y 
of a ware ness  
Pr o d uct C o m plai nt 
f or m 
N/ A  
U p date d P C 
i nf or mati o n 
—  
—  
As s o o n as p ossi ble 
u p o n site a ware ness  
Ori gi nall y 
c o m plete d Pr o d uct 
C o m plai nt f or m 
wit h all c ha n ges 
si g ne d a n d date d b y 
t he i n vesti gat or 
N/ A  
P C (if 
i n vesti gat or 
bec o mes a ware)  
Partici pati o n 
i n st u d y has 
e n de d 
N/ A  
Pr o m ptl y  
Pr o d uct C o m plai nt 
f or m 
 
a Deat h ca use d b y disease pr o gressi o n s h o ul d n ot be re p orte d as a n S A E.  
b  Seri o us a d verse e v e nts, i ncl u di n g deat h ca use d b y disease pr o gressi o n, s h o ul d n ot be re p orte d u nless t he 
i n vesti gat or dee ms t he m t o be p ossi bl y relate d t o st u d y i nter ve nti o n or st u d y partici pati o n. 
 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 5  
1 0. 7.  
A p pe n di x 7: I n d ucers a n d Str o n g I n hi bit ors of C Y P 3 A 4   
T he i nf or mati o n i n t his ta ble is pr o vi de d f or g ui da nce t o i n vesti gat ors a n d d oes n ot precl u de t h e 
use of t hese me dicati o ns if cli nicall y i n dicate d.  Please refer t o Secti o n 6. 8  C o nc o mita nt  T hera p y.  
T his list is n ot i nte n de d t o be e x ha usti ve . Wit h a v aila ble i nf or mati o n c o nti n uall y e v ol vi n g, t he 
stat us of e ver y rele va nt dr u g ca n n ot be g uara nt ee d. Please c o ns ult wit h t he me dical m o nit or i n 
case of a n y d o u bt a b o ut a p ote ntial dr u g -dr u g i nteracti o n.  
 
Str o n g I n d ucers of C Y P 3 A 4  
A mi n o gl utet hi mi de  
A pal uta mi de  
Car ba maze pi ne ( dail y d ose e xcee di n g 6 0 0 m g)  
E nzal uta mi de  
F os p he n yt oi n (see als o p he n yt oi n)  
I v osi de ni b 
L u macaft or  
Mit ota ne  
P he n o bar bital  
P he n yt oi n  
Rifa b uti n  
Rifa m pici n (rifa m pi n)  
Rifa p e nti ne  
St J o h n’s w ort  
 
M o der ate I n d ucers of C Y P 3 A 4  
B ose nta n  
Car ba maze pi ne ( dail y d ose 6 0 0 m g or l o wer)  
Ce n o ba mate  
Da brafe ni b  
Da ns he n ( S alvi a milti orr hiz a ) 
Efa vire n z  
Ela g oli x  
E nc orafe ni b  
Etra viri ne  
Ge nistei n  
L o pi na vir (al o ne)  
L orlati ni b  
M o dafi nil  
Nafcilli n (i ntra v e n o us)  
Pe nt o bar bital  
Pri mi d o ne  
S ot orasi b  
T hi ori dazi ne  
T ociliz u ma b (atliz u ma b)  
 
Str o n g I n hi bit ors of C Y P 3 A 4  
Ataza n a vir a n d c o bicistat  
B oce pre vir  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 6  
Ceriti ni b  
Clarit hr o m yci n  
C o bicistat (see ataza n a vir a n d c o bicistat)  
C o ni va pta n  
Da n o pre vir a n d rit o na vir  
El vite gra vir a n d rit o na vir  
F osa m pre na vir a n d rit o na vir  
Gra p efr uit j uice  
I delalisi b 
I n di na vir a n d rit o na vir  
Itrac o naz ole 
J osa m yci n 
Ket o c o naz ole  
L o nafar ni b  
L o pi na vir a n d rit o na vir  
Mife prist o ne  
Nefaz o d o ne  
Nelfi na vir  
Nir matrel vir a n d rit o na vir  
P osac o naz ole  
Ri b ocicli b  
Rit o na vir  
Sa q ui na vir a n d rit o na vir  
Telit hr o m yci n  
Ti pra n a vir a n d rit o na vir  
T ucati ni b  
Vie kira x  ( parita pre vir a n d rit o na vir a n d o m bitas vir a n d/ or dasa b u vir a n d ri b a viri n ) 
V oric o naz ole  
 
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 7  
 
1 0. 8.  
A p pe n di x 8: C o u ntr y -s pecific Re q uire me nts  
1 0. 8. 1.  
Re m o v al of t he Le g all y A ut h orize d Re pres e nt ati ve, Le g al G u ar di a n, a n d 
P are nts i n Ger m a n y   
T his secti o n descri bes pr ot oc ol c ha n ges a p plica bl e f or a d ult partici pa nts i n st u d y sites i n 
Ger ma n y.  
T his ta ble descri bes t he c ha n ges a n d pr o vi d es a rati o nale f or t he c ha n ges.  
 
Pr ot oc ol Secti o n N u m ber a n d N a m e  
Descri pti o n of t he C h a n ge  
Brief R ati o n ale  
7. 2.  
Partici pa nt 
Disc o nti n uati o n/ Wit h dra w al 
fr o m t he St u d y 
 
8. 3.  
A d verse E ve nts, Seri o us A d verse 
E ve nts, a n d Pr o d uct C o m plai nts  
 
1 0. 1. 3.  I nf or me d C o nse nt Pr ocess 
 
1 0. 1 2. A p pe n di x 1 2: A b bre viati o ns a n d 
Defi niti o ns  
Delete d refere nces t o 
“le g all y a ut h orize d 
re prese ntati ve,” “le g al 
g uar dia n,” “ pare nts”  
T he Ger ma n Dr u g La w 
( Arz nei mittel gesetz –  A M G) re q uires 
per Para gra p h 4 0 ( 1 -3) a n d Para gra p h 
4 1 ( 3) t hat a d ult partici pa nts act o n 
t heir o w n be half a n d pr o vi de t heir o w n 
writte n i nf or me d c o nse nt. If writte n 
c o nse nt i s n ot p ossi ble, ver bal c o nse nt 
wit h a wit ness is acce pta ble. N o le gal 
re prese ntati ve c o nse nt is acce pte d. 
 
T he re vise d te xt i n t he f oll o wi n g secti o ns s h o w t he c ha n g es a p plica ble f or a d ult partici pa nts at 
st u d y sites i n Ger ma n y. Deleti o ns are i d e ntifie d b y stri ket hr o u g h f or mat. 
7. 2.  
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al  fr o m t he St u d y 
A partici pa nt will be disc o nti n ue d fr o m t he st u d y i n t he f oll o wi n g circ u msta nces:  
● at a n y ti me at t he partici p a nt’s o w n re q u est.  
● at t he re q uest of t h e parti ci pa nt’s desi g nee (f or e x a m ple, pare nts or l e gal 
g uar dia n).  
● at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral , c o m plia nce, or 
a d mi nistrati ve reas o ns.  
● partici pati o n i n t he st u d y nee ds t o be st o p pe d f or me dical, safet y, re g ulat or y, or 
ot her reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G C P.  
 
8. 3.  
A d verse E ve nts, Seri o us A d verse E ve nts, a n d Pr o d uct C o m pl ai nts  
T he defi niti o ns of t he f oll o wi n g e ve nts ca n be f o u n d i n S ecti o n 1 0. 3 , A p pe n di x 3: 
 A d verse e ve nts ( A Es)  
 Seri o us a d verse e ve nts ( S A Es)  
 Pr o d uct c o m plai nts ( P Cs)  
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C O N FI D E N TI A L  
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1 0 8  
A d verse  e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt's le gall y a ut h orize d re prese nt ati ve). 
 
1 0. 1. 3.  
I nf or me d C o nse nt Pr ocess 
● T he i n vesti gat or or t he i n vesti gat or’s re prese ntati v e will e x plai n t h e nat ure of t he 
st u d y, i ncl u di n g t he ris ks a n d be nefits, t o t he partici pa nt or t he partici pa nt’s 
le gall y a ut h orize d re pres e ntati ve, a n d a ns w er all q uesti o ns re gar di n g t he st u d y.  
● Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y. Partici pa nts or 
t heir le gall y a ut h orize d re prese nt ati ves will be re q uire d t o si g n a state me nt of 
i nf or me d c o nse nt t hat meets t he re q uire m e nts of 2 1 C F R 5 0, l ocal re g ulati o ns, 
I C H g ui deli nes, pri vac y a n d data pr otecti o n re q uire me nts, w here a p plica ble, a n d 
t he I R B/I E C or st u d y c e nter. 
● T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore t he partici pa nt was e ntere d i n t he st u d y a n d t he date t he writt e n 
c o nse nt was o btai ne d. T h e a ut h orize d p ers o n o btai ni n g t he i nf or me d c o nse nt m ust 
als o si g n t he I C F.  
● Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g 
t heir partici pati o n i n t he st u d y. 
● A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt o r t he partici pa nt’s 
le gall y a ut h orize d re pres e ntati ve a n d is ke pt o n fil e.  
 
1 0. 1 2.  
A p pe n di x 1 2: A b bre vi ati o ns a n d Defi niti o ns  
E nt er  
Partici pa nts e ntere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or t hr o u g h t heir le gall y acce pta ble re prese ntati ves.  
1 0. 8. 1. 1.  Re m o v al of M U G A sc a ns i n Ger m a n y   
T he re vise d te xt i n t he f oll o wi n g secti o ns s h o w t he c ha n g es a p plica ble f or a d ult partici pa nts at 
st u d y sites i n Ger ma n y. Deleti o ns are i d e ntifie d b y stri ket hr o u g h f or mat. 
 
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C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 0 9  
1. 3. Sc he d ule of Acti vities ( S o A)  
 
 
Scree ni n g  
O n Tre at m e nt a 
C ycle = 2 8 d a ys  
P ost -Tre at m e nt  
I nstr ucti o ns 
C ycles/ Da ys  
Da ys pri or  
t o  
Ra n d o mizati o n  
E ver y 
C ycle  
 
D a y 1  
C ycle 1 & 
C ycle 2  
 
D a y 1 5  
C ycle 3  
 
 
D a y 1 5  
S h ort -Ter m 
F oll o w -u p b  
V 8 0 1  
L o n g -Ter m 
F oll o w -u p  
V 8 0 2 –  8 X X 
( Q 9 0 Da ys) 
 
Inter val 
t olera n ce 
≤2 8  
≤1 4  
± 3  
± 3  
± 3  
± 7  
± 1 4  
C ycle 1 Da y 1 s h o ul d occ ur ≤7 da ys after ra n d o mizati o n.  
Ot her Cli nic al Assess m e nts  
Car diac E C H O 
or M U G A sca n  
X  
  
  
  
  
  
Re peat if cli nicall y i n dicate d.  
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C O N FI D E N TI A L  
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1 1 0  
1 0. 1 1. A p pe n di x 1 1: Pr o visi o ns f or C h a n ges i n St u d y C o n d uct D uri n g E xce pti o n al 
Circ u mst a nces  
Ot her alter n ati ve l o c ati o ns:    
I n e xce pti o nal circ u msta nces, i ma gi n g pr oce d ures re q uire d d uri n g s cree ni n g, o n-st u d y treat me nt, 
or f oll o w -u p ma y be p erf or me d at a n alter nate l ocati o n t ha n t he st u d y site or desi g nate d facilit y. 
I ma gi n g i ncl u d es:  C T or M RI sca n ( of c hest, a b d o me n, a n d pel vis), ra di o n ucli de b o ne sca n, 
M RI/ C T ( M RI preferre d) of t he brai n  (if cli nicall y i n dicate d), a n d E C H O/ M U G A sca ns. 
1 0. 8. 2.  
Disc o nti n u ati o n of St u d y Dr u g i n I n a d verte ntl y E nr olle d P artici p a nts i n C a n a d a   
If t he sp o ns or or in vesti g at or i de ntifies a partic i pa nt w h o di d n ot meet e nr oll me nt criteria a n d 
was i na d vert e ntl y e nr olle d, t he n t he partici pa nt s h o ul d be disc o nti n ue d fr o m st u d y treat me nt a n d 
safet y f oll o w-u p s h o ul d be perf or me d as o utli ne d i n Secti o n 1. 3  ( Sc he d ule of Acti vities), Secti o n 
8. 3  ( A d vers e E ve nts, Seri o us A d verse E ve nts, a n d Pr o d uct C o m plai nts), a n d Secti o n 8. 2  ( Safet y 
Assess me nts ) of t he pr ot oc ol. 
 
