A Phase II Clinical Trial of the PARP Inhibitor Talazoparib in BRCA1 and BRCA2 Wild Type Patients With Advanced Triple Negative Breast Cancer and Homologous Recombination Deficiency or Advanced HER2 Negative Breast Cancer or Other Solid Tumors With a Mutation in Homologous Recombination Pathway Genes
Phase: PHASE2
Conditions: Advanced Breast Cancer, HER2/Neu Negative, Triple-Negative Breast Cancer
Sponsor: Melinda Telli

I R B-3 1 9 1 3 versi o n 8  
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A P h ase  2 cli nic al tri al of t he P A R P i n hi bit or t al az o p ari b i n B R C A 1 a n d B R C A 2 wil d -t y pe 
p atie nts wit h a d v a nce d tri ple -ne g ati ve bre ast c a ncer a n d h o m ol o g o us rec o m bi n ati o n 
deficie nc y or a d v a nce d H E R 2 -ne g ati ve bre ast c a ncer or ot her s oli d t u m o rs wit h a m ut ati o n 
i n h o m ol o g o us rec o m bi n ati o n p at h w a y ge nes 
C o or di n ati n g Ce nter  
Sta nf or d Ca ncer I nstit ute  
8 7 5 Bla ke Wil b ur Dri ve  
Sta nf or d, C A 9 4 3 0 5  
I n vesti g at ors 
Meli n d a  L  Telli,  M D  
Assista nt Pr ofess or of M e dici ne  
Di visi o n of O nc ol o g y  
Sta nf or d U ni versit y Sc h o ol of Me dic i ne 
8 7 5 Bla ke Wil b ur Dr,  Sta nf or d, C A  9 4 3 0 5  
Tele p h o ne : 
;  Fa x: 
  
E mail: 
  
J os h u a  Gr u ber,  M D,  P h D  
P ost -D oct oral Fell o w  
De part me nts of M e dici ne a n d Ge netics  
Sta nf or d U ni v ersit y Sc h o ol of Me dici ne  
3 1 6 5 P orter Dr,  Pal o Alt o, C A  9 4 3 0 4  
Tele p h o ne: 
 
E mail: 
 
Bi ost atistici a n  
Ale x Mc Milla n, P h D  
Se ni or Researc h Scie ntist  
Bi o me dical D ata Scie nce  
Sta nf or d  U ni versit y Sc h o ol of Me dici ne  
H R P Re d w o o d B uil di n g, R o o m T 1 6 0 A  
2 5 9 Ca m p us Dr,  Sta nf or d, C A  9 4 3 0 5  
P h o ne: 
;  Fa x: 
 
E mail: 
 
St u d y C o or di n at or  
W yatt  F orrest  Gr oss , B S  
8 0 0 Welc h R oa d, R o o m F C 3 C 4 5  
Sta nf or d, C A  9 4 3 0 4  
P h o ne: 
;  Fa x: 
 
E mail:  
 
 
I R B-3 1 9 1 3  
B R S 0 0 5 0  
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T A B L E:  S U M M A R Y O F C H A N G E S  
Re visi o n D ate  
C h a n ges  
Pri or 
a me n d me nts  
 Title c orrecte d o n pa ge 1 a n d t hr o u g h o ut  
 Clarifie d S A E re p orti n g g ui da nce f or Pfizer, t he n e w st u d y s p o ns or.  A d de d S CI 
S A E re p orti n g g ui deli nes f or i n vesti gat or -i nitiate d trials i n A p pe n di x B.  
 Clarifie d st u d y  cale n dar –  c ha n ge d st u d y wee ks t o st u d y c ycl es.  
 Clarifie d defi niti o n of c hil d beari n g p ot e ntial o n eli gi bilit y c hec klist a n d i n 
eli gi bilit y criteria secti o n i n pr ot oc ol  
 Clarifie d nee d e d i ma gi n g at baseli ne o n eli gi bilit y c hec klist  
 A d de d t he f oll o wi n g t o e li gi bilit y c hec klist 
o  A vaila bilit y of arc hi val t u m or tiss ue fr o m pri mar y breast/t u m or site  
o  A de q uate fres h or arc hi v al t u m or tiss ue fr o m metastatic bi o ps y site, if bi o ps y 
is tec h nicall y feasi ble 
o  S u bjects of c hil d beari n g p ote ntial m ust be willi n g t o ha ve a d d iti o nal uri ne 
pre g na nc y t ests d uri n g t h e st u d y.  
o  Clarifie d t hat le pt o me ni n geal disease is e xcl u de d  
T he a b o ve c ha n ges were pre vi o usl y re p orte d t o t h e I R B, b ut are retai ne d f or 
ali g n me nt wit h t his versi o n of t he pr ot oc ol, as s u b mitte d t o t he I N D.  
 Eli gi bilit y  Criteria har m o nize d wit h Eli gi bilit y  C h ec klist, a n d prese nt e d as a 
si n gle i nsta nce at Secti o n 3. 1.  
o  U p date d t he refere nce t o N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts ( C T C A E) versi o n  4 t o versi o n  5 . . 
2  Se pte m ber  2 0 2 0  I n a d vert e ntl y o mitte d te xt is rest ore d 
 

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T A B L E O F C O N T E N T S  
 
I N V E S TI G A T O R S ....................................................................................................................... 1  
P R O T O C O L S Y N O P SI S  ............................................................................................................. 5  
S T U D Y S C H E M A  ........................................................................................................................ 8  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  .............................................. 9  
1.  
O B J E C TI V E S  ..................................................................................................................... 1 0  
1. 1  
P RI M A R Y O BJ E C TI V E  ..................................................................................................... 1 0  
1. 2  
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................... 1 0  
1. 3  
C O R R E L A TI V E O BJ E C TI V E S  ............................................................................................ 1 0  
2.  
B A C K G R O U N D  ................................................................................................................. 1 0  
2. 1   
B R C A 1/ 2 -M U T A TI O N A S S O CI A T E D B R E A S T C A N C E R  ................................................... 1 0  
2. 2  
S P O R A DI C T RI P L E -N E G A TI V E B R E A S T C A N C E R  ............................................................. 1 1  
2. 3  
C A N C E R S WI T H G E R M LI N E  O R S O M A TI C D E FI CI E N C Y I N D N A  D O U B L E -S T R A N D R E P AI R
  
1 1  
2. 4  
T H E M Y RI A D H O M O L O G O U S R E C O M B I N A TI O N D E FI CI E N C Y (H R D ) A S S A Y  .................. 1 3  
2. 5  
O V E R VI E W O F T H E S T U D Y  A G E N T T A L A Z O P A RI B  ............................................................ 1 4  
2. 6  
R A TI O N A L E  .................................................................................................................... 1 8  
2. 7  
S T U D Y D E SI G N  .............................................................................................................. 2 0  
3.  
P A R TI CI P A N T S E L E C TI O N A N D E N R O L L M E N T P R O C E D U R E S  ...................... 2 1  
3. 1  
E LI GI BI LI Y C RI T E RI A  A N D P A R TI CI P A N T E LI GI BI LI T Y C H E C K LI S T  ... E R R O R ! B O O K M A R K 
N O T D E FI N E D . 
3. 2  
IN F O R M E D C O N S E N T P R O C E S S  ....................................................................................... 2 1  
3. 3  
R A N D O MI Z A TI O N P R O C E D U R E S  ..................................................................................... 2 6  
3. 4  
S T U D Y T I M E LI N E ........................................................................................................... 2 6  
4.  
T R E A T M E N T P L A N  ......................................................................................................... 2 6  
4. 1  
S C R E E NI N G P R O C E D U R E S  .............................................................................................. 2 6  
4. 2  
D O SI N G A N D A D MI NI S T R A TI O N S C H E D U L E  .................................................................... 2 7  
4. 3  
P R E -T R E A T M E N T E V A L U A TI O N S  .................................................................................... 2 8  
4. 4  
E N D O F T R E A T M E N T P R O C E D U R E S  ................................................................................ 2 8  
4. 5  
G E N E R A L C O N C O MI T A N T M E DI C A TI O N A N D S U P P O R TI V E C A R E G UI D E LI N E S  ............... 2 9  
4. 6  
D U R A TI O N O F T H E R A P Y A N D F O L L O W -U P  ..................................................................... 2 9  
4. 7  
C RI T E RI A F O R R E M O V A L F R O M S T U D Y  .......................................................................... 2 9  
4. 8  
A L T E R N A TI V E S  .............................................................................................................. 2 9  
4. 9  
C O M P E N S A TI O N  ............................................................................................................. 3 0  
5.  
I N V E S TI G A TI O N A L A G E NT/ D E VI C E/ P R O C E D U R E I N F O R M A TI O N  ............... 3 0  
5. 1  
IN V E S TI G A TI O N A L A G E N T  ............................................................................................. 3 0  
5. 2  
P H A R M A C O D Y N A MI C P R O P E R TI E S  ................................................................................. 3 0  
5. 3  
P H A R M A C O KI N E TI C P R O P E R TI E S  .................................................................................... 3 1  
5. 4  
S U P P LI E R  ....................................................................................................................... 3 1  
5. 5  
D O S A G E F O R M  ............................................................................................................... 3 1  
5. 6  
A G E N T O R D E RI N G A N D P A C K A GI N G  .............................................................................. 3 1  
5. 7  
S T O R A G E A N D S H E L F LI F E  .............................................................................................. 3 2  

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5. 8  
N A T U R E A N D C O N T E N T S O F C O N T AI N E R  ....................................................................... 3 2  
5. 9  
S P E CI A L P R E C A U TI O N S F O R D I S P OS A L A N D O T H E R H A N D LI N G  ..................................... 3 2  
6.  
D O S E M O DI FI C A TI O N S  ................................................................................................. 3 2  
7.  
A D V E R S E E V E N T S A N D R E P O R TI N G P R O C E D U R E S  ........................................... 3 3  
7. 1  
P O T E N TI A L A D V E R S E E V E N T S  ....................................................................................... 3 3  
7. 2  
A D V E R S E E V E N T A N D P R E G N A N C Y R E P O R TI N G  ............................................................ 3 5  
7. 3  
P R O D U C T C O M P L A I N T S R E P O R TI N G  ............................................................................... 3 6  
8.  
C O R R E L A TI V E  S T U DI E S  .............................................................................................. 3 6  
9.  
S T U D Y C A L E N D A R  ......................................................................................................... 3 8  
1 0.  
M E A S U R E M E N T S  ........................................................................................................ 3 9  
1 0. 1  
P RI M A R Y E N D P OI N T  ...................................................................................................... 3 9  
1 0. 2     S E C O N D A R Y E N D P OI N T S  .................................................................................................. 3 9  
1 0. 3  
C O R R E L A TI V E E N D P OI N T S  ............................................................................................. 4 0  
1 1.  
R E G U L A T O R Y C O N SI D E R A TI O N S  ........................................................................ 4 0  
1 1. 1  
IN S TI T U TI O N A L R E VI E W O F P R O T O C O L  .......................................................................... 4 0  
1 1. 2  
D A T A A N D S A F E T Y M O NI T O RI N G P L A N  ......................................................................... 4 0  
1 1. 3  
D A T A M A N A G E M E N T P L A N  ........................................................................................... 4 1  
1 2.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................... 4 1  
1 2. 1  
A N A L Y TI C P L A N F O R S T U D Y O BJ E C TI V E S  ..................................................................... 4 1  
1 2. 2  
A N A L Y SI S P O P U L A TI O N  .................................................................................................. 4 2  
1 2. 3  
S A M P L E S I Z E C A L C U L A TI O N S  ........................................................................................ 4 2  
1 2. 4   A C C R U A L E S TI M A T E S A N D F E A SI BI LI T Y  ........................................................................ 4 2  
R E F E R E N C E S  ............................................................................................................................ 4 3  
A P P E N DI X A :  
S A E R E P O R TI N G G UI D E L I N E S; S CI S O P 1 0-1 6 -2 0 1 4  ...................... 4 6  
 

I R B-3 1 9 1 3 versi o n 8  
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P R O T O C O L S Y N O P SI S  
Title of St u d y:   A p hase  2  cli nical trial of t he P A R P i n hi bit or talaz o parib  i n B R CA 1 a n d B R C A 2 
wil d -t y pe patie nts wit h a d va nce d tri ple-ne gati ve breast ca ncer a n d h o m ol o g o us rec o m bi nati o n 
deficie nc y or  a d va nce d H E R 2 -ne gati ve breast  ca ncer  or ot her s oli d t u m ors  wit h a m utati o n i n 
h o m ol o g o us rec o m bi nati o n pat h wa y ge nes  
C o nce pt a n d R ati o n a le:  I n t his p hase 2  pr o of -of -c o nce pt cli nical trial, we pr o p ose t o test t he 
efficac y of  talaz o pari b, a p ote nt, orall y-bi oa vaila ble P A R P i n hi bit or, wit h a n esta blis he d P hase  2  
rec o m me n de d d ose, i n t he treat me nt of a d va nce d B R C A wil dt y pe ( W T ), H E R 2-n e gati ve  breast 
ca ncer a n d ot her s oli d t u m ors  wit h h o m ol o g o us rec o m bi nati o n ( H R ) deficie nc y.  T he trial is 
c o m p ose d of t w o patie nt c o h orts .  C o h ort  A  c o nsists of patie nts wit h a d va nce d tri ple-ne gati ve 
breast ca ncer ( T N B C ) a n d a hi g h h o m ol o g o us rec o m bi nati o n defici e nc y ( H R D ) sc ore as assesse d 
b y t he M yria d  H R D  assa y.  C o h ort  B  c o nsists of patie nts wit h a d va nce d H E R 2 -ne gati ve breast 
ca ncer or ot her s oli d t u m ors  wit h a ger mli ne  or s o matic m utati o n i n a ge ne li n ke d t o t he  H R 
pat h wa y .  Patie nts alrea d y i de ntifie d as har b ori n g a deleteri o us or s us pecte d deleteri o us ger mli ne  
or s o matic m utati o n i n t he  H R pat h wa y will be i m me diatel y eli gi ble f or treat me nt i n C o h ort  B.  
      T he 
M yria d  H R D  assa y is a t u m or tiss ue -base d assa y t hat has bee n de vel o pe d usi n g a n 
i n direct a p pr oach t hat all o ws f or t he detecti o n of  H R D  as assesse d b y q ua ntif yi n g le vels of 
ge n o mic i nsta bilit y .  T he Sta nf or d Breast Ca ncer gr o u p has pre vi o usl y assesse d t his assa y i n a 
plati n u m -base d ne oa dj u va nt p hase  2  trial a n d s h o we d t hat a hi g h H R D  sc ore si g nifica ntl y 
c orrelates wit h a fa v ora ble pat h ol o gic res p o nse i n earl y -sta ge T N B C wit h a n d wit h o ut a ger mli ne  
B R C A 1/ 2 m utati o n .  Li ke wise, Isa k off a n d c ollea g ues rece ntl y re p orte d t he c orrelati ve e n d p oi nts 
of t he T B C R C 0 0 9 st u d y, a si n gle -ar m p hase  2  trial of plati n u m t hera p y i n metastatic T N B C.  
W hile esta blis he d bi o mar kers, i ncl u di n g p 6 3/ p 7 3 rati o a n d p 5 3 a n d PI K 3 C A m utati o ns faile d t o 
pre dict f or plati n u m res p o nse,  H R D  assa ys di d i de ntif y s p ora dic T N B C t u m ors t hat were m ore 
res p o nsi ve t o plati n u m t hera p y.  
      A s e parate a p pr oac h t o detecti n g  H R D  ma y be t he use of  m ulti ple x ge ne pa nels t hat e val uate  
n o n -B R C A 1/ 2  ger mli ne  m utati o ns i m plicate d i n h o m ol o g o us rec o m bi nati o n .  M utati o ns i n ge nes 
li n ke d t o t he H R pat h wa y, s uc h as A T M, P A L B 2 a n d R A D 5 1  a m o n g ot hers , are h y p ot hesize d t o 
ha ve si milar c he m ose nsiti vit y t o D N A -da ma gi n g t hera pies as m utati o ns i n B R C A 1 a n d B R C A 2 
gi ve n a si milar s y nt heticall y let hal effect .  I de ntificati o n of s o m atic m utati o ns i n  H R -relate d 
ge nes t hr o u g h c o m merciall y a vaila ble ne xt -ge nerati o n D N A se q ue nci n g of t u m or tiss ues als o has 
p ote ntial t o i de ntif y patie nts w h o ma y deri ve be nefit fr o m D N A re pair defect -tar gete d t hera p y.  
H o we ver, n o st u dies t o -date ha ve directl y e val uate d t he r ole of D N A -da ma gi n g t hera pies i n s uc h 
patie nt p o p ulati o ns.  
Pri m ar y O bjecti ve(s):   
T o deter mi ne w het her si n gle a ge nt talaz o pari b ca n res ult i n a 3 0 % or greater o bjecti ve res p o nse 
i n patie nts wit h a d va nce d s p or a dic tri ple-ne gati ve breast ca ncer wit h h o m ol o g o us rec o m bi nati o n 
deficie nc y as assesse d b y t he  H R D  assa y ( C o h ort  A)  or a d va nce d H E R 2 ne gati ve (ie , T N or 
E R/ P R p ositi ve) breast ca ncer or  ot her  s oli d t u m ors wit h a ger mli ne  or s o m atic m utati o n i n 
t he H R pat h wa y, e xcl u di n g B R C A 1/ 2 ( C o h ort  B).  
Sec o n d ar y O bjecti ve(s):  
1. T o deter mi ne t he cli nical be nefit rate (c o m plete res p o nse, partial res p o nse or sta ble diseas e 
≥ 2 4  wee ks)  
2 . T o deter mi ne pr o gressi o n-free s ur vi val 
3 . T o e val uate t he safet y of talaz o pari b i n t his patie nt p o p ulati o n 
C orrel ati ve O bjecti ve(s):  
1. T o c o m pare t he rate of res p o nse i n s u bjects wit h T N B C wit h or wit h o ut a n u n derl yi n g 

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ger mli ne  H R pat h wa y m utati o n (C o h ort  A).  
2. T o c o m pare t he  H R D  sc ores i n res p o n ders vers us n o n-res p o n ders wit h u n derl yi n g deleteri o us 
or s us pecte d deleteri o us ger mli ne  or s o matic  H R ge ne m utati o ns ( C o h ort  B).  
3. T o assess t he c o nc or da nce of t he  H R D  sc ores i n t he pri mar y t u m or tiss ue wit h t hat i n t he 
metastatic t u m or tiss ue.  
4. T o assess i n metastatic t u m or bi o ps y sa m ples, t he R A D 5 1 stat us of t he t u m or at baseli ne 
(a bse nt or prese nt) as a f u ncti o nal rea d o ut of H R ca pacit y a n d c orrelate t his wit h  H R D  a n d 
m utati o nal stat us  
Pri m ar y E n d p oi nt(s):  
T he o bjecti ve res p o nse rate of  talaz o pari b usi n g R E CI S T 1. 1 criteria  
Sec o n d ar y E n d p oi nt(s):   
1. Cli nical be nefit rate  
2 . Pr o gressi o n-free s ur vi val 
3 . Safet y 
C orrel ati ve E n d p oi nt(s):  
1. O bj ecti ve res p o nse rate i n s u bjects wit h T N B C wit h or  wit h o ut a n u n derl yi n g ger mli ne  H R 
pat h wa y m utati o n i n C o h ort  A  
2. C orrelati o n of  H R D  sc ores wit h res p o nse i n s u bj ects  wit h u n derl yi n g  ger mli ne  or s o matic  H R 
ge ne m utati o ns i n C o h ort  B  
3. C orrelati o n of  H R D  sc ores i n t he pri mar y t u m or tiss ue a n d t he metastatic t u m or tiss ue. 
4. C orrelati o n of R A D 5 1 stat us i n t he metastatic t u m or wit h H R D  a n d m utati o nal stat us. 
St u d y Desi g n:  A si n gle -ar m, p hase  2  cli nical trial c o nsisti n g of 2 patie nt c o h orts 
( parallel desi g n), usi n g a n o pti mal t w o -sta ge desi g n.  T he t w o pa tie nt c o h orts are t he f oll o wi n g: 
C o h ort  A:   T N B C patie nts wit h  H R deficie nc y as meas ure d b y t he M yria d  H R D  assa y 
C o h ort  B:   H E R 2 -ne gati ve (ie , tri ple-ne gati ve or estr o ge n/ pr o gester o ne rece pt or -p ositi ve) breast 
ca ncer or ot her s oli d t u m or  patie nts wit h a ge r mli ne or s o m atic m utati o n i n a  H R pat h wa y ge ne .  
Ge ne m utati o ns of i nterest are:  P T E N ;  P A L B 2 ;  C H E K 2 ;  A T M ;  N B N ;  B A R D 1 ;  B RI P 1 ;  
R A D 5 0 ;  R A D 5 1 C ;  R A D 5 1 D ;  M R E 1 1 ;  A T R ;  Fa nc o ni a ne mia c o m ple me ntati o n gr o u p of 
ge nes ( F A N C A ;  F A N C C ;  F A N C D 2 ;  F A N C E ;  F A N C F ;  F A N C G ;  F A N C L).  
N u m ber of P atie nts:  We will accr ue 1 0 patie nts, if we o bser ve a res p o nse i n at least 2 patie nts, 
t he n we will accr ue 10  a d diti o nal patie nts f or a t otal of 2 0  patie nts i n eac h c o h ort , a n d re q uire a 
res p o nse i n at least 3 patie nts o ut of 2 0 t o declare statistical si g nifica nce at a o ne si de d 
si g nifica nce le vel of 5 %, i n or der t o ass ure 8 0 % p o wer.   It is e x pecte d t hat at least 
1 0  H E R 2 -ne gati ve breast ca ncer patie nts will be e nr olle d i n C o h ort  B.  
S u m m ar y of Eli gi bilit y :  
 A d ults wit h a s ol i d t u m or meas ura ble per R E CI S T v 1. 1,  wit h o ut s us pecte d deleteri o us 
ger mli ne B R C A 1 or B R C A 2 ge ne m utati o n i n t he ger mli ne, a n d ha vi n g recei ve d at least 1 
pri or s yste mic t h era p e utic re gi me n.  Eli gi ble s u bjects will ha ve E C O G perf or ma nce 
stat us of 0 t o 2 a n d a de q uate or ga n f u ncti o n, wit h a de q uate birt h c o ntr ol preca uti o ns.  Please 
see c o m plete Eli gi bilit y Criteria at Secti o n 3 . 1.  
I nter ve nti o n a n d M o de of Deli ver y:   T alaz o pari b , 1 m g  P O dail y (c o nti n u o us d osi n g) o n a 
2 8 -da y c ycle.  Patie nts will be e val uate d  pri or t o eac h c ycle.  T his will i ncl u de a cli nical 
e val uati o n, i ncl u di n g safet y assess me nt a n d p h ysical e xa m, as well as la b orat or y assess me nt.  
D ur ati o n of I nter ve nti o n a n d E v al u ati o n:   T he n o mi nal d urati o n of treat me nt is 3 6  c ycles 

