untitled h1
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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 R B-3 1 9 1 3 B R S 0 0 5 0 N C T 0 2 4 0 1 3 4 7 Versi o n 8 / Versi o n Date: 0 2 Se pte m ber 2 0 2 0  
| T A B L E:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | S U           | M   | M A R Y O F C H A N G E S   |
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| Re visi o n D ate                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | C h a n ges   |     |                             |
|  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 x cl 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 Pri or  a me n d me nts                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |               |     |                             |
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untitled h2

| INVESTIGATORS                                                                                       |                                                                                      |                                               |
|-----------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|-----------------------------------------------|
| PROTOCOL SYNOPSIS                                                                                   |                                                                                      |                                               |
| STUDY SCHEMA .                                                                                      |                                                                                      |                                               |
| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.................................................... 9 |                                                                                      |                                               |
| OBJECTIVES .                                                                                        |                                                                                      |                                               |
| 1.                                                                                                  | 1.1                                                                                  | PRIMARY OBJECTIVE                             |
| 1.2                                                                                                 | SECONDARY OBJECTIVES                                                                 |                                               |
| 1.3                                                                                                 | CORRELATIVE OBJECTIVES .                                                             |                                               |
| BACKGROUND .                                                                                        |                                                                                      |                                               |
| 2.                                                                                                  | 2.1                                                                                  | BRCA1/2-M UTATION A SSOCIATED B REAST C ANCER |
| 2.2                                                                                                 | SPORADIC TRIPLE-NEGATIVE BREAST CANCER                                               |                                               |
| 2.3                                                                                                 | CANCERS WITH GERMLINE OR SOMATIC DEFICIENCY IN DNA DOUBLE-STRAND REPAIR              |                                               |
| 11                                                                                                  |                                                                                      |                                               |
| 2.4                                                                                                 | THE MYRIAD HOMOLOGOUS RECOMBINATION DEFICIENCY (HRD) ASSAY ................... 13    |                                               |
| 2.5                                                                                                 | O OVERVIEW OF THE STUDY AGENT TALAZOPARIB                                            |                                               |
| 2.6                                                                                                 | R R ATIONALE                                                                         |                                               |
| 2.7                                                                                                 | S S TUDY D ESIGN                                                                     |                                               |
| PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 21                          |                                                                                      |                                               |
| 3.                                                                                                  |                                                                                      |                                               |
| 3.1                                                                                                 | E LIGIBILIY C RITERIA AND P ARTICIPANT E LIGIBILITY C HECKLIST ... E RROR! B OOKMARK |                                               |
| NOT DEFINED.                                                                                        |                                                                                      |                                               |
| 3.2                                                                                                 | I I NFORMED C ONSENT P ROCESS                                                        |                                               |
| 3.3                                                                                                 | R R ANDOMIZATION P ROCEDURES .                                                       |                                               |
| 3.4                                                                                                 | S S TUDY T IMELINE .                                                                 |                                               |
| 4.                                                                                                  | TREATMENT PLAN .                                                                     |                                               |
| 4.1                                                                                                 | S S CREENING P ROCEDURES                                                             |                                               |
| 4.2                                                                                                 | D DOSING AND A DMINISTRATION S CHEDULE                                               |                                               |
| 4.3                                                                                                 | PRE-TREATMENT EVALUATIONS                                                            |                                               |
| 4.4                                                                                                 | END OF TREATMENT PROCEDURES  .                                                       |                                               |
| 4.5                                                                                                 | GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ................ 29    |                                               |
| 4.6                                                                                                 | D D URATION OF T HERAPY AND F OLLOW - U P                                            |                                               |
| 4.7                                                                                                 | CRITERIA FOR REMOVAL FROM STUDY                                                      |                                               |
| 4.8                                                                                                 | A A LTERNATIVES                                                                      |                                               |
| 4.9                                                                                                 | COMPENSATION .                                                                       |                                               |
| INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION .............. 30                                |                                                                                      |                                               |
| 5.                                                                                                  |                                                                                      |                                               |
| 5.1                                                                                                 | I I NVESTIGATIONAL A GENT  .                                                         |                                               |
| 5.2                                                                                                 | P P HARMACODYNAMIC P ROPERTIES .                                                     |                                               |
| 5.3                                                                                                 | P P HARMACOKINETIC P ROPERTIES                                                       |                                               |
| 5.4                                                                                                 | S S UPPLIER  .                                                                       |                                               |
| 5.5                                                                                                 | D DOSAGE F ORM                                                                       |                                               |
| 5.6                                                                                                 | AGENT ORDERING AND PACKAGING                                                         |                                               |
| 5.7                                                                                                 | S S TORAGE AND SHELF LIFE                                                            |                                               |  
| 5.8                                     | NATURE AND CONTENTS OF CONTAINER .                                      |                               |
|-----------------------------------------|-------------------------------------------------------------------------|-------------------------------|
| 5.9                                     | SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING                     |                               |
| 6.                                      | DOSE MODIFICATIONS .                                                    |                               |
| ADVERSE EVENTS AND REPORTING PROCEDURES |                                                                         |                               |
| 7.                                      | 7.1                                                                     | P P OTENTIAL A DVERSE E VENTS |
| 7.2                                     | A A DVERSE E VENT AND P REGNANCY R EPORTING                             |                               |
| 7.3                                     | PRODUCT COMPLAINTS REPORTING                                            |                               |
| CORRELATIVE STUDIES                     |                                                                         |                               |
| 8.                                      |                                                                         |                               |
| 9.                                      | STUDY CALENDAR .                                                        |                               |
| MEASUREMENTS .                          |                                                                         |                               |
| 10.                                     |                                                                         |                               |
| 10.1                                    | PRIMARY ENDPOINT .                                                      |                               |
| 10.2                                    | SECONDARY ENDPOINTS                                                     |                               |
| CORRELATIVE ENDPOINTS                   |                                                                         |                               |
| 10.3                                    | REGULATORY CONSIDERATIONS                                               |                               |
| 1.                                      | INSTITUTIONAL REVIEW OF PROTOCOL                                        |                               |
| 11.1                                    |                                                                         |                               |
| 11.2                                    | DATA AND SAFETY MONITORING PLAN                                         |                               |
| 1.3                                     | D DATA M ANAGEMENT P LAN                                                |                               |
| 12.                                     | STATISTICAL CONSIDERATIONS .                                            |                               |
| 12.1                                    | A A NALYTIC P LAN FOR S TUDY O BJECTIVES .                              |                               |
| 12.2                                    | A A NALYSIS POPULATION                                                  |                               |
| 12.3                                    | S S AMPLE S IZE C ALCULATIONS                                           |                               |
| 12.4                                    | A A CCRUAL E STIMATES AND F EASIBILITY .                                |                               |
| REFERENCES                              |                                                                         |                               |
| APPENDIX A:                             | SAE REPORTING GUIDELINES; SCI SOP 10-16-2014 ....................... 46 |                               |
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p r o t o