 
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C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 1 1  
1 0. 9.  
A p pe n di x 9: Pr ot oc ol J P E G R E CI S T Criteri a 1. 1  f or S oft Tiss ue  
Res p o nse E val uati o n Criteria i n S oli d T u m ors (R E CI S T ) versi o n 1. 1 criteri a will be use d t o 
assess res p o nse a n d pr o gressi o n of  s oft tiss ue dise ase  i n t his st u d y (Eise n ha uer et al. 2 0 0 9).  
Me as ur a bilit y of T u m or at B aseli ne  
T u m or lesi o ns/l y m p h n o des will be cate g orize d at baseli ne as me as ura ble or n o n meas ura ble. 
Meas ura ble dis ease is defi ne d b y t he pres e nce of at least 1 meas ura ble lesi o n.  
Me as ur a ble  
T u m or lesi o ns: Meas ure d i n at least 1 di me nsi o n (l o n gest dia meter i n t he pl a ne of meas ure me nt 
is t o be rec or de d) wit h a mi ni m u m size of: 
 1 0 m m b y c o m p ute d t o m o gra p h y ( C T) or m a g neti c res o na n ce i ma gi n g ( M RI) 
sca n (slice t hic k n ess 5 m m)  
 1 0 m m cali per meas ur e m e nt b y cli nical e xa m i nati o n ( n o n meas ura ble lesi o ns if 
ca n n ot be acc uratel y meas ure d wit h cali pers)  
 2 0 m m b y c hest X -ra y. 
Mali g na nt l y m p h n o des: T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l y m p h 
n o de m ust be 1 5 m m i n s h ort a xis w he n assess e d b y C T sca n ( C T sca n t hic k ness rec o m me n d e d 
t o be 5 m m).  
N o n me as ur a ble  
A ll ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h n o des 
wit h 1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y n o n meas ura ble l esi o ns. Lesi o ns c o nsi dere d tr ul y 
n o n meas ura ble i n cl u de: ascites, ple ural/ peri car dial eff usi o ns, l y m p ha n gitis c utis/ p ul m o nis, 
l y m p ha n gitis i n v ol ve me nt of s ki n or l u n g, a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d 
b y p h ysical e xa m i nati o n t hat is n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues. 
S peci al C o nsi der ati o ns f or Lesi o n Me as ur a bility  
B o ne lesi o ns:   
 L ytic b o ne lesi o ns or mi xe d l ytic -blastic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss -secti o nal i ma gi n g tec h ni q ues s uc h as 
C T or M RI, ca n be c o nsi dere d meas ura ble l esi o ns if t he s oft tiss ue c o m p o ne nt 
meets t he defi niti o n of meas ura bilit y.  
C ystic lesi o ns:   
 Si m ple c ysts s h o ul d n ot be c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble 
n or n o n meas ur a ble)  
 C ystic lesi o ns t h o u g ht t o re pres e nt c ystic metastas es ca n be c o nsi dere d as 
meas ura ble l esi o ns if t he y meet t he defi niti o n of meas ura bilit y. If n o nc ystic 
lesi o ns are prese nte d i n t he sa me patie nts, t hese are preferre d f or s electi o n as 
tar get lesi o ns. 
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1 1 2  
Lesi o ns wit h Pri or L ocal Treat me nt:  
 T u m or lesi o ns sit uate d at a pre vi o usl y irra di ate d area, or i n a n area s u bjecte d t o 
ot her l oc o -re gi o nal t hera p y, are n o n meas ura ble u nless t here has b ee n 
de m o nstrate d pr o gressi o n i n t he lesi o n.   
B aseli ne D oc u me nt ati o n of T ar get a n d N o n -T ar get Lesi o n  
T ar get Lesi o ns   
W he n m ore t ha n 1 m eas ura ble lesi o n is prese nt at ba seli ne, all lesi o ns u p t o a ma xi m u m of 5 
lesi o ns t otal (a n d a ma xi m u m of 2 lesi o ns per or ga n) re prese nt ati ve of all i n v ol ve d or ga ns s h o ul d 
be i de ntifie d as tar g et lesi o ns a n d will be rec or de d a n d meas ure d at baseli n e. N o n -n o dal tar get 
lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re pres e ntati ve of all i n v ol ve d or ga ns, a n d ca n be re pr o d uce d i n re peate d m eas ure m e nts. 
Meas ura ble l y m p h n o des are tar get lesi o ns if t he y meet t he criteri a of a s h ort a xis of 1 5 m m b y  
C T sca n. All meas ure m e nts are t o be rec or de d i n t he C R F i n milli meters ( or deci mal fracti o ns of 
ce nti meters [c m]).  
N o nt ar get Lesi o ns  
All ot her lesi o ns ( or sites of disease) are i d e ntifie d as n o ntar get lesi o ns  (c h ose n base d o n t heir 
re pres e ntati ve ness of in v ol ve d or ga ns a n d t he a bilit y t o be re pr o d uce d i n re peate d meas ure me nts) 
a n d s h o ul d be rec or de d at baseli ne. Meas ure me nt of t hese lesi o ns are n ot re q uire d b ut s h o ul d be 
f oll o we d as “prese nt, ” “a bse nt, ” or i n rare cases “u ne q ui v ocal pr o gressi o n. ” I n a d ditio n, it is 
p ossi ble t o rec or d m ulti ple n o ntar get lesi o ns i n v ol vi n g t he sa me or ga n as a si n gle ite m o n t he 
C R F (f or e x a m ple, m ulti ple li ver metastases rec or de d as 1 li ver lesi o n).  
L y m p h n o des wit h s h ort a xis 1 0 m m b ut < 1 5 m m s h o ul d be c o nsi dere d n o ntar get l esi o ns. 
N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n pat h ol o gical a n d are n ot rec or de d or 
f oll o we d. 
S pecific ati o ns b y Met h o ds of Me as ure me nt  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g a r uler or cali pers if cli nicall y 
assesse d. All baseli ne e v al uati o ns s h o ul d be perf or me d as cl osel y as p ossi ble t o t he be gi n ni n g of 
treat me nt a n d ne v er m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt. 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haract erize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p. I ma gi n g -bas e d e val uati o n is 
s h o ul d al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d 
ca n n ot be i ma ge d b ut are assesse d b y cli nical e xa m i nati o n.   
A n a de q uat e v ol u me of a s uita ble c o ntrast a ge nt s h o ul d be gi ve n s o t hat t he metastases are 
de m o nstrate d t o best effect a n d a c o nsiste nt met h o d is use d o n s u bse q ue nt e xa mi nati o ns f or a n y 
gi ve n patie nt. If pri or t o e nr oll me nt it is k n o w n a patie nt is n ot a bl e t o u n der g o C T sca ns wit h I V 
c o ntrast d ue t o aller g y or re nal i ns uffici e nc y, t he decisi o n as t o w het her a n o n -c o ntrast C T or 
M RI ( wit h or wit h o ut I V c o ntrast) s h o ul d be use d t o e val uate t he patie nt at baseli ne a n d f oll o w -
u p s h o ul d be g ui de d b y t he t u m or t y pe u n der i n vesti gati o n a n d t he a nat o mic l ocati o n of t he 
disease.  
Cli nic al Lesi o ns: Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w h e n t he y are s u p erfici al 
a n d 1 0 m m dia meter as assesse d usi n g cali pers (f or e xa m ple, s ki n n o d ules). F or t he case of s ki n 
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1 1 3  
lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n 
is rec o m me n de d. W he n l esi o ns ca n be e val uate d b y b ot h cli nical e xa mi nati o n a n d i ma gi n g, 
i ma gi n g e val uati o n s h o ul d be u n derta k e n si nce it is m ore o bjecti ve a n d m a y be re vie we d at t he 
e n d of t he st u d y.  
C hest X -r ay:  C hest C T is preferre d o v er c h est X-ra y w he n pr o gressi o n is a n i m p orta nt e n d p oi nt. 
Lesi o ns o n c hest X -ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y defi ne d a n d s urr o u n de d 
b y aerat e d l u n g.  
C T  a n d M RI :  C T sca n is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o ns e ass ess me nt. Meas ura bilit y of lesi o ns o n C T sca n is base d o n t he 
ass u m pti o n t hat C T slice t hic k ness is 5 m m. W he n C T sca n ha ve slice t hic k ne ss > 5 m m, t he 
mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k n ess. M RI is als o acce pta bl e 
i n certai n sit uati o ns (f or e xa m ple, f or b o d y s ca ns). If t here is c o ncer n a b o ut ra diati o n e x p os ure at 
C T, M RI ma y be us e d i nstea d of C T i n selecte d i nsta nces.   
Ultr as o u n d:   Ultras o u n d s h o ul d n ot be use d t o meas ure lesi o n size. Ultras o u n d e xa mi nati o ns 
ca n n ot be re pr o d uce d i n t heir e ntiret y f or i n de pe n d e nt re vie w at a later d ate a n d, beca use t he y are 
o perat or d e pe n de nt, it c a n n ot be g uara ntee d t hat t he sa me tec h ni q u e a n d m eas ure m e nts will be 
ta ke n fr o m o ne assess me nt t o t he ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse 
of t he st u d y, c o nfir mati o n b y C T or M RI is a d vise d.  
E n d osc o py, L a p ar osc o py : T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is 
n ot a d vise d. H o we v er, s u c h tec h ni q ues ca n be us ef ul t o c o nfir m c o m plete p at h ol o gical res p o nse 
w he n bi o psies are o btai ne d or t o deter mi ne rela ps e i n trials w here rec urre n ce f oll o wi n g c o m plete 
res p o nse or s ur gi cal r esecti o n is an e n d p oi nt.  
T u m or M arkers :  T u m or mar kers al o n e ca n n ot b e use d t o assess t u m or res p o nse. If mar kers are 
i nitiall y a b o ve t he u p per n or mal li mit, t he y m ust n or malize f or a patie nt t o be c o nsi dere d i n 
c o m plete res p o nse ( C R). S pecific g ui deli nes f or b ot h pr ost ate-s pecifi c a nti ge n ( P S A) res p o nse 
(i n rec urre nt pr ostat e ca n cer) a n d C A-1 2 5 res p o ns e (i n rec urre nt o varia n ca ncer) h a ve b ee n 
p u blis he d.  
Cyt ol o gy, Hist ol o gy :  T hese tec h ni q ues ca n b e use d t o differe ntiate bet wee n partial res p o nses 
( P R) a n d C R i n rare cases, if re q uire d b y pr ot oc ol (f or e x a m ple, resi d ual lesi o ns i n t u m or t y pes 
s uc h as ger m cell t u m ors, w here k n o w n resi d ual b e ni g n t u m ors ca n re m ai n). W he n eff usi o ns are 
k n o w n t o be a p ote ntial a d verse effect of treat me nt (f or e xa m ple, wit h cert ai n ta xa ne c o m p o u n ds 
or a n gi o ge nesis i n hi bit ors), t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n 
t hat a p pears or w ors e ns d uri n g treat me nt ca n be c o nsi dere d if t he meas ura bl e t u m or has met 
criteria f or res p o ns e or st a ble disease ( S D) i n or der t o dif fere ntiate bet wee n res p o nse ( or S D) a n d 
pr o gressi ve dise ase.  
Pet Sc a n ( F D G -P E T, P E T C T):   P E T is n ot rec o m me n de d f or lesi o n ass ess me nt. If a ne w lesi o n 
is f o u n d b y P E T, a n ot her assess me nt m ust be d o ne b y C T, u nless t he P E T C T is of dia g n ostic 
q ualit y. If C T is d o ne t o c o nfir m t he res ults of t he earlier P E T sca n, t he dat e of pr o gressi o n m ust 
be re p ort e d as t he earlier date of t he P E T sca n.  
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Res p o nse Criteri a  
Ev al u ati o n of T ar get Lesi o ns  
C o m plete Res p o nse:   Disa p peara nce of all tar g et lesi o ns. A n y pat h ol o gica l l y m p h n o des 
( w het her t ar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. T u m or mar ker 
res ults m ust ha ve n or malize d. 
P arti al Res p o nse:   At least a 3 0 % decreas e i n t he s u m of dia meter of tar get lesi o ns, ta ki n g as 
refere nce t he bas eli ne s u m dia meters. 
Pr o gressive Dise ase:   At least a 2 0 % i ncreas e i n t he s u m of t he dia meters of tar get lesi o ns, 
ta ki n g as refere n ce t he s mallest s u m o n st u d y (i ncl u di n g t he baseli ne s u m if t hat is t he s mallest). 
I n a d diti o n t o t he relati ve i ncreas e of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs olute i ncrease 
of at least 5 m m.  T he a p p eara n ce of 1 or m ore n e w lesi o ns is als o c o nsi dere d pr o gressi o n.  
F or e q ui v o cal fi n di n gs of pr o gressi o n (f or e xa m pl e, ver y s mall a n d u n certai n ne w lesi o ns, c ystic 
c ha n ges, or n ecr osis i n e xisti n g lesi o ns), treat me nt ma y  c o nti n ue u ntil t he ne xt sc he d ule d 
assess me nt. If at t he n e xt sc he d ule d ass ess me nt, pr o gressi o n is c o nfir me d, t he date of 
pr o gressi o n s h o ul d be t h e earlier date w he n pr o gressi o n was s us pecte d.  
St a ble Dise ase:   N eit her s ufficie nt s hri n ka ge t o q u alif y f or P R  n or s ufficie nt i ncrease t o q u alif y 
f or P D, ta ki n g as refere n ce t he s mallest s u m dia meters w hile o n st u d y. 
N ot Ev al u a ble:  W he n a n i nc o m plete ra di ol o gic assess me nt of tar get lesi o ns is perf or me d or 
t here is a c h a n ge i n t he m et h o d of meas ure me nt fr o m baseline t hat i m pacts t he a bilit y t o ma ke a 
relia ble e v al uati o n of res p o nse. 
Ev al u ati o n of N o nt ar get Lesi o ns  
C o m plete Res p o nse:   Disa p peara nce of all n o ntar g et lesi o ns a n d n or malizati o n of t u m or mar ker 
le vel. All l y m p h n o des m ust be n o n-pat h ol o gical or n or mal i n  size ( < 1 0 m m s h ort a xis). 
N o n -C R/ n o n -P D:   Persiste nce of 1 or m ore n o ntar get lesi o ns a n d/ or mai nte na nce of t u m or 
mar ker le v el a b o ve t he n or mal li mits.  
Pr o gressive Dise ase:  U ne q ui v ocal pr o gressi o n of e xisti n g n o ntar get lesi o ns. T he a p peara n ce of 
1 or m ore  ne w l esi o ns is als o c o nsi dere d pr o gressi o n.  
N ot Ev al u a ble :  W he n a c ha n ge i n met h o d of meas ure me nt fr o m bas eli ne o cc urs a n d i m pacts t he 
a bilit y t o ma ke a relia ble e val uati o n of res p o nse . 
E v al u ati o n of Best O ver all Res p o nse  
T he best o verall res p o nse is t he  best res p o nse rec or de d fr o m t he start of t he st u d y i nter ve nti o n 
u ntil t he earliest of o bjecti ve pr o gressi o n or start of ne w a ntica ncer t hera p y, ta ki n g i nt o acc o u nt 
a n y re q uir e me nt f or c o nfir mati o n. T he patie nt’s b est o verall res p o ns e assi g n me nt will de pe n d o n 
t he fi n di n gs of b ot h tar get a n d n o ntar get diseas e a n d will als o ta ke i nt o c o nsi derati o n t he 
a p peara nce of ne w lesi o ns. T he Best O verall Res p o nse will be calc ulat e d via a n al g orit h m usi n g 
t he assess me nt res p o ns es pr o vi de d b y t he i n vesti gat or o ver t he co urse of t he trial.  
Ti me P oi nt Res p o nse  
It is ass u me d t hat at eac h pr ot oc ol-s pecifi e d ti me p oi nt, a res p o nse ass ess me nt occ urs. W he n n o 
i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he patie nt is n ot e val ua ble ( N E) at 
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t hat ti me p oi nt. T he ta ble i m me diatel y bel o w pr o vi des a s u m mar y of t he o v erall res p o ns e stat us 
calc ulati o n at e ac h ti me p oi nt f or patie nts w h o ha v e me as ur a ble dise ase  at baseli ne.  
Ti m e P oi nt Res p o nse:  P atie nts wit h T ar get ( N o nt ar get) Dise ase  
T ar g et Lesi o ns  
N o n -T ar g et Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D or n ot all e val uate d  
N o  
P R  
S D  
N o n -P D or n ot all e val uate d  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
A b bre viati o ns:  C R = c o m plete res p o nse; P R = partial res p o nse; S D = sta ble disease; P D = pr o gressi ve disease; 
N E  =  n ot e v al ua ble. 
 
T he ta ble bel o w  is t o be use d w he n patie nts ha v e n o n meas ura ble disease o nl y. 
Ti m e P oi nt Res p o nse:  P atie nts wit h N o nt ar get Dise ase O nl y  
N o nt a r g et Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
N o  
C R  
N o n -C R/ n o n -P D  
N o  
N o n -C R/ n o n -P D a 
N ot all e val uate d  
N o  
N E  
U ne q ui v ocal P D  
Yes or N o  
P D  
A n y  
Yes  
P D  
A b bre viati o ns:  C R = c o m plete res p o nse; N E = n o t e val ua ble; P D = pr o gressi ve disease.  
a n o n -C R/ n o n -P D is preferre d o ver sta ble disease f or n o ntar get disease.  
 