I R B-3 1 9 1 3 versi o n 8  
P a ge 7  of 4 6   
2  Se pte m ber  2 0 2 0  
( 2 8 da ys per c ycle),  b ut C R, P R, or S D patie nts ma y  c o nti n ue t hera p y u ntil e vi de nce of 
pr o gressi ve disease or u nacce pta ble t o xicit y occ urs.  Pr ot oc ol t hera p y will be disc o nti n ue d f or 
pr o gressi ve disease at a n y ti me .  Patie nts are free t o halt t hera p y at t heir re q uest .  Treat m e nt ma y 
be disc o nti n ue d if i nterc urre nt c o -m or bi dities occ ur, w hic h, i n t he o pi ni o n of t he treati n g 
p h ysicia n, w o ul d precl u de safe a d mi nistrati o n of st u d y dr u gs.  
F u n di n g, Re g ul at or y, a n d F e asi bilit y Iss ues:   T his i n vesti gat or -i nitiate d P hase 2  cli nical t rial 
will be f u n de d b y  Pfizer P har mace utical, I nc.  T his p har mace utical c o m pa n y has c o m mitte d t o 
pr o vi di n g t he st u d y dr u g, talaz o pari b.  
P atie nt Acce pt a bilit y/ Et hics a n d C o nse nt Iss ues:   Gi ve n t he lac k of tar gete d t hera p y o pti o ns 
f or T N B C patie nts, we belie ve t his trial will be a welc o me d alter nati ve c o m pare d t o sta n dar d 
c yt ot o xic c he m ot hera p y i n t his patie nt p o p ulati o n.  Of p ossi ble c o ncer n t o t he patie nt or a d v ocate 
c o m m u nit y ma y be t hat we will re q uire t u m or tiss ue of a metastatic site f or trial partici pati o n .  
T his bi o ps y is critical f or t he s uccessf ul c o n d uct of t his st u d y .  F urt her m ore, as patie nts will 
re q uire ge netic testi n g, we will offer ge netic c o u nseli n g t o all patie nts e nr olle d i n t his trial.  
 

I R B-3 1 9 1 3 versi o n 8  
P a ge 8  of 4 6   
2  Se pte m ber  2 0 2 0  
S T U D Y S C H E M A  
 
 

I R B-3 1 9 1 3 versi o n 8  
P a ge 9  of 4 6   
2  Se pte m ber  2 0 2 0  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI T I O N O F T E R M S 
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A S T  
As partate a mi n otra nsferase  
BI D  
T wice dail y  
B S A  
B o d y s urface area  
C B C  
C o m plete bl o o d c o u nt  
CI  
C o nfi de nce i nter val  
C M A X  
Ma xi m u m c o nce ntrati o n of dr u g  
C N S  
Ce ntral ner v o us s yste m  
C R F  
Case re p ort/ Rec or d f or m  
C R  
C o m plete res p o nse  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
D L T  
D ose Li miti n g T o xicit y  
D S M C  
Data Safet y M o nit ori n g C o m mittee  
E C G  
Electr 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 R  
Estr o ge n rece pt or  
F D A  
U S f o o d a n d dr u g a d mi nistrati o n  
F F P E  
F or mali n -fi xe d paraffi n e m be d de d 
G C P  
G o o d cli nical practice  
H g b  
He m o gl o bi n  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
H N S T D  
Hi g hest n o n -se verel y t o xic d ose 
H R  
H o m ol o g o us Rec o m bi nati o n  
H R D  
H o m ol o g o us Rec o m bi nati o n Deficie nc y  
I B 
I n vesti gat or's br oc h ure 
I P 
I n vesti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntra ve n o us 
L F T  
Li ver f u ncti o n test  
L O H  
L o ss of heter oz yg osit y  
M T D  
Ma xi m u m t olerate d d ose  
O S  
O verall s ur vi val  
P A R P  
P ol y -A D P ri b o se p ol y merase 
p C R  
P at h ol o gic c o m plete res p o nse  
P D  
Pr o gressi ve disease d  or P har mac o d y na mic s 
P F S  
Pr o gressi o n -free s ur vi val  
P K  
P har mac o ki netic  
Plt  
Platelet c o u nt  
P R  
P artial res p o nse  or Pr o gester o ne rece pt or  
Q D  
O nce dail y  
R E CI S T  
Res p o nse e val uati o n cr iteria i n s oli d t u m ors 
R R  
Res p o nse rate  
S A E  
Seri o us a d verse e ve nt  
S D  
Sta ble disease  
S R C  
Scie ntific Re vie w C o m mittee  
T N  
Tri ple -ne gati ve  
T K  
T o xic o ki netic  
T N B C  
Tri ple -ne gati ve breast ca ncer  
U L N  
U p per li mit of n or mal  
W B C  
W hite bl o o d cell  

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 0  of 4 6   
2  Se pte m ber  2 0 2 0  
1.   
O B J E C TI V E S  
1. 1   
Pri m ar y O bjecti ve  
  
T o deter mi ne w het her si n gle a ge nt talaz o pari b pr o d uces better t ha n e x pecte d res p o nses  i n 
patie nts 
wit h a d va nce d  s p or a dic tri ple-ne gati ve breast ca ncer 
wit h h o m ol o g o us 
rec o m bi nati o n deficie nc y as assess e d b y t he  H R D  assa y (C o h ort  A)  a n d/or  a d va n ce d 
H E R 2 -ne gati ve ( ie, T N - or E R/ P R -p ositi ve) breast  ca n cer or ot her n o n -breast s oli d 
t u m ors wit h  a ger mli ne  or s o m atic m utati o n i n t he H R pat h wa y , e x cl u di n g B R C A 1 or 
B R C A 2 (C o h ort  B).   
1. 2   
Sec o n d ar y O bjecti ves  
1. 2. 1  T o deter mi ne cli nical b e ne fit rate (c o m plete res p o nse, partial res p o ns e or sta ble 
disease ≥ 2 4  wee ks)  
1. 2. 2   T o deter mi ne pr o gressi o n -free s ur vi val i n b ot h c o h orts 
1. 2. 3  T o e val uate t he s afet y of talaz o pari b i n b ot h patie nt p o p ulati o n s 
1. 3   
C orrel ati v e O bjecti v es  
1. 3. 1  T o c o m pare t h e rate of res p o nse i n s u bjects wit h T N B C wit h or wit h o ut a n 
u n de rl yi n g ger mli ne  H R pat h wa y m utati o n ( C o h ort  A).  
1. 3. 2  T o c o m pare t h e  H R D  sc ores i n res p o n ders vers us n o n-res p o n ders wit h u n derl yi n g 
deleteri o us or s us pecte d deleteri o us ger mli ne  or s o matic  H R ge n e m utati o ns 
(C o h ort  B).  
1. 3. 3  T o assess t he c o n c or da n ce of t he  H R D  sc ores i n t h e pri mar y t u m or tiss ue wit h 
t hat i n t he metastatic t u m or tiss ue. 
1. 3. 4  T o assess i n metastatic t u m or bi o ps y sa m ples, t he R A D 5 1 stat us of t he t u m or at 
baseli ne (a bs e nt or pres e nt) as a f u ncti o nal rea d o ut of  H R ca pacit y a n d c orrelate 
t his wit h  H R D  a n d m utati o nal stat us 
2.   
B A C K G R O U N D  
2. 1  
B R C A 1/ 2 -M ut ati o n Ass oci ate d Bre ast C a ncer  
Ca ncer is a ge netic dise ase ca use d b y a n acc u m ulati o n of c ha n ges i n t he D N A s e q ue nce o ver 
ti me, ge n erall y i n v ol vi n g t u m or s u p pressor ge nes or pr ot o -o nc o ge n es .1 Cells c o nti n uall y ac q uire 
D N A da ma ge a n d ha v e r o b ust a n d re d u n d a nt D N A da ma ge re pair mec h a nis ms t hat f u ncti o n t o 
mai n tai n ge n o mic sta bilit y.  D o u ble -stra n d D N A brea ks are e xtre mel y c yt ot o xic a n d t heir re pair 
via  n o n -h o m ol o g o us e n d j oi ni n g a n d h o m ol o g o us rec o m bi nati o n are criticall y i m p orta nt .  
E x cisi o n re pair pat h wa ys, i ncl u di n g base e x cisi o n re pair, n ucle oti de e x cisi o n re pair a n d 
mis matc h re pair, als o pla y i m p orta nt r oles i n rest ori n g t he n or mal D N A s e q ue nce.  
Breast ca ncers t hat arise i n B R C A 1 a n d B R C A 2 
m utati o n carriers are c haract erize d b y 
h o m ol o g o us rec o m bi nati o n D N A re pair defici e n c y d ue t o l oss of t he f u ncti o ni n g w il d-t y p e 
B R C A 1 or B R C A 2 allele .  T he B R C A 1 a n d B R C A 2 ge n e pr o d ucts are critical f or D N A 
d o u ble -stra n d brea k re p air via h o m ol o g o us rec o m bi nati o n.1  P ol y ( A D P -ri b ose) p ol y merase-1 
( P A R P 1) a n d P A R P 2 are n uclear e nz y mes cr ucial f or recr uit me nt of a cell's base e x cisi o n re pair 
mac hi ner y t o sites of D N A da ma ge .  It h as b ee n esta blis he d t hat P A R P 1/ 2 i n hi bit ors ca n ca use 
selecti ve c yt ot o xicit y i n cell li nes m uta nt f or B R C A 1 or B R C A 2, d ue t o stalli n g of re plicati o n 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 1  of 4 6   
2  Se pte m ber  2 0 2 0  
f or ks i n d uce d b y a bse n ce of P A R P e nz y me a n d s u bse q ue nt s h utti n g of t he D N A da ma ge t o 
d o u blestra n d brea ks .  Wit h 
c o nc urre nt l oss of h o m ol o g o us rec o m bi nati o n -de pe n de n t D N A 
d o u ble -stra n d brea k re pair, t his lea ds t o a s y nt h eticall y let hal i nteracti o n .2 -7   
2. 2   
S p or a dic Tri ple -Ne g ati ve Bre ast C a ncer   
F or s o me ti me, it has bee n a p preciate d t hat t he maj orit y of i n vasi ve breast ca nce rs t hat de v el o p 
i n 
w o me n 
wit h deleteri o us 
B R C A 1 ger mli ne  m utati o ns are tri ple -ne gati ve, 8, 9 defi ne d 
pat h ol o gicall y as lac ki n g e x pressi o n of t he estr o ge n a n d pr o gester o ne rece pt ors ( E R/ P R) wit h n o 
a m plificati o n of t h e H E R 2/ ne u o nc o ge ne ,1 0 a n d t his has pr o vi de d fasci nati n g mec h a nistic cl ues 
t o u n derl yi n g t u m or bi ol o g y a n d p ossi ble t hera pe utic tar gets.  Base d o n si milarities bet wee n 
s p ora dic tri ple-n e gati ve breast ca ncer a n d B R C A 1 -deficie nt breast ca n cer a n d t he k n o w n r ole of 
B R C A 1 i n D N A re pair, t he h y p ot hesis h as e mer ge d t hat s p ora d ic tri ple-ne gati ve  breast t u m ors 
ma y p ossess si milar D N A re p air d efects a n d de m o nstrate si milar c h e m ose nsiti vit y as B R C A 1 
m utati o n -ass ociate d breast  t u m ors.  Pre -cli nicall y, tri ple-ne gati ve  breast ca ncer cell li nes, li k e 
B R C A 1 -defi cie nt ca ncer cell li nes, de m o nstrat e i ncrea se d se nsiti vit y t o P A R P i n hi bito rs, 
cis plati n a n d ge mcita bi n e. 1 1  A d diti o nall y, t hese ce ll li nes are m ore se nsiti ve t o o xi dati ve D N A 
da ma ge c o m pare d t o l u mi nal breast t u m or cells or n or mal breast e pit heli al cells a n d h a ve b ee n 
s h o w n t o be deficie nt i n base e x cisi o n re pair. 1 2  
T he acti vit y of ola pari b,  a b o na fi de P A R P i n hi bit or, was i n vesti gate d i n a s mall c o h ort of 
u nselecte d s p ora dic tri pl e -ne gati ve breast ca n cer patie nts, h o we ver, n o o bjecti ve res p o ns es were 
n ote d a n d f u rt her de vel o p me nt was halte d.1 3  U nf or t u natel y, t his e x perie n ce t h warte d t he cli nical 
pr o gress of P A R P i n hi bit ors i n s p ora dic tri ple -n e gati ve breast ca n cer.  T he i na bilit y t o select 
B R C A 1/ 2 wil d -t y p e t u m ors wit h u n derl yi n g D N A re pair defects f urt her c o m p o u n de d t he 
pr o ble m .  D ue t o t hese earl y c halle n ges, t he r ole of P A R P i n hi biti o n i n t he treat me nt of s p ora di c 
tri ple-ne gati ve breast c a n cer has re mai ne d u n d efi ne d.  
2. 3   
C a ncers wit h Ger mli ne  or S o m atic Deficie nc y i n D N A D o u ble -Str a n d Re p air  
I n t he past year, tar get e d ge n e p a nels h a ve arise n t hat e val u ate ger mli ne  m utati o ns i n D N A re p air 
pat h wa ys i m plicate d i n ca ncer de vel o p me nt a n d pr o gressi o n .  M utati o ns i n ge nes li n ke d t o 
c hec k p oi nt c o ntr ol a n d re g ulati o n of t he D N A -d o u ble stra n d brea k re p air pat h wa y, s uc h as 
A T M, P A L B 2 a n d R A D 5 1 are h y p ot hesiz e d t o h a ve si milar c he m os e nsiti vit y t o D N A -da ma gi n g 
t hera pies, s uc h as P A R P i n hi bit ors, as m utati o ns i n B R C A 1 a n d B R C A 2 gi ve n a si milar 
s y nt heticall y l et hal effect.  H o we ver, n o st u dies t o date h a ve directl y e val uate d t h e r ole of 
D N A -da m a gi n g t hera pies i n s uc h patie nt p o p ulati o ns, i n part d ue t o a lac k of c o m merciall y 
a vaila ble m ulti ple x ge ne pa nels usi n g n e xt ge nerati o n D N A se q ue nci n g u ntil rece ntl y as well as 
t he l o w pre vale nce of s uc h m utati o ns i n t he ge neral p o p ulati o n. 
I n a Fre nc h st u d y p u blis he d t his year, ne xt -ge nerati o n -seq ue n ci n g -base d s cree ni n g i n 
7 0 8  patie nts wit h eit her a pers o nal hist or y of breast or o varia n ca n cer at a y o u n g a ge, male breast 
ca ncer, or str o n g fa mil y hist or y d e m o nstrate d a n o verall m utati o nal rate of B R C A 1 a n d B R C A 2 
of 1 0. 8 % .  In a d diti o n, 1 0 i nacti vati n g m utati o ns were f o u n d i n P A L B 2 a n d R A D 5 1 C a n d 
1 0  i nacti vati n g m utati o ns f o u n d i n C H E K 2 a n d A T M, wit h a c ollecti ve c o ntri b uti o n esti mate d t o 
be at least 3 % (s ee fi g ure). 1 4 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 2  of 4 6   
2  Se pte m ber  2 0 2 0  
 