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.
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p ri m ar y

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 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
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p ri m ar y

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.
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s u m m ar

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
( 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.
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study schema

Advanced HER2-negative breast cancer  
  
| 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 |  
```
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 . Cells c o nti n uall y ac q uir e

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. 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

```  
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
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2. 2 s p or

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 n e d.
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2. 3 c a ncers

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 dir ectl 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  
  
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 d e str o n g 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 defi cie 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 c a 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.
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2 . 4 t he

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 / m 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 h e 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 / m 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 / m 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.
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2. 5 . 1 n

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. 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 h e 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 tr eate 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 h e 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 x e 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.
table of contents
t hree st u dies

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) tr eate 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 y 2 5
.  
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 m ac 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 observed, including Grade 3-4 events.  The events of fatigue, nausea, constipation, diarrhea, vomiting, cough, pyrexia, headache, alopecia, decreased appetite, abdominal pain, back pain, dyspnea, pain in the extremities, hypokalemia, anxiety, arthralgia, and dizziness have also been observed in subjects receiving talazoparib.  All patients are being monitored for myelo-suppression in the ongoing studies.  
The table below summarizes the safety data of talazoparib as assessed by the phase 1 trial in patients with advanced solid tumors. 24 Table 1. Safety data for phase 1 dose escalation/expansion trial for patients with solid cancers 25  
| SAFETY: DOSE ESCALATION AND EXPANSION Data as of 04/18/14   |                     |           |           |         |
|-------------------------------------------------------------|---------------------|-----------|-----------|---------|
| Number of patients = 105 (%)                                |                     |           |           |         |
| Drug Related                                                |                     |           |           |         |
| Adverse Events                                              | Grade  1            | Grade 2   | Grade 3   | Grade 4 |
| 20 (19.0)                                                   | 12 (11.4)           | 2 (1.9)   |           |         |
| Fatigue                                                     | 0                   |           |           |         |
| Nausea                                                      | 26 (24.8)           | 4 (3.8)   | 0         | 0       |
| Alopecia                                                    | 2 (21.0)            | 3 (2.9)   | 0         | 0       |
| Diarrhea                                                    | 8 (7.6)             | 1 (1.0)   | 0         | 0       |
| Vomiting                                                    | 6 (5.7)             | 1 (1.0)   | 0         | 0       |
| SAFETY: HEMATOLOGIC TOXICITY                                | Data as of 04/18/14 |           |           |         |
| Number of patients = 105 (%)                                |                     |           |           |         |
| Hematologic                                                 |                     |           |           |         |
| Adverse Events                                              | Grade 1             | Grade 2   | Grade 3   | Grade 4 |
| Anemia                                                      | 42 (40.0)           | 31 (29.5) | 23 (21.9) | 0       |
| Thrombocytopenia                                            | 36 (34.3)           | 8 (7.6)   | 1 (10.5)  | 7 (6.7) |
| Neutropenia                                                 | 17 (16.2)           | 29 (27.6) | 1 (10.5)  | 1 (1.0) |  
  
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 ol es i n D N A re pair . 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 . 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 bl e m. 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 -defi cie 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 v al 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 hes e 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 . 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 alr ea 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 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.
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3. 1 eli gi bilit

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.  
| Protocol Title :                                                   | A Phase 2 clinical trial of 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 non-breast solid tumors with a mutation in  |                                                              |
| homologous recombination pathway genes                             |                                                              |
| Protocol Number:                                                   | IRB-31913 / BRS0050                                          |
| Principal Investigator:                                            | Melinda Telli, MD                                            |
| Co-Investigator:                                                   | Joshua Gruber, MD, PhD                                       |
| I. Subject Information:                                            |                                                              |
| Subject Name/ID:                                                   |                                                              |
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participant eligibility checklist ii. study