Fre q ue nc y of T u m or Re -E v al u ati o n  
A baseli ne t u m or e v al uati o n m ust be perf or me d wit hi n 4 wee ks bef ore pati e nt be gi ns st u d y 
i nter ve nti o n. Fre q ue nc y of t u m or re-e val uati o n w hile o n a n d a da pte d t o tr eat me nt s h o ul d be 
pr ot oc ol -s pecifi c a n d a d a pte d t o t he t y pe a n d sc he d ule of treat me nt. I n t h e c o nte xt of P hase 2 
st u dies i n w hic h t he be neficial effect t hera p y is n ot k n o w n, f oll o w-u p e ver y 6 t o 8 wee ks is 
reas o na bl e. N or mall y, all tar get a n d n o ntar get sites are e v al uate d at eac h assess me nt usi n g t he 
sa me met h o d. H o we v er, b o ne sca ns ma y n ee d t o be re peate d o nl y w hen C R is i de ntifie d i n tar get 
disease or w h e n pr o gressi o n i n b o ne is s us pecte d.  
C o nfir m at or y Me as ure me nt/ D ur ati o n of Res p o nse  
C o nfir m ati o n  
T he mai n g oal of c o nfir mati o n of o bje cti ve res p o nse i n cli nical trials is t o a v oi d o veresti mati n g 
t he res p o nse rate o bser ve d. T he c o nfir mati o n of res p o nse is partic ularl y i m p orta nt i n 
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n o nr a n d o mize d tri als  i n w hic h res p o nse ( C R/ P R) is t he pri mar y e n d p oi nt. I n t his setti n g, t o be 
assi g ne d a stat us of P R/ C R, c ha n ges i n t u m or meas ure me nts m ust be c o nfir me d  b y re peat 
assess me nts t hat s h o ul d be perf or me d n o less t ha n 4 wee ks after t he criteri a f or res p o nse are first 
met . T o c o nfir m a res p o nse of C R, a f ull assess me nt of all tar get a n d n o ntar get lesi o ns t hat were 
prese nt at bas eli ne m ust occ ur, i ncl u di n g t h ose m eas ure d b y b o n e sc a n. T o c o nfir m a P R or S D, a 
f ull assess me nt of tar get l esi o ns t hat were prese nt at baseli ne m ust occ ur; assess me nt of 
n o ntar gets is n ot re q uire d.  
H o we ver, i n r a n d o mize d tri als ( P hase 2 or 3) or st u dies i n w hic h S D or pr o gressi o n is t he 
pri mar y e n d p oi nt, c o nfir mati o n of res p o nse is n ot re q uire d. H o we ver, eli mi nati o n of t he 
re q uire me nt ma y i n creas e t he i m p orta nce of ce ntr al re vie w t o pr ot ect a gai nst bias, i n partic ular 
of st u dies t hat are n ot bli n de d.  
I n t he cas e of S D, f oll o w-u p meas ure m e nts m ust ha ve met t he S D criteria at least o nce after start 
of st u d y i nter ve nti o n at a mi ni m u m i nter val n ot less t ha n 6 wee ks meas ure d fr o m first d ose.  
D ur ati o n of Over all Res p o nse  
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R or P R ( w hic he ver is first rec or de d) u ntil t he first date t hat disease is rec urre nt or o bjecti ve 
pr o gressi o n is o bser ve d (ta ki n g as refere n ce f or P D t he s mallest meas ure m e nts rec or de d o n 
st u d y). 
T he d urati o n of o verall C R is meas ure d fr o m t he ti me me as ure m e nt criteria are first met f or C R 
u ntil t he first date t hat rec urre nt disease is o bjecti vel y d oc u me nte d.  
D ur ati o n of St a ble Dise ase  
Sta ble disease is meas ur e d fr o m t he start of t he tr eat me nt (i n ra n d o mize d tri als, fr o m date of 
ra n d o mizati o n) u ntil t he criteria f or o bjecti ve pr o gressi o n are m et, ta ki n g as refere n ce t he 
s mallest s u m o n st u d y (if t he baseli ne s u m is t he s mallest, t hat is t he refere nce f or calc ul ati o n of 
P D).  
I n de pe n de nt Re vie w of Res p o nse a n d Pr o gressi o n 
W he n o bjecti ve res p o nse ( C R + P R) is t he pri mar y e n d p oi nt, a n d w he n ke y dr u g de vel o p me nt 
decisi o ns are b ase d o n t h e o bser vati o n of a mi ni m u m n u m ber of res p o n d ers, it is rec o m me n de d 
t hat all clai me d res p o nses be re vie we d b y a n e x pert(s) i n de pe n d e nt of t he st u d y. If t h e st u d y is a 
ran d o mize d trial, i deall y re vie wers s h o ul d be bli n de d t o treat me nt assi g n m e nt.  
 
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1 0. 1 0.  
A p pe n di x 1 0 : Pr ot oc ol J P E G C T C A E 5. 0 Di arr he a/ P ne u m o nitis/ A L T a n d A S T I ncre ase d 
Defi niti o ns   
Diarr hea/ P ne u m o nitis/ A L T a n d A S T i ncrease d will be e val uate d i n t his st u d y usi n g t he criteria pr o p ose d b y C T C A E v 5. 0 re vise d:  
Gastr oi ntesti nal dis or ders, Res pirat or y, T h oracic, a n d Me diasti nal Dis or ders, a n d I n vesti gati o ns.  
Gr a de  
A d verse E ve nt  
1  
2  
3  
4  
5  
G astr oi ntesti n al Dis or ders  
Di arr he a  
I ncrease of < 4 st o ols 
per da y o ver baseli ne; 
mil d i ncrease i n 
ost o m y o ut p ut 
c o m pare d t o baseli ne  
I ncrease of 4 t o 
6  st o ols per da y o ver 
baseli ne; m o derate 
i ncrease i n ost o m y 
o ut p ut c o m pare d t o 
baseli ne; li miti n g 
i nstr u me ntal A D L 
I ncrease of ≥7 st o ols per 
da y o ver baseli ne; 
h os pitalizati o n i n dicate d; 
se vere i ncrease i n ost o m y 
o ut p ut c o m pare d t o 
baseli ne; li miti n g self -care 
A D L  
Life -t hreate ni n g 
c o nse q ue n ces; ur ge nt 
i nter ve nti o n i n dicate d 
Deat h  
Defi niti o n:  a dis or der c h aracterize d b y a n i ncrease i n fre q ue nc y a n d/ or l o ose water y b o wel m o ve me nts.  
Res pir at or y, T h or acic, a n d Me di asti n al Dis or ders  
P ne u m o nitis  
As y m pt o matic; 
cli nical or dia g n ostic 
o bser vati o ns o nl y; 
i nter ve nti o n n ot 
i n dicate d 
S y m pt o matic; me dical 
i nter ve nti o n i n dicate d; 
li miti n g i nstr u me ntal 
A D L  
Se vere s y m pt o ms; li miti n g 
self-care A D L; o x y ge n 
i n dicate d 
Life -t hreate ni n g 
res pirat or y c o m pr o mise; 
ur ge nt i nter ve nti o n 
i n dicate d (f or e x a m ple, 
trac he ot o m y or 
i nt u bati o n) 
Deat h  
Defi niti o n:  a dis or der c h aracterize d b y i nfla m mati o n f ocall y or diff usel y affecti n g t he l u n g pare nc h y ma.  
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I n vesti g ati o ns 
Al a ni ne 
a mi n otr a nsfer ase 
( A L T) i ncre ase d  
> U L N t hr o u g h 3. 0 x 
U L N if baseli ne was 
n or mal; 1. 5 t hr o u g h 
3. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 3. 0 t hr o u g h 5. 0 x 
U L N if baseli ne was 
n or mal; > 3. 0 t hr o u g h 
5. 0 x baseli ne if 
baseli ne was a b n or mal  
> 5. 0 t hr o u g h 2 0. 0 x U L N if 
baseli ne was n or mal; > 5. 0 
t hr o u g h 2 0. 0 x baseli ne if 
baseli ne was a b n or mal  
> 2 0. 0 x U L N if basel i ne 
was n or mal; > 2 0. 0 x 
baseli ne if baseli ne was 
a b n or mal 
Deat h  
Defi niti o n:  a fi n di n g base d o n la b orat or y test res ults t hat i n dicate a n i ncrease i n t he le vel of ala ni ne a mi n otra nsferase ( A L T or S G P T) i n t he 
bl o o d s peci me n.  
As p art ate 
a mi n otr a nsfer ase 
( A S T) i ncre ase d 
> U L N t hr o u g h 3. 0 x 
U L N if baseli ne was 
n or mal; 1. 5 t hr o u g h 
3. 0 x baseli ne if 
baseli ne was 
a b n or mal 
> 3. 0 t hr o u g h 5. 0 x 
U L N if baseli ne was 
n or mal; > 3. 0 t hr o u g h 
5. 0 x baseli ne if 
baseli ne was a b n or mal  
> 5. 0 t hr o u g h 2 0. 0 x U L N if 
baseli ne was n or mal; > 5. 0 
t hr o u g h 2 0. 0 x baseli ne if 
baseli ne was a b n or mal  
> 2 0. 0 x U L N if baseli ne 
was n or mal; > 2 0. 0 x 
baseli ne if baseli ne was 
a b n or mal 
Deat h  
Defi niti o n:  a fi n di n g base d o n la b orat or y test res ults t hat i n dicate a n i ncrease i n t he le vel of as partate a mi n otra nsferase ( A S T or S G O T) i n a 
bl o o d s peci me n.  
A b bre viati o n s:  A D L = acti vities of dail y li vi n g; S G O T = ser u m gl uta mic-o xal oacetic tra nsa mi nase; S G P T = ser u m gl uta mic -p yr u vic tra nsa mi nase; 
U L N  =  u p per li mit of n or mal.  
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1 0. 1 1.  
A p pe n di x 1 1 : Pr o visi o ns f or C h a n ges i n St u d y C o n d uct D uri n g 
E xce pti o n al Circ u mst a nces   
I m ple me nt ati o n of t his A p pe n di x 
T he c ha n g es t o pr oce d ures descri be d i n t his a p p e n di x are te m p orar y meas ures i nte n de d t o be 
use d o nl y d uri n g s pecific ti me peri o ds as direct e d b y t he s p o ns or i n c o ns ultati o n wit h t he 
i n vesti gat or. 
E xce pti o n al Circ u mst a nces  
E xce pti o nal circ u msta n ce s are rare e v e nts  t hat ma y ca use disr u pti o ns t o t he c o n d uct of t he st u d y. 
E xa m ples i ncl u de pa n d e mics or nat ural disasters. T hese disr u pti o ns ma y li mit t he a bilit y of t he 
i n vesti gat ors, partici pa nts, or b ot h t o atte n d o n-site visits or t o c o n d uct pla n ne d st u d y pr oce d ures. 
Im ple me nti n g C h a n ges u n der E xce pti o n al Circ u mst a nces  
I n a n e xce pti o nal circ u msta nce, after recei vi n g t he s p o ns or’s writte n a p pr o val, sites ma y 
i m ple me nt c ha n ges if per mitte d b y l ocal re g ulati o ns.  
A d diti o nal n otificati o n t o t hese gr o u ps will n ot t y picall y b e re q uir e d u nless t he y ha ve s pecific 
c o n diti o ns i n w hic h n otificati o n is re q uire d. T o pr otect t he safet y of st u d y partici pa nts, ur ge nt 
c ha n ges ma y b e i m ple me nte d bef ore a p pr o val b ut nee d t o be re p orte d as s o o n as p ossi ble. All 
a p pr o vals m ust be ret ai ne d i n  t he st u d y rec or ds. 
If t he s p o ns or gra nts writte n a p pr o val f or c ha n g es i n st u d y c o n d uct, t he s p o ns or will als o pr o vi de 
a d diti o nal writte n g ui da nce, if nee de d.  
C o nsi der ati o ns f or M a ki n g a C h a n ge  
T he pre v aili n g c o nsi derati o n f or ma ki n g a c h a n ge is e ns uri n g t he safet y of st u d y partici pa nts. 
A d diti o nal i m p orta nt c o nsi derati o ns f or ma ki n g s u c h c ha n g es are c o m plia nce wit h G C P, 
e na bli n g partici pa nts t o c o nti n ue safel y i n t he st u d y, a n d mai ntai ni n g t he i nte grit y of t he st u d y.  
I nf or me d C o nse nt 
A d diti o nal c o nse nt fr o m t he partici pa nt will be o btai ne d, if re q uir e d, f or:  
 partici pati o n i n re m ote visits, as defi ne d bel o w i n Secti o n 1, Re m ote visits  
 alter nate d eli ver y of st u d y i nter ve nti o n a n d a ncillar y s u p plies, a n d  
 pr o visi o n of t heir pers o nal or me dical i nf or m ati o n re q u ire d pri or t o 
i m ple me ntati o n of t hese acti vities.  
C h a n ges i n St u d y C o n d uct D uri n g E xce pti o n al Circ u mst a nces  
C ha n ges i n st u d y c o n d uct n ot descri be d i n t his a p pe n di x, or n ot c o nsiste nt wit h a p plica ble l ocal 
re g ulati o ns, are n ot all o we d. 
T he f oll o wi n g c ha n g e s i n st u d y c o n d uct (f or e xa m ple, tele me dici ne vers us o n-site) will n ot be 
c o nsi dere d pr ot oc ol de vi ati o ns.  
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1.  Re m ote visits  
I n e xce pti o nal circ u msta nces, st u d y visits ma y be d o ne re m otel y usi n g tele me dici ne. I n 
s o urce d oc u m e nts a n d t he C R F, t he st u d y site m ust ca pt ure t he visit met h o d, wit h a s pecific 
e x pla nati o n f or a n y data missi n g a n d d oc u me nt as pr ot oc ol vi olati o ns, w he n a p plica ble.   
Tele me dici ne:  
Tele me dici ne visits usi n g i nteracti ve tec h n ol o g y -assista nce (t hat is, at a mi ni m u m vi de o 
a n d/ or a u di o tec h n ol o g y) ma y be perf or me d b y a n i n vesti gat or i n lie u of o n -site visits t o 
c o m plete re q uir e d st u d y assess me nts as o utli ne d i n Secti o n 1. 3 . 
St u d y pr oce d ures  t hat ma y be perf or me d b y a n i n v esti gat or usi n g tele me dici ne i ncl u de t he 
f oll o wi n g: 
 I nf or me d c o ns e nt 
 I n cl usi o n/e xcl usi o n assess me nts; me dical hist or y 
 Tele healt h p h ysical e xa mi nati o n (if all o we d b y l ocal re g ulati o n)  
 A E assess me nts; re vie w a n d u p date o n c o n c o mita nt me dicati o ns  
 E C O G perf or ma nce stat us  
 E val uati o n of s y m pt o matic pr o gressi o n  
 P R O assess me nts; re vie w of patie nt diar y; dr u g c o m plia nce e val uati o ns f or all st u d y 
i nter ve nti o n 
 S ur vi val stat us; p ost -disc o nti n uati o n a ntica ncer t h era pies.  
Ot her alter n ati ve l o c ati o ns:    
I n e xce pti o nal circ u msta nces, i ma gi n g pr oce d ures re q uire d d uri n g s cree ni n g, o n-st u d y 
treat me nt, or f oll o w-u p ma y be perf or me d at a n alter nate l oc ati o n t ha n t he st u d y site or 
desi g nate d facilit y. I ma gi n g i ncl u des:  C T or M RI sca n ( of c hest, a b d o me n, a n d pel vis), 
ra di o n ucli de b o ne s ca n, M RI/ C T ( M RI preferre d) of t he brai n (if cli nicall y i n dicate d), a n d 
E C H O/ M U G A sca ns. See Secti o n 1. 3  f or det ails. 
T he pr ot oc ol re q uire me nts re gar di n g t he re p orti n g of A Es, S A Es, a n d pr o d u ct c o m plai nts 
re mai n u nc ha n g e d. F urt h er m ore, e ver y eff ort s h o ul d be ma de t o e na bl e partici pa nts t o ret ur n 
t o o n-site visits as s o o n as reas o na bl y p ossi ble, w hile e ns uri n g t he safet y of b ot h t he 
partici pa nt a n d t he site st aff.  
2.  L oc al l a b or at or y testi n g o pti o n  
L ocal la b orat or y testi n g ma y be c o n d uct e d i n lie u of ce ntr al la b orat or y t esti n g. T he l ocal 
la b orat or y m ust be q ualifie d i n acc or da nce wit h a p plica ble l ocal r e g ulati o ns. 
3.  St u d y i nter ve nti o n a n d a ncill ar y s u p plies (i ncl u di n g p artici p a nt di aries)  
W he n a  p artici pa nt is u na ble t o g o t o t he site t o recei ve st u d y i nter ve nti o n or st u d y t o ols (f or 
e xa m ple, partici p a nt diaries) d uri n g re g ularl y sc he d ule d o n -site visits, t he site s h o ul d w or k 
wit h t he s p o ns or t o deter mi ne a p pr o priate acti o ns. T hese acti o ns ma y i ncl u de:   
o  as ki n g t he partici pa nt’s care gi ver or desi g ne e t o g o t o t he site a n d recei ve st u d y 
i nter ve nti o n or st u d y t o ols o n a partici pa nt’s b e half, or  
o  arra n gi n g d eli ver y of st u d y i nter ve nti o n a n d/ or st u d y s u p plies.  
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T hese re q uire me nts m ust be met a n d d oc u me nt e d i n t he partici pa nt’s me dical rec or ds bef ore 
acti o n is ta ke n:  
 Alter nate deli ver y of st u d y i nter ve nti o n s h o ul d be perf or me d i n a ma n ner t hat d oes 
n ot c o m pr o mise i nter ve nti o n bli n di n g a n d e ns ures pr o d uct i nte grit y. T he e xisti n g 
pr ot oc ol re q uire m e nts f or pr o d uct acc o u nta bilit y re mai n u nc ha n g e d, i ncl u di n g 
verificati o n of p artici pa nt’s recei pt of st u d y i nter ve nti o n.  
 W he n deli veri n g st u d y i nter ve nti o n t o a l ocati o n ot her t ha n t he st u d y site (f or 
e xa m ple, partici p a nt’s h o me), t he i n vesti gat or or d esi g nate d site staff s h o ul d f oll o w 
l ocal re g ulati o n a n d e ns ure o versi g ht of t he s hi p pi n g pr ocess t o e ns ure acc o u nta bilit y 
a n d pr o d uct q ualit y (t hat is, st ora ge c o n diti o ns mai ntai ne d a n d i ntact pac ka gi n g u p o n 
recei pt). 
 I nstr u cti o ns s h o ul d be pr o vi de d t o t he partici pa nt or care gi ver o n t he fi nal dis p ositi o n 
of a n y u n use d st u d y i nter ve nti o n, e m pt y pr o d uct b ottles, or c o m plete d patie nt diaries . 
4.  Scree ni n g peri o d g ui d a nce  
T o e ns ure safet y of st u d y partici pa nts, la b orat or y val ues a n d ot her eli gi bilit y assess me nts 
c o m plete d d uri n g scree ni n g are re q uire d as o utli ne d i n t he pr ot oc ol.   
I n e xce pti o nal circ u msta nces, C ycle 1 Da y 1 visit m ust occ ur wit hi n 3 5 da ys fr o m date of 
si g ne d i nf or me d c o nse nt a n d will n ot c o nstit ute as a pr ot oc ol vi olati o n. A n y scree ni n g 
pr oce d ures t hat fall o utsi de of t he re q uire d wi n d o ws per t he S o A  ( Secti o n 1. 3 ) m ust be 
re peat e d. See Secti o n 5. 4  f or a d diti o nal details o n scree n fail ures. 
Partici pa nts w h o are u n a ble t o c o m plete scree ni n g wit hi n t he 3 5 -da y wi n d o w a n d are n ot a ble 
t o re peat scree ni n g pr oce d ures will be d oc u me nte d i n C R F as a scree n fail ure d ue t o 
e xce pti o nal circ u msta nces.  
5.  A dj ust me nts t o visit wi n d o ws  
W he ne v er p ossi ble a n d s afe t o d o s o, as d eter mi ne d b y t he i n vesti gat or’s discreti o n, 
partici pa nts s h o ul d c o m plete t he us ual S o A  o utli ne d i n Secti o n 1. 3 . T o ma xi mize t he 
p ossi b ilit y t hat t hese visits ca n be c o n d ucte d as o n-site visits, t he wi n d o ws f or visits ma y be 
a dj uste d, u p o n f urt her g ui da nce fr o m t he s p o ns or. T his mi ni mizes missi n g data a n d preser ves 
t he i nte n de d c o n d uct of t he st u d y. 
T his ta ble descri bes t he all o we d a dj ust me nts t o visit wi n d o ws.  
Visit N u m ber  T oler a nce  
Da y 1 of all 
c ycles  
T he relati ve da y wit hi n d osi n g c ycle a n d visit wi n d o w ma y 
be a dj uste d t o ± 5 da ys.  
All ot her 
treat me nt 
visits  
F oll o w S o A  ( Secti o n 1. 3 ).  
 