Fi g ure 1.  Cas tera L, et al .  E ur o pea n J o ur nal of H u ma n Ge netics, J a n uar y 2 0 1 4. 
T he m y Ris k ge ne p a nel de vel o pe d b y M yria d Ge netics similarl y e val u ates a set of 2 5 ca ncer 
s usce pti bilit y ge nes i m plicate d i n here ditar y breast a n d o varia n ca n cer b y ne xt ge n erati o n 
se q ue nci ng .  In  an  a bstract pres e nte d at t he 2 0 1 3 Sa n A nt o ni o Breast Ca n cer S y m p osi u m , 1 9 5 5 
pr os pecti vel y accr ue d patie nt cases (e x cl u di n g p atie nts of 
As h ke n azi J e wis h herita ge t o 
deter mi ne rel ati ve pre vale nce i n t he ge neral p o p ulati o n) were teste d, a n d de m o nstrate d t hat 
2 7 5  ( 1 4. 0 7 %) were m utati o n carriers i n at least o ne of t he 2 5 ge nes .  I nteresti n gl y, 1 8 2 ( 9. 3 %) of 
patie nts ha d a m utati o n i n B R C A 1 or B R C A 2, w hile 9 6  ( 4. 9 1 %) of patie nts ha d a m utati o n i n 
ot her ge nes, i n cl u di n g A T M, C H E K 2, N B N, a n d P A L B 2 .  1 7 3 8 o ut  of t he 1 9 5 5 patie nts i n t he 
st u d y ha d a pers o nal hist or y of breast ca ncer, wit h 6 3 % dia g n ose d pri or t o t he a ge of 5 0, a n d 
3 7 % at or after t he a ge 5 0.  N ota bl y 1 9 0 2 ( 9 7. 2 9 %) patie nts ha d a varia nt of u ncertai n 
si g nifica n ce i n at least o ne of t he ge n es teste d a n d a n a vera ge of t hree v aria nts was f o u n d per 
patie nt. 1 5  
I n a d diti o n t o breast ca ncer, h o m ol o g o us rec o m bi nati o n pat h wa y m utati o ns ha ve bee n i m plicate d 
i n m ulti ple ot her s oli d t u m ors i ncl u di n g o varia n, pr ostate, pa n creas, a n d gastri c ca n cers a m o n g 
ot hers a n d are p ost ulate d t o res ult i n a ‘ B R C A ness’ p he n ot y p e .  F or e x a m ple, a rece nt st u d y has 
s h o w n t hat ger mli ne  m utati o ns i n D N A -re pair ge nes ca n be detecte d i n a p pr o xi matel y 1 0 % of 
patie nts wit h 
metastatic pr ostate ca ncer. 2 8  Of patie nts wit h i de ntifie d 
m utati o ns, B R C A 2  
m utati o ns c o m prise d 4 4 % of t otal m utati o ns.  Ot her m utati o ns i de ntifie d i ncl u de d A T M  i n 1 3 %, 
C H E K 2  i n 1 2 %, B R C A 1  i n 7 %, R A D 5 1 D  i n 4 %, a n d P A L B 2  i n 4 %.  T hese data pr o vi de str o n g 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 3  of 4 6   
2  Se pte m ber  2 0 2 0  
rati o nale f or t he use of P A R P i n hi bit ors i n s oli d t u m ors wit h h o m ol o g o us re pair deficie nc y 
o utsi de of B R C A 1/ 2  m utati o ns i n t u m ors ot her t ha n breast ca ncer.  
F urt her m ore, i de ntificati o n of s o matic m utati o ns i n  H R -relate d ge nes t hr o u g h c o m merciall y 
a vaila ble ne xt ge nerati o n se q ue nci n g of t u m or tiss ues als o has p ote ntial t o i de ntif y p atie nts wit h 
s o matic D N A re pair alterati o n w h o ma y d eri ve p ote ntial be nefit fr o m D N A defect -t ar gete d 
t hera p y, s uc h as a P A R P i n hi bit or.  St u dies t o assess t he efficac y of t his a p pr oac h are c urre ntl y 
n ot a vaila ble.   
2 . 4  
T he M yri a d H o m ol o g o us Rec o m bi n ati o n Deficie nc y ( H R D ) Ass a y  
T he M yria d H o m ol o g o us Rec o m bi nati o n Defici e n c y ( H R D ) Assa y is a n o v el assa y t hat h as bee n 
de vel o pe d usi n g a n i n direct a p pr oac h t hat all o ws f or t he d etecti o n of  H R D  re gar dless of its 
eti ol o g y or  mec ha nis m as meas ure d b y le vels of ge n o mic i nsta bilit y .  T he assa y is c o m pati ble 
wit h f or mali n -fi x e d paraffi n-e m be d de d ( F F P E) t u m or tiss ue a n d B R C A 1 a n d B R C A 2 t u m or 
se q ue nce d ata is si m ulta ne o usl y ge nerate d.  Earl y i n assa y d e vel o p me nt, ge n o mic re gi o ns of  l oss 
of heter oz y g osit y ( L O H) of i nter me diate le n gt h ( >  1 5  M b a n d <  1  c hr o m os o me) were s h o w n t o 
be hi g hl y ass o ciate d wit h  H R deficie nc y a n d t he  H R D -L O H sc ore was deri ve d as a c o u nt of 
L O H re gi o ns of t his le n gt h acr oss t he t u m or ge n o me .1 6  
O ur gr o u p has pre vi o usl y ass esse d t he  H R D -L O H  assa y i n Pr E C O G 0 1 0 5,  a ne oa dj u v a nt trial 
t hat e x pl ore d a n o n-a nt hrac ycli ne, n o n -t a x a ne, plati n u m-base d re gi me n i n patie nts 
wit h 
tri ple-ne gati ve or B R C A 1/ 2 m utati o n -ass ociate d breast ca ncer .  We  s h o we d t hat a hi g h H R D  
sc ore si g nifica ntl y c orrel ates wit h fa v ora ble pat h ol o gic res p o nse t o a plati n u m -base d re gi me n i n 
earl y-sta ge tri ple-n e gati v e  a n d B R C A 1 or B R C A 2 m utati o n -ass ociate d breast ca ncer 1 7 I n t his 
st u d y, patie nts recei ve d car b o plati n A U C 2 a n d ge m cita bi ne 1 0 0 0  m g / m2 o n da ys 1 a n d 8 e ver y 
2 1  da ys i n a d diti o n t o i ni pari b o n da ys 1, 4, 8, a n d 1 1. 1 8, 1 9 T he o verall p C R rate i n t he 
i nte nt-t o-treat p o p ulati o n was 3 6 % ( 9 0 % CI:  2 7 -4 6 %) .  N ota bl y, B R C A 1 a n d B R C A 2 m utati o n 
stat us was c o m pre he nsi v el y ass esse d a n d T N B C patie nts wit h a ger mli ne  B R C A 1 or B R C A 2 
m utati o n ac hie ve d a hi g her rate of p C R ( 5 6 %)  c o m pare d t o patie nts w h o were B R C A 1 a n d 
B R C A 2 wil d -t y pe ( 3 3 %).1 8, 1 9  A maj or ai m of Pr E C O G 0 1 0 5 was t o e val uate bi o mar kers of 
res p o nse t o t his ne o a dj u v a nt t hera p y i n patie nts wit h s p ora dic T N B C.  T he  H R D  assa y s c ore was 
assesse d i n a c o h ort of 7 7 t u m ors i n Pr E C O G 0 1 0 5 w here p at h ol o gic res p o nse was ass esse d 
usi n g t he resi d ual ca ncer b ur de n ( R C B) i n de x. 1 7, 2 0  T he a vera ge  H R D  assa y sc ore f or res p o n ders 
was 1 6. 2 a n d t he a vera ge sc ore f or n o n -res p o n ders 1 1. 2 ( p =  0. 0 0 0 3)  usi n g t he  H R D -L O H assa y .  
I nteresti n gl y, n o differen ce i n me dia n  H R D  sc ores was  n ote d bet wee n B R C A 1/ 2 -deficie nt vers us 
B R C A 1/ 2 -pr oficie nt res p o n ders .  F urt her m or e, if B R C A 1/ 2 -deficie nt sa m ples were e x cl u de d 
( n =  5 8), t he ass ociati o n bet wee n res p o ns e t o treat me nt a n d  H R D  assa y sc ore re mai n e d 
si g nifica nt ( p =  0. 0 0 0 6) .  O verall, 7 0 % of pati e nts wit h a n  H R D  assa y sc ore of  1 0 or a 
deleteri o us B R C A 1/ 2 m utati o n res p o n d e d c o m pare d wit h 1 2 % of p atie nts wit h a n  H R D  assa y 
sc ore of <  1 0 a n d i ntact B R C A 1/ 2 stat us ( p  =  0. 0 0 0 0 2). 1 7 T hese data s u g gest t hat t u m or 
meas ures of L O H ma y be i m p orta nt bi o mar kers i n t he i de ntificati o n of ger mli ne  B R C A 1 a n d 
B R C A 2 wil d -t y pe p atie nts w h o ma y be n efit fr o m D N A defect-tar get e d t hera p y, s uc h as plati n u m 
or a P A R P i n hi bit or.  
A d diti o nall y, t he  H R D -L O H  assa y h as bee n vali d ate d i n t w o pr os pecti ve b reast ca n cer c o h orts.  
T he Cis plati n -1 c o h ort i ncl u de d 2 8, mai nl y s p ora dic, tri ple -n e gati ve breast ca ncer patie nts 
treate d wit h ne oa dj u va nt cis plati n, 7 5 m g / m2 e ver y 2 1 da ys f or 4 c ycles .  T he Cis plati n -2 c o h ort 
i ncl u de d 5 1 tri ple-n e gati ve breast ca ncer pa tie nts treate d wit h ne o a dj u va nt cis plati n 7 5 m g / m2 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 4  of 4 6   
2  Se pte m ber  2 0 2 0  
e ver y 2 1 da ys f or 4 c ycl es pl us be vaciz u ma b 1 5  m g / k g f or 3 c ycl es.  T he pat h ol o gic res p o nse i n 
t hese st u dies was assesse d b y t he Miller-Pa y n e ( M P) sc ore, wit h res p o n ders ha vi n g a M P sc ore 
of 4 or 5, a n d n o n -res p o n ders M P sc ores of 1 t o 3 .  A nal yses were als o perf or me d i n patie nts 
ac hie vi n g a p C R vers us n o p C R .  T he a nal ysis of  H R D  sc ore vers us pat h ol o gic res p o ns e was 
perf or me d o n t he c o m bi ne d dataset .  T he mea n  H R D  sc ore a m o n g res p o n ders ( M P 4-5) vers us 
n o n -res p o n ders ( M P 1-3) was 1 8. 0 vers us 1 2. 9 wit h a n o d ds rati o of 3. 6 ( 3. 2 -4. 0) a n d p -v al ue of 
0. 0 1 3 .  Mea n  H R D  sc ores a m o n g patie nts wit h a p C R vers us n o n-p C R was 2 0. 6 vers us 1 3. 4 wit h 
a n o d ds rati o of 7. 4 ( 6. 3 -8. 6) a n d a p -v al ue of 0. 0 0 4 8 .  I m p orta ntl y, a mo n g patie nts wit h a n  H R D  
sc ore <  1 0, n o patie nts ac hie ve d a p C R w hile 2 4 % of patie nts wit h a n  H R D  ≥ 1 0 ac hie ve d a p C R 
res ulti n g i n 1 0 0 % se nsiti vit y a n d 1 0 0 % ne gati ve pre dicti ve v al ue f or p C R.  I n t his c o m bi ne d 
c o h ort, 7 2 % of patie nts ha d a n  H R D  sc ore of 1 0 or great er. 
Rece ntl y, t he  H R D  ass a y h as bee n f urt her o pti mize d a n d c urre ntl y i n c or p orat es a d diti o nal 
meas ures of ge n o mic i nsta bilit y, i ncl u di n g tel o meric allelic i m bala nce ( T AI; t he n u m ber of 
re gi o ns wit h allelic i m bala nce t hat e xte n d t o t he s u btel o mere, b ut d o n ot cr oss t he ce ntr o mere) 
a n d lar ge-scale state tra nsiti o ns ( L S T; t he n u m ber of c hr o m os o mal  brea ks bet wee n a djace nt 
ge n o mic re gi o ns l o n ger t ha n 1 0 M b after filteri n g o ut re gi o ns s h orter t ha n 3 M b). 2 1, 2 2 T he  H R D  
sc ore is c urre ntl y calc ul ate d b y a d di n g t he L O H, T AI a n d L S T s c ores a n d is re p orte d as a 
c o ntin u o us sc ore fr o m 0 -1 0 0 .  A n  H R D  sc ore of <  4 1 ( pre vi o usl y <  1 0) is defi ne d as  H R 
pr oficie nt a n d  H R D  s c ore of ≥ 4 2 ( pre vi o usl y ≥ 1 0) as  H R -deficie nt .  Usi n g t his c ut off, ~ 4 8 % of 
T N B C patie nts are classifie d as  H R -deficie nt.  
2. 5   
O ver vie w of t he st u d y a ge nt t al az o p ari b 
2. 5 . 1 N o ncli nic al St u dies of t al az o p ari b 
Talaz o pari b  is a hi g hl y p ote nt a n d s pecific i n hi bit or of P A R P 1 a n d 2 wit h acti vit y i n t u m or cell 
li nes beari n g D N A re p air deficie ncies.2 3, 2 4 talaz o pari b i n hi bits P A R P i n vitr o at a l o wer 
c o nce ntr ati o n (I C 5 0  =  0. 5 7  n M ) t ha n A B T 8 8 8 (I C 5 0 =  4. 7 3  n M ), A G 1 4 4 4 7 (I C 5 0 =  1. 9 8  n M ), 
or ola pari b (I C 5 0  =  1. 9 4  n M ).  Talaz o pari b  als o e x ert s si n gle-a ge nt s y nt hetic let halit y of B R C A 
1 a n d 2 a n d P T E N deficie nt cell li nes .  I n B R CA 2 ne gati ve Ca pa n 1 -cells, talaz o pari b was m ore 
p ote nt as si n gle a ge nt t ha n A B T -8 8 8 ( 1 0, 0 0 0 ti mes), A G 1 4 4 4 7 ( 6 0 9 ti mes) a n d ola pari b 
( 2 5 9 ti mes) i n i n hi biti n g P A R P acti vit y.  I n a ni mal m o dels, p ote nt a nti-t u m or acti vit y was 
o bser ve d at oral dail y d oses <  1  m g / k g/ da y.  C o m plete s u p pressi o n of B R C A 1 -deficie nt t u m or 
gr o wt h i n t he M X 1 m o d el was ac hie ve d i n a 3 -m o nt h st u d y w he n d os e d at 0. 1 6 5  m g / k g BI D .2 4 
Si milarl y, s u p pressi o n of P T E N -deficie nt t u m or gr o w t h was ac hie ve d i n x e n otra ns pla nt 
e x peri me nts wit h talaz o pari b d ose d at 0. 3 3  m g / k g o nce dail y f or 2 8 c o nsec uti ve da ys.2 4  
T he oral bi oa vaila bilit y, calc ulate d fr o m t he rati o of t he area u n d er t he c o n ce ntrati o n -ti me c ur ve 
( A U C) f oll o wi n g oral a d mi nistrati o n relati v e t o t he 
A U C f ollo wi n g i ntra v e n o us (I V) 
a d mi nistrati o n ( A U C oral/ A U CI V), was >  4 2. 7 % i n rats a n d >  5 0. 5 % i n d o gs base d o n si n gle d ose 
c o m paris o ns .  T he c o m p o u n d was meta b oli call y sta ble.  T he ter mi nal half -life of talaz o pari b at 
vari o us d oses i n rats a n d d o gs ra n ges fr o m 2 8 . 5 t o 3 2. 0 hr  a n d 6 9. 7 t o 9 1. 2  hr , res pecti vel y, 
w hic h all o ws f or o nce dail y d osi n g.  
P har mac o ki netic st u dies ha ve b ee n p erf or me d i n rats a n d d o gs .  Stea d y st ate c o n ce ntrati o ns were 
reac h e d o n Da y  1 5 i n rats a n d o n Da y  2 0 i n d o gs usi n g dail y a d mi nistrati o n  of talaz o pari b.  
C o m pari n g Da y  1 5 a n d 2 8 wit h Da y  1 f or all d ose le vels i n d o gs, A U C a n d C ma x  i ncrease d fr o m 
Da y  1 t o Da y  1 5 t o Da y  2 8.  

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 5  of 4 6   
2  Se pte m ber  2 0 2 0  
Fi ve -da y re peat d ose t o xicit y a n d t o xic o ki netic ( T K) st u dies wit h 2 8 -da y rec o ver y were 
c o n d ucte d i n rats a n d d o gs .  I n d o gs (t he m ost se nsiti ve s pecies), talaz o pari b was a d mi nistere d at 
d ose l e vels of 0. 0 0 3, 0. 0 1, 0. 0 3, 0. 1  m g / k g/ da y o ver 5 c o nsec uti ve da ys.  Se vere pa n c yt o p e nia 
was o bser ve d i n d o gs tr eate d wit h t he t w o hi g h est d ose gr o u ps ( 0. 0 3 a n d 0. 1  m g / k g/ da y).  At 
t hese d oses, t he m ea n ( or me dia n) retic ul oc yte na dir occ urre d o n Da y  6 a n d t he platel et a n d 
W B C na dirs o n Da y  1 1.  T hese c h a n ges were re v erse d i n t he gr o u p treate d at 0. 0 3  m g / k g/ da y o n 
da ys  1 7  t o 1 8 ( ie, 1 2  t o 1 3 da ys after t he last d ose of t he dr u g) .  M ortal ities occ urre d i n a ni mals 
gi ve n 0. 1  m g / k g/ da y d ue t o bact erial s e ptice mia s ec o n dar y t o b o n e marr o w h y p ocell ularit y a n d 
l y m p h oi d or ga n de pleti o n o n Da y  1 2  t o 1 3 .  C oa g ul ati o n para meters were u naffecte d .  After 
re peat-d ose a d mi nistrati o n of dail y oral tal az opari b  i n d o gs f or 5-da ys, t he hi g h est n o n -se v erel y 
t o xic d ose ( H N S T D) was 0. 0 3 m g / k g/ da y.  T we nt y -ei g ht d a y re p eat d ose t o xicit y a n d T K st u dies 
wit h 2 8 -da y rec o v er y were als o c o n d u cte d i n rats a n d d o gs .  I n d o gs, talaz o pari b was 
a d mi nistere d at d osa ge le ve ls of 0. 0 0 0 5, 0. 0 0 1 5, 0. 0 0 5, 0. 0 1 m g / k g/ da y o ver 2 8 c o nsec uti ve 
da ys .  Tal az o pari b -rel ate d si g ns i ncl u de d he mat ol o g y fi n di n gs i n males a n d fe males gi ve n 0. 0 0 5 
or 0. 0 1  m g / k g/ da y s uc h as mil dl y l o w er re d cell mass, mil dl y t o m o derat el y l o wer platelet a n d 
a bsol ute retic ul oc yte c o u nts, a n d mi ni mall y t o mil dl y l o wer w hite bl o o d cell c o u nts wit h a 
ge n eralize d d ecrease i n all le u k oc yt es .  All of t hese si g ns re verse d or were re versi n g b y t he e n d 
of t he rec o v er y p h ase .  After re peat -d ose a d mi nistrati o n of dail y oral  talaz o pari b i n d o g f or 2 8 
da ys, t he H N S T D was 0. 0 1  m g / k g/ da y. 
I n c o n cl usi o n, t he mai n n o ncli nical fi n di n gs of earl y he m at ol o gical c ha n ges, a n d s u bse q ue nt 
b o ne marr o w a n d l y m p h oi d or ga n d e pleti o n as well as f ocal n ecr osis after re p eat a d mi nistrati o n 
of talaz o pari b are i n acc or da nce wit h t he mec ha nis m of acti o n a n d t he e x p os ure/ distri b uti o n 
patter n .  T hese fi n di n gs were re versi ble a n d t he decrease d retic ul oc yte, platelet, re d bl o o d cell 
( R B C) a n d W B C c o u nts were s e nsiti ve a n d earl y mar kers of tar get or ga n t oxicit y .  Decreases i n 
he mat ol o g y p ara meters were us e d t o cli nicall y m o nit or safet y .  A starti n g cli nical d ose was 
esti mate d usi n g t h e d o g H N S T D as t he d o g was m ore se nsiti ve t o tal az o pari b-rel ate d pri mar y 
t o xicities t ha n t he rat.  Base d o n a 6 ti mes safet y  fact or relati ve t o t he 2 8-da y t o xicit y st u d y i n 
d o g H N S T D, t he esti mat e d safe cli nical starti n g d ose is 1  μ g / k g/ da y.  T he differe n ce i n relati ve 
bi oa vaila bilit y after a d mi nistrati o n of t he ca ps ule a n d oral ga va ge s us pe nsi o n of talaz o pari b was 
a p pr o xi matel y t w o -f ol d.  Ta ki n g i nt o acc o u nt t he relati ve c ha n ge i n e x p os ure wit h t he ca ps ul e 
vers us t he oral ga v a ge s us pe nsi o n, t he esti mate d safe cli nical starti n g d os e was recalc ulate d a n d 
is 0. 5 μ g / k g/ da y t alaz o pari b.  T heref ore, t he sta rti n g fi xe d cli nical d os e of 2 5 μ g  talaz o pari b i n a 
ca ps ule f or m c orres p o n ds t o 0. 4 2  μ g / k g/da y f or a 6 0 -k g a d ult.  
2. 5 . 2 Cli nic al St u dies of T al az o p ari b   
T hree st u dies o n g oi n g  at t he ti me of t his u p date : 
 P R P -0 0 1, i nitiate d o n J a n uar y 3r d 2 0 1 1, is a si n gl e -ar m, o pe n -la bel st u d y t o assess t h e safet y, 
p har mac o ki netics ( P K), p har mac o d y n a mics ( P D), a n d preli mi nar y efficac y of talaz o pari b i n 
patie nts wit h a d va nce d t u m ors wit h D N A -re pair pat h wa y a b n or malities, partic ularl y t h ose 
ass ociate d wit h B R C A - a n d P T E N-d ysf u ncti o n .  T he i nitial c o h or t of patie nts was treate d 
wit h 2 5  µ g talaz o pari b o nce dail y .  T his t w o -sta ge p h ase  1  st u d y was u p date d at t he 2 0 1 4 
A S C O A n n ual Meeti n g .  At t his ti me e x pa nsi o n p hase e nr oll me nt i n s mall cell l u n g ca ncer, 
ger mli ne  B R C A breast a n d o varia n ca n cer a n d E wi n g's sarc o ma is c o m plete.  T he M T D a n d 
Rec o m me n de d P has e 2 D ose ( R P 2 D) was esta blis he d at 1  m g / d i n 3 9 pts ( 3 3 F/ 6 M) treate d at 
d oses ra n gi n g fr o m 2 5 t o 1 1 0 0  μ g / d.  D ose -li miti n g t hr o m b oc yt o p e nia occ urre d i n 1/ 6 a n d 
2/ 5 pts at 9 0 0 a n d 1 1 0 0  μ g / d, res p ecti vel y2 5. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 6  of 4 6   
2  Se pte m ber  2 0 2 0  
 6 7 3 -3 0 1, i nitiate d o n Oct o ber 3 0,  2 0 1 3 is a n o pe n -la bel, ra n d o mize d, parallel, 2-ar m st u d y of 
talaz o parib  vers us pr ot oc ol -s pecific p h ysicia n's c h oice t hera p y i n s u bjects wit h ger mli ne  
B R C A m utati o n  wit h  l ocall y a d v a nce d a n d/ or met astatic breast ca ncer.  
 6 7 3 -2 0 1: 2 -sta ge, 2-c o h ort p hase  2 trial is t o e val uate t he safet y a n d efficac y of talaz o pari b i n 
s u bjects wit h l ocall y a d v a nce d or m etastatic breast ca ncer wit h a deleteri o us ger mli ne  B R C A 
1 or B R C A 2 m utati o n .  S u bjects will be assi g ne d t o eit her C o h ort  1 or 2 base d o n pri or 
c he m ot hera p y f or metast atic disease:  
 C o h ort  1) S u bjects w h o ha ve pre vi o usl y res p o n d e d t o plati n u m -c o ntai ni n g re gi me n f or 
metastatic diseas e wit h disease pr o gressi o n 
>  8 wee ks f oll o wi n g t he last d ose of 
plati n u m; or  
 C o h ort  2) S u bjects w h o ha ve recei ve d >  2 c h e m ot hera p y re gi me ns a n d w h o ha ve ha d n o 
pri or plati n u m t hera p y f or metastatic dise as e  
I n a d diti o n, a f o o d effect st u d y ( 6 7 3-1 0 3) i n 1 8 healt h y v ol u nteers has bee n c o m plete d .  T he f o o d 
effect st u d y s h o w e d t hat, w hile a hi g h -fat, hi g h-cal orie meal del a ye d t he a bs or pti o n of orall y 
a d mi nistere d talaz o pari b, it di d n ot affect t he o v erall e xte nt of a bs or pti o n .  Si n gle 5 0 0 µ g d os es 
were s afe a n d well t olerate d i n healt h y m ale v ol u nteers.  
Preli mi nar y P K data fr o m Part 1 of P R P -0 0 1, t hr o u g h C ycle 1, was a v aila ble at t he ti me of t his 
re p ort.  O verall, plas ma c o nce ntrati o ns of t alaz o pari b i ncrease d i n a d ose-de pe n d e nt ma n ner, 
wit h m ost patie nts o btai ni n g ste a d y -state plas ma c o nce ntrati o ns b y t he e n d of t he s ec o n d wee k of 
dail y d osi n g ( Da y  2 2) .  As i n dicate d b y l o g -li near c o n ce ntrati o n-ti me pr ofiles o n Da y  1 a n d 
Da y  3 5, talaz o pari b eli mi nati o n a p pear e d t o f oll o w bi p hasic ki netics.  
C u m ulati vel y, t here h a v e bee n 1 1 1 S A Es re p orte d i n cli nical st u dies wit h talaz o pari b as of 
N o ve m ber 3 0 t h 2 0 1 3.  T he m ost c o m m o n reas o ns f or S A Es ha ve bee n i nfecti o us ( 3 3 e ve nts), 
gastr oi ntesti nal dis or d ers ( 1 6 e v e nts), bl o o d  a n d l y m p hatic dis or ders ( 1 3 e ve nts), a n d res pir at or y 
dis or ders ( 1 2 e ve nts) .  T he m ost c o m m o nl y re p orte d S A Es b y preferre d ter m i ncl u de fe brile 
ne utr o pe nia ( 9 e ve nts), ne utr o pe nic s e psis ( 7 e ve nts), as cites  ( 5 e ve nts), a n d bactere mia ( 5 
e ve nts).  All b ut 9  of t hese 1 1 1 S A Es were assesse d b y t he i n vesti gat ors as n ot relate d t o 
treat me nt wit h talaz o pari b. 
A d verse e v e nts occ urri n g i n at least 1 0 % of patie nts i n t he p o ole d st u d y p o p ulati o n of P R P -0 0 1, 
P R P -0 0 2, 6 7 3 -1 0 3 a n d 6 7 3 -3 0 1 ha ve i ncl u de d: fati g ue, na usea,  a n e mia, c o nsti pati o n, diarr hea, 
v o miti n g, t hr o m b oc yt o p e nia, c o u g h, p yre xia, hea dac he, n e utr o pe nia, al o peci a, decrease d 
a p petite, a b d o mi nal pai n, bac k pai n, d ys p nea, pai n i n e xtre mities, h y p o kal e mia, a n xiet y, 
art hral gia, a n d dizzi ness .  A d verse reacti o ns h a v e n ot w orse n e d wit h c o nti n ue d t hera p y at t he 
sa me or re d u ce d d os e.  
Base d o n its mec ha nis m of acti o n, precli nical acti vit y a n d p har mac o ki netic ( P K) a n d t o xicit y 
pr ofile , talaz o pari b was selecte d f or cli nical e val u ati o n i n t u m ors wit h de m o nstrate d or p ote ntial 
defects i n D N A re pair pat h wa ys, s uc h as B R C A m utati o ns, P T E N d ysf u ncti o n or a b n or mal 
R A D 5 1 f oci f or mati o n .  Talaz o pari b  has b ee n s h o w n t o be hi g hl y selecti ve a n d p ote nt c yt ot o xic 
a ge nt i n h u ma n ca n cer cell li nes a n d i n a ni mal m o dels of t u m ors h ar b ori n g m utati o ns t hat 
c o m pr o mise 
D N A re p air pat h wa ys .  P har mac o ki netic para meters de m o nstrate d a hi g h 
bi oa vaila bilit y wit h a distri b uti o n pr ofile i n dicati n g e xte nsi ve tiss ue distri b uti o n, a n d a d urati o n 
of e x p os ure s ufficie nt t o s u p p ort o nce dail y d osi n g .  C ha n ges i n he mat ol o g y para meters were 
earl y mar kers of t o xic ol o g y fi n di n gs .  A ne mia, t hr o m b oc yt o pe ni a, a n d n e utr o pe nia ha v e all b ee n 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 7  of 4 6   
2  Se pte m ber  2 0 2 0  
o bser ve d, i ncl u di n g Gra de  3 -4 e ve nts .  T he e v e nts of fati g ue, n a usea, c o nsti pati o n, diarr hea, 
v o miti n g, c o u g h, p yre xia, hea dac h e, al o p ecia, d ecrease d a p petite, a b d o mi nal pai n, bac k pai n, 
d ys p nea, pai n i n t he e xtre mities, h y p o k ale mia, a n xiet y, art hral gia, a n d diz zi ness ha ve als o b ee n 
o bser ve d i n s u bjects recei vi n g 
talaz o pari b.  All 
patie nts are 
bei n g 
m o nit ore d f or 
m yel o -s u p pressi on i n t he o n g oi n g st u dies.  
T he  ta ble b el o w s u m marize s t he safet y d ata of  t alaz o pari b as ass esse d b y t he p hase  1  tri al i n 
patie n ts wit h a d va nce d s oli d t u m ors.2 5 
T a ble 1 .  Safet y dat a f or p hase  1  d ose es calati o n/e x pa nsi o n trial f or patie nts wit h s oli d ca ncers 2 5 
 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 8  of 4 6   
2  Se pte m ber  2 0 2 0  
 