SRC-approved IV. Inclusion/Exclusion Criteria  
| Inclusion Criteria                                       | Supporting                                         |    |    |
|----------------------------------------------------------|----------------------------------------------------|----|----|
| No                                                       |                                                    |    |    |
| Yes                                                      |                                                    |    |    |
| (From IRB approved protocol)                             | Documentation*                                     |    |    |
| 1.                                                       | Individuals (men and women) aged 18 years or older |    | D  |
| 2.                                                       | Solid tumor by cohort as follows.                  |    |    |
| Cohort A:  Tumor must be histologically-confirmed        |                                                    |    |    |
| triple-negative breast cancer (estrogen                  |                                                    |    |    |
| receptor (ER) ≤ 5%;  progesterone receptor (PR) ≤ 5%;    |                                                    |    |    |
| AND HER2-negative via IHC or FISH per 2013               |                                                    |    |    |
| ASCO/CAP guidelines), with homologous recombination      |                                                    |    |    |
| deficiency (HRD) score of > 42 from a metastatic biopsy  |                                                    |    |    |
| site.  In the event that metastatic tumor biopsy is not  |                                                    |    |    |
| feasible, the HRD score can be assessed from the primary |                                                    |    |    |
| breast biopsy.                                           |                                                    |    |    |
| Cohort B :  Must be histologically-confirmed metastatic  |                                                    |    |    |
| or recurrent HER2-negative breast cancer (IHC or FISH    |                                                    |    |    |
| per 2013 ASCO/CAP guidelines) or other                   | □                                                  | □  |    |
| histologically-confirmed metastatic solid tumor.         |                                                    |    |    |
| Cohort B : Tumor must have a deleterious or suspected    |                                                    |    |    |
| deleterious germline or somatic gene mutation implicated |                                                    |    |    |
| in the HR pathway (excluding BRCA1 or BRCA2), based      |                                                    |    |    |
| on multiplex germline gene testing or direct tumor next  |                                                    |    |    |
| generation DNA sequencing.  The genes include:  PTEN;    |                                                    |    |    |
| PALB2; CHEK2; ATM; NBN; BARD1; BRIP1;                    |                                                    |    |    |
| RAD50; RAD51C; RAD51D; MRE11; ATR; Fanconi               |                                                    |    |    |
| anemia complementation group of genes (FANCA;            |                                                    |    |    |
| FANCC; FANCD2; FANCE; FANCF; FANCG;                      |                                                    |    |    |
| FANCL);  plus other HR-related genes at the discretion   |                                                    |    |    |
| of the primary investigators.                            |                                                    |    |    |  
| Inclusion Criteria                                          | Supporting                                         |    |
|-------------------------------------------------------------|----------------------------------------------------|----|
| Yes                                                         | No                                                 |    |
| (From IRB approved protocol)                                | Documentation*                                     |    |
| 3.                                                          | No deleterious or suspected deleterious BRCA1 or   |    |
| BRCA2 gene mutation in the germline, based on               |                                                    |    |
| comprehensive testing including full sequencing and         | □                                                  | -  |
| comprehensive rearrangement testing at an external          |                                                    |    |
| reference laboratory.  Patients with variants of unknown    |                                                    |    |
| significance will be eligible.                              |                                                    |    |
| Patients must have measurable disease per RECIST v1.1       |                                                    |    |
| 4.                                                          | (CT CAP with contrast and bone scan or PET/CT with |    |
| IV contrast needed within 28 days of Cycle 1 Day 1.         | □                                                  | □  |
| If patients have a history of brain metastases, a           |                                                    |    |
| MRI-brain or CT-head with contrast is required.).           |                                                    |    |
| 5.                                                          | Must have progressed on at least 1 prior systemic  |    |
| therapy regimen for the treatment of advanced breast or     | □                                                  | □  |
| other non-breast metastatic cancer.  There is no upper      |                                                    |    |
| limit on the number of prior therapies.                     |                                                    |    |
| 6.                                                          | No evidence of progression on a platinum agent     |    |
| (g, carboplatin or cisplatin) or within 8 weeks of          | →                                                  | →  |
| stopping platinum                                           |                                                    |    |
| 7.                                                          | An ECOG performance status of 0 to 2               | -  |
| 8.                                                          | Serum aspartate aminotransferase (AST) and alanine |    |