F or partici pa nts w h ose visits ha ve e xte n de d wi n d o ws, a d diti o nal st u d y i nter ve nti o n ma y nee d 
t o be pr o vi de d t o a v oi d i nterr u pti o n a n d mai ntai n o verall i nte grit y of t he st u d y.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 2  
D oc u me nt ati o n  
C ha n ges t o st u d y c o n d uct will be d oc u me nte d:  
 Sites will d oc u me nt al l re m ote visits i n t he st u d y files a n d C R F ( w here 
a p plica ble) i ncl u di n g tele me dici ne, l ocal i ma gi n g a n d pr oce d ures, st u d y 
i nter ve nti o n, or scree ni n g peri o d g ui da nce. D oc u me ntati o n s h o ul d i ncl u de details 
of w hic h partici p a nts, visits t y pe, a n d st u d y pr oce d u res were affecte d b y 
e xce pti o nal circ u msta nces.  
 Dis pe nsi n g/s hi p me nt rec or ds of st u d y i nter ve nti o n a n d rele va nt c o m m u nicati o ns, 
i ncl u di n g dele gati o n, s h o ul d be file d wit h site st u d y rec or ds. 
S o urce d oc u me nts ge n erate d d uri n g a tele m e dici n e visit s h o ul d be p art of t he i n vesti gat or’s 
s o urce d oc u m e ntati o n.  
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 3  
1 0. 1 2.  
A p pe n di x 1 2 : A b bre vi ati o ns a n d Defi niti o ns   
T er m  
D efi niti o n  
a b u s e  
Use of a st u d y i nter ve nti o n f or recreati o nal p ur p oses or t o mai ntai n a n a d dicti o n or 
de p e n de nce . 
A D R  
a d verse dr u g reacti o n  
A D T  
a n dr o ge n de pri vati o n t hera p y  
A E  
a d verse e ve nt 
AI  
ar o matase i n hi bit or  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A Q A  
A nal gesic Q ua ntificati o n Al g orit h m  
A R  
a n dr o ge n rece pt or 
A S C O  
A merica n S ociet y of Cli nical O nc ol o g y  
A S T  
as partate a mi n otra nsferase  
A T P  
a d e n osi ne tri p h os p hate  
A U C  
area u n der t he c o nce ntrati o n -vers us -ti me c urve  
a ut h ori z e d A x M P  
A p plic a ble t o t he E U o nly : a me dici nal pr o d uct a ut h orize d i n acc or da nce wit h 
Re g ulati o n ( E C) N o 7 2 6/ 2 0 0 4, or i n a n y Me m ber State c o ncer ne d i n acc or da nce wit h 
Directi ve 2 0 0 1/ 8 3/ E C, irres pecti ve of c ha n ges t o t he la beli n g of t he me dici nal pr o d uct, 
w hic h is use d as a n a u xiliar y me dici nal pr o d uct . 
a ut h ori z e d I M P  
A p plic a ble t o t he E U o nly : a me dici nal pr o d uct a ut h orize d i n acc or da nce wit h 
Re g ulati o n ( E C) N o 7 2 6/ 2 0 0 4 or i n a n y Me m ber State c o ncer ne d i n acc or da nce wit h 
Directi ve 2 0 0 1/ 8 3/ E C, irres pecti ve of c ha n ges t o t he la beli n g of t he me dici nal pr o d uct, 
w hic h is us e d as a n i n vesti gati o nal me dici nal pr o d uct . 
A x M P  
a u xiliar y me dici nal pr o d uct. See als o NI M P.  
A me dici nal pr o d uct use d f or t he nee ds of a cli nical trial as descri be d i n t he pr ot oc ol, 
b ut n ot as a n i n vesti gati o nal me dici nal pr o d uct. E xa m ples i ncl u de resc ue me dicati o n, 
c h alle n ge a g e nts, a ge nts t o assess e n d p oi nts i n t he cli nical trial, or bac k gr o u n d 
treat me nt. A x M P d oes n ot i ncl u de i n vesti gati o nal me dici nal pr o d uct (I M P) or 
c o nc o mita nt me dicati o ns. C o nc o mita nt me dicati o ns are me dicati o ns u nrelate d t o t he 
cli nical trial a n d n ot rele v a nt f or t he desi g n of t he cli nical trial . 
BI C R  
bli n de d i n de pe n de nt -ce ntral re vie w  
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T
C CI