Fi g ure 2 .  B R C A 1/ B R C A 2  breast c a ncer R E CI S T waterfall pl ot i n p hase  1  trial of talaz o pari b2 5 
2. 6   
R ati o n ale   
P ol y ( A D P -ri b ose) p ol y merase-1 ( P A R P 1) a n d P A R P 2 pla y i m p orta nt r oles i n D N A re pair .7 T he 
cli nical de v el o p me nt of P A R P 1/ 2 i n hi bit ors a d va nce d w he n t he pri n ci ple of c h e mical s y nt hetic 
let halit y was esta blis he d i n B R C A 1/ 2-deficie nt cells .2 S y nt hetic let halit y st e ms fr o m t he i na bilit y 
of B R C A -defi cie nt cells t o u n der g o h o m ol o g o us rec o m bi nati o n -me diate d d o u ble -stra n d D N A 
brea k re pair, ma ki n g t he m s usce pti ble t o D N A da ma ge ca us e d b y a P A R P i n hi bit or .3, 5, 6 T w o 
p hase  2  pr o of -of -c o n ce pt st u dies d oc u me nte d o bjecti ve res p o nses t o si n gle a ge nt ola pari b, a n 
oral P A R P i n hi bit or, i n B R C A 1/ 2  m utati o n carri ers wit h a d v a n ce d o v aria n a n d breast ca n cer .1 3, 2 6  
Gi ve n t hat s p ora dic tri ple -ne gati ve breast ca n cers s h are ma n y p at h ol o gical a n d m olec ular 
feat ur es wit h breast ca ncers arisi n g i n t he setti n g of a here ditar y B R C A m utati o n, it was 
s u g geste d t hat t hese s p ora dic t u m ors mi g ht s hare si milar D N A re p air defects a n d s h o w si milar 
c he m ose nsiti vit y t o B R C A m utati o n -ass ociate d t u m ors .  T he acti vit y of si n gle -a ge nt ol a pari b, a 
b o na fi de P A R P i n hi bit or, 
was i n vesti gate d i n a s mall c o h ort of u nselecte d s p ora dic 
tri ple-ne gati ve breast ca ncer patie nts, h o we ver, n o o bjecti ve res p o nses were n ote d a n d f urt h er 
i n vesti gati o n was h alte d.1 3 T hese e x perie nces t h warte d t h e cli nical d e ve l o p me nt of P A R P 
i n hi bit ors i n s p ora dic tri ple-ne gati ve breast ca ncer .  T he i na bilit y t o select B R C A 1/ 2 wil d -t y p e 
t u m ors wit h u n derl yi n g D N A re p air defects f urt her c o m p o u n de d t he pr o ble m. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 1 9  of 4 6   
2  Se pte m ber  2 0 2 0  
D ue t o t hes e earl y c halle n ges, t he r ole of P A R P i n hi biti o n i n t he tre at me nt of s p ora di c 
tri ple-ne gati ve breast ca n cer h as re mai n e d u n defi ne d .  T he c halle n ge at h a n d is t o a p pr o priat el y 
select patie nts lac ki n g a ger mli ne  B R C A 1/ 2 m utati o n f or t he ne xt ge nerati o n of cli nical trials .  
Patie nt C o h ort  A of o ur pr o p ose d st u d y wit h  t h e P A R P i n hi bit or talaz o pari b ai ms t o a d dress t his 
i m p orta nt q uesti o n b y selecti n g a s u b p o p ulati o n of s p ora dic, tri ple-ne gati ve breast ca ncer 
patie nts e nric he d f or h o m ol o g o us rec o m bi nati o n deficie nc y (H R D ) as assesse d b y a n o vel 
tiss ue-base d assa y d e vel o p e d b y M yri a d Ge netics .  T he  H R D  assa y has bee n de vel o pe d usi n g a n 
i n direct a p pr oac h t hat all o ws f or t he detecti o n of H R D  re gar dless of its eti ol o g y or mec ha nis m as 
assesse d b y l e vels of ge n o mic i nsta bilit y.1 6 O ur gr o u p has pre vi o usl y e val u ate d t he  H R D  assa y i n 
a ne o a dj u va nt p has e  2  tri al of ge mcita bi ne, car b o plati n a n d i ni pari b a n d s h o we d t hat a hi g h H R D  
sc ore si g nifi ca ntl y c orrel ate d wit h fa v ora ble pat h ol o gic res p o nse t o t his plati n u m -base d re gi me n 
i n earl y-sta ge tri ple-ne gati ve breast ca n cer p atie nts wit h a n d wit h o ut a ger mli ne  B R C A 1/ 2 
m utati o n .1 7, 1 9  
Gi ve n o ur fi n di n gs, we h y p ot hesize t hat t he  H R D  assa y ca n be use d t o select tri ple -ne gati ve 
breast ca n cer patie nts m ost li k el y t o deri ve be nefit fr o m a si n gle -a ge nt P A R P i n hi bit or treat me nt 
strate g y.  Talaz o pari b  is a n o vel oral P A R P 1/ 2 i n hi bit or s h o w n i n precli ni cal m o dels t o be m ore 
p ote nt t ha n ot her a ge nts i n its class a n d a rec o m m e n de d phas e  2  d ose has b ee n deter mi ne d .2 4, 2 5, 2 7 
As s uc h, it is a n i deal dr u g t o e val uat e i n a pr o of -of -c o nce pt st u d y of si n gle -a ge nt P A R P 
i n hi bit or t hera p y i n patie nts wit h a d va nce d tri ple-ne gati ve breast ca ncer, w h o lac k a ger mli ne  
B R C A 1 or B R C A 2 m utati o n,  b ut are  H R -deficie nt b y t he  H R D  assa y.  
O ur sec o n d p atie nt c o h ort ( C o h ort  B) ai ms t o e val uate t he efficac y a n d s afet y of tal az o pari b i n a n 
e mer gi n g s u b -gr o u p of breast ca ncer patie nts , or ot her n o n -breast metastatic s oli d t u m ors  wit h 
hi g h li keli h o o d of  H R  d eficie nc y st e m mi n g fr o m ger mli ne  or s o matic m utati o ns i n ge nes ot h er 
t ha n B R C A 1 a n d B R C A 2 i m plicate d i n t he d o u bl e-stra n de d D N A brea k re pair pat h w a y.  Bas e d 
o n t he li mite d c urre nt data, t he pre vale nce of s uc h here ditar y breast a n d o varia n ca ncer 
s y n dr o mes is esti mate d t o be as hi g h as 5 % of t he ge neral breast ca ncer p atie nt p o p ulati o n. 1 4, 1 5 
Gi ve n t he i n crease d utilizati o n of c o m mercial m ulti ple x ger mli ne  ge ne pa nels  as well as t h e 
i ncreas e d a v aila bilit y of ne xt generati o n t u m or se q ue nci n g , we will li kel y  ca pt ure m ore of t hese 
pati e nts i n c o m m u nit y a n d aca de mic  o nc ol o g y  practices  i n c o mi n g years; h o we ver, d ue t o t he 
c urre nt lac k of  cli nical trials assessi n g t he utilit y of P A R P i n hi bit ors i n t his heter o ge ne o us gr o u p 
of breast ca ncer patie nts, we d o n ot yet k n o w t he efficac y of s uc h a strate g y .  T h us, t his 
pr o of -of -c o nce pt st u d y will assess t he r ole of P A R P i n hi biti o n i n a d va nce d H E R 2 -ne gati v e 
breast ca ncer a n d ot h er n o n -breast s oli d t u m ors wit h pres u me d u n derl yi n g  H R -deficie nc y d ue t o 
a ger mli ne  or s o matic m utati o n i n t he  H R pat h wa y .  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 0  of 4 6   
2  Se pte m ber  2 0 2 0  
2. 7   
St u d y Desi g n  
T his is a si n gle -ar m, o pe n -la bel treat me nt pr ot oc ol desi g ne d t o e val uate t he efficac y a n d s afet y 
of talaz o pari b i n 2  patie nt c o h orts:  
 C o h ort  A : A d v a nce d s p ora dic, tri ple -n e gati ve breast ca n cer wit h h o m ol o g o us rec o m bi nati o n 
deficie nc y b ase d o n a hi g h  H R D  assa y sc ore (H R D  sc ore ≥ 4 2 ) 
 C o h ort  B : A d va n ce d H E R 2 -ne gati ve ( ie, E R a n d/ or P R p ositi ve or T N) breast ca n cer or 
ot her n o n -breast metastatic  ca ncer wit h  a d eleteri o us  or s us pecte d del eteri o us ger mli ne  or 
s o matic ge n e m utati o n i n t he h o m ol o g o us rec o m bi nati o n pat h wa y, e x cl u di n g B R C A 1 a n d 
B R C A 2 .  M utati o ns of i nterest are:  
o  P T E N ;  P A L B 2 ;  C H E K 2 ;  A T M ;  N B N ;  B A R D 1 ;  B RI P 1 ;  R A D 5 0 ;  R A D 5 1 C ;  
R A D 5 1 D ;  M R E 1 1 ;  A T R ;  Fa nc o ni a ne mia c o m ple me ntati o n gr o u p of ge nes ( F A N C A ;  
F A N C C ;  F A N C D 2 ;  F A N C E ;  F A N C F ;  F A N C G ;  F A N C L) ;  pl us ot her  H R -relate d 
ge n es a t t he discreti o n of t he pri mar y i n vesti gat ors . 
T his st u d y 
will pr ocee d 
wit h 2  p hases: scree ni n g a n d treat me nt .  D uri n g scree ni n g, 
all 
partici pa nts will be as ke d t o pr o vi de a metastatic t u m or  bi o ps y sa m ple t o assess t he H R D  sc ore 
base d o n t he  H R D  assa y.  T his res ult is re q uire d f or eli gi bilit y deter mi nati o n i n C o h ort  A .  If t he 
patie nt d oes n ot ha ve a n a de q uate  t u m or bi o ps y sa m ple fr o m a metastatic site, bi o ps y will be 
perf or me d d uri n g scree ni n g .  If t his is n ot feasi ble, we will use t he pri mar y  t u m or f or H R D  sc ore 
assess me nt .  At t his ti me, we will n ot be offeri n g s cree ni n g ger mli ne  testi n g t o assess t he 
prese nce of a delet eri o us B R C A 1 or B R C A 2 m utati o n n or t he ot her  H R pat h wa y ge n es of 
i nterest i n t his trial.  Patie nts w h o ha ve alrea d y bee n i de ntifie d as h ar b ori n g a  deleteri o us  or 
s us pecte d d eleteri o us  ger mli ne  m utati o n i n t h e  H R pat h w a y o n m ulti ple x ger mli ne  p a nels 
(M y Ris k, A m br y, I n Vitae, B R O C A, or ot her C LI A a p pr o ve d assa y ) or t h ose patie nts w h o ha d an  
deleteri o us or s us p ecte d deleteri o us  H R pat h wa y s o matic m utati o n i de ntifie d t hr o u g h ne xt 
ge n erati o n s e q ue n ci n g  of t heir t u m or ( F o u n dati o n O ne or ot her C LI A a p pr o ve d assa y) will be 
eli gi ble f or tr eat me nt i n C o h ort  B .  All p atie nts will be as ke d t o pr o vi de a bl o o d s a m ple t o r u n 
t he m y Ris k here ditar y 2 5-ge ne pa n el f or researc h p ur p oses o nl y. 
Patie nts w h o are eli gi ble f or treat me nt i n C o h ort  A  i ncl u de t h os e w h o are B R C A 1 a n d B R C A 2 
wil d -t y pe, h a ve a d v a nce d  T N B C a n d a t u m or H R D  sc ore of ≥ 4 2 .  
Patie nts w h o are eli gi ble f or treat me nt i n C o h ort  B  i ncl u de t h ose w h o are B R C A 1 a n d B R C A 2 
wil d -t y pe wit h H E R 2-n e gati ve a d va n ce d breast ca ncer or ot her n o n -breast s oli d t u m ors a n d 
eit her a d eleteri o us or s us pecte d del eteri o us ger mli ne  or  s o matic m utati o n i n H R pat h wa y -relate d 
ge n es be y o n d B R C A 1 a n d B R C A 2 .  T hese ge nes i ncl u de:  
P T E N ;  P A L B 2 ;  C H E K 2 ;  A T M ;  N B N ;  B A R D 1 ;  B RI P 1 ;  R A D 5 0 ;  R A D 5 1 C ;  R A D 5 1 D ;  
M R E 1 1 ;  A T R ;  Fa n c o ni a ne mia c o m ple m e ntati o n gr o u p of ge n es ( F A N C A ;  F A N C C ;  
F A N C D 2 ;  F A N C E ;  F A N C F ;  F A N C G ;  F A N C L) ;  pl us ot her  H R -relate d ge nes at t he 
discreti o n of t he pri mar y i n vesti gat ors .  
T he n o mi nal d urati o n of treat me nt is 3 6  c ycl es ( 2 8  da ys per c ycle), b ut C R, P R, or S D patie nts 
ma y c o nti n ue t hera p y u ntil e vi de nce of pr o gressi ve disease or u nacce pta ble t o xicit y occ urs .  
Pr ot oc ol t hera p y will be disc o nti n ue d  f or pr o gressi ve disease at a n y ti me.  Patie nts are free t o 
halt t hera p y at t heir re q u est.  Treat me nt ma y b e disc o nti n ue d if i nterc urre nt c o -m or bi dities occ ur, 
w hic h, i n t he o pi ni o n of t he treati n g p h ysicia n, w o ul d precl u de safe a d mi nistrati o n of st u d y dr u gs  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 1  of 4 6   
2  Se pte m ber  2 0 2 0  
P ati e nts will be sc he d ule d f or f oll o w-u p  ge netic c o u nseli n g if acti o n a ble m ut ati o ns are 
f o u nd.   
3.   
P A R TI CI P A N T S E L E C TI O N A N D E N R O L L M E N T P R O C E D U R E S  
3. 1  Eli gi bilit y Criteri a a n d P artici p a nt Eli gi bilit y C hec klist  
I n cl usi o n a n d E x cl usi o n Criteria are pr o vide d o n t he Eli gi bilit y  C hec klist f oll o wi n g, w hic h is t o 
be e xtracte d fr o m t his d o c u me nt f or use i n scree ni n g p ote ntial s u bjects.  F or eac h pr os pecti ve 
st u d y partici p a nt t hat is scree n e d, t his c hec klist will be pri nte d, c o m plete d i n its e ntiret y a n d t h e 
results rec or de d, a n d t he c hec klist will be file d i n t he res pecti ve s u bject  bi n der or file.  It is 
a ntici pate d t hat n ot all pr os pecti ve st u d y p artici pa nts t hat are scree n e d will be e nr olle d.   
P urs ua nt t o Sta nf or d Me dici ne S O P “ C o nfir mati o n of Partici pa nt Eli gi bilit y i n Cli nical Trials,” 
t he treati n g P h ysici a n (i n vesti gat or);  t he St u d y C o or di nat or;  a n d a n I n d e p e n de nt  Re vie wer will  
verif y t hat t he s u bject’s eli gi bilit y is acc urate;  c o m plete;  a n d le gi ble i n s o urce rec or ds.  
A  descri pti o n of t he eli gi bilit y v erificati o n pr o cess will be i ncl u de d i n t he E PI C or ot her 
Electr o nic Me dical Rec or d pr o gress n ote.  
  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 6  of 4 6   
2  Se pte m ber  2 0 2 0  
3. 2   
I nf or me d C o nse nt Pr ocess 
All pa tie nts m ust be pr o vi de d a c o nse nt f or m descri bi n g t he st u d y wit h s ufficie nt i nf or mati o n f or 
parti ci pa nts t o ma ke a n i nf or me d decisi o n re gar di n g t heir partici pati o n.  Partici pa nts m ust si g n 
t he I R B a p pr o ve d i nf or me d c o nse nt pri or t o partici pati o n i n a n y st u d y s pecific pr oce d ure.  T he 
partici pa nt m ust recei v e a c o p y of t he si g ne d a n d date d c o nse nt d o c u m e nt.  T he ori gi nal si g ne d 
c o p y of t he c o ns e nt d oc u me nt m ust be retai ne d i n t he me dical rec or d or res earc h file.  
3. 3   
R a n d o miz ati o n Pr o ce d ures  
Patie nts will n ot be ra n d o mize d i n t his st u d y, as it is a n o pe n-la bel si n gle ar m trial c o nsisti n g of 
2  c o h orts, b o t h of w hic h will recei ve t he st u d y dr u g.  At least 1 0 H E R 2 -ne gati ve breast ca ncer 
patie nts will be e nr olle d i n C o h ort  B.  
3. 4   
St u d y Ti meli ne  
Pri m ar y C o m pleti o n:   T he st u d y will reac h  pri mar y c o m pleti o n 3 6  m o nt hs fr o m t he ti me t he 
st u d y o pe ns t o accr ual.  T his is t he esti mate d ti me of accr ual of t he last patie nt ( n u m ber  2 0 ) i n 
eac h c o h ort . 
St u d y C o m pleti o n:  T he st u d y will reac h st u d y c o m pleti o n 3 6  m o nt hs fr o m t he ti me t he st u d y 
o pe ns t o accr ual.   
4.   
T R E A T M E N T P L A N  
4. 1   
Scree ni n g Pr oce d ures  
I nf or me d c o nse nt m ust be d oc u me nte d bef ore a n y trial-s pecific pr oce d ures or treat me nts are 
c o n d ucte d.  T his st u d y will ha ve a m olec ular pre -scree n c o ns e nt f or C o h ort  A  t o assess t he H R D  
sc ore usi n g F F P E t u m or tiss ue e val uate d b y t he M yria d H R D  assa y.  All patie nts w h o m eet 
eli gi bilit y criteria base d o n t he pre-s cree n c o nse nt will be pr o vi de d  a writte n m ai n st u d y 
i nf or me d c o nse nt  d o c u me nt .  At t his ti me we will n ot be offeri n g s cree ni n g f or ger mli ne  or 
s o matic m utati o ns i n t he H R pat h wa ys ge nes of i nterest .  All patie nts e nr ol le d i n C o h ort  B of t his 
trial will ha ve a k n o w n deleteri o us or s us pecte d deleteri o us ger mli ne  or s o matic m utati o n i n a 
ge n e of i nterest pri or t o st u d y e nr oll me nt.  
T he f oll o wi n g s cree ni n g pr oce d ures will be perf or me d o n s u bjects c o nse nti n g f or m olec ular 
pre -scree ni n g f or C o h ort  A : 
 Deter mi nati o n of  H R D  s c ore bas e d o n f or mali n fi xe d paraffi n e m be d d e d ( F F P E) 
metastatic t u m or site c ore bi o ps y .  If t he patie nt d oes n ot ha ve a n a de q uat e t u m or bi o ps y 
sa m ple fr o m a metast atic site, bi o ps y will be perf or me d d uri n g scree ni n g.  If t his is n ot 
feasi ble, we will use t he pri mar y t u m or f or H R D  s c ore ass ess me nt. 
T he f oll o wi n g scree ni n g pr oce d ures will be perf or me d o n c o nse nt e d a n d eli gi ble s u bjects after 
t he mai n st u d y c o ns e nt is si g ne d wit hi n 2 8 da ys  of i nitiati n g st u d y tre at me nt:  
 Me dical hist or y  
 C o m plete p h ysical e x a mi nati o n, i ncl u di n g hei g ht a n d wei g ht  
 Vital si g n assess me nt, i n cl u di n g bl o o d press ure a n d p ulse  
 Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us assess me nt  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 7  of 4 6   
2  Se pte m ber  2 0 2 0  
 La b orat or y e val uati o n, i n cl u di n g C B C wit h d iffere ntial, c o m pre he nsi ve met a b olic pa nel, 
a n d uri ne pre g na nc y t est  
 Pat h ol o g y re vie w (i ncl u di n g re vi e w of E R/ P R/ H E R 2  f or breast ca ncers) of t u m or fr o m 
metastatic site or a bi o ps y of met astatic site, if n ot d o ne pre vi o usl y .  
 C T sca n wit h I V c o ntr ast of c he st, a b d o me n, a n d pel vis or P E T/ C T sca n wit h I V c o ntrast 
f or c o m plete disease e v al uati o n.  C o ntin ue t o use t he sa me e v al uati o n met h o d d uri n g t he 
st u d y as use d f or i nitial e val uati o n 
 M RI brai n  or C T h ea d, if pri or hist or y of brai n metastases 
 F or patie nts eli gi ble f or C o h ort  B, deter mi nati o n of  H R D  sc ore b ase d o n f or mali n fi xe d 
paraffi n e m be d de d ( F F P E) metastatic t u m or site c ore bi o ps y is r e q uire d, b ut is n ot nee de d 
f or eli gi bilit y a n d d oes n ot nee d t o be re p orte d pri or t o treat me nt i nitiati o n.  If t he patie nt 
d oes n ot ha ve a n a de q uat e t u m or bi o ps y sa m ple fr o m a metastatic site, bi o ps y will be 
perf or me d d uri n g scree ni n g .  If t his is n ot feasi ble, we will use t he pri mar y t u m or 
f or H R D  sc ore assess me nt. 
 Researc h ger mli ne  bl o o d c ollecti o n  
 Researc h M y Ris k ger mli ne  bl o o d c ollecti o n  
 Researc h pl as ma c ollecti o n  
 S u b missi o n of arc hi val t u m or tiss ue fr o m t he pri mar y breast t u m or  
4. 2   
D osi n g a n d A d mi nistr ati o n Sc he d ule  
N O T E:     1  c ycle =  2 8  d a ys  
Talaz o pari b  will be a d mi nistere d at 1 milli gra m orall y dail y .  Talaz o pari b  s h o ul d be ta ke n at 
a p pr o xi matel y t he sa me ti me eac h d a y .  Talaz o pari b  will be ta ke n orall y a n d s wall o we d w h ole.  
All d osa ges prescri be d a n d dis pe nse d t o t he patie nt a n d all d ose c ha n ges d uri n g t h e st u d y m ust 
be rec or de d .  Me dicati o n la bels will c o m pl y wit h U S 
le gal re q uire m e nts a n d be pri nte d i n 
E n glis h .  T he y will s u p pl y n o i nf or m ati o n a b o ut t he patie nt.  
T he I P is talaz o pari b, a w hite t o off-w hite cr ystalli ne p o w der .  T he dr u g s u bsta n ce is a 
4 -met h yl be nze n es ulf o nat e (t os ylate) salt of talaz o pari b free base, the acti ve m oiet y .  T he dr u g 
pr o d uct c o nsists of t he dr u g s u bsta n ce f or m ulate d wit h a p har mace uticall y -s uita ble e x ci pie nt 
fille d i nt o h y dr o x y met h yl pr o p ylcell ul ose ca ps ul es.  Ca ps ules will be pr o vi de d t o t he site i n 3 
d ose stre n gt hs of 0. 1 0  m g , 0. 2 5 m g , a n d 1. 0  m g  ca ps ules .  T he d ose str e n gt hs are base d o n t he 
acti ve m oiet y ( t alaz o pari b free bas e).  T he ca ps ules are pr o vi de d i n d ose -s pecifi c c ol ors t o 
pr o vi de a vis ual met h o d of disti n g uis hi n g d ose stre n gt hs .  St u d y dr u g s h o ul d be st ore d at r o o m 
te m perat ur e ( 15  t o 3 0° C;  5 9  t o 8 6° F) .  T he ca ps ules are s u p plie d i n 3 0 -c o u nt i n d ucti o n -seale d 
hi g h -de nsit y p ol yet h yle ne ( H D P E) b ottles.  
T he i n vesti gat or s h o ul d pr o m ote c o m plia nce b y i nstr ucti n g t he p atie nt t o ta ke t he st u d y dr u g 
e x actl y as pres cri be d a n d b y st ati n g t ha t c o m plia nce is necessar y f or t he p atie nt’s safet y a n d t he 
vali dit y of t he st u d y .  T he patie nt s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gat or if he/s he is 
u na ble f or a n y reas o n t o ta ke t he st u d y dr u g as prescri be d.  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 8  of 4 6   
2  Se pte m ber  2 0 2 0  
C a ps ules  
T he ca ps ules  s h o ul d be s wall o we d w h ole wit h a glass of water a n d s h o ul d n ot be c he we d or 
cr us he d.  If v o miti n g occ urs, n o atte m pt s h o ul d be ma de t o re place t he v o mite d d ose.  Patie nts 
s h o ul d be i nstr ucte d t hat if t he y miss a d ose o n o ne da y, t he y m ust n ot ta ke a n y e xtra d ose t he 
ne xt d a y, b ut i nstea d t o i m me diatel y c o ntact t he st u d y ce nter as s o o n as p ossi ble t o as k f or 
a d vice.  
Patie nts 
ma y c o nti n ue c o nc o mita nt 
me dicati o ns  f or ot her c o n diti o ns a n d a n y a d diti o nal 
a p pr o priate s u p p orti ve care me dicati o ns or treat me nts.   
4. 3   
Pre -T re at me nt E v al u ati o ns  
Patie nts will be e val uate d i n cli nic o n Da y  1 of eac h c ycle .  F or t he first c ycle, we will als o 
re q uire a mi d-c ycle p h ysi cia n's visit .  F urt her m ore,  wee kl y C B C wit h diff will be re q uire d f or t he 
first c ycle ( q 7 d a ys +/- 3  da ys) a n d bi wee kl y  ( q 14 da ys +/ - 3  da ys)  C B C wit h diff will be 
re q uire d f or t he sec o n d c ycl e.  S u bse q ue nt t o t his, we will o nl y re q uire a C B C wit h diff per c ycle 
( q 4 wee ks +/- 3  da ys) .  La b orat or y tests ca n be p er f or me d e xter nall y a n d fa x e d t o t he PI/researc h 
tea m.  T he f oll o wi n g ass ess me nts will be perf or me d at eac h p h ysicia n's visit : 
 P h ysical e xa mi nati o n, i ncl u di n g wei g ht  
 Vital si g ns, i ncl u di n g bl o o d press ure, p ulse, a n d te m perat ure  
 E C O G Perf or ma nce Stat us assess me nt  
 Cli nical la b orat or y tests:  C B C wit h differe ntial a n d c o m pre he nsi ve m eta b olic pa nel  
 Uri ne pre g n a nc y test  (fe male s u bjects of c hil d beari n g p ote ntial) 
 Assess me nt of c o nc o mita nt me dicati o ns  
 Assess me nt of a d verse e ve nts a n d d ose m o dificati o ns as necessar y.  A d verse e ve nts 
s h o ul d be m o nit ore d c o nti n u o usl y 
 T u m or e val uat i o n wit h i ma gi n g e v er y 2 c ycles ( 8 wee ks +/- 1 wee k)  
4. 4   
E n d of Tre at me nt Pr o ce d ures  
If patie nts are n o l o n ger recei vi n g treat me nt, t he assess me nts s h o ul d be c o m plete d wit hi n 
3 0  da ys of t he last d ose of talaz o pari b.   
 P h ysical e xa mi nati o n, i ncl u di n g wei g ht  
 Vital si g ns, i ncl u di n g bl o o d press ure, p ulse, a n d te m perat ure  
 E C O G Perf or ma nce Stat us assess me nt  
 Cli nical la b orat or y tests: C B C wit h differe ntial, c o m pre he nsi ve meta b olic pa nel  
 Uri ne pre g n a nc y test  (fe male s u bjects of c hil d beari n g p ote ntial) 
 Assess me nt of  a d verse e ve nts  
 St u d y dr u g c o m plia nce ( pill diar y)  