| aminotransferase (ALT) ≤ 2.5 x upper limit of normal        | -                                                  | -  |
| (ULN); if liver function abnormalities are due to hepatic   |                                                    |    |
| metastasis, then AST and ALT ≤ 5 x ULN                      |                                                    |    |
| Total serum bilirubin ≤ 1.5 x ULN ( ≤ 3 x ULN for           |                                                    |    |
| 9.                                                          | □                                                  | □  |
| Gilbert's syndrome)                                         |                                                    |    |
| 10. Calculated creatinine clearance ≥ 30 mL/min or serum    | □                                                  | →  |
| creatinine ≤ 1.5 mg/dL                                      |                                                    |    |
| 1. Hemoglobin ≥ 9.0 g/dL with last transfusion at least     | □                                                  | -  |
| 14 days before Day 1 of study drug                          |                                                    |    |
| 12. Absolute neutrophil count (ANC) ≥ 1500/mm³              | [                                                  | -  |
| 13. Platelet count ≥ 100,000/mm³                            | -                                                  | -  |
| 14. Able to take oral medications                           | -                                                  | □  |
| 15. Willing and able to provide written, signed informed    |                                                    |    |
| consent after the nature of the study has been explained,   | -                                                  | -  |
| and prior to any research-related procedures                |                                                    |    |
| 16. Sexually-active patients of childbearing potential must |                                                    |    |
| be willing to use an acceptable method of contraception     |                                                    |    |
| such as an intrauterine device or double barrier            | -                                                  | -  |
| contraception during treatment and for 45 days after the    |                                                    |    |
| last dose of study drug (hormonal contraception is not      |                                                    |    |
| considered an acceptable method of contraception)           |                                                    |    |  
| Inclusion Criteria                                            | Supporting                                             |    |    |
|---------------------------------------------------------------|--------------------------------------------------------|----|----|
| Yes                                                           | No                                                     |    |    |
| (From IRB approved protocol)                                  | Documentation*                                         |    |    |
| 17. If pre-menopausal, females of childbearing potential      |                                                        |    |    |
| must have a negative urine pregnancy test at screening        |                                                        |    |    |
| and be willing to have additional urine pregnancy tests       |                                                        |    |    |
| during the study.  Females considered not of                  | □                                                      | -  |    |
| childbearing potential include those who have had no          |                                                        |    |    |
| menstrual period for at least 2 years, or had tubal           |                                                        |    |    |
| ligation at least 1 year prior to screening, or who have      |                                                        |    |    |
| had total hysterectomy                                        |                                                        |    |    |
| 18. Willing and able to comply with all study procedures      | u                                                      |    |    |
| 19. Availability of archival tumor tissue from primary breast | □                                                      | □  |    |
| cancer                                                        |                                                        |    |    |
| 20. Adequate fresh or archival tumor tissue from metastatic   | -                                                      | -  |    |
| biopsy site, if biopsy is technically feasible                |                                                        |    |    |
| Exclusion Criteria                                            |                                                        |    |    |
| (From IRB approved protocol)                                  |                                                        |    |    |
| Prior progression on or within 8 weeks of the last dose       |                                                        |    |    |
| 1.                                                            | of a platinum agent (ie, cisplatin or carboplatin) for | □  |    |
| □                                                             |                                                        |    |    |
| recurrent or metastatic disease.                              |                                                        |    |    |
| Any patient with a deleterious or suspected deleterious       |                                                        |    |    |
| 2.                                                            | □                                                      |    |    |
| BRCA1 or BRCA2 gene mutation                                  |                                                        |    |    |
| Prior treatment with a PARP inhibitor                         |                                                        |    |    |
| 3.                                                            |                                                        |    |    |
| 4.                                                            | Pregnant or lactating                                  |    | -  |
| Any anti-cancer therapy within the 21 days before the         |                                                        |    |    |
| 5.                                                            | □                                                      | □  |    |
| first day of treatment                                        |                                                        |    |    |