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 4  
bli n di n g  
A si n gle -bli n d st u d y is o ne i n w hic h t he i n vesti gat or a n d/ or t he i n vesti gat or’s staff are 
a ware of t he treat me nt b u t t he partici pa nt is n ot, or vice versa, or w he n t he s p o ns or is 
a ware of t he treat me nt b ut t he i n vesti gat or a n d/ t he i n vesti gat or’s staff a n d t he 
partici pa nt are n ot.  
A d o u ble -bli n d st u d y is o ne i n w hic h neit her t he partici pa nt n or a n y of t he i n vesti gat or 
o r s p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he s u bjects 
are a ware of t he treat me nt recei ve d.  
B P  
bl o o d press ure  
B PI -S F  
Brief Pai n I n ve nt or y -S h ort F or m  
C D K  
c y cli n de p e n de nt ki nase  
C D K 4  & 6  
c y cli n de p e n de nt ki nase 4 a n d 6  
C F R  
c o de of fe deral re g ulati o ns  
CI  
c o nfi de n ce i nter val  
C K  
creati ne ki nase  
C N S  
ce ntral ner v o us s yste m  
C o m p a ni o n di a g n o sti c  A n i n vitr o dia g n ostic de vice (assa y or test) t hat pr o vi des i nf or mati o n t hat is esse ntial 
f or t he safe a n d effecti ve use of a c orres p o n di n g t hera pe utic pr o d uct . 
C o m pl ai nt  
A c o m plai nt is a n y writte n, electr o nic, or oral c o m m u nicati o n t hat alle ges deficie n cies 
relate d t o t he i de ntit y, q ualit y, p urit y, d ura bilit y, relia bilit y, safet y or effecti ve ness, or 
perf or ma n ce of a dr u g or dr u g deli ver y s yste m.  
c o m pli a n c e  
A d here n ce t o all st u d y -relate d, g o o d cli nical practice ( G C P), a n d a p plica ble re g ulat or y 
re q uire me nts. 
C R  
c o m plete res p o nse  
C R F  
case re p ort f or m; a pri nte d, o ptical, or electr o nic d oc u me nt desi g ne d t o rec or d all of t he 
pr ot oc ol -re q uire d i nf or mati o n t o be re p orte d t o t he s p o ns or f or eac h trial partici pa nt. 
C R P / C R S 
cli nical researc h p h ysicia n /cli nical researc h scie ntist :  I n di vi d ual res p o nsi ble f or t he 
me dical c o n d uct of t he st u d y. Res p o nsi bilities of t he C R P / C R S ma y be p erf or me d b y a 
p h ysicia n,  cli nical researc h scie ntist, gl o bal safet y p h ysicia n or ot her me dical officer.  
C R P C  
castrati o n -resista nt pr ostate ca ncer 
C S R  
cli nical st u d y re p ort  
C T  
c o m p ute d t o m o gr a p h y 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C Y C L O N E 1  
St u d y I 3 Y -M C -J P C Y 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 5  
C Y C L O N E 2  
St u d y I 3 Y -M C -J P C M 
C Y C L O N E 3  
St u d y I 3 Y-M C -J P E G 
D 1  
a pr otei n t hat hel ps c o ntr ol cell di visi o n . 
D B L  
direct bilir u bi n  
D M C  
data m o nit ori n g c o m mittee . A data m o nit ori n g c o m mittee, or data m o nit ori n g b oar d 
( D M B) is a gr o u p of i n de pe n de nt scie ntists w h o are a p p oi nte d t o m o nit or t he safet y a n d 
scie ntific i nte grit y of a h u ma n researc h i nter ve nti o n, a n d t o ma ke rec o m me n dati o ns t o 
t he s p o ns or re gar di n g t he st o p pi n g of a st u d y f or efficac y, or f or har ms, or f or f utilit y. 
T he c o m p ositi o n of t he c o m mittee is de pe n de nt u p o n t he scie ntific s kills a n d 
k n o wle d ge re q uire d f or m o nit ori n g t he partic ular st u d y.  
D R F S  
dista nt rela pse free s ur vi val  
E C G  
electr ocar di o gra m 
E C H O  
ec h ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F  
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure s yste m  
E nr oll  
T he act of assi g ni n g a partici pa nt t o a treat me nt. Partici pa nts w h o are e nr olle d i n t he 
st u d y are t h ose w h o ha ve bee n assi g ne d t o a treat me nt. 
E nt er  
Partici pa nts e ntere d i nt o a st u d y are t h ose w h o si g n t he i nf or me d c o nse nt f or m directl y 
or t hr o u g h t heir le gall y acce pta ble re prese ntati ves.  
E Q -5 D -5 L  
E ur o pea n Q ualit y of Life –  5 di me nsi o ns –  5 le vel  
E R  
estr o ge n rece pt or  
E R +  
estr o ge n rece pt or p ositi ve  
E T  
e n d ocri ne t hera p y  
F A C T -P  
F u ncti o nal Assess me nt of Ca ncer T hera p y –  Pr ostate  
F A C T -G  
F u ncti o nal Assess me nt of Ca ncer T hera p y –  Ge neral  
G C P  
g o o d cli nical practice  
G -C S F  
gra n ul oc yte c ol o n y -sti m ulati n g fact or 
G F R  
g l o mer ular filtrati o n rate 
G G T  
ga m ma -gl uta m yl tra nsferase  
GI  
gastr oi ntesti nal  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 6  
H E R 2 - 
h u ma n e pi der mal gr o w t h fact or rece pt or 2 ne gati ve 
H R  
hazar d rati o  
H R +  
h or m o ne rece pt or p ositi ve  
H S  
h or m o ne se nsiti ve 
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I D F S 
i n vasi ve disease-free s ur vi val 
I E C 
I n de p e n de nt Et hics C o m mittee 
I H C 
I m m u n o hist oc h e mistr y 
I L D 
i nterstitial l u n g disease 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct (see als o “i n vesti gati o nal pr o d uct”) 
A me dici nal pr o d uct w hic h is bei n g teste d or use d as a refere nce, i ncl u di n g as a 
place b o, i n a cli nical trial.  
i nf or m e d c o n s e nt  
A pr ocess b y w hic h a partici pa nt v ol u ntaril y c o nfir ms t heir willi n g ness t o partici pate i n 
a partic ular st u d y, after ha vi n g bee n i nf or me d of all as pects of t he st u d y t hat are 
rele v a nt t o t he partici pa nt’s decisi o n t o partici pate. I nf or me d c o nse nt is d oc u me nte d b y 
mea ns of a writte n, si g ne d a n d date d i nf or me d c o nse nt f or m . 
i nt eri m a n al y si s 
A n i nteri m a n al ysis is a n a nal ysis of cli nical st u d y data, se parate d i nt o treat me nt gr o u ps, 
t hat is c o n d ucte d bef ore t he fi nal re p orti n g data base is create d/l oc ke d. 
i n v e sti g ati o n al 
pr o d u ct  
A p har mace utical f or m of a n acti ve i n gre die nt or place b o bei n g teste d or use d as a 
refere n ce i n a cli nical trial, i ncl u di n g pr o d ucts alrea d y o n t he mar ket w he n use d or 
asse m ble d (f or m ulate d or pac ka ge d) i n a wa y differe nt fr o m t he a ut h or ize d f or m, or 
mar kete d pr o d ucts use d f or a n u na ut h orize d i n dicati o n, or mar kete d pr o d ucts use d t o 
gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.  See als o “I M P.”  
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
i nte nti o n t o treat:  T he pri nci ple t hat asserts t hat t he effect of a treat me nt p olic y ca n be 
best assesse d b y e val uati n g o n t he basis of t he i nte nti o n t o treat a partici pa nt (t hat is, t he 
pla n ne d treat me nt re gi me n) rat her t ha n t he act ual treat me nt gi ve n. It has t he 
c o nse q ue n ce t hat partici pa nt a ll ocate d t o a treat me nt gr o u p s h o ul d be f oll o we d u p, 
assesse d, a n d a n al yze d as me m bers of t hat gr o u p irres pecti ve of t heir c o m plia nce t o t he 
pla n ne d c o urse of treat me nt.  
I V 
i ntra v e n o us 
I W R S 
i nteracti ve we b-res p o nse s yste m 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 7  
L H R H  
l utei nizi n g h or m o ne -releasi n g h or m o ne 
M A T E 1  
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n 1  
M B C  
metastatic breast ca ncer  
m C R P C  
metastatic castrati o n -resista nt pr ostate ca ncer 
M e d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m e di c ati o n err or  
Err ors i n t he prescri bi n g, dis pe nsi n g, or a d mi nistrati o n of a st u d y i nter ve nti o n, 
re g ar dless of w het her or n ot t he me dicati o n is a d mi nistere d t o t he partici pa nt or t he 
err or lea ds t o a n A E. Me dicati o n err or ge nerall y i n v ol ve s a fail ure t o u p h ol d o ne or 
m ore of t he fi ve “ri g hts” of me dicati o n use: t he ri g ht partici pa nt, t he ri g ht dr u g, t he 
ri g ht d ose, ri g ht r o ute, at t he ri g ht ti me. 
I n a d diti o n t o t he c ore fi ve ri g hts, t he f oll o wi n g ma y als o re prese nt me dicati o n err ors:  
• d ose o missi o n ass ociate d wit h a n A E or a pr o d uct c o m plai nt  
• dis pe nsi n g or use of e x pire d me dicati o n 
• use of me dicati o n past t he rec o m me n de d i n-use date  
• dis pe nsi n g or use of a n i m pr o perl y st ore d me dicati o n 
• use of a n a d ulterate d d osa ge f or m or a d mi nistrati o n tec h ni q ue i nc o nsiste nt wit h t he 
me dicati o n ’s la beli n g (f or e xa m ple, S u m mar y of Pr o d uct C haracteristics, I B, l ocal 
la bel, pr ot oc ol), or 
• s hare d use of cartri d ges, prefille d pe ns, or b ot h. 
m H S P C  
metastatic h or m o ne -se nsiti ve pr ostate ca ncer 
mi s u s e  
Use of a st u d y i nter ve nti o n f or self-treat me nt t hat eit her is i nc o nsiste nt wit h t he 
prescri be d d osi n g re gi me n, i n dicati o n, or b ot h, or is o btai ne d wit h o ut a prescri pti o n . 
M RI  
ma g netic  res o na nce i ma gi n g 
M U G A  
m ulti -gate d ac q uisiti o n sca n  
N E  
n ot e val ua ble  
NI M P  
N o n -i n vesti gati o nal Me dici nal Pr o d uct. See A x M P. 
A me dici nal pr o d uct use d f or t he nee ds of a cli nical trial as descri be d i n t he pr ot oc ol, 
b ut n ot as a n i n vesti gati o nal me dici nal pr o d uct. E xa m ples i ncl u de resc ue me dicati o n, 
c h alle n ge a g e nts, a ge nts t o assess e n d p oi nts i n t he cli nical trial, or bac k gr o u n d 
treat me nt. 
N R  
n ot reac h e d  
N R S  
n u meric rati n g scale  
O R R  
o bjecti ve res p o nse rate  
O S  
o verall s ur vi val  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 8  
p arti ci p a nt  
E q ui vale nt t o  C DI S C ter m  “s u bject”: a n i n di vi d ual w h o partici pates i n a cli nical trial , 
eit her as reci pie nt of a n i n vesti gati o nal me dici nal pr o d uct or as a c o ntr ol . 
P C  
pr o d uct c o m plai nt  
P C W G  
T he Pr ostate Ca n cer Cli nical Trials W or ki n g Gr o u p  
P C W G 2  
T he Pr ostate Ca n cer Cli nical Trials W or ki n g Gr o u p 2  
P C W G 3  
T he Pr ostate Ca n cer Cli nical Trials W or ki n g Gr o u p 3  
P D  
pr o gressi ve disease  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P F S  
p r o gressi o n-free s ur vi val 
P K  
p har mac o ki netics  
P P S  
per -pr ot oc ol set:  T he set of data ge nerate d b y t he s u bset of partici pa nt  w h o s ufficie ntl y 
c o m plie d wit h t he pr ot oc ol t o e ns ure t hat t hese data w o ul d be li kel y t o e x hi bit t he 
effects of treat me nt, acc or di n g t o t he u n derl yi n g scie ntific m o del.  
P R  
partial res p o nse  
P R O  
patie nt -re p orte d o utc o mes 
P S A  
pr ostate -s pecific a nti ge n 
P S M A  
pr ostate -s pecific me m bra ne a nti ge n 
P T -I N R 
p r ot hr o m bi n ti me –  i nter nati o nal n or malize d rati o 
Q D  
o nce dail y  
Q T c  
c orrecte d Q T i nter val  
R b  
reti n o blast o ma 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R P 2 D  
rec o m me n de d p hase 2 d ose 
r P F S 
ra di o gra p hic pr o gressi o n-free s ur vi val 
R T  
ra di ot hera p y 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a n al ysis pla n 
S cr e e n  
T he act of deter mi ni n g if a n i n di vi d ual meets mi ni m u m re q uire me nts t o bec o me part of 
a p o ol of p ote ntial ca n di dates f or partici pati o n i n a cli nical st u d y.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 2 9  
S o A  
sc h e d ule of acti vities 
S O C  
s yste m or ga n class  
S S E  
s y m pt o matic s keletal e ve nt 
S M D  
se ni or ma n a g e me nt desi g nee  
S U S A R s  
sus pecte d u ne x pecte d seri o us a d verse reacti o ns  
T B L  
t otal bilir u bi n 
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt: A n u nt o war d me dical occ urre nce t hat e mer ges 
d uri n g a defi ne d treat me nt peri o d, ha vi n g bee n a bse nt pretreat me nt, o r w orse ns relati ve 
t o t he pretreat me nt state, a n d d oes n ot necessaril y ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  
V T E  
ve n o us t hr o m b oe m b olic e ve nt  
 
 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 0  
1 0. 1 3.  
A p pe n di x 1 3: Pr ot oc ol A me n d me nt Hist or y   
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y bef ore t he Ta bl e of C o nte nts ( T O C).  
A me n d me nt [ d] ( 1 8-J ul -2 0 2 3)   
T his a me n d me nt is c o nsi dere d t o be n o ns u bsta ntial.  
O ver all R ati o n ale f or t he A me n d me nt d  
T he pr ot oc ol was a me n d e d t o a dj ust t he ti mi n g of t he f utilit y a nal ysis t o acc o u nt f or act ual 
e nr oll me nt rate a n d t o p ossi bl y be c o n d ucte d i n c o nj u ncti o n wit h a pla n ne d safe t y re vi e w. I n 
a d diti o n, mi n or c ha n ges were ma d e t o c orrect a t y p o gra p hical err or i ntr o d uce d i n t he pre vi o us 
a me n d me nt re g ar di n g t he i ma gi n g pr oce d ure; a n d t o clarif y o n: t he c ollecti o n of et h nicit y, c ycle 
dela ys d ue t o l o gistical reas o ns, diarr hea ma na g e m e nt, a n d cli nical la b orat or y tests. T he ta ble 
listi n g str o n g a n d m o derate i n d ucers a n d str o n g i n hi bit ors of C Y P 3 A 4 was als o u p date d.  
 
C ha n ges a n d rati o nale are s u m marize d i n t he ta bl e bel o w; mi n or t y p o gra p hical or f or matti n g 
e dits are n ot pres e nte d i n t he ta ble. 
Secti o n # a n d N a me  Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3.  Sc he d ule of 
Acti vities ( S o A)  
 
a n d  
 
4. 2. Scie ntific 
Rati o nale f or St u d y 
Desi g n  
“et h nicit y” was a d de d t o t he i nstr ucti o ns 
i n t he de m o gra p hics li ne ite m. 
 
 
 
“et h nicit y” was a d de d i n t he 2 se nte nces 
i n fi nal para gra p h. 
Clarificati o n  
 
 
 
 
T o get her wit h race, 
et h nicit y will als o be 
c ollecte d.  
1. 3.  Sc he d ule of 
Acti vities ( S o A)  
  
C orrecte d a t y p o gra p hical err or 
i ntr o d uce d i n t he pre vi o us a me n d me nt 
(c). Re verte d t o ori gi nal t e xt t o n o w rea d 
“ C T or M RI of c h est, a b d o me n, a n d 
pel vis A N D W h ole -b o d y b o ne sca n”  
E dit orial  
6. 2. 1.  Selecti o n a n d 
Ti mi n g of D oses  
I n t he first se nte nce i n t he f o urt h 
para gra p h, a d d e d “ or vacati o n”  
Clarificati o n  
6. 8. 2.  S u p p orti ve 
Ma na ge me nt f or 
Diarr hea  
I n t he s ec o nd t o last para gra p h, delete d 
“ br oa d-s p ectr u m a nti bi otics s uc h as 
fl u or o q ui n ol o nes m ust be prescri be d ” a n d 
a d de d “a nti bi otics s h o ul d be c o nsi dere d”  
Clarificati o n  
8. 1. Efficac y 
Assess me nts  
C orrecte d a t y p o gra p hical err or 
i ntr o d uce d i n t he pre vi o us a me n d me nt 
(c). I n t he s ec o n d p ara gra p h, re vert e d t o 
ori gi nal te xt t o n o w rea d “ F or all patie nts, 
E dit orial  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 1  
Secti o n # a n d N a me  Descri pti o n of C h a n ge  
Brief R ati o n ale  
i ma gi n g (C T or M RI of t he c hest, 
a b d o me n, a n d pel vis a n d  ra di o n ucli de 
b o ne  sca n) will be perf or me d …” 
9. 3. A nal yses Sets  
Delete d “a n d ha v e baseli ne” fr o m 
descri pti o n of P K a nal ysis p o p ulati o n  
Clarificati o n  
9. 4. 2. Pri mar y 
E n d p oi nt/ Esti ma n d 
A nal ysis  
U p date d ti mi n g of f utilit y a nal ysis i n t hir d 
para gra p h a n d i n t he Statistical A nal ysis 
Milest o nes ta ble. A d de d se nte nce at t he 
e n d of t he t hir d para gra p h  
T o e ns ure a d e q uate 
f oll o w-u p ti me at t he ti me 
of t he f utilit y a nal ysis, 
after acc o u nti n g f or act u al 
rate of e nr oll me nt t o t he 
st u d y. A d diti o nall y, f or 
l o gistical reas o ns, 
e na bli n g a n i nteri m 
a nal ysis t o be c o n d ucte d 
at t he ti me of a pla n ne d 
safet y re vi e w per t he 
I D M C’s rec o m me n d ati o n 
1 0. 2. A p pe n di x 2: 
Cli nical La b orat or y 
Tests  
I n t he “ Differe ntial” li ne ite m, re place d 
“a n d “ wit h “ or”, t o r ea d “( Perce nt or 
A bs ol ute C o u nts)”  
Clarificati o n  
1 0. 7. A p pe n di x 7: 
I n d u cers a n d Str o n g 
I n hi bit ors of 
C Y P 3 A 4  
U p date d ta b le listi n g str o n g a n d m o derate 
i n d ucers a n d str o n g i n hi bit ors of C Y P 3 A 4 
U p date  
 