I R B-3 1 9 1 3 versi o n 8  
P a ge 2 9  of 4 6   
2  Se pte m ber  2 0 2 0  
4. 5   
Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes  
C o nc o mita nt treat me nt is per mitte d if t he me dicati o n is n ot e x pecte d t o i nterfere wit h t he 
e val uati o n of safet y or efficac y of t he st u d y dr u g .  D uri n g t he st u d y, if t he use of a n y 
c o nc o mita nt treat me nt bec o mes necessar y ( e g, f or treat me nt of a n a d verse e ve nt), t he treat me nt 
m ust be d oc u me nte d, i ncl u di n g t he reas o n f or treat me nt, ge neric na me of t he dr u g, d osa ge, r o ute, 
a n d start a n d st o p da tes of a d mi nistrati o n. 
A ll s u p p orti ve meas ures c o nsiste nt wit h o pti mal patie nt care will be gi ve n t hr o u g h o ut t he st u d y.  
T he cli nical t olera nce of t he patie nt, t he o verall t u m or res p o nse, a n d t he me dical j u d g me nt of t he 
i n vesti gat or will deter mi ne if it is i n t he patie nt’s best i nterest t o c o nti n ue or disc o nti n ue 
treat me nt.  If treat me nt is disc o nti n ue d d ue t o a n y t o xicit y, t he p atie nt m ust be f oll o we d t o 
m o nit or d urati o n of t o xicit y, res p o nse a n d ti me t o pr o gressi o n or s ur vi val a n d i nitiati o n of a n y 
ne w s y st e mic t hera p y.  
4. 6   
D ur ati o n of T her a p y a n d F oll o w -U p  
T he n o mi nal d urati o n of treat me nt is 3 6  c ycl es ( 2 8  da ys per c ycle), b ut C R, P R, or S D patie nts 
will c o nti n ue t hera p y u ntil e vi de nce of pr o gressi ve disease or  u n acce pta ble t o xicit y occ urs.  
Pr ot oc ol t he ra p y will be disc o nti n ue d f or pr o gressi ve disease at a n y ti me.  Patie nts are free t o 
halt t hera p y at t heir re q u est.  Treat me nt ma y b e disc o nti n ue d if i nterc urre nt c o -m or bi dities occ ur, 
w hic h, i n t he o pi ni o n of t he treati n g p h ysicia n, w o ul d precl u de safe a d mi nistrati o n of st u d y 
dr u gs.  
4. 7   
Criteri a f or Re m o v al f r o m St u d y  
Patie nts M U S T be disc o nti n ue d fr o m st u d y t hera p y A N D be wit h dra w n fr o m t he st u d y f or t he 
f oll o wi n g reas o ns:  
 Wit h dra wal of t he patie nt’s c o nse nt ( patie nt’s d ecisi o n t o wit h dra w f or a n y reas o n)  
 A n y cli nical a d verse e v e nt, la b orat or y a b n or malit y or i nterc urre nt ill ness w hic h, i n 
t he o pi ni o n of t he i n vesti gat or, i n dicates t hat c o nti n ue d partici pati o n i n t he st u d y is 
n ot i n t he best i nterest of t he s u bject  
 I n a bilit y t o c o m pl y wit h pr ot oc ol  
 Dis creti o n of t he i n vesti gat or  
 Disease pr o gressi o n ( pati e nt c o nti n ue t o be f oll o we d f or s ur vi val) 
 Deat h  
If a s u bject is wit h dra w n bef ore c o m pleti n g t h e st u d y, t he reas o n f or wit h dra wal m ust be e ntere d 
o n t he a p pr o priat e cas e re p ort f or m.   
4. 8   
Alter n ati ves  
Alt er nati ves t o partici pati o n i n t his cli nical trial i ncl u de use of c he m ot hera pe utic a ge nts f or t h e 
treat me nt of metastatic tri ple-ne gati ve breast ca ncer .  Alter n ati ves f or metastatic E R a n d/ or 
P R -p ositi ve, H E R 2 -ne gati ve breast c a ncer i ncl u de a nti-estr o ge n t hera p y a n d c he m ot hera p e utic 
a ge nts.  

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 0  of 4 6   
2  Se pte m ber  2 0 2 0  
4. 9   
C o m pe ns ati o n  
Patie nts ma y be eli gi ble f or tra vel a n d m eal rei m b urse me nt if t he y li ve m ore t ha n 5 0 miles fr o m 
st u d y site.   
5.   
I N V E S TI G A TI O N A L A G E N T/ D E VI C E/ P R O C E D U R E I N F O R M A TI O N  
5. 1   
I n vesti g ati o n al A ge nt   
Please n ote t hat more c o m plete i nf or mati o n ca n b e o btai ne d fr o m t he I n vesti gat or’s Br oc h ure 
(I B). 
Talaz o pari b  is a n o vel p ol y( A D P-ri b ose) p ol y merase ( P A R P) i n hi bit or.  T he acti ve i n gre die nt is 
talaz o pari b; t he c he mical na me is 3H -P yri d o[ 4, 3, 2 -de] p ht halazi n -3 -o ne, 
5 -flu or o -8 -( 4-fl u or o p he n yl)-2, 7, 8, 9 -tetra h y dr o-9 -( 1-met h yl -1 H -1, 2, 4 -triaz ol-5 -yl) -, ( 8S , 9R )-, 
4 -met h yl be nze nes ulf o nate ( 1: 1).  
C he mical str uct ure of talaz o pari b: 
 
M olec ular F or m ula ( tal az o pari b): C 2 6 H 2 2 F 2 N 6 O 4 S 
M olec ular Wei g ht ( talaz o pari b): 5 5 2. 5 6 2 4 
Talaz o par i b is 
ma n ufact ure d b y c he mical s y nt hesis i n acc or da nce 
wit h c urre nt 
G o o d 
Ma n ufact uri n g Practices (c G M P) .  T he dr u g pr o d uct is a ca ps ule f or m ulati o n c o m prise d of a 
ble n d of talaz o pari b dr u g s u bsta nce a n d silicifie d 
micr ocr ystalli ne cell ul ose fille d i nt o a 
h y pr o mell ose ca ps ule .  T he ca ps ule is prese nte d i n f o ur stre n gt hs –  2 5 -μ g ;  5 0 -μ g ;  2 5 0 -μ g ;  or 
1 -m g talaz o pari b free bas e e q ui vale nt –  t hat are disti n g uis he d eit her b y ca ps ule c ol or or size. 
Talaz o pari b is c o nsi dere d a c yt ot o xic a ge nt; preca uti o ns re gar di n g a p pr o priate sec ure st ora ge 
a n d ha n dli n g m ust b e us e d b y h ealt hcare pr ofessi o nals, i ncl u di n g pers o nal pr otecti ve cl ot hi n g, 
dis p osa ble gl o ves a n d e q ui p me nt .  S u bjects s h o ul d be a d vise d t hat oral a ntica n cer a ge nts are 
t o xic s u bsta nces a n d t h at ( ot her t h a n the s u bject) care gi vers s h o ul d al wa ys use gl o v es w he n 
ha n dli n g t he ca ps ules.  
5. 2   
P h ar m a c o d y n a mi c Pr o perties   
Pri mar y P D st u dies ass esse d talaz o pari b a n d relate d c o m p o u n ds f or i n vitr o a n d i n viv o 
p har mac ol o gical acti vities .  Assess me nt of tal az o pari b effect s i n t u m or cell i nc u bati o ns re veale d 
selecti ve a n d p ote nt c yt ot o xicit y i n h u ma n ca ncer cell li nes har b ori n g m utati o ns t hat c o m pr o mise 
D N A re pair p at h wa ys .  Ge ne m utati o ns t hat c o nfer sel ecti ve t u m or cell c yt ot o xicit y i ncl u de d 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 1  of 4 6   
2  Se pte m ber  2 0 2 0  
B R C A 1 ( M X -1 ma m mar y t u m or cell s);  B R C A 2 ( Ca pa n -1 pa n creatic t u m or cells) ;  P T E N 
( M D A-M B -4 6 8 ma m mar y ;  L N Ca p a n d P C -3 pr ostate t u m or cells) ;  a n d M L H -1 m utati o ns 
( H C T-1 1 6 c ol or ectal t u m or cells) .  T he I C 5 0 val ues of tal az o pari b i n t hese t u m or cell li nes were 
i n t he si n gl e di git na n o m olar or s u b -na n o m olar ra n ge .  I n c o ntrast, t he I C 5 0 of talaz o pari b a gai nst 
n or mal h u ma n pri mar y cell M R C -5 a n d se veral t u m or cell li nes t hat d o n ot ha ve re p orte d D N A 
re pair-relat e d m utati o ns are si g nifica ntl y greater ( 2 5 0 n M  t o >  1 0 0 0  n M ). 
5. 3   
P h ar m a c o ki neti c Pr o perties   
T he p har mac o ki n etic ( P K) res ults f or t he d ose escalati o n p hase of P R P -0 0 1 ha ve bee n assess e d 
wit h preli mi nar y c o nce ntrati o n data fr o m 2 5  μ g / da y t hr o u g h 1 1 0 0 μ g / d a y.  I n c ycl e 1, sa m ples 
were c ollecte d f or a wee k after t he first si n gle d ose ( Da y  1) of a c o h ort, pre -d ose sa m ples were 
c ollecte d d uri n g dail y d osi n g (tr o u g hs), a n d sa m ples were c ollect e d f or a wee k after t he last d ose 
i n c ycle 1 (Da y  3 5) .  F oll o wi n g a si n gle d ose ( Da y  1), mea n plas ma C ma x  a n d A U C 0 -2 4 hr  ra n ge d 
fr o m 
6 0. 0 t o 1 3, 2 0 0  p g /m L  a n d fr o m 
9 5 3  t o 9 2, 1 0 0  p g -hr/ m L , res pecti vel y, 
o ver t he 
2 5  t o 1 1 0 0  μ g  d ose ra n ge .  F oll o wi n g m ulti ple dail y d osi n g ( Da y  3 5), mea n plas ma C ma x  a n d 
A U C 0 -2 4 hr ra n ge d fr o m 3 0 0 t o 2 3, 4 0 0  p g/ m L  a n d fr o m 3 9 6 0  t o 2 0 3, 0 0 0  p g -hr/ m L , res pecti vel y, 
o ver t he 2 5 t o 1 1 0 0  μ g / da y d os e ra n ge.  At t he defi ne d ma xi m u m t olerate d d ose ( M T D) of 
1 0 0 0  μ g / da y, 
mea n ( S D) 
Cma x  a n d A U C 0 -2 4 hr  were 2 1, 0 0 0 ( 7, 9 9 0)  p g /m L  a n d 2 0 3, 0 0 0 
( 5 4, 8 0 0) p g -hr/ m L , res p ecti vel y, o n Da y  3 5 .  T he plas ma pr ofiles i n dicate e nter o he p atic c ycli n g 
of talaz o pari b beca us e of t he a d diti o nal c o n ce ntrati o n pea ks be y o n d T ma x .  Eli mi nati o n a p pears t o 
be 
bi -e x p o ne ntial .  Mea n  
talaz o pari b t1/ 2 
ra n ge d fr o m 
5 3. 5 t o 2 3 4  h o urs  a n d fr o m 
4 0. 4  t o 1 1 5  h o urs  o n Da y  1 a n d Da y  3 5, res p ecti vel y .  At t he u p per e n d of t he d ose ra n ge 
e val uate d ( 9 0 0  t o 1 1 0 0  μ g ), t1/ 2 ra n ge d fr o m 5 3. 5 t o 6 6. 1  h o urs  a n d fr o m 4 0. 4  t o 5 1. 8  h o urs  o n 
Da y  1 a n d Da y  3 5, res pecti vel y .  Stea d y state was a p pare nt i n m ost patie nts b y t w o wee ks wit h 
dail y d osi n g .  Acc u m ulati o n base d o n A U C 0 -2 4 hr  was o bser ve d f or all pati e nts c o m pari n g Da y  3 5 
wit h Da y  1 a n d 
mea n val ues ra n ge d fr o m 2. 4 2  t o 9. 9 2 a n d fr o m 2. 4 2  t o 3. 6 9 acr oss t he 
2 5  t o 1 1 0 0  μ g  d ose ra n ge a n d t h e 9 0 0  t o 1 1 0 0  μ g  d os e ra n ge, res pecti vel y .  F oll o wi n g si n gle 
d oses, talaz o pari b C ma x  a n d A U C 0 -2 4 hr  were li near bet wee n 4 0 0 a n d 1 1 0 0  μ g .  F oll o wi n g 
m ulti ple d oses, talaz o pari b C ma x  a n d A U C 0 -2 4 hr  were li near bet w ee n 2 5 a n d 1 1 0 0  μ g / da y.  
A f o o d effect st u d y ( 6 7 3 -1 0 3) i n 1 8 healt h y v ol u nteers has bee n c o m plete d .  T his st u d y s h o we d 
t hat w hile a hi g h-fat, hi g h cal orie m eal dela ye d t h e a bs or pti o n of orall y a d mi nistere d talaz o pari b, 
it di d n ot affect t he o verall e xte nt of t he a bs or pti o n.  Base d o n t hese fi n di n gs, talaz o pari b ca n be 
a d mi nistere d wit h o ut re gar d t o f o o d.  
5. 4   
S u p plier  
T he i n vesti gati o nal a ge nt, talaz o pari b, will be pr o vi de d b y Pfizer P har mace utical, I nc.   
5. 5   
D os a ge F or m  
Talaz o pari b  will be s u p plie d as ca ps ules f or oral a d mi nistrati o n.  
5. 6   
A ge nt Or deri n g  a n d P a c k a gi n g  
Re q uests f or s hi p me nts of t he i n vesti gati o nal a ge nt will be c o or di nate d b y t he st u d y c o or di nat or 
directl y wit h  Pfizer  P har mace utical, I nc.  B ottles will c o ntai n a s uffici e nt n u m ber of ca ps ules f or 
o ne c ycle of d osi n g.   