| Prior progression on or within 8 weeks of the last dose       |                                                        |    |    |
| 6.                                                            | of a platinum agent (ie, cisplatin or carboplatin) for | -  | -  |
| recurrent or metastatic disease                               |                                                        |    |    |
| 7.                                                            | Brain or CNS metastases OR leptomeningeal              |    |    |
| carcinomatosis.  EXCEPTION:  Adequately treated               |                                                        |    |    |
| brain metastases documented by baseline CT or MRI             |                                                        |    |    |
| scan that have not progressed since previous scans and        |                                                        |    |    |
| do not require corticosteroids (prednisone ≤ 5 mg/day or      | □                                                      | -  |    |
| equivalent allowed) for management of CNS symptoms.           |                                                        |    |    |
| A repeated CT or MRI following the identification of          |                                                        |    |    |
| CNS metastases (obtained at least 2 weeks after               |                                                        |    |    |
| definitive therapy) must document adequately-treated          |                                                        |    |    |
| brain metastases                                              |                                                        |    |    |
| 8.                                                            | Other malignancy that is either active or for which    |    |    |
| patient has received treatment in the last 5 years            | □                                                      | □  |    |
| excluding non-melanoma skin cancer and carcinoma              |                                                        |    |    |
| in situ of the cervix                                         |                                                        |    |    |
| 9.                                                            | Radiation therapy in the last 14 days                  |    |    |  
| Exclusion Criteria                                                                            |                                                 |    |
|-----------------------------------------------------------------------------------------------|-------------------------------------------------|----|
| (From IRB approved protocol)                                                                  |                                                 |    |
| 10. Known to be human immunodeficiency                                                        | →                                               | →  |
| virus (HIV)-positive                                                                          |                                                 |    |
| 1. Either known active hepatitis B or hepatitis C virus                                       | □                                               | →  |
| infection                                                                                     |                                                 |    |
| 12. Use of any investigational product (IP) or                                                |                                                 |    |
| investigational medical device within 28 days before                                          | -                                               | →  |
| Day 1 of study drug                                                                           |                                                 |    |
| 13. Major surgery requiring a prolonged hospitalization or                                    | □                                               | →  |
| recovery within 21 days before Day 1 of study drug                                            |                                                 |    |
| 14. Concurrent disease or condition that would interfere                                      |                                                 |    |
| with study participation or safety, such as any of the                                        |                                                 |    |
| following:                                                                                    |                                                 |    |
| o                                                                                             | Active, clinically-significant infection either |    |
| Grade > 2 by National Cancer Institute (NCI)                                                  |                                                 |    |
| Common Terminology Criteria for Adverse                                                       | →                                               | →  |
| Events (CTCAE) v5 or requiring the use of                                                     |                                                 |    |
| parenteral anti-microbial agents within 7 days                                                |                                                 |    |
| before Day 1 of study drug                                                                    |                                                 |    |
| o                                                                                             | Clinically-significant bleeding diathesis or    |    |
| coagulopathy, including known platelet function                                               |                                                 |    |
| disorders                                                                                     |                                                 |    |
| 15. Known hypersensitivity to any of the components of                                        | →                                               | →  |
| talazopanb                                                                                    |                                                 |    |
| *All subject files must include supporting documentation to confirm subject eligibility.  The |                                                 |    |  
*All subject files must include supporting documentation to confirm subject eligibility.  The method of confirmation can include, but is not limited to, laboratory test results, radiology test results, subject self-report, and medical record review.
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3. 2 i nf or