A me n d me nt [c] (2 0 -O ct -2 0 2 2)  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial beca use it is li kel y t o ha ve a si g nifica nt i m pact 
o n eli gi bilit y f or st u d y partici pati o n.  
O ver all R ati o n ale f or t he A me n d me nt c  
T he pri mar y reas o n f or t his a me n d me nt is t o  a d dress e xter nal i n vesti gat or fee d bac k, as 
s u m marize d bel o w 
 e xcl u de partici pa nts w h o recei v e d pri or d oceta xel f or metastatic pr ostat e ca ncer i n 
acc or da nce wit h t he e v ol vi n g m H S P C treat me nt la n dsca pe a n d t o li mit heter o ge neit y of 
t he st u d y p o p ulati o n. 
 all o w t he hi g h -ris k criteri a t o be c o nfir m e d i n de pe n de nt of t he AD T i nitiati o n, t o c o nf or m 
t o c urre nt a n d a ntici pate d c ha n ges i n dia g n ostic a n d cli nical practice, a n d 
 all o w o ne c o urs e of palli ati ve ra di ot hera p y or s ur ger y d uri n g st u d y wit h o ut re q uiri n g 
partici pa nts t o disc o nti n ue st u d y i nter ve nti o n t o ali g n wit h cli nica l practice a n d 
rec o m me n dati o ns f or s y m pt o m ma na ge me nt.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 2  
C ha n ges a n d rati o nale are s u m marize d i n t he ta bl e bel o w; mi n or t y p o gra p hical or f or matti n g 
e dits are n ot pres e nte d.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Title pa ge a n d 
1. 1.  S y n o psis  
U p date d t he E U tri al n u m ber fr o m 2 0 2 2 -
5 0 0 4 6 1 -2 8 -0 0 t o 2 0 2 2 -5 0 0 4 6 1 -2 8 -0 6  
T o reflect t he c urre nt 
n u m ber o n C TI S  
1. 1. S y n o psis  
St u d y P o p ulati o n, sec o n d para gra p h: 
u p date d t he descri pti o n of t he s yste mic 
treat me nt per mitte d pri or t o ra n d o mizati o n 
F or c o nsiste n c y wit h 
t he re vise d i ncl usi o n 
criteri o n [ 4] a n d 
e xcl usi o n criteri o n [ 1 2]  
St u d y P o p ulati o n, f o urt h para gra p h: 
delete d “ pit uitar y dis or der”  
F or c o nsiste n c y wit h 
t he re vise d e x cl usi o n 
criteri o n [ 2 1]  
1. 1. S y n o psis, 
1. 2.  Sc he ma, a n d 
4. 1.  O verall D esi g n  
Stratificati o n fact ors: del ete d “ pri or 
d oceta xel ”   
F or c o nsiste n c y wit h 
re visi o ns t o e xcl usi o n 
criteri o n [ 1 2]  
1. 1. S y n o psis, 
3.  O bjecti ves, 
E n d p oi nts, a n d 
Esti ma n ds  
Delete d “a n d/ or s y m pt o matic”  
 Secti o n 1. 1: Treat me nt Ar ms a n d 
D urati o n, Bli n de d st u d y dr u g, last 
para gra p h, sec o n d se nte nce  
 Secti o n 3: Pri mar y esti ma n d, sec o n d 
para gra p h, t hir d maj or b ullet 
( Treat me nt c o n diti o n), sec o n d 
se nte nce 
F or c o nsiste n c y wit h 
c ha n ge ma de i n 
Secti o ns 6. 8 a n d 7. 1.  
1. 3. Sc he d u le of 
Acti vities ( S o A)  
T he i ma gi n g r o w ( C T of c hest or C T/ M RI 
of a b d o me n a n d p el vis A N D w h ole -b o d y 
b o ne sca n):  
U p date d t he r o w st u b  
F or c o nsiste n c y wit h 
re visi o ns i n Secti o n 8. 1 
 
U p date d t he c o m me nts f or t he “ O n 
Treat me nt” a n d “I nstr u cti o ns” c ol u m ns.  
Clarit y a n d c o nsiste nc y 
wit h re vise d 
Secti o ns  6. 8 a n d 7. 1, as 
well as Secti o n 8. 1  
5. 1. I n cl usi o n Criteria  
U p date d t he f oll o wi n g i n cl usi o n criteria:  
 
 2: a d de d  “ pre d o mi na nt”  
Clarit y  
 3: u p date d t o all o w t he hi g h -ris k criteria 
t o be c o nfir me d i n de p e n de nt of t he 
A D T i nitiati o n.  
T o c o nf or m t o c urre nt 
a n d a ntici pate d c h a n ges 
i n dia g n ostic a n d 
cli nical practice   
 4: clarifie d t he pri or A D T re q uire me nt  
Clarit y  
 6:  
C orrecti o n  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 3  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
o  u p date d t he u nit of meas ure f or 
ser u m p otassi u m: fr o m “ m M” t o 
“ m m ol/ L” 
o  u p date d criteria f or b aseli ne re nal 
f u ncti o n t o be base d o n e G F R 
i nstea d of ser u m creati ni ne 
F or c o nsiste n c y wit h 
cli nical practice  
 8: u p date d t he c o ntrace pti o n 
re q uire me nts 
F or c o nsiste n c y wit h 
c ha n ges t o 
Secti o n  1 0. 4, 
A p pe n di x  4  
5. 2. E xcl usi o n Criteria  U p date d t he f oll o wi n g e x cl usi o n criteria:  
 
 1 2:  
o  delete d pri or d o ceta xel  
o  referre d t o i ncl usi o n criteri o n [ 4] 
f or pri or A D T 
Partici pa nts w h o 
recei v e d pri or d oceta xel 
f or metastatic pr ostat e 
ca ncer will n o l o n ger be 
eli gi ble per e xter n al 
rec o m me n dati o ns, i n 
acc or da nce wit h t he 
e v ol vi n g m H S P C 
treat me nt la n dsca pe a n d 
t o li mit heter o ge neit y of 
t he st u d y p o p ulati o n. 
 1 3:  
o  u p date d t he descri pti o n of t he 
ra diati o n t hera p y 
o  u p date d t he wi n d o w f or per mitte d 
palliati ve ra diati o n or s ur gical 
t hera p y fr o m 4 wee ks t o 2 wee ks 
pri or t o ra n d o mizati o n  
Clarit y  
 2 1: delete d “ or pit uitar y dis or der”  
Clarit y  
 2 2: u p date d t he wi n d o w f or a maj or 
s ur ger y fr o m 4 wee ks t o 2 wee ks pri or 
t o ra n d o mizati o n 
C o nsiste nc y wit h t he 
re vise d e x cl usi o n 
criteri o n [ 1 3].  
 2 3: a d de d “ or” (“ w h o are i n re missi o n 
a n d/or w h ose li keli h o o d of rec urre n ce 
…”)  
Clarit y  
5. 3. Lifest yle 
C o nsi derati o ns  
U p date d t he c o ntr ac e pti o n re q uire me nts  
F or c o nsiste n c y wit h 
c ha n ges t o Secti o n 
1 0. 4, A p pe n di x 4.  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 4  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 1. 2. Bac k gr o u n d 
T hera p y or Sta n d ar d -
of -Care  
Re vise d t he f oll o wi n g se nte nce t o rea d 
“ T he c h oic e of L H R H a g o nist/a nta g o nist  
will be p h ysicia n’s c h oice  a n d s u p plie d b y 
t he site.” 
Fle xi bilit y  
6. 3. 3. E mer ge nc y 
U n bli n di n g  
T hir d se nte nce: d elete d “ ma ke e ver y eff ort 
t o” 
Clarit y  
6. 5. 2. D ose 
M o dificati o ns - 
A be macicli b/ Place b o  
Sec o n d para gra p h: u p dat e d t o rea d 
“ Partici pa nts u n der g oi n g n o n -t u m or relate d 
s ur gical pr oce d ures … ”  
Clarit y  
T o xicit y D ose M o dificati o ns ta ble: 
u p date d t he V T E -relat e d i nf or mati o n a n d 
prese nte d it all i n a se p arate r o w at t he e n d 
of t he ta ble.  
F or c o nsiste n c y wit h 
d ose m o dificati o ns use d 
w he n V T E occ urs 
d uri n g a be maci cli b 
treat me nt f or a p pr o ve d 
i n dicati o ns (s uc h as 
M B C)  
6. 8. C o nc o mita nt 
T hera p y  
M o difie d t o all o w o ne c o urse of palliati ve 
ra di ot hera p y or s ur ger y d uri n g st u d y  
T o ali g n wit h cli nical 
practice a n d 
rec o m me n dati o ns f or 
s y m pt o m ma na ge me nt 
7. 1. Disc o nti n uati o n 
of St u d y I nter ve nti o n  
Re m o ve d t he re q uir e me nt t o disc o nti n ue 
st u d y i nter ve nti o n f or partici pa nts wit h 
s y m pt o matic pr o gressi o n 
F or c o nsiste n c y wit h 
c ha n ge ma de i n 
Secti o n  6. 8  
 
U p date d t he des cri pti o n of sc he d ule d 
assess me nts f oll o wi n g disc o nti n uati o n  
Clarit y  
8. 1. Efficac y 
Assess me nts  
U p date d i nf or mati o n pertai ni n g t o i ma gi n g  F or c o nsiste n c y wit h 
t he re vise d e x cl usi o n 
criteria [ 1 2] a n d [ 1 3]  
8. 2. 5. G ui da nce f or 
Ve n o us 
T hr o m b oe m b olic 
E ve nts  
Last para gra p h: re pl ace d “ h o n-he mat ol o gic 
t o xicities” wit h “ V T E” 
Per re visi o ns i n 
Secti o n  6. 5. 2  
9. 4. 3. 3. Castrati o n -
Resista nt Pr ostate 
Ca ncer ( C R P C) -free 
S ur vi val  
A d de d a refere nce t o Secti o n 9. 4. 3. 5  
Clarit y  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 5  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1 0. 4. A p pe n di x 4, 
C o ntrace pti ve a n d 
Barrier G ui d a nce  
1 0. 4. 1. Defi niti o ns  
U p date d t he defi niti o n of w o me n n ot of 
c hil d beari n g p ote ntial  
Per u p date d i nter n al 
c o ntrace pti o n g ui da nce 
a n d t o be ali g ne d wit h 
t he a birater o ne la bel 
1 0. 4. 2. C o ntrace pti o n G ui da nce  
U p date d  
 
Ol d pa ge 1 4 1, wit h 
ma n uall y a d de d 
a p pr o vers’ na mes  
Delete d.  
T his i nf or mati o n will 
be ge nerate d 
a ut o maticall y i n t he 
Lill y d oc u me nt 
ma na ge me nt s yste m.  
A me n d me nt [ b] ( 0 5-A u g -2 0 2 2)  
T his a me n d me nt is c o nsi dere d t o be n o ns u bsta ntial base d o n t he criteria set f ort h i n Article 1 0 (a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n . 
O ver all R ati o n ale f or t he A me n d me nt b:  
T he St u d y J P E G pr ot oc ol was a me n de d t o a d dress t he Re q uest f or I nf or mati o n b y t he E ur o pea n 
Me dici nes A ge n c y. C ha n ges are s u m marize d i n t h e ta ble bel o w; mi n or t y p o gra p hical or 
f or matti n g e dits are n ot prese nte d.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
1. 3 Sc he d ule of 
Acti vities  
A d de d clarif yi n g la n g ua g e re gar di n g o n 
st u d y brai n i ma gi n g f or patie nts wit h 
hist or y of pretreate d C N S metastases  
 
Clarificati o n  
5. 1. I n cl usi o n Criteria  A me n de d i ncl usi o n criteri o n 4 t o all o w f or 
patie nts starti n g A D T t o c o nti n ue first 
ge nerati o n a nti -a n dr o ge n f or 2 wee ks after 
C ycle 1 Da y 1  
 
Per re g ulat or y fee d b ac k  
5. 2 E xcl usi o n Criteria  
Re m o ve d test oster o ne la b val ues (≤5 0 
n g/ d L; ≤1. 7 3 n m ol/ L) fr o m e xcl usi o n 
criteria 1 1  
Clarificati o n  
6. 8. C o nc o mita nt 
T hera p y  
A d de d la n g ua g e re g ar di n g t he a v oi da nce 
of li ve vacci n es d uri n g, a n d u p t o 9 0 da ys 
after t he l ast d ose of st u d y t reat me nt 
Per re g ulat or y re q uest  
7. 2. 1. Disc o nti n uati o n 
of I na d verte ntl y 
Ra n d o mize d Patie nts  
U p date d title t o: “ Disc o nti n uati o n of 
I n a d vert e ntl y E nr olle d  Ra n d o mize d 
A d mi nistrati ve  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 6  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Patie nts”; delete d la n g ua ge re gar di n g 
i na d verte ntl y e nr olle d p atie nts 
 
 
1 0 . 1. 4 Data Pr otecti o n A d de d refere nce t o t he Ge neral D ata 
Pr otecti o n Re g ulati o n a n d t he E ur o pea n 
Cli nical Trial Re g ulati o n Articles 5 6, 5 7, 
5 8  
Per re g ulat or y re q uest  
1 0. 8. 1. 1. Re m o val of 
M U G A sca ns i n 
Ger ma n y  
A d de d ne w s u bsecti o n f or st u d y sites i n 
Ger ma n y; Re m o ve d M U G A sca ns f or 
st u d y sites i n Ger ma n y 
Per re g ulat or y re q uest  
T hr o u g h o ut  
U p date d “a nal o g ues” t o 
“a g o nist/a nta g o nist”  
Clarificati o n  
 
A me n d me nt [ a]: (2 5 -M ar -2 0 2 2 ) 
T his a me n d me nt is c o nsi dere d t o be n o ns u bsta ntial base d o n t he criteria set f ort h i n Article 1 0 (a) 
of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n . 
 