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 2  of 4 6   
2  Se pte m ber  2 0 2 0  
5. 7   
St or a ge a n d s helf life  
Sta bilit y d ata o btai n e d f or b ot h pr ot ot y pe a n d cli nical dr u g pr o d uct bat c hes c urre n tl y s u p p ort 
retest dati n g of 3 6 m o nt hs f or dr u g pr o d uct .  B ot h dr u g pr o d uct a n d dr u g s u bsta nce e x hi bit 
e x celle nt sta bilit y tr e n ds .  T he dr u g pr o d uct is st ore d at r o o m te m perat ure ( 1 5  t o 3 0  de g  C; 
5 9  t o 8 6  de g  F) a n d s h o ul d be pr otecte d fr o m li g ht.  
5. 8   
N at ure a n d C o nte nts of C o nt ai ner  
T he ca ps ules a re pac k a ge d i n perf orate d u nit-d ose blister car ds c o m p ose d of c ol d f or m 
al u mi n u m f oil a n d p us h t hr o u g h al u mi n u m li d di n g .  T he 4  ca ps ule stre n gt hs are pac k a ge d i nt o 
t he sa me blister car d desi g n.  A d diti o nall y, 2 5 0 -μ g ca ps ules ( o pa q ue w hite, size 4) are pac k a ge d 
i n 3 0-c o u nt H D P E b ottles wit h a n i n d ucti o n seal a n d c hil d -resista nt ca p.  
5. 9   
S peci al Prec a uti o ns f or Dis p os al a n d Ot her H a n dli n g  
A n y u n us e d pr o d uct or waste material is t o be dis p ose d of i n acc or da n ce wit h l ocal re q uire me nts.   
6.   
D O S E M O DI FI C A TI O N S  
Dail y d osi n g of talaz o pari b ca n be i nterr u pte d f or rec o ver y fr o m t o xicit y f or u p t o 2 8  da ys .  
T hereafter,  tr eat me nt at t he sa me or a re d u ce d d ose ca n be c o nsi dere d bas e d o n t he discreti o n of 
t he pri mar y i n vesti gat or if t he s u bject has n ot de vel o pe d pr o gressi ve disease.  D ose 
m o dificati o ns  s h o ul d be ma de base d o n o bs er ve d t o xicit y as f oll o ws: 
 Gra de  1 or 2 t o xicit y:  N o re q uire me nt f or d ose i nterr u pti o n or d ose re d ucti o n .  If t he 
t o xicit y persists at Gra de  2, a d ose re d u cti o n t o t he ne xt l o wer d ose le vel (e g,  fr o m 
1. 0  m g / da y t o 0. 7 5  m g/ da y) ma y be i m ple me nte d at t he discreti o n of t he I n vesti gat or  
 Gra de  3 t o xicit y:  Dail y d osi n g s h o ul d be st o p pe d .  Talaz o pari b  d osi n g ma y res u me at  t he 
ne xt l o wer d ose le vel (e g,  fr o m 1. 0 m g / da y t o 0. 7 5  m g / da y; 0. 7 5  m g / da y t o 0. 5  m g / da y;  
0. 2 5  m g / da y t o 0. 1 0  m g / da y) w he n t o xicit y res ol ves t o Gra de  1 or ret ur ns t o baseli ne  
 Gra de  4 t o xicit y:  Dail y d osi n g s h o ul d be st o p pe d .  Talaz o pari b  ma y res u m e at a l o wer 
d ose le vel ( 1  t o 2 d ose le vel decrease) wit h t he a p pr o val of t he PI  w he n t o xicit y res ol v es 
t o Gra de  1 or ret ur ns t o b aseli ne  
T a ble 3 .  D ose m o dificati o ns f or t o xicities  
  
D ose Le vel  
I nitial d ose le vel  
1. 0  m g / da y 
First d ose le vel r e d ucti o n  
0. 7 5  m g / da y 
Sec o n d d ose le vel r e d ucti o n  
0. 5  m g / da y 
T hir d d ose le vel r e d ucti o n  
0. 2 5  m g / da y 
F o urt h d ose le vel re d ucti o n  
0. 1 0  m g / da y 
Talaz o pari b  will be per m a ne ntl y disc o nti n ue d f or i n di vi d ual s u bjects as a res ult of a n y  
u nres ol ve d Gra de  3 or Gra de  4 t o xicit y or base d o n a decisi o n b y t he s u bject or I n vesti gat or t hat 
c o nti n ue d talaz o pari b treat me nt is n ot i n t he s u bject’s best i nterest. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 3  of 4 6   
2  Se pte m ber  2 0 2 0  
7 .  
A D V E R S E E V E N T S A N D R E P O R TI N G P R O C E D U R E S  
7. 1   
P ote nti al A d verse E ve nts  
Acc or di n g t o t he I C H defi niti o n, a n a d verse e ve nt ( A E) is a n y u nt o w ar d m e dical occ urre nce i n a 
patie nt or cli nical i n vesti gati o n s u bjec t a d mi nistere d a p har mace utical pr o d uct, a n d t hat d oes n ot 
necessaril y h a ve a ca us al relati o ns hi p wit h t his treat me nt.  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 la b orat or y fi n di n g), s y m pt o m, or 
disease te m p orall y as s ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, w het her or 
n ot c o nsi dere d relate d t o t he i n vesti gati o nal pr o d uct.  
T his defi niti o n i ncl u des i nterc urre nt ill nesses or i nj uries t hat re pres e nt a n e x acer bati o n (i ncreas e 
i n fre q ue nc y, s e verit y, or s pecificit y) of pre-e xisti n g c o n diti o ns.  
W he ne ver p ossi ble, it is 
prefera ble t o rec or d a dia g n osis as t he A E t er m rat her t ha n a s eries of ter ms relati n g t o a 
dia g n osis .  A d verse e ve nt i nf or mati o n will be c ollecte d i n a n o n g oi n g fas hi o n t hr o u g h p atie nt 
re p orti n g A Es t o t heir p h ysicia n or healt h care pr o vi der.  Seri o us n ess a n d relate d n ess will be 
assesse d b y t he treati n g p h ysicia n, wit h a p pr o priat e re p orti n g.  
A desi g nate d pri mar y c o ntact pers o n base d at t he treat me nt ce nter will be res p o nsi ble f or t he 
c ollecti o n a n d re p orti n g of A Es f or patie nts partici pati n g i n t he pr o gra m.   
A d verse e ve nts t hat be gi n or w orse n after i nf or m e d c o ns e nt s h o ul d be rec or de d i n t h e A d verse 
E ve nts C R F .  C o n diti o ns t hat were alrea d y pres e nt at t he ti me of i nf or me d c o nse nt s h o ul d b e 
rec or de d i n t he Me dical Hist or y pa ge of t he patie nt’s C R F.  A d verse e ve nt m o nit ori n g s h o ul d be 
c o nti n ue d f or at least 3 0  da ys ( or 5  half -li ves, w hic he ver is l o n ger) f oll o wi n g t he last d ose of 
st u d y tr eat me nt.  A d verse e v e nts (i ncl u di n g la b a b n or malities t hat c o nstit ute A Es) s h o ul d be 
descri be d usi n g a dia g n osis w he ne ver p ossi ble, rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d 
s y m pt o ms.  W he n a cl ear dia g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be 
re p orte d as a se p arate A d verse E ve nt. 
T he occ ur re nce of a d v erse e v e nts s h o ul d be s o u g ht b y n o n-directi ve q u esti o ni n g of t he patie nt at 
eac h visit d uri n g t he st u d y.  A d verse e ve nts als o ma y be det ecte d w he n t he y are v ol u nteere d b y 
t he patie nt d uri n g or bet wee n visits or t hr o u g h p h ysical e x a mi nati o n, la borat or y test, or ot her 
assess me nts .  As far as p ossi ble, eac h a d v erse e ve nt s h o ul d be e val uate d t o deter mi ne:  
 T he se verit y gra de ( C T C A E Gra d e  1  t o 4)  
 Its d ur ati o n (start a n d e n d dates or if c o nti n ui n g at t he Safet y F oll o w-u p Visit)  
 Its r elati o ns hi p t o t he st u d y treat me nt ( Reas o n a ble p ossi bilit y t hat A E is rel ate d: N o, Yes)  
 Acti o n ta ke n wit h res p ect t o st u d y or i n vesti gati o nal treat me nt ( n o ne, d ose a dj uste d, 
te m p oraril y i nterr u pte d, per ma ne ntl y disc o nti n ue d, h os pitalize d, u n k n o w n, n ot 
a p plica ble)  
 W het her me dicati o n or t hera p y was gi ve n ( n o c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y, 
c o nc o mita nt me dicati o n/ n o n -dr u g t hera p y)  
 O utc o me ( n ot  rec o vere d/ n ot res ol ve d;  rec o v ere d/res ol ve d;  rec o veri n g/res ol vi n g;  
rec o vere d/r es ol ve d wit h se q ualae;  fatal;  u n k n o w n)  
 W het he r it is seri o us, w here a s eri o us a d v erse e ve nt ( S A E) is defi ne d as i n Secti o n  7. 1. 2  

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 4  of 4 6   
2  Se pte m ber  2 0 2 0  
All a d verse e ve nts s h o ul d be treate d a p pr o priatel y .  S uc h treat me nt ma y i ncl u de c ha n ges i n st u d y 
dr u g tr eat me nt i ncl u di n g p ossi ble i nterr u pti o n or disc o nti n uati o n, starti n g  or st o p pi n g 
c o nc o mita nt treat me nts, c ha n ges i n t h e fre q ue n c y or nat ure of assess me nts, h os pitalizati o n, or 
a n y ot her me dicall y re q uire d i nter ve nti o n .  O nce a n a d v erse e ve nt is d etecte d, it s h o ul d be 
f oll o we d u ntil its res ol uti o n, a n d assess me nt s h o ul d be ma de at eac h visit ( or m ore fre q ue ntl y, if 
necessar y) of a n y c ha n ges i n se v erit y, t h e s us pecte d rel ati o ns hi p t o t he st u d y dr u g, t he 
i nter ve nti o ns re q uire d t o treat it, a n d t he o utc o me. 
I nf or mati o n a b o ut c o m m o n si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal dr u g ca n b e 
f o u n d i n t he I n v esti gat ors’ Br oc h ure.  T his i nf or mati o n s h o ul d be i n cl u de d i n t he p atie nt 
i nf or me d c o nse nt a n d s h o ul d be disc usse d wit h t he patie nt d uri n g t he st u d y as nee de d.  A d verse 
e ve nt m o nit ori n g s h o u l d be c o nti n ue d f or at least 3 0 da ys f oll o wi n g t he last d ose of st u d y 
treat me nt. 
Gi ve n ot her dr u gs i n t his class ha ve bee n ass oci ate d wit h he mat ol o gic mali g na n cies, s uc h as 
m yel o d ys plastic s y n dr o me ( M D S) a n d ac ute le u ke mias, a n y pr ol o n ge d c yt o p e nias, defi ne d as 
greater t ha n 6  wee ks, wil l be t h or o u g hl y e v al uate d i ncl u di n g referral t o he mat ol o g y cli nic, w here 
r o uti ne pr oce d ures i ncl u di n g b o ne marr o w bi o ps y, if dee me d a p pr o priate, will be c o n d ucte d.  
7. 1. 1  L a b or at or y test a b n or m alities  
La b orat or y a b n or malit ies t hat c o nstit ute a n A d verse Eve nt i n t heir o w n ri g ht (are c o nsi dere d 
cli nicall y si g nifica nt, i n d uce cli nical si g ns or s y m pt o ms, re q uire c o nc o mit a nt t hera p y or re q uire 
c ha n ges i n st u d y treat me nt), s h o ul d be rec or de d o n t he A d verse E ve nts C R F .  W he ne ver 
p ossi ble, a dia g n osis, rat her t ha n a s y m pt o m s h o ul d be pr o vi de d ( e g, a ne mia i nstea d of l o w 
he m o gl o bi n) .  La b orat or y a b n or malities t hat meet t he criteria f or A d verse E ve nts s h o ul d b e 
f oll o we d u ntil t he y h a ve ret ur n e d t o n or mal or a n a de q u ate e x pla nati o n of t he a b n or malit y is 
f o u n d.  W he n a n a b n or mal la b orat or y or test res ult c orres p o n ds t o a si g n/s y m pt o m of a n alrea d y 
re p orte d a d v erse e ve nt, it is n ot necessar y t o se p aratel y rec or d t he la b/test res ult as a n a d diti o nal 
e ve nt.  
La b orat or y a b n or malities, t hat d o n ot meet t he defi niti o n of a n a d v e rse e ve nt, s h o ul d n ot be 
re p orte d as a d verse e ve nts.  A Gra de  3 or 4 e ve nt (se vere) as per C T C A E d oes n ot a ut o maticall y 
i n dicate a S A E u nless it meets t he defi niti o n of seri o us as defi ne d bel o w a n d/ or as p er 
i n vesti gat or’s discreti o n.  A d ose h ol d or me dic ati o n f or t he la b a b n or malit y ma y be re q uire d b y 
t he pr ot oc ol a n d is still, b y defi niti o n, a n a d verse e ve nt. 
7. 1. 2   Seri o us A d verse E ve nts  ( S A E)  
A seri o us a d verse e v e nt is a n u n desira ble si g n, s y m pt o m or me dical c o n diti o n w hic h:  
 is fatal or life-t hr eate ni n g 
 res ults i n persiste nt or si g nifica nt disa bilit y/i n ca pacit y 
 c o nstit utes a c o n ge nital a n o mal y/ birt h defect  
 re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is f or:  
o  electi ve or pre-pla n ne d treat me nt f o r a pre-e xisti n g c o n diti o n t hat is u nrelat e d t o 
t he i n dicati o n u n der st u d y a n d h as n ot w orse n e d si nce t he start of st u d y dr u g 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 5  of 4 6   
2  Se pte m ber  2 0 2 0  
o  treat me nt o n a n e m er ge n c y o ut p atie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E gi v e n a b o ve a n d n ot res ulti n g i n h os pital a d missi o n  
o  s ocial reas o ns a n d res pite care i n t he a bse n ce of a n y det eri orati o n i n t he pati e nt’s 
ge n eral c o n diti o n  
o  is me dicall y si g nifica nt, i e, defi ne d as a n e v e nt t hat je o par dizes t he patie nt or ma y 
re q uire me di cal or s ur gical i nter ve nti o n to pre ve nt o ne of t he o utc o mes liste d 
a b o ve  
7. 1. 3  Pre g n a nc y  
If a patie nt bec o mes pre g na nt d uri n g t he st u d y, st u d y dr u g a d mi nistrati o n m ust be disc o nti n ue d 
a n d t he p re g na n c y m ust  be re p orte d i m me diatel y ( wit hi n 2 4  h o urs  of b ec o mi n g a ware of t h e 
pre g na nc y) t o  Pfizer Safet y p ortal s yste m b y usi n g t h e F D A 3 5 0 0 A ( Me d Watc h F or m).  E ver y 
eff ort s h o ul d be ma de t o f oll o w t he patie nt t hr o u g h res ol uti o n of t he pre g na nc y (ter mi nati o n or 
deli ver y) a n d re p ort t he res ol uti o n of t he F D A 3 5 0 0 A ( Me d Watc h F or m) t o Pfizer Safet y p ortal 
s yste m (
). 
7. 2   
A d verse E ve nt a n d Pre g n a nc y Re p orti n g  
A d verse e v e nts will be gra de d acc or di n g t o C T C A E v 5 .  B ot h Seri o us a n d N o n -Seri o us A d verse 
E ve nts will be clearl y  n ote d i n s o urce d o c u me nt ati o n a n d liste d o n st u d y s pecific Case Re p ort 
F or ms ( C R Fs).  T he Pr ot oc ol Direct or ( P D) or d esi g nee will ass ess eac h A d verse E ve nt ( A E) t o 
deter mi ne w het her it is u ne x pecte d acc or di n g t o t he I nf or me d C o nse nt, Pr ot oc ol D oc u me nt, or  
I n v esti gat or’s Br oc h ure, a n d relate d t o t he i n vesti gati o n.  All Seri o us A d verse E ve nts ( S A Es) 
will be trac ke d u ntil res ol uti o n, or u ntil 3 0 da ys after t he last d ose of t h e st u d y treat me nt.  
S A Es C T C A E Gra de  3 a n d a b o ve, a n d all s u bse q ue nt f oll o w -u p re p ort s will be re p orte d t o t he 
Sta nf or d Ca ncer I nstit ute Data a n d Safet y 
M o nit ori n g C o m mittee ( D S M C) usi n g t he st u d y 
s pecific C R F wit hi n 2 4  h o urs of n otificati o n of e v e nt re gar dless of t he e v e nt’s relate d n ess t o t he 
i n vesti gati o n.  Please f oll o w ste ps i n A p pe n d i x B: Sta nf or d Ca n cer I nstit ute S A E re p orti n g 
g ui deli nes f or i n vesti gat or-i nitiate d trials.  
I n i n vesti gat or I N D st u dies, talaz o pari b seri o us, relate d, u nla bele d, ( u ne x pecte d) a d v erse e ve nts 
will be re p orte d t o t he F D A as re q uire d b y 2 1 C F R § 3 1 2. 3 2 b y t he I n v esti gat or  wit hi n 2 4  h o urs of 
n otificati o n of t he e v e nt.  T he  Me d Watc h  F or m ( F or m  3 5 0 0 A 
Ma n d at or y Re p orti n g) a n d 
F D A  F or m  1 5 7 1 m ust be c o m plete d a n d se nt t o t h e F D A.  
All S A Es (e x pecte d or u ne x pecte d, ca usall y rel ate d or n ot) a n d pre g n a nc y re p orts m ust al s o be 
re p orte d t o Pfizer Safet y p ortal s yste m, 
, a n d fa x e d t o Pfizer 
 wit hi n 2 4  h o urs  of t he I n vesti gat or’s a ware ness.   Pfizer will re vie w t h e A E d ata as 
d oc u me nte d i n t he site’s fi nal st u d y re p ort.  
F or C o m parat or Dr u gs/ Sec o n dar y S us pects ( C o nc o mita nt 
Me dicati o ns), all seri o us a d verse 
e x perie nces will be f or war de d t o t he pr o d u ct ma n ufact urer.  
T he peri o d d uri n g w hic h all n o n -seri o us A Es a n d S A Es will be re p orte d be gins after i nf or me d 
c o nse nt is o btai ne d a n d will c o nti n ue t hr o u g h 3 0  da ys after t he last st u d y visit or 3 0 da ys after 
t he last d ose of st u d y m e dicati o n, w hic he ver c o m es first. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 6  of 4 6   
2  Se pte m ber  2 0 2 0  
7. 3   
Pr o d uct C o m pl ai nts Re p orti n g  
A pr o d uct c o m plai nt (“ C o m plai nt”) is a n y direct, writte n, electr o ni c, or oral c o m m u nicati o n of 
dissatisfacti o n t hat alle ges deficie ncies rel ate d t o t he i de ntit y, q ualit y, d ura bilit y, la beli n g, p urit y, 
sta bilit y, a p p eara nce, effecti ve ness, s afet y, a n d/ or desi g n of a dr u g pr o d uct after it is release d f or 
d istri b uti o n.  
C o m plai nts t hat si m ulta ne o usl y fall u n der A d verse E ve nt defi niti o ns u n der t his Pr ot oc ol nee d 
o nl y be re p orte d vi a t he A d verse E v e nt re p orti n g pr oce d ure set f ort h i n t his Pr ot oc ol.   
I n v esti gat or or desi g nee ( Re p orter) s h all ca pt ure t he f oll o wi n g C o m plai nt i nf or mati o n as relates 
t o talaz o pari b ( B M R N 6 7 3 ) use d u n der t his Pr ot oc ol:  
• 
Date c o m plai nt recei ve d  
• 
Pr o d uct Na me a n d L ot N u m ber  
• 
I n dicate if t he pr o d uct is a vaila ble f or ret ur n t o Pfizer f or i n vesti gati o n  
• 
Q ua ntit y Affecte d  
• 
Detaile d Des cri pti o n  of c o m plai nt  
• 
St u d y Pr ot o c ol N u m ber  
• 
I n v esti gat or Na me 
• 
Site C o ntact  
• 
Site N u m ber  
• 
S u bject N u m ber  
• 
Na me a n d c o ntact i nf or mati o n of t he pers o n w h o is re p orti n g t he c o m plai nt as well as 
na me a n d c o ntact i nf or mati o n of t he c o m plai n a nt.  T he re p orter will be c o nta cte d b y 
Pfizer Pr o d uct C o m plai nt Q ualit y Ass ura nce De p art me nt.  
I n v esti gat or or desi g nee ( Re p orter) will use his or her b est eff orts t o re p ort C o m plai nts t o Pfizer 
wit hi n fi ve da ys of l ear ni n g of t he C o m plai nt .  I n v esti gat or or desi g nee will s u b mit t he c o mplai nt 
i nf or mati o n b y e mail.  
8 .  
C O R R E L A TI V E   S T U DI E S  
T his st u d y is d esi g n e d t o assess h ere ditar y a n d s o matic defects i n ge nes t hat s u p p ort  
h o m ol o g o us rec o m bi nati o n d o u ble -stra n d brea k re pair defects be y o n d 
B R C A a n d t heir 
i m plicati o n i n t u m ori ge n esis.  T he g oal is t o use s uc h i de n tifia ble defects as bi o mar kers t o tail or 
dr u g t hera p y  utilizi n g t he pri nci ple of s y nt hetic let halit y ; i n t his case wit h talaz o pari b, a p ote nt 
P A R P i n hi bit or .  C orrelati ve st u dies will be c o n d ucte d t o assess u n d erl yi n g ger mli ne  m u tati o ns, 
ge n o mic i nsta bilit y  as assesse d b y t h e t u m or  H R D  sc ore, a n d res p o nse t o dr u g .  All partici p a nts 
will be as ke d t o pr o vi de a bl o o d sa m ple t o r u n t he m y Ris k here ditar y 2 5 -ge ne pa n el  o n a 
researc h basis.  T he m y Ris k here ditar y 2 5 -ge n e pa nel  e val uat es a br oa d n u m ber of here ditar y 
ca ncer s y n dr o mes i ncl u di n g se v eral ge n es i m plicate d i n  H R d o u ble -stra n de d D N A re pair .  A 
se parat e res earc h ger mli ne  bl o o d sa m ple  a n d plas ma sa m ple  will als o be c ollecte d .  F urt her m ore , 
all partici pa nts will be as ke d t o pr o vi de an a de q u ate  metastatic t u m or  bi o ps y t o assess t he  H R D  
sc ore base d o n t he H R D  assa y a n d R A D 5 1 stat us .  O nl y i n cases w here a metastatic bi o ps y is n ot 
tec h nicall y feasi ble will t he H R D  sc ore or R A D 5 1 stat us  be assesse d o n t he pri mar y t u m or .  All 
s u bjects will be as ke d t o s u b mit a n arc hi val s a m ple of t heir pri mar y breast t u m or.  T he R A D 5 1 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 7  of 4 6   
2  Se pte m ber  2 0 2 0  
stat us of t he t u m or will be assesse d usi n g i m m u n o hist oc he mistr y at baseli ne (a bse nt or prese nt) 
as a f u ncti o nal r ea d o ut of  H R ca pacit y a n d t his will be c orrelate d wit h  H R D  stat us.  
All c orrelati ve e n d p oi nts will be meas ure d usi n g u ni variate a n d m ulti variate l o gisti c re gressi o n 
m o dels , rec o g nizi n g t hat t hese are e x pl orat or y a n al yses a n d t h us ma y be i ns ufficie ntl y p o were d 
f or statistical p ur p oses.  F or s pecifi c c orrelati ve e n d p oi nts  a nd t he statistical met h o ds use d f or 
e val uati o n, please refer t o Secti o n  1 2 . 3. 
Tiss ue bi o psies, w h ole bl o o d a n d plas ma will be s a m ple d i n t his st u d y .  T he y will be st ore d a n d 
ma y b e use d f or f ut ure researc h p ur p os es pr o vi de d t he patie nt has gi ve n his/ h er c o nse nt .  All 
s uc h sa m ples will be la bele d wit h a u ni q ue n u meric i de ntifier t hat will be c o de d f or patie nt 
pri vac y .  O nl y a ut h orize d st u d y pers o n nel will ha ve access t o t hese tiss ues.  If t he patie nt 
decli nes t his o pti o n, re mai ni n g tiss ue a n d bl o o d will  be discar de d after s pecifie d c orrelati ve 
st u d y pr oce d ures ha ve b ee n perf or me d. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 8  of 4 6   
2  Se pte m ber  2 0 2 0  
9.   
S T U D Y C A L E N D A R  
 
Pre -St u d y 
Scree ni n g  
C ycle 1  
( 1 c ycle = 2 8 d a ys) 
+/ - 3 d a ys  
C ycle 2  
( 1 c ycle = 2 8 d a ys) 
+/ - 3 d a ys  
C ycle 3  t o 3 6  
( 1 c ycle = 2 8 
d a ys)  
+/ - 3 d a ys  
E n d of  
St u d y  b  
 
D a ys -2 8 t o 0  
D 1   D 8   D 1 5   D 2 2   
D 1   
D 1 5   
D 1   
 
I nf or me d c o nse nt 
X  
  
  
  
  
  
 
 
 
De m o gra p hics  
X  
  
  
  
  
  
 
 
 
Me dical hist or y  
X  
   
  
  
  
 
 
 
Fa mil y hist or y  
X  
  
  
  
  
  
 
 
 
C o nc urre nt me ds  
X  
  
  
  
  
  
 
 
 
Tala z o pari b dis pe nsi n g a n d dail y d osi n g 
f or 2 8 da ys st arti n g c ycle Da y  1  
  
X   
  
  
  
X   
 
X  
 
P h ysical e xa m  
X   
X   
  
X   
  
X   
 
X   
X  
Vital si g ns  
X   
X   
  
X   
  
X   
 
X   
X  
Hei g ht  
X   
  
  
  
  
  
 
 
 
Wei g ht  
X   
X   
  
X   
  
X   
 
X   
X  
P erf or ma nce stat us  
X   
X   
  
X   
  
X   
 
X   
X  
C B C w/ diff  ( +/ - 3 da ys)  
X   
X   
X   
X   
X   
X   
X   
X   
X  
Ser u m c he mistr y  a ( +/- 3 da ys)  
X   
X   
  
X   
  
X   
 
X   
X  
A d verse e ve nt e val u ati o n   
  
X   
  
X   
  
X   
 
X   
X  
Uri ne pre g na nc y ( w o me n of 
c hil d beari n g p ote ntial)  
X   
X  
  
  
  
X  
 
X   
X  
Assess me nt of  H R D  sc ore usi n g H R D  
assa y fr o m c ore bi o ps y of metastatic 
site.  If a n a de q uate metastatic bi o ps y 
is n ot a vaila ble, a fres h bi o ps y will be 
perf or me d.  Res ults ar e re q uire d pri or 
t o treat me nt i nitiati o n f or C o h ort A 
o nl y.  
X  
  
  
  
  
  
 
 
 
S u b missi o n of arc hi val t u m or sa m ple of 
pri mar y t u m or  
X  
  
  
  
  
  
 
 
 
M yria d M y Ris k bl o o d c ollecti o n  
X  
  
  
  
  
  
 
 
 
W h ole bl o o d c ollecti o n  
X  
  
  
  
  
  
 
 
 
Plas ma c ollecti o n  
X  
  
  
  
  
  
 
 
X  
T u m or meas ure me nts  
X  
T u m or meas ure me nts are re peate d e ver y 8 we e ks t hr o u g h 
c ycle 8 ( o pti o n t o re peat e ver y 1 2 we e ks after c ycle 8).  
D oc u me ntati o n m ust b e pr o vi d e d f or patie nts re m o ve d fr o m 
st u d y f or pr o gressi ve diseas e. 
X  
Ra di ol o gic e val uati o n ( C T wit h I V 
c o ntrast a nd b o ne sca n or  P E T C T 
wit h I V c o ntrast, pl us M RI brai n or 
C T h ea d if hist or y of brai n 
metastases).  
X  
Ra di ol o gic meas ure me nts s h o ul d be perf or me d e ver y 8  wee ks 
±  1  wee ks.  T here is t he o pti o n t o decrease ra di ol o gic e val u ati o n 
t o e ver y 1 2 wee ks after c ycle 8.  
X  
a. Al b u mi n, al kali ne p h os p hatase, t otal bilir u bi n, bicar b o nate, B U N, calci u m, c hl ori d e, creati ni ne, gl u c ose, p otassi u m, t otal pr otei n, 
S G O T[ A S T], S G P T[ A L T], s o di u m.  
b .  T o be c ollecte d at first cli nic visit after e vi d e nce of disease pr o gressi o n ( ±  7  da ys).  

I R B-3 1 9 1 3 versi o n 8  
P a ge 3 9  of 4 6   
2  Se pte m ber  2 0 2 0  
1 0 .  
M E A S U R E M E N T S  
1 0 . 1 
Pri m ar y E n d p oi nt  
T he o bjecti ve res p o nse r ate of t al az o p ari b defi ne d as c o m plete res p o nse or p arti al res p o nse 
per  R E CI S T v 1. 1  
O bjecti ve res p o nse rate is defi ne d as c o m plete res p o nse or partial res p o nse a n d deter mi ne d b y 
R E CI S T  v 1. 1 criteri a.  All st u d y p artici pa nts will ha ve meas ura ble disease at st u d y i nitiati o n.  
O bjecti ve res p o ns es are defi ne d usi n g R E CI S T v. 1. 1 criteria:  
 C o m plete Res p o nse ( C R): Disa p peara nce of all tar get lesi o ns .  A n y p at h ol o gical l y m p h 
n o des ( w het her tar get or n o n -tar get) m ust ha v e re d ucti o n i n s h ort a xis t o <  1 0 m m.  
 Partial Res p o nse ( P R):  At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, 
ta ki n g as refere n ce t he baseli ne s u m dia meters.  
 Pr o gressi ve Diseas e ( P D): At least a 2 0 % i ncrease i n t he s u m of 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 (t his i ncl u des t he baseli ne s u m if t hat is t he 
s mallest o n st u d y).  I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o 
de m o nstrate a n a bs ol ute i ncreas e of a t least 5 m m.  ( N ote: t he a p peara nce of o ne or m ore n e w 
lesi o ns is als o c o nsi dere d pr o gressi o n)  
C o nfir mati o n of a res p o nse re q uires a re p eat o bser vati o n at least 4 wee ks a part.  
F or t he p ur p oses of t his st u d y, patie nts s h o ul d be e val uate d f or res p o nse at 8  wee ks  +/ - 1  wee k, 
t he n re-e val u ate d f or res p o nse e ver y 8  wee ks  +/ - 1  wee k, or s o o n er if t here is a cli nical or 
la b orat or y fi n di n g t hat is c o ncer ni n g f or disease pr o gressi o n.  T he t y pe of i ma gi n g m o dalit y is 
de pe n de nt o n sites of metastases b ut will mai nl y  c o nsist of C T c hest, a b d o me n a n d pel vis wit h 
c o ntrast a n d b o n e sca n or P E T C T wit h I V c o ntrast .  All baseli ne e val uati o ns s h o ul d be 
perf or me d as cl os el 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 h a n 4  wee ks 
bef ore i nitiati o n.  
Res p o nse a n d pr o gressi o n will be e val uat e d i n t his st u d y usi n g t he i nter nati o nal criteria pr o p ose d 
b y t h e re vise d 
Res p o nse 
E val uati o n 
Criteria i n 
S oli d 
T u m ors ( R E CI S T) 
g ui deli ne 
(v ersi o n 1. 1).  2 9  C ha n ges i n t he lar gest dia meter ( u ni -di me nsi o nal meas ure me nt) of t he t u m or 
lesi o ns a n d t he s h ortest dia meter i n t he cas e of mali g na nt l y m p h n o d es are us e d i n t he R E CI S T 
criteria.  T he Eise n ha uer 2 0 0 9 E ur o pea n J o ur nal of Ca ncer ma n uscri pt details t he c o m plete 
descri pti o n of R E CI S T  v 1. 1 criteria f or res p o ns e assess me nt a n d will be f oll o we d f or t his st u d y.  
1 0. 2  
Sec o n d ar y E n d p oi nts  
1 0. 2. 1  Cli nic al be nefit r ate ≥ 2 4  wee ks  
T his is defi ne d as c o m plete res p o nse, partial res p o nse or sta ble diseas e as assesse d after at least 
2 4  wee ks o n t he i n vesti gati o nal dr u g .  R es p o nse a n d pr o gressi o n will be e v al uate d usi n g 
R E CI S T  g ui deli ne v 1. 1 .  I ma gi n g will be perf or me d e ver y 8  wee ks .  
1 0 . 2.2  P r o g ressi o n -free s ur vi v al 
Pr o gressi o n -free s ur vi val is defi ne d as t he ti me fr o m ra n d o mizati o n t o d oc u me nte d diseas e 
pr o gressi o n or deat h.   Patie nts wit h o ut pr o gressi o n at t he e n d of t he st u d y will be ce ns ore d at t he 
date of t heir last ra di o gra p hic e val uati o n.  

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 0  of 4 6   
2  Se pte m ber  2 0 2 0  
1 0 . 2.3  S afet y of t al az o p ari b i n t his st u d y p o p ul ati o n 
All a d verse e ve nts will be gra de d acc or di n g t o C T C A E  v 5 . 
1 0. 3  
C orrel ati v e E n d p oi nts  
1 0. 3. 1  O bjecti ve res p o nse r ate i n s u bjects wit h T N B C wit h or wit h o ut a n  u n derl yi n g 
ger mli ne  H R p at h w a y m ut ati o n i n C o h ort  A  
T he 2 5 -ge n e M y Ris k ger mli ne  m utati o n pa nel will be perf or me d o n all s u bjects o n a res earc h 
basis i n C o h ort  A .  O bjecti ve res p o nse rates b y R E CI S T v 1. 1 will be c o m pare d i n s u bjects wit h 
a n d wit h o ut a n i de ntifie d  H R pat h wa y ge n e m ut ati o n of i nterest.  
1 0. 3. 2  C orrel ati o n of  H R D  sc o res wit h res p o nse i n s u bjects wit h u n derl yi n g deleteri o us  or 
s us pecte d deleteri o us  ger mli ne  or s o m atic  H R g e ne m ut ati o ns i n C o h ort  B  
T he  H R D  sc ore is a c o nti n u o us meas ure me nt ( 0 t o 1 0 0) t hat will be assesse d fr o m metastatic 
F F P E t u m or tiss ue usi n g t he M yri a d  H R D  assa y o n a researc h b asis i n s u bjects e nr olle d o n 
C o h ort  B .  Base d o n pri or st u dies, a n  H R D  c ut off sc ore of 4 2  or hi g h er will be use d t o defi ne  
H R -deficie nt breast c a ncer .  We will c orrel ate t he mea n  H R D  sc ores a n d di c h ot o m o us H R D  
sc ores (H R D  d eficie n t v ers us H R D  i ntact) wit h t hera p y res p o nse. 
1 0. 3. 3  C orrel ati o n of  H R D  sc o res i n t he pri m ar y t u m o r tiss ue a n d t he met ast atic t u m or 
tiss ue. 
All s u bjects will ha ve b ot h metastatic a n d arc hi val pri mar y breas t t u m or sa m ples assesse d 
f or H R D .  We will assess t he c orrelati o n of sc ores ( mea n a n d dic h ot o m o us sc ores) f or t hese t w o 
t u m or sa m ple t y pes wit hi n eac h p atie nt.  Patie nts i n w h o m a metastatic bi o ps y was dee me d n ot 
feasi ble will be e x cl u de d. 
1 0. 3. 4  C orrel ati o n of R A D 5 1 st at us i n t he met ast atic t u m or wit h  H R D  a n d m ut ati o n al 
st at us. 
R A D 5 1 b y i m m u n o hist oc he mistr y as a f u ncti o nal rea d o ut of  H R ca pacit y will be assesse d i n 
baseli ne F F P E metastatic t u m or bi o ps y sa m ples .  R A D 5 1 stat us, a bse nt or prese nt, will be 
c orrel ate d wit h H R D  a n d m utati o nal stat us.  
1 1 .  
R E G U L A T O R Y C O N SI D E R A TI O N S  
1 1 . 1 
I nstit uti o n al Re vie w of Pr ot oc ol 
T he pr ot oc ol, t he pr o p os e d i nf or me d c o ns e nt a n d all f or ms of partici pa nt i nf or mati o n relate d t o 
t he st u d y (e g, a d vertise m e nts use d t o recr uit p arti ci pa nts) will be re vie we d a n d a p pr o ve d b y t h e 
Sta nf or d I R B a n d Sta nf or d Ca ncer I nstit ute Scie ntific Re vie w C o m mittee ( S R C).  A n y c ha n ges 
ma de t o t he pr ot oc ol will be s u b mitte d as a m o dificati o n a n d will be a p pr o ve d b y t he I R B pri or 
t o i m ple me ntati o n.  T he Pr ot oc ol Direct or will disse mi nate t he pr ot oc ol a me n d me nt i nf or mati o n 
t o all partici pati n g i n vesti gat ors. 
1 1 . 2 
D at a a n d S afet y M o nit ori n g Pl a n  
T he Sta nf or d Ca n cer I nstit ute Data a n d Safet y 
M o nit ori n g C o m mittee ( D S M C) will be t he 
m o nit ori n g e ntit y f or t his st u d y.  T he D S M C will a u dit st u d y -relate d acti vities t o deter mi ne 
w het her t he st u d y has bee n c o n d ucte d i n acc or da nce wit h t he pr ot oc ol, l ocal sta n dar d o perati n g 
pr oce d ures, F D A re g ulati o ns, a n d  G o o d Cli nical Practice  ( G C P).  T his ma y i ncl u de re vie w of t he 
f oll o wi n g t y pes of d oc u me nts partici pati n g i n t he st u d y: re g ulat or y bi n d ers, case re p ort f or ms, 

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 1  of 4 6   
2  Se pte m ber  2 0 2 0  
eli gi bilit y c h ec klists, a n d s o urce d oc u me nts.  I n a d diti o n, t he D S M C will re g ularl y re vie w 
seri o us a d verse e ve nts a n d pr ot oc ol de vi ati o ns ass ociate d wit h t he re searc h t o e ns ure t he 
pr otecti o n of h u ma n s u bjects.  Res ults of t he D S M C a u dit will be c o m m u nicate d t o t he I R B a n d 
t he a p pr o pri ate re g ulat or y a ut h orities at t he ti me of c o nti n ui n g re vi e w, or i n a n e x pe dite d 
fas hi o n, as nee de d. 
1 1 . 3 
D at a M a n a ge me nt Pl a n  
Elec tr o nic Cas e Re p ort F or ms ( C R Fs) will be us e d t o rec or d all pr ot oc ol -relate d i nf or mati o n o n 
eac h trial partici pa nt .  C R Fs will s u m marize t he cli nical fi n di n gs a n d o bser vati o ns necessar y t o 
e ns ure safet y of partici pa nts o n t he st u d y, a n d t o d oc u me nt t he st u d y o utc o mes.  
Re d Ca p Electr o nic Cas e Re p ort F or ms (e C R F) will be us e d t o rec or d all pr ot oc ol -relate d 
i nf or mati o n o n eac h tri al partici pa nt.  A C R F will be c o m plete d f or eac h e nr olle d st u d y 
partici pa nt .  It is t he i n vesti gat or's res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, clarit y, 
a n d ti meli ness of t h e dat a re p orte d i n t h e partici pa nt's C R F .  S o urce d o c u me ntati o n s u p p orti n g 
t he C R F dat a s h o ul d i n dicate t he patie nt's p arti ci pati o n i n t he st u d y a n d s h o ul d d oc u me nt t h e 
date a n d det ails of st u d y pr oce d ur es, A Es, ot her o bser vati o ns a n d patie nt st at us.  
T he i n vesti gat or is re q uire d t o pre pare a n d mai ntai n a de q uate a n d acc urate case hist ories 
desi g ne d t o rec or d all o bser vati o ns a n d ot h er data perti ne nt t o t he st u d y f or eac h st u d y 
partici pa nt .  T he st u d y data f or eac h e nr olle d partici pa nt will be e ntere d i nt o a C R F b y site 
pers o n nel usi n g a sec ure, vali date d, we b -bas e d electr o nic data ca pt ure a p plicati o n .  A n y c ha n ges 
t o st u d y d ata will be ma de t o t he C R F a n d d oc u me nte d i n a n a u dit trail t hat will be mai ntai ne d 
wit hi n t he cli nical data base.  
1 2 .  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 2 . 1 
A n al ytic Pl a n f or St u d y O bjecti ves  
1 2. 1. 1  Pri m ar y O bjecti ve  
T o deter mi ne t he o bjecti ve res p o nse rate, defi ne d as c o m plete res p o nse or  partial  res p o nse per 
R E CI S T 1. 1 , t he o bjecti ve res p o ns e rate a n d 9 5 % c o nfi de nce i nter val will be calc ul ate d usi n g t he 
e x act bi n o mial m o del.   
1 2. 1. 2  Sec o n d ar y O bjecti ves  
T o deter mi ne t he cli nical be nefit rate, defi ne d as c o m plete res p o nse, partial res p o nse or sta ble 
disease ≥ 2 4  wee ks per R E CI S T  v 1. 1 , t he clinical be nefit rate a n d 9 5 % c o nfi de nce i nter val will 
be calc ul ate d usi n g t h e e x act bi n o mial m o del.   
T o deter mi ne pr o gressi o n -free s ur vi val, Ka pla n -Meier  c ur ves will be calc ulate d , al o n g wit h a 
9 5 % c o nfi de n ce i nter val f or P F S at o ne year, calc ulate d usi n g G ree n w o o d’s f or m ula.   
T o assess safet y of t alaz o pari b i n t his st u d y p o p ulati o n, ad verse e v e nts will be gra d e d usi n g 
C T C A E v 5  a n d s u m marize d descri pti vel y as descri be d i n Secti o n  7. 1.  
1 2. 1. 3  C orrel ati v e O bjecti v es  
I n c orrelati n g H R D  sc ore (ra n gi n g o ver 0 t o 1 0 0) wit h a bi nar y varia ble s uc h o bjecti ve res p o nse 
stat us, R A D 5 1 stat us a n d s o o n, we will calc ulate t he mea n a n d sta n d ar d de viati o n of  H R D  sc ore 
i n t he t w o s u bsets a n d e v al uate t he stre n gt h of t h e ass ociati o n usi n g t he Wilc o x o n ra n k s u m 
statistic.  