O ver all R ati o n ale f or t he A me n d me nt  
T he St u d y J P E G pr ot oc ol was a me n de d t o cl arif y t he i n vesti gat or’s res p o nsi bilit y per Re g ulati o n 
N o. 5 3 6/ 2 0 1 4 a n d t o si m plif y t he ta ble relate d t o st u d y i nter ve nti o ns i n Secti o n 6. 1. C ha n ges are 
s u m marize d i n t he ta ble bel o w; mi n or t y p o gra p hical or f or m atti n g e dits are n ot prese nte d.  
Secti o n # a n d N a me  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
6. 1. St u d y 
I nter ve nti o n(s) 
A d mi nistere d  
I n t he t a ble 
- Delete d t he r o ws f or i n vesti gati o nal 
stat us, t y pe, f or m ulati o n, a n d stre n gt h(s) of 
st u d y i nter ve nti o ns 
- Delete d t he L H R H a nal o g ue c ol u m n  
- Re place d y es or n o b y t e xt t o clarif y E U 
a ut h orizati o n stat us  
- Delete d f o ot n ote a 
Deleti o n/ E dit orial  
1 0. 1. 1. Re g ulat or y 
a n d Et hical 
C o nsi derati o ns  
- A d de d “ Re p orti n g t o t he s p o ns or or 
desi g nee si g nifica nt iss ues relate d t o 
partici pa nt safet y, partici pa nt ri g hts, or 
data i nte grit y.”  
Clarificati o n  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 7  
1 1.  
Refere nces   
A birater o n e  acetate [p ac ka ge i nsert ]. H ors ha m, P A : Ja nsse n Bi otec h, I nc.; 2 0 2 0 .   
At ki ns o n T M,  Me n d oza T R, Sit L, et al.  T he Brief Pai n I n v e nt or y a n d its “ Pai n at its W orst i n 
t he last 2 4 H o urs” ite m: cli nical  trial e n d p oi nt  c o nsi derati o ns.  P ai n Me d . 2 0 1 0; 1 1( 3): 3 3 7-
3 4 6.  htt ps:// d oi. or g/ 1 0. 1 1 1 1/j. 1 5 2 6 -4 6 3 7. 2 0 0 9. 0 0 7 7 4  
Ar mstr o n g AJ, I g uc hi T, Aza d A A, et al . Fi n al o verall s ur vi val a nal ysis fr o m A R C H E S: a p hase 
3, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d st u d y of e nzal uta mi de pl us a n dr o ge n 
de pri vati o n t hera p y i n m e n wit h metastatic h or m o ne -se nsiti ve pr ostate ca n cer. A bstr act 
prese nte d at: 2 0 2 1 E S M O C o n gress; Se pte m ber 1 6 -2 1, 2 0 2 1; Paris, Fra n ce. A bstract L B A 2 5.  
Ar mstr o n g AJ, Sz m ule witz R Z, Petr yla k D P, et al. A R C H E S: A ra n d o mize d, p hase III st u d y of 
an dr o ge n d e pri vati o n thera p y wit h enzal uta mi de or p lace b o i n m e n wit h m etastatic h or m o ne -
se nsiti ve p r ostate ca n cer.  J Cli n O nc ol . 2 0 1 9; 3 7( 3 2): 2 9 7 4 -2 9 8 6.  
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 1 9. 0 0 7 9 9  
Basc h  E, Ree ve B B, Mitc hell S A,  et al. De v el o p me nt of t he Nati o nal Ca n cer I nstit ute’s patie nt -
re p orte d o utc o m es versi o n of t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( P R O-
C T C A E).  J N atl C a ncer I nst . 2 0 1 4; 1 0 6( 9): dj u 2 4 4. htt ps:// d oi. or g/ 1 0. 1 0 9 3/j nci/ dj u 2 4 4 
Be n nett A V,  D uec k A C, Mitc hell S A, et al. M o de e q ui vale nce a n d acce pt a bilit y of ta blet 
c o m p uter-, i nteracti ve v oice res p o nse s yst e m-, a n d pa per-b ase d a d mi nistrati o n of t he U. S. 
Nati o nal Ca n cer I nstit ute’s Patie nt -Re p orte d O utc o mes versi o n of t he C o m m o n Ter mi n ol o g y 
Criteria f or A d v erse E v e nts ( P R O -C T C A E).  He alt h Q u al Life 
O utc o mes . 2 0 1 6; 1 4: 2 4.  htt ps:// d oi. or g/ 1 0. 1 1 8 6/s 1 2 9 5 5 -0 1 6 -0 4 2 6 -6  
Cella  D,  Nic h ol  M B,  Et o n  D,  et al. Esti mati n g cli nicall y mea ni n gf ul c ha n g es f or t he F u ncti o nal 
Assess me nt of Ca ncer T hera p y -Pr ostat e: res ults fr o m a cli nical trial of p atie nts wit h metastatic 
h or m o ne -refract or y pr ost ate ca n cer. V al ue He alt h . 2 0 0 9; 1 2( 1): 1 2 4-
1 2 9.  htt ps:// d oi. or g/ 1 0. 1 1 1 1/j . 1 5 2 4-4 7 3 3. 2 0 0 8. 0 0 4 0 9  
Cella D F, T uls k y D S, Gra y G, et al. T he F u ncti o n al Assess me nt of Ca ncer T hera p y Scale: 
de vel o p me nt a n d vali dati o n of t he ge neral meas ure.  J Cli n O nc ol . 1 9 9 3; 1 1( 3): 5 7 0-5 7 9. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 1 9 9 3. 1 1. 3. 5 7 0   
C ha p ma n  C R,  L oeser  J D, e dit ors. A d va nces i n  pai n  researc h a n d t h era p y. V ol. 1 2. Iss ues i n P ai n 
Me as ure me nt . Ra ve n Press,  Ne w Y or k ; 1 9 8 9 : p p.  3 9 1 -4 0 3.   
C he n R, Re n S , Y iu M K, et al. ; C hi nese Pr ostate Ca ncer C o ns orti u m. Pr ostate ca n cer i n Asia: A 
c olla b orati ve re p ort. Asi a n J Ur ol . 2 0 1 4; 1( 1): 1 5-2 9. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.aj ur. 2 0 1 4. 0 8. 0 0 7  
C hi K N, A gar wal N, Bjartell A, et al. A pal uta mi d e f or m etastatic, castr ati o n -se nsiti ve p r ostate 
ca ncer. N E n gl J Me d . 2 0 1 9; 3 8 1( 1): 1 3-2 4.  htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 1 9 0 3 3 0 7  
C hi g utsa E, Ka m b ha m pati S R P, Kare n S y kes A, et al. De vel o p me nt a n d a p plicati o n of a 
mec ha nistic p o p ulati o n m o deli n g a p pr oac h t o descri be a b e macicli b p har mac o ki netics. C P T 
P h ar m ac o metrics Syst P h ar m ac ol . 2 0 2 0; 9( 9): 5 2 3-5 3 3. htt ps:// d oi . or g/1 0. 1 0 0 2/ ps p 4. 1 2 5 4 4  
C h o w d h ur y S, Bjartell A, Merse b ur ger A S, et al. A pal uta mi de (a p a) f or metastatic castr ati o n -
se nsiti ve pr ostate ca n cer ( mcs pc): O utc o mes i n hi g h-v ol u me ( h v) a n d l o w -v ol u me (l v) disease 
fr o m t he tita n fi nal a nal ysis (fa). E ur Ur ol . 2 0 2 1; 7 9( S 1):S 1 1 8 0 -S 1 1 8 1 .  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 8  
C h u n g K C, Barle v A, Bra u n A H, et al. Ass essi n g anal gesic u se i n p atie nts wit h ad va nce d ca n cer: 
d e vel o p me nt of a n e w scale— t he A nal g esic Q ua ntificati o n Al g orit h m. P ai n Me d . 
2 0 1 4; 1 5( 2): 2 2 5 -2 3 2. htt ps:// d oi. or g/ 1 0. 1 1 1 1/ p me. 1 2 2 9 9  
Clar ke N W, Ali A, I n gle b y F C, et al. A d diti o n of d oceta xel t o h or m o nal t h era p y i n l o w- a n d 
hi g h -b ur de n metastatic h or m o ne se nsiti ve pr ostate ca ncer: l o n g -ter m s ur vi v al res ults fr o m t he 
S T A M P E D E trial. A n n O nc ol.  2 0 1 9; 3 0( 1 2): 1 9 9 2 -2 0 0 3. 
htt ps:// d oi. or g/ 1 0. 1 0 9 3/a n n o nc/ m dz 3 9 6  
C o x D R. Re gre ssi o n m o dels a n d life-ta bles. J R o y al St at S oc Ser B . 1 9 7 2;3 4( 2): 1 8 7 -2 2 0.  
Cra wf or d J, Ar mita ge J, Bal d ucci L, et al.; Nati o n al C o m pre he nsi ve Ca ncer Net w or k. M y el oi d 
gr o wt h fact ors. J N atl C o m pr C a ncer Net w . 2 0 0 9; 7( 1): 6 4-8 3.  
htt ps:// d oi. or g/ 1 0. 6 0 0 4/j ncc n. 2 0 0 9. 0 0 0 6  
Da vis I D, Marti n AJ, St o c kler M R, et al. E nzal uta mi de wit h sta n dar d first-li ne thera p y i n 
m etastatic p r ostate c a ncer. N E n gl J Me d . 2 0 1 9; 3 8 1( 2): 1 2 1-1 3 1.  
htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 1 9 0 3 8 3 5  
Dic kler M N, T ola n e y S M, R u g o H S, et al. M O N A R C H 1, A P hase II st u d y of a be macicli b, a 
C D K 4 a n d C D K 6 i n hi bit or, as a si n gle a g e nt, i n patie nts wit h refract or y H R +/ H E R 2 − 
metastatic breast ca ncer. Cli n C a ncer Res.  2 0 1 7; 2 3( 1 7): 5 2 1 8 -5 2 2 4.  
htt ps:// d oi. or g/ 1 0. 1 1 5 8/ 1 0 7 8 -0 4 3 2. C C R -1 7 -0 7 5 4  
D uec k A C, Me n d o za T R, Mitc hell S A,  et al.; Nati o nal Ca ncer I nstit ute P R O -C T C A E St u d y 
Gr o u p. Vali dit y a n d relia bilit y of t he U S Nati o nal Ca ncer I nstit ute’s patie nt -re p orte d o ut c o mes 
versi o n of t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts ( P R O -C T C A E).  J A M A 
O nc ol . 2 01 5; 1( 8): 1 0 5 1 -1 0 5 9. htt ps:// d oi. or g/ 1 0. 1 0 0 1/ja ma o nc ol. 2 0 1 5. 2 6 3 9   
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e v al uati o n criteria i n s oli d t u m o urs: 
re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J C a ncer.  2 0 0 9; 4 5( 2): 2 2 8 -2 4 7.  
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.ejca. 2 0 0 8. 1 0. 0 2 6  
Es per P, M o F,  C h o da k  G,  et al. Meas uri n g q ualit y of life i n me n wit h pr ostate ca n cer usi n g t he 
F u ncti o nal Assess me nt of Ca ncer T hera p y -Pr ostat e ( F A C T -P) 
i nstr u me nt. Ur ol o gy . 1 9 9 7; 5 0( 6): 9 2 0 -9 2 8.  htt ps:// d oi. or g/ 1 0. 1 0 1 6/ S 0 0 9 0 -4 2 9 5 ( 9 7) 0 0 4 5 9-7   
E ur o Q ol  Researc h F o u n d ati o n. E Q -5 D -5 L us er g ui de, versi o n 3. 0. U p date d Se pte m ber 2 0 1 9. 
htt ps://e ur o q ol. or g/ p u blicati o ns/ user -g ui des  
Fizazi K, Galc era n J C, F o ul o n S. A p hase III tri al wit h a 2 x 2 fact ori al desi g n i n me n wit h de 
n o v o metastatic c astr ati o n -se nsiti ve pr ostate ca ncer: O verall s ur vi val wit h a birater o n e acetate 
pl us pre d nis o ne i n P E A C E -1. A n n O nc ol . 2 0 2 1a; 3 2: S 1 2 8 3-S 1 3 4 6.  
Fizazi K, Mal d o na d o X, F o ul o n S, et al. A p hase 3 trial wit h a 2 x 2 fact ori al desi g n of a birater o ne 
acetat e pl us pred nis o ne a n d/ or l ocal ra di ot hera p y i n me n wit h de n o v o metastatic castrati o n -
se nsiti ve pr ostate ca n cer ( m C S P C): First res ults of P E A C E-1. J Cli n O nc ol.  
2 0 2 1 b ; 3 9( 1 5): 5 0 0 0. htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 2 1. 3 9. 1 5 _s u p pl. 5 0 0 0  
Fizazi K, Tra n N, Fei n L, et al.; L A TI T U D E I n vesti gat ors. A birater o n e pl us pre d nis o ne i n 
metastatic, castr ati o n -se nsiti ve pr ostate ca ncer. N E n gl J Me d . 2 0 1 7; 3 7 7( 4): 3 5 2 -3 6 0.  
htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 1 7 0 4 1 7 4  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 3 9  
Fizazi K, Tra n N, Fei n L, et al. A birater o ne  acetat e pl us pre d nis o ne i n patie nts wit h ne wl y 
dia g n ose d hi g h -ris k metastatic castrati o n-se nsiti ve pr ostate ca n cer ( L A TI T U D E): fi nal o verall 
s ur vi val a nal ysis of a ra n d o mise d, d o u ble-bli n d, p hase 3 trial. L a ncet O n c ol . 2 0 1 9; 2 0( 5): 6 8 6-
7 0 0.  htt ps:// d oi. or g/ 1 0. 1 0 1 6/ S 1 4 7 0 -2 0 4 5( 1 9) 3 0 0 8 2 -8  
Fra n ci ni E, Gra y K P, Xie W, et al. Ti me of metast atic disease prese ntati o n a n d v ol u me of disease 
are pr o g n ostic f or metast atic h or m o ne se nsiti ve pr ostate ca ncer ( m H S P C). Pr ost ate . 
2 0 1 8; 7 8( 1 2): 8 8 9 -8 9 5. htt ps:// d oi. or g/ 1 0. 1 0 0 2/ p r os. 2 3 6 4 5 
Ha h n A W, H ale P, Rat hi N, A gar wal N. N o vel a n dr o ge n a xis s yste mic t hera pies f or metast atic 
h or m o ne -se nsiti ve pr ostate ca ncer. C urr O pi n Ur ol . 2 0 1 7; 2 7( 6): 5 5 9-5 6 5.  
htt ps:// d oi. or g/ 1 0. 1 0 9 7/ M O U. 0 0 0 0 0 0 0 0 0 0 0 0 0 4 4 3  
Ha milt o n E,  C ortes J, Dieras V,  et al. A bstract P D 1 -1 1: ne xt M O N A R C H 1: P hase 2 st u d y of 
a be maci cli b pl us ta m o xife n or a be m acicli b al o ne i n H R +, H E R 2 - a d va n ce d breast c a ncer. 
C a ncer Res . 2 0 1 9( 7 9)( 4 S u p pl) P D 1 -1 1 . htt ps:// d oi. or g/ 1 0. 1 1 5 8/ 1 5 3 8 -7 4 4 5. S A B C S 1 8 -P D 1 -1 1  
Har bec k N, Rast o gi P, Marti n M , et al. m o narc h E C o m mittee Me m bers. A dj u va nt a be macicli b 
c o m bi ne d wit h e n d ocri ne t hera p y f or hi g h -ris k earl y breast ca n cer: u p d ate d efficac y a n d Ki-6 7 
a nal ysis fr o m t he m o narc h E st u d y. A n n O nc ol . 2 0 2 1; 3 2( 1 2): 1 5 7 1-1 5 8 1. 
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.a n n o nc. 2 0 2 1. 0 9 . 0 1 5 
H o yle A P, Ali A, Ja mes N D, et al. S T A M P E D E I n vesti gat ors. A birater o n e i n “Hi g h -” a n d 
“L o w -ris k” m etastatic h or m o ne -se nsiti ve p r ostate ca ncer. E ur Ur ol . 2 0 1 9; 7 6( 6): 7 1 9-7 2 8. 
htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.e ur ur o. 2 0 1 9. 0 8. 0 0 6  
[I N Ca] I nstit ute Nati o nal  of  Ca ncer  we b  site. Accesse d N o ve m ber 3 0, 2 0 2 1 . htt ps:// w w w.e -
ca ncer.fr/ Pr ofessi o n nels -de -sa nte/ Les-c hiffres -d u -ca ncer-e n-Fra n ce/ E pi de mi ol o gie -des -
ca ncers/ Les -ca ncers-l es-pl us -fre q ue nts/ Ca ncer-d e -la-pr ostate  
Ja mes N D, S y des M R, Clar ke N W, et al. A d diti o n of d oceta xel, z ole dr o ni c aci d, or b ot h t o first -
li ne l o n g-ter m h or m o ne t hera p y i n pr ostate ca n cer ( S T A M P E D E): s ur vi val res ults fr o m a n 
a da pti ve, m ultiar m, m ultista ge, platf or m ra n d o mise d c o ntr olle d trial. L a nc et. 
2 0 1 6; 3 8 7( 1 0 0 2 4): 1 1 6 3 -1 1 7 7.  htt ps:// d oi. or g/ 1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6( 1 5) 0 1 0 3 7 -5  
Ja mes N D, de B o n o J S, S pears M R, et al. A birater o ne f or pr ostate ca ncer n ot p re vi o usl y treate d 
wit h h or m o ne thera p y.  N E n gl J Me d . 2 0 1 7; 3 7 7( 4): 3 3 8-3 5 1.  
htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 1 7 0 2 9 0 0  
J o h nst o n S R D, Har bec k N, He g g R, et al. A be macicli b c o m bi ne d wit h e n d ocri ne t hera p y f or t h e 
a dj u va nt treat me nt of H R +, H E R 2 -, n o de-p ositi ve, hi g h -ris k, earl y breast c a ncer ( m o n arc h E). 
J Cli n O nc ol . 2 0 2 0; 3 8( 3 4): 3 9 8 7-3 9 9 8. htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0. 0 2 5 1 4  
J o h nst o n S, Marti n M, Di Le o A, et al. M O N A R C H 3 fi nal P F S: a ra n d o mi ze d st u d y of 
a be maci cli b as i nitial t hera p y f or a d va nce d breast ca ncer. N PJ Bre ast C a ncer . 2 0 1 9; 5: 5. 
htt ps:// d oi. or g/ 1 0. 1 0 3 8/s 4 1 5 2 3 -0 1 8 -0 0 9 7 -z 
K n u dse n E S, Pazza gli C, B or n T L, et al. Ele vate d c ycli ns a n d c ycli n-d e pe n de nt ki nase acti vit y i n 
t he r ha b d o m y osarc o ma cell li ne R D. C a ncer Res.  1 9 9 8; 5 8( 9): 2 0 4 2 -2 0 4 9.   
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 4 0  
K yria k o p o ul os C E, C he n Y H, Car d ucci M A, et al. C he m o h or m o nal thera p y i n m etastatic 
h or m o n e-se nsiti ve p r ostate ca ncer: lo n g -ter m sur vi val anal ysis of t he ra n d o mize d p hase III 
E 3 8 0 5 C H A A R T E D Trial. J Cli n O nc ol . 2 0 1 8; 3 6( 1 1): 1 0 8 0-1 0 8 7. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 1 7. 7 5. 3 6 5 7  
Mae da H, Ta ke d a K, Ur us hi hara H, K ur o ka wa T. Searc hi n g f or p ote ntial s urr o gate e n d p oi nts of 
o verall s ur vi val i n cli nical trials f or patie nts wit h pr ostate ca n cer. C a n cer R e p  ( H o b oke n). 
2 0 2 1; 4( 3):e 1 3 3 4. htt ps:// d oi. or g/ 1 0. 1 0 0 2/c nr 2. 1 3 3 4  
M ottet N, C or nf or d P , Briers E, et al. Me m bers of t he E A U –  E S T R O –  E S U R –  SI O G Pr ostate 
Ca ncer G ui d eli nes Pa nel. E A U –  E S T R O –  E S U R –  SI O G G ui deli nes o n Pr ostate Ca ncer. 
P u blis he d 2 0 2 1.  Accesse d Ja n uar y 1 9, 2 0 2 2. htt ps:// ur o we b. or g/ g ui deli ne/ pr ostate -ca ncer/  
[ N C C N] Nati o nal C o m pr e he nsi ve Ca ncer Net w or k. N C C N Cli nical Practice G ui deli nes i n 
O nc ol o g y ( N C C N G ui deli nes ®). Pr ostate Ca ncer Versi o n 3 . 2 0 22 . P u blis he d Ja n uar y 1 0, 2 0 2 2.  
Access e d Ja n uar y 1 4 , 2 0 2 2 . htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ pr ostate. p df 
[ N CI] Nati o nal Ca n cer I nstit ute. Ca ncer T hera p y E val uati o n Pr o gra m, C o m m o n Ter mi n ol o g y 
Criteria f or A d v erse E v e nts, Versi o n 5. 0, D C T D, N CI, NI H, D H H S. 2 0 1 7. P u blis h e d: 
N o ve m ber  2 7,  2 0 1 7.  
[ N CI] Nati o nal Ca n cer I nstit ute. G ui deli ne o n Patie nt-Re p orte d O utc o mes vers i o n of t he 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( P R O -C T C A E ™). P u blis he d 2 6 A pril 
2 0 2 0. Access e d 1 7 Se pte m ber 2 0 2 1. htt ps:// healt hcare d eli ver y.ca ncer. g o v/ pr o -ctcae/  
[ NI C E] N ati o nal I nstit ute f or Healt h a n d Care E x celle nce . NI C E  im pact p r ostate ca ncer. 
P u blis he d N o ve m ber 2 0 2 0 . Access e d  N o ve m ber 3 0 , 2 0 2 1. 
htt ps:// w w w. nice. or g. u k/ Me dia/ Defa ult/ A b o ut/ w hat -we -d o/I nt o -practice/ m eas uri n g -
u pta ke/ pr ostate -ca ncer/ ni ce -i m pact-pr ostate -ca n cer. p df  
O ke n M M, Creec h R H, T or me y D C,  et al. T o xicit y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol.  1 9 8 2; 5: 6 4 9 -6 5 5.  
Orte ga S, Mal u m bres M, Bar baci d M. C ycli n D -de pe n de nt ki nases, I N K 4 i n hi bit ors a n d ca ncer. 
Bi oc hi m Bi o p hys Act a . 2 0 0 2; 1 6 0 2( 1): 7 3-8 7.  htt ps:// d oi. or g/ 1 0. 1 0 1 6/s 0 3 0 4 -4 1 9 x( 0 2) 0 0 0 3 7 -9  
Oz g ur o gl u M, C h o w d h ur y S, Bjartell A, et al. A pal uta mi de ( A P A) f or met astatic castrati o n -
se nsiti ve pr ostate ca n cer ( m C S P C) i n TI T A N: o utc o mes i n patie nts ( pts) wit h l o w - a n d hi g h -
ris k disease. J Cli n O nc ol . 2 0 20; 3 8(s u p pl _ 6): 8 7. 
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 2 0. 3 8. 6 _s u p pl. 8 7  
Pal S K, Patel J, He M, et al. I d e ntificati o n of mec h a nis ms of resista nce t o treat me nt wit h 
a birater o n e acetate or e n zal uta mi de i n patie nts wit h castrati o n -resista nt pr ostate ca ncer 
( C R P C). C a ncer.  2 0 1 8; 1 2 4( 6): 1 2 1 6 -1 2 2 4.  htt ps:// d oi. or g/ 1 0. 1 0 0 2/c ncr. 3 1 1 6 1  
Par ker C, Castr o E, Fizazi K, et al .; E S M O G ui deli nes C o m mittee. Pr ostate ca ncer: E S M O 
cli nical 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 2 0; 3 1( 9): 1 1 1 9 -1 1 3 4. htt ps:// d oi. or g/ 1 0. 1 0 1 6/j.a n n o nc. 2 0 2 0. 0 6. 0 1 1  
Pear ma n T P, Bea u m o nt  J L, Mr ocze k  D, et al. Vali dit y a n d usef ul ness of a si n gle-ite m meas ure 
of patie nt -re p orte d b ot her fr o m si de effects of ca n cer t hera p y. C a ncer.  2 0 1 8; 1 2 4( 5): 9 9 1 -9 9 7. 
htt ps:// d oi. or g/ 1 0. 1 0 0 2/c ncr. 3 1 1 3 3  
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 4 1  
Rat h k o pf D E, Beer T M, L ori ot Y, et al. Ra di o gra p hic p r o gressi o n-free sur vi val as a cli nicall y 
m ea ni n gf ul en d p oi nt i n m etastatic castr ati o n -resista nt p r ostate ca n cer: T he P R E V AI L 
ra n d o mize d cli nic al trial. J A M A O nc ol . 2 0 1 8; 4( 5): 6 9 4-7 0 1. 
htt ps:// d oi . or g/1 0. 1 0 0 1/ja ma o nc ol. 2 0 1 7. 5 8 0 8  
Rizz o J D, Br o u wers M, H urle y P, et al.; A merica n S ociet y of Cli nical O nc ol o g y; A merica n 
S ociet y of He mat ol o g y. A merica n S ociet y of Cli nical O nc ol o g y/ A merica n S ociet y of 
He mat ol o g y cli nical pr actice g ui deli ne u p date o n t he use of e p o eti n a n d dar be p oeti n i n a d ult 
patie nts wit h ca ncer. J Cli n O nc ol.  2 0 1 0; 2 8( 3 3): 4 9 9 6 -5 0 1 0.  htt ps:// d oi. or g/ 1 0. 1 1 8 2/ bl o o d -
2 0 1 0 -0 8 -3 0 0 5 4 1  
[ S E E R] S ur veilla nce, E pi de mi ol o g y , a n d E n d Res ults Pr o gra m. Ca ncer Stats Facts : Pr ostate 
Ca ncer  p a ge.  A ccess e d N o ve m ber 3 0, 2 0 2 1.  htt ps://seer.ca n cer. g o v/statf acts/ ht ml/ pr ost. ht ml  
S herr CJ. Ca ncer cell cy cles. Scie nce . 1 9 9 6; 2 7 4: 1 6 7 2-1 6 7 7.  
htt ps:// d oi. or g/ 1 0. 1 1 2 6/scie nce. 2 7 4. 5 2 9 3  
Sle d ge G W Jr, T oi M, N e ve n P, et al. M O N A R C H 2: A be macicli b i n co m bi nati o n wit h 
ful vestra nt i n w o me n w it h H R +/ H E R 2- ad va n ce d b reast ca ncer w h o h a d p r o gresse d w hile 
recei vi n g en d o cri ne th era p y. J Cli n O nc ol . 2 0 1 7; 3 5( 2 5): 2 8 7 5-2 8 8 4.  
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 1 7. 7 3. 7 5 8 5  
Sle d ge G W Jr, T oi M, N e ve n P, et al. T he effect of abe macicli b p l us ful vestra nt o n o verall 
sur vi val i n h or m o ne rece pt or -p ositi ve, E R B B 2 -n e gati ve b reast ca ncer that p r o gresse d o n 
en d ocri ne thera p y -M O N A R C H 2: a ra n d o mize d c li nical trial. J A M A O nc ol . 2 0 2 0; 6( 1): 1 1 6-
1 2 4.  htt ps:// d oi. or g/ 1 0. 1 0 0 1/ja ma o nc ol. 2 0 1 9. 4 7 8 2  
S mit h TJ, B o hl ke K, L y ma n G H, et al.; A meri ca n S ociet y of Cli nical O nc ol o g y. 
Rec o m me n dati o ns f or t h e Use of W B C gr o wt h fact ors: A merica n S oci et y of Cli nical 
O nc ol o g y cli nical practice g ui deli ne u p date. J Cli n O nc ol. 2 0 1 5; 3 3( 2 8): 3 1 9 9 -3 2 1 2.  
htt ps:// d oi. or g/ 1 0. 1 2 0 0/J C O. 2 0 1 5. 6 2. 3 4 8 8  
S u n g H, Ferla y J, Sie gel R L, et al. Gl o bal ca n cer statistics 2 0 2 0: G L O B O C A N esti mates of 
i nci de nce a n d m ortalit y w orl d wi de f or 3 6 ca n cers i n 1 8 5 c o u ntries. C A C a ncer J Cli n . 
2 0 2 1; 7 1( 3): 2 0 9 -2 4 9. htt ps:// d oi. or g/ 1 0. 3 3 2 2/caac. 2 1 6 6 0  
S wee ne y CJ, C he n Y H, Car d ucci M, et al. C he m o h or m o nal thera p y i n m etastatic h or m o ne -
se nsiti ve p r ostate ca n cer. N E n gl J Me d . 2 0 1 5; 3 7 3( 8): 7 3 7-7 4 6.  
htt ps:// d oi. or g/ 1 0. 1 0 5 6/ N EJ M oa 1 5 0 3 7 4 7  
T orres -G uz má n R, Ba q u er o C, Ga na d o M P, et al. A bstract 4 8 5 0: Tar geti n g pr ostate ca n cer wit h 
t he C D K 4 a n d C D K 6 i n hi bit or a be macicli b. C a ncer Res . 2 0 2 0; 8 0(s u p pl 1 6).   
T ur ner N C, Sla m o n DJ, R o J,  et al. O verall sur vi val wit h p al b ocicli b a n d ful vestra nt i n ad va nce d 
b reast c a ncer. N E n gl J Me d . 2 0 1 8; 3 7 9( 2 0): 1 9 2 6-1 9 3 6. 
htt ps:// d oi . or g/1 0. 1 0 5 6/ N EJ M oa 1 8 1 0 5 2 7  
Ver ze ni o [ pac ka ge i nsert] . I n dia na p olis, I N: L ill y U S A, L L C; 2 0 2 1. 
A p pr o ve d o n 0 6 J u n 2 0 2 4 G M T