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 2  of 4 6   
2  Se pte m ber  2 0 2 0  
I n eval uati n g t he c o n c or da nce of  H R D  sc ore i n t he pri mar y t u m or a n d H R D  i n t he metastatic 
t u m or, t he Wilc o x o n si g ne d ra n k test will be use d. 
All re mai ni n g c o m paris o n i n v ol ve c orrel ati n g t w o bi nar y v aria bl es, w hic h will be d o n e b y 
prese nti n g pr o p orti o ns wit h 9 5 % e x act c o nfi de nce i nter vals .  T he si g nifica n ce of t he c orrelati o n 
will be assesse d usi n g Fis her’s e x act test.   A t w o -si de d P val ue of 5 % or less will be c o nsi dere d 
statisticall y si g nifica nce. 
T he p r o p orti o n of s pecific mutati o ns wit h its 9 5 % c o nfi de nce i nter val will be calc ulate d usi n g 
t he e x act bi n o mial m o del. 
1 2 . 2 
A n al ysis p o p ul ati o n   
Safet y a n al ysis will be c o n d ucte d o n all patie nts w h o recei ve d at l east o n e d ose of tri al t hera p y .  
Efficac y a n al ysis will be perf or me d o n all patie nts w h o recei ve at least 1 c ycl e of t hera p y u nl ess 
t he reas o n f or c o m pleti n g less t ha n 1 c ycle of t h era p y was attri b uta ble t o disease pr o gressi o n.  
Patie nts w h o c o me off trial bef ore c o m pleti n g 1 c ycle of t hera p y f or reas o ns ot her t ha n disease 
p r o gressi o n will be c o nsi dere d n o n-e val ua bl e f or res p o nse a n d will be re place d.  
1 2 . 3 
S a m ple Size C alc ul ati o ns  
T his 
p hase  2  pr o of -of -c o nce pt trial is a n o pe n -la bel st u d y i n patie nts 
wit h a d va nce d, 
H E R 2 -ne gati ve breast ca ncer or n o n -breast metastatic ca ncer .  A t w o -sta ge desi g n will be use d 
f or e nr oll me nt of st u d y partici pa nts se paratel y i n C o h ort  A a n d  i n C o h ort  B wit h a set 
n ull  h y p ot hesis of  5 % o bjecti ve res p o nse rate a n d alter nati ve res p o ns e rate of  3 0 % base d o n 
sta n dar d R E CI S T v 1. 1 criteria.  
I nteri m anal ysis will be perf or me d, se paratel y i n eac h c o h ort, after accr ual of 1 0  patie nts a n d 
ha ve ha d at least o ne res p o nse assess me nt i n t hat c o h ort.  P atie nts will be o bser ve d f or res p o ns es 
e ver y 8  wee ks +/ - 1  wee k .  If at least t w o o ut of t he 1 0  patie nts r es po n ds, t he n we will accr ue 
1 0  a d ditio nal patie nts f or a t otal of 2 0  patie nts i n eac h c o h ort (t otal n u m ber of patie nts f or t he 
trial =  4 0) .  Bas e d o n o ur statistical c o nstrai nts, at least 3  patie nts o ut of t he 2 0 res p o n d i n eac h 
c o h ort t o declare statistical  si g nifica nce at a o ne-si de d 5 % le vel wit h 8 0 % p o wer or b etter 
1 2 . 4  Accr u al Esti m ates a n d Fe asi bilit y    
 
We see >  7 5 ne w patie nts wit h a d va nce d, tri ple -ne gati ve breast ca n cer at t he Sta nf or d W o me n’s 
Ca ncer Ce nter eac h year a n d fr o m 2 0 0 9  t o 2 0 1 3 h a ve c o nsis te ntl y e nr olle d >  2 5 patie nts p er year 
t o tri ple-ne gati ve s pecifi c cli nical trials.  Base d o n o ur pre vi o us ne oa dj u va nt st u d y utilizi n g 
t he H R D  assa y, a p pr o xi matel y half of s p ora dic, tri ple -ne gati ve breast ca ncer patie nts ha ve 
a n H R D  sc ore t hat is greater tha n or e q u al t o 4 2 .  As s uc h we are c o nfi de nt t hat we ca n accr ue 
o ur  patie nts i n t he pr oject e d ti meli ne pr o vi de d.  
Gi ve n t h at t he  utilizati o n of m ulti ple x  ge n e p a nels t o assess ger mli ne  m ut ati o ns i n t he H R re pair 
pat h wa y h as rece ntl y e mer ge d  a n d b eca us e t he  use of t u m or N G S is j ust rece ntl y o n t h e rise , we 
ha ve n o hist orical meas ures t o h el p esti mate t he n u m ber of patie nts we will be accr ue i n 
C o h ort  B wit hi n  o ur  si n gle i nstit uti o n.  T hat b ei n g sai d, we are e nc o u nteri n g a n i ncreasi n g 
n u m ber of t h ese p atie nts  t hr o u g h o ur Ca ncer Ge n o mics Pr o gra m.  We will w or k cl os el y wit h t he 
here ditar y ca n cer n o n -pr ofit or ga nizati o n F O R C E t o p u blicize t his trial .  S h o ul d accr ual be 
li mite d, we will c o nsi der a d di n g a d diti o nal st u d y sites t o c o m plete t his c o h ort accr ual. 

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 3  of 4 6   
2  Se pte m ber  2 0 2 0  
R E F E R E N C E S  
1.  F or d J M, Kasta n M B. D N A da ma ge res p o nse pat h wa ys a n d ca ncer. 4t h e d: C h urc hill 
Li vi n gst o n; 2 0 0 8.  
2.  As h w ort h A. A s y nt hetic let hal t hera pe utic a p pr oac h: p ol y( A D P) ri b ose p ol y m erase 
i n hi bit ors f or t he treat me nt of ca ncers deficient i n D N A d o u ble -str a n d brea k re pair. J o ur nal 
of cli nical o nc ol o g y : offi cial j o ur nal of t he A m erica n S ociet y of Cli nical O nc ol o g y 
2 0 0 8; 2 6: 3 7 8 5 -9 0.  
3.  Br ya nt H E, Sc h ultz N, T h o mas H D, et al . S pecifi c killi n g of B R C A 2-deficie nt t u m o urs wit h 
i n hi bit ors of p ol y( A D P-ri b ose) p ol y m eras e. Nat ure 2 0 0 5; 4 3 4: 9 1 3-7.  
4.  Cleat or S, Heller W, C o o m bes R C. Tri ple -ne gati v e breast ca ncer: t hera pe utic o pti o ns. T he 
la ncet o nc ol o g y 2 0 0 7; 8: 2 3 5-4 4.  
5.  Far mer H, Mc Ca b e N, L or d CJ, et al . Tar geti n g t he D N A re pair defect i n B R C A m utant cells 
as a t hera pe utic strate g y. Nat ure 2 0 0 5; 4 3 4: 9 1 7 -2 1.  
6.  L or d CJ, As h w ort h A. T he D N A da m a ge res p o ns e a n d ca ncer t hera p y. Nat ure 
2 0 1 2; 4 8 1: 2 8 7 -9 4.  
7.  R o ulea u M, Patel A, He n dzel MJ, Ka uf ma n n S H, P oirier G G. P A R P i n hi biti o n: P A R P 1 a n d 
be y o n d. Nat ur e re vie ws Ca ncer 2 0 1 0; 1 0: 2 9 3 -3 0 1.  
8.  F o ul kes W D, Stefa nss o n I M, C ha p p uis P O, et al . Ger mli ne  B R C A 1 m utati o ns a n d a basal 
e pit helial p he n ot y p e i n breast c a ncer. J o ur nal of t he Nati o nal Ca ncer I nstit ute 
2 0 0 3; 9 5: 1 4 8 2 -5.  
9.  S orlie T, Ti bs hira ni R, Par ker J, et al . Re peate d o bser vati o n of breast t u m or s u bt y pes i n 
i n de pe n de nt ge n e e x pressi o n data sets. Pr ocee di n gs of t he Nati o nal Aca de m y of Scie n ces of 
t he U nite d States of A merica 2 0 0 3; 1 0 0: 8 4 1 8-2 3.  
1 0.  Nielse n T O, Hs u F D, J e nse n K, et al . I m m u n o hist oc he mical a n d cli nical c haract erizati o n of 
t he basal-li ke s u bt y pe of i n vasi ve breast carci n o ma. Cli nical Ca ncer Res earc h 
2 0 0 4; 1 0: 5 3 6 7 -7 4.  
1 1.  Hasta k K, Alli E, F or d J M. S y ner gistic c h e m ose nsiti vit y of tri ple -ne gati ve breast ca ncer cell 
li nes t o p ol y( A D P-Ri b os e) p ol y m eras e i n hi biti o n, ge m cita bi ne, a n d cis plati n. Ca ncer 
researc h 2 0 1 0; 7 0: 7 9 7 0-8 0.  
1 2.  Alli E, S har ma V B, S u n d eresa k u m ar P, F or d J M. Defecti ve re p air of o xi dati ve d na da ma ge 
i n tri ple-ne gati ve breast c a ncer c o nfers se nsiti vit y t o i n hi biti o n of p ol y( A D P -ri b ose) 
p ol y me rase. Ca ncer researc h 2 0 0 9; 6 9: 3 5 8 9-9 6.  
1 3.  Gel m o n K A, Tisc h k o wit z M, Mac ka y H, et al . Ol a pari b i n patie nts wit h rec urre nt hi g h-gra de 
ser o us or p o orl y differe ntiate d o varia n carci n o ma or tri ple-ne gati ve breast ca ncer: a p has e 2, 
m ultice ntre, o pe n -la bel, n o n-ra n d o mise d st u d y. T he la ncet o n c ol o g y 2 0 1 1; 1 2: 8 5 2-6 1.  
1 4.  Castera L, Kri e ger S, R o usseli n A, et al . Ne xt-ge n erati o n se q ue n ci n g f or t h e dia g n osis of 
here ditar y breast a n d o varia n ca n cer usi n g ge n o mi c ca pt ure tar geti n g m ulti ple ca n di date 
ge n es. E ur o pea n j o u r nal of h u ma n ge netics : EJ H G 2 0 1 4. 
1 5.  T u n g N, Bat elli C, Alle n B, et al . Pre val e nce of ge ne m utati o ns a m o n g here ditar y breast a n d 
o varia n ca ncer patie nts usi n g a 2 5 ge ne pa n el ( A bstract P D 4 -8).  Sa n A nt o ni o Breast Ca ncer 
S y m p osi u m; 2 0 1 3; Sa n A nt o ni o, T X.  
1 6.  A b ke vic h V, Ti m ms K M, He n ness y B T, et al . Patter ns of ge n o mic l oss of heter oz y g osit y 
pre dict h o m ol o g o us rec o m bi nati o n re pair defects i n e pit helial o varia n ca ncer. Britis h j o ur nal 
of ca ncer 2 0 1 2; 1 0 7: 1 7 7 6 -8 2.  
1 7.  Telli M, J e nse n K, A b ke vic h V, et al . H om ol o g o us Rec o m bi nati o n Deficie nc y ( H R D ) sc ore 
pre dicts pat h ol o gic res p o nse f oll o wi n g n e oa dj u va nt plati n u m -base d t hera p y i n tri ple -n e gati ve 

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 4  of 4 6   
2  Se pte m ber  2 0 2 0  
a n d B R C A 1/ 2 m utati o n -ass ociate d breast ca ncer ( B C).  Sa n A nt o ni o Breast Ca ncer 
S y m p osi u m; 2 0 1 2; Sa n A nt o ni o, T X.  
1 8.  Telli M L , J e nse n K C, K uria n A W. Pr E C O G 0 1 0 5: Fi nal efficac y res ults fr o m a p hase II 
st u d y of ge m cita bi ne ( G) a n d car b o plati n ( C) pl us i ni pari b ( B SI-2 0 1) as ne o a dj u va nt t hera p y 
f or tri ple-ne gati ve ( T N) a n d B R C A 1/ 2 m utati o n -ass ociate d breast ca n cer.  3 1. J o u r nal of 
cli nical o nc ol o g y : offici al j o ur nal of t he A merica n S ociet y of Cli nical O n c ol o g y 
2 0 1 3; 3 1: A bstract 1 0 0 3.  
1 9.  Telli M L , J e nse n K C, K uria n A W, et al . Pr E C O G 0 1 0 5: Fi nal effi cac y res ults fr o m a p hase II 
st u d y of ge m cita bi ne ( G) a n d car b o plati n ( C) pl us i ni pari b ( B SI-2 0 1) as ne o a dj u va nt t hera p y 
f or tri ple-ne gati ve ( T N) a n d B R C A 1/ 2 m utati o n -ass ociate d breast ca n cer.  A S C O A n n ual 
Meeti n g; 2 0 1 3; C hica g o, U S A: J Cli n O nc ol 3 1, 2 0 1 3 (s u p pl; a bstr 1 0 0 3).  
2 0.  S y m m a ns W F, Pei nti n ger F, Hatzis C, et al . Meas ure me nt of resi d ual breast ca ncer b ur de n t o 
pre dict s ur vi val after ne o a dj u va nt c he m ot hera p y. J o ur nal of cli nical o nc ol o g y : offi cial 
j o ur nal of t he A meri ca n S ociet y of Cli nical O n c ol o g y 2 0 0 7; 2 5: 4 4 1 4-2 2.  
2 1.  P o p o va T, Ma nie E, Rie u nier G, et al . Pl oi d y a n d l ar ge-s cale ge n o mic i nsta bilit y c o nsiste ntl y 
i de ntif y bas al-li ke breast carci n o mas wit h B R C A 1/ 2 i nacti vati o n. Ca ncer researc h 
2 0 1 2; 7 2: 5 4 5 4 -6 2.  
2 2.  Bir k ba k NJ, Wa n g Z C, Ki m J Y, et al . Tel o meric allelic i m bala nce i n dicates defecti ve D N A 
re pair a n d se nsiti vit y t o D N A -da m a gi n g a ge nts. Ca ncer disc o v er y 2 0 1 2; 2: 3 6 6 -7 5.  
2 3.  S he n Y, Re h ma n F L, Fe n g Y, et al . B M N 6 7 3, a n o vel a n d hi g hl y p ote nt P A R P 1/ 2 i n hi bit or 
f or t he treat me nt of h u ma n ca ncers wit h D N A re pair deficie nc y. Cli nical ca ncer researc h : a n 
official j o ur nal o f t h e A merica n Ass o ciati o n f or Ca ncer Res earc h 2 0 1 3; 1 9: 5 0 0 3-1 5.  
2 4.  S he n YJ, Fe n g Y, Wa n g B, C h u D, M yers P, P ost L. A bstract 3 5 1 4: L T -0 0 6 7 3, a hi g hl y 
p ote nt P A R P i n hi bit or, s h o ws a ntit u m or acti vit y a gai nst cells wit h D N A re pair defici e ncies.  
A A C R 1 0 1st  A n n ual Meeti n g: Ca ncer Researc h; 2 0 1 0; Was hi n gt o n D C.  
2 5.  Wai n ber g Z A, Rafi S, Ra ma nat ha n R K, et al . Safet y a n d a ntit u m or acti vit y of t he P A R P 
i n hi bit or B M N 6 7 3 i n a P hase I trial recr uiti n g m etastatic s mall-cell l u n g ca ncer ( S C L C) a n d 
B R C A m utati o n carrie r ca ncer patie nts.  A S C O A n n ual Meeti n g; 2 0 1 4; C hica g o. 
2 6.  T utt A, R o bs o n M, Gar ber J E, et al . Oral p ol y( A D P-ri b ose) p ol y m erase i n hi bit or ola pari b i n 
patie nts wit h B R C A 1 or B R C A 2 m utati o ns a n d a d va nce d breast ca ncer: a pr o of -of -c o nce pt 
trial. La ncet 2 0 1 0;3 7 6: 2 3 5 -4 4.  
2 7.  de B o n o J S, Mi na L A, G o nzalez M, et al . A bstract 2 5 8 0: First-i n-h u ma n trial of n o vel oral 
P A R P i n hi bit or B M N 6 7 3 i n patie nts wit h s oli d t u m ors. A S C O A n n ual Meeti n g; 2 0 1 3; 
C hica g o, I L.  
2 8. Pritc har d C C, Mate o J,  Wals h M F et al . I n h erite d D N A-Re p air Ge n e M utati o ns i n Me n wit h 
Metastatic Pr ostate Ca ncer. N EJ M 2 0 1 6; 3 7 5: 4 4 3 -4 5 3.  
2 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 Ca ncer 2 0 0 9; 4 5( 2): 2 2 8-4 7  
 

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 5  of 4 6   
2  Se pte m ber  2 0 2 0  
A P P E N DI C E S  

I R B-3 1 9 1 3 versi o n 8  
P a ge 4 6  of 4 6   
2  Se pte m ber  2 0 2 0  
A P P E N DI X A :   
S A E Re p orti n g G ui deli nes; S CI S O P 1 0 -1 6 -2 0 1 4  
H O W T O R E P O R T S E RI O U S A D V E R S E E V E N T S ( S A E s)  
I N I N V E S TI G A T O R-I NI TI A T E D T RI A L S 
 1. D et er mi n e if t h e e v e nt m e et s crit eri a f or S A E i n St u d y pr ot o c ol a n d St a nf or d S O P  
( all S A E s Gr a d e  3 a n d a b o v e, m u st b e s u b mitt e d t o C C T O/ St a nf or d).  
 2. C o m pl et e A L L fi el d s of C C T O S A E C a s e R e p ort F or m  ( C R F) a n d v erif y wit h 
i n v e sti g at or.  
 3. C o nfir m wit h i n v e sti g at or S A E gr a d e, E x p e ct e d or U n e x p e ct e d a n d Attri b uti o n.  
 4.  O bt ai n i n v e sti g at or si g n at ur e o n t h e f or m aft er  filli n g o ut all t h e i nf or m ati o n. 
 5. S e n d si g n e d C C T O S A E f or m t o 
 vi a S E C U R E e m ail 
wit hi n 2 4  h o ur s of n otifi c ati o n o f t h e e v e nt. C C T O S af et y will e nt er it i nt o O n C or e. 
 6. V erif y wit h i n v e sti g at or if t h e S A E i s U n a nti ci p at e d Pr o bl e m  ( U P: u n e x p e cte d, 
r el at e d t o r e s e ar c h a n d h ar mf ul) a n d r e p ort it t o I R B, wit hi n 2 4  h o ur s of n otifi c ati o n 
of t h e e v e nt . 
 Cli c k o n r e p ort i n e Pr ot o c ol.  
 U pl o a d t h e c o m pl et e S A E r e p ort.  
 Fill o ut e Pr ot o c ol r e p ort f or m.  
 Cli c k o n “ S u b mit pr ot o c ol” b utt o n o n t h e l eft.  
 7. If S A E i s n ot U P, t h e n r e p ort d uri n g n e xt I R B r e n e w al.  
F or I n v e sti g at or -i niti at e d st u d y wit h a n I N D a n d If S A E i s U n a nti ci p at e d Pr o bl e m  
( U P) t h e n r e p ort t o F D A wit hi n 2 4 h o ur s of n otifi c ati o n of t h e e v e nt  
 8. C o m pl et e M e d W at c h F or m ( F or m 3 5 0 0 A) .  T h e f or m M U S T b e t y p e d!  F or 
a s si st a n c e c o nt a ct 
. A ct u al li n k f or t h e f or m:  
htt p s:// w w w. p dffill er. c o m/ e n/ pr oj e ct/ 1 5 0 7 0 0 5 2 0. ht m ?f
h a s h = 7 a 4 e 5 d &r el o a d =tr u e   
 9. Wit h a s si st a n c e fr o m t h e r e g ul at or y f a cilit at or, s e n d t h e c o m pl et e d M e d W at c h 
f or m a n d F D A F or m  1 5 7 1 t o t h e F D A f oll o wi n g t h e w e b sit e i n str u cti o n s.  
 1 0. If r e q uir e d, n otif y m a n uf a ct ur er.  D e -i d e ntif y a p pli c a bl e s o ur c e d o c u m e nt s:  
M D  n ot e s ( a d mi s si o n, pr o gr e s s n ot e, di s c h ar g e n ot e, a n d d at e of d e at h 
if a v ail a bl e), l a b or at or y r e p ort s, r a di ol o g y r e p ort s, m e di c al a d mi ni str ati o n r e c or d s.  
 1 1. S e n d si g n e d C C T O S A E f or m  a n d d e -i d e ntifi e d s o ur c e d o c u m e nt s. 
 1 2. Fil e S A E r e p ort  i n p ati e nt r e s e ar c h c h art. 
 1 3. F oll o w S A E a n d s u b mit u p d at e d r e p ort s t o St a nf or d a n d/ or S p o n s or u ntil:  
 R e s ol uti o n of e v e nt.  
 R e s ol uti o n of e v e nt wit h s e q u el a e.  
 D e at h of p ati e nt.  
U nl e s s ot h er wi s e s p e cifi e d b y s p o n s or