C O N FI D E N TI A L  
Pr ot oc ol I 3 Y -M C -J P E G(e) 
1 4 2  
W o o S, S u h C H, Wi b mer A G, et al. C orrelati o n b et wee n ima gi n g -b as e d inter me diate en d p oi nts 
a n d o verall sur vi val i n m e n w it h m etastatic castr ati o n -resista nt p r ostate ca n cer: an al ysis of 2 8 
ra n d o mize d trials u si n g t he Pr ostate Ca ncer Cli nical Trials W or ki n g Gr o u p ( P C W G 2) criteria 
i n 1 6, 5 1 1 p atie nts. Cli n Ge nit o uri n C a ncer . 2 0 2 1;S 1 5 5 8 -7 6 7 3( 2 1) 0 0 2 1 8 -4. 
htt ps:// d oi . or g/1 0. 1 0 1 6/j.cl gc. 2 0 2 1. 1 1. 0 0 7  
X u Y, C he n S Y, R oss K N, Bal k S P. A n dr o ge ns i n d uce pr ostate ca n cer cell pr oliferati o n t hr o u g h 
ma m malia n tar get of ra p a m y ci n acti vati o n a n d p ost -tra nscri pti o nal i ncreas es i n c ycli n D 
pr otei ns. C a ncer Res.  2 0 0 6; 6 6( 1 5): 7 7 8 3 -7 7 9 2.  htt ps:// d oi. or g/ 1 0. 1 1 5 8/ 0 0 0 8 -5 4 7 2. C A N -0 5 -
4 4 7 2  
 
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