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.
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3. 3 r a n

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.
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3. 4 st u d

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.
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4. 1 scree ni n

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 d e 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 m ali n fi x e 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  
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,  
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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 x e 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.

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/r esearc h

tea m. T he f oll o wi n g ass ess me nts will be perf or m e 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)

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4. 5 ge ner al

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 tr eat 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.
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4. 6 d ur ati

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.
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4. 7 criteri a f

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 dr a 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 m alit 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 dr a 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 c a 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. 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.
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5. 1 i n vesti

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 siz e.  
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.
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5. 2 p h ar

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 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 hes e 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 ntr ast, t he I C5 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 ).
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5. 3 p h ar

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 ntr ati 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 w e 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.
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5. 6 a ge nt

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.  
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, siz e 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 uir e 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.
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7. 1 p ote nti

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 u ct.  
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 alr ea 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-dir ecti 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/r es 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 All a d verse e ve nts s h o ul d be treate d a p pr o pri atel 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 ur e 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.
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7. 1. 1 l a

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 m al 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.
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7. 1. 2 seri o

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 tr eat 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  
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 r es 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
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7. 1. 3 pre g

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 ( .
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7. 2 a d verse

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 aft er 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 ur er.  
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 aft er t he last d ose of st u d y m e dicati o n, w hic he ver c o m es first.
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7. 3 pr o d

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 o c 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 Pfi zer 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.
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8 . c o r

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 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 h e 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.  
| 9.                                                                                                                                                                                                                                                                                                                                   | S T U D Y C A L E N D A R                                                        | C ycle 3 t o 3 6  ( 1 c ycle = 2 8  d a ys)   | E n d of   |       |     |       |     |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------|-----------------------------------------------|------------|-------|-----|-------|-----|----|----|
| +/ - 3 d a ys                                                                                                                                                                                                                                                                                                                        | St u d y                                                                         |                                               |            |       |     |       |     |    |    |
| 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                                                                                                                                                                                                                                                                                |                                                                                  | X                                             | X          | X     |     |       |     |    |    |
| f or 2 8 da ys st arti n g c ycle Da y 1                                                                                                                                                                                                                                                                                             |                                                                                  |                                               |            |       |     |       |     |    |    |
| 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 ( +/- 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                                                                                                                                                                                                                                                                                                   | X                                                                                | X                                             |            | X     | X   | X     |     |    |    |
| c hil d beari n g p ote ntial)                                                                                                                                                                                                                                                                                                       |                                                                                  |                                               |            |       |     |       |     |    |    |
| 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.                                     | 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                                                                                                                                                                                                                                                                                              |                                                                                  |                                               |            |       |     |       |     |    |    |
| Pre -St u d y  Scree ni n g  X                                                                                                                                                                                                                                                                                                       |                                                                                  |                                               |            |       |     |       |     |    |    |
| S u b missi o n of arc hi val t u m or sa m ple of                                                                                                                                                                                                                                                                                   | X                                                                                |                                               |            |       |     |       |     |    |    |
| pri mar y t u m or                                                                                                                                                                                                                                                                                                                   |                                                                                  |                                               |            |       |     |       |     |    |    |
| 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 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.                                                                 |                                                                                  |                                               |            |       |     |       |     |    |    |
| T u m or meas ure me nts                                                                                                                                                                                                                                                                                                             | X                                                                                | X                                             |            |       |     |       |     |    |    |
| Ra di ol o gic e val u ati 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  metastas es).                                                                                                                                              | 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       |                                               |            |       |     |       |     |    |    |
| X                                                                                                                                                                                                                                                                                                                                    | ± 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 | X                                             |            |       |     |       |     |    |    |
| t o e ver y 1 2 wee ks after c ycle 8.                                                                                                                                                                                                                                                                                               |                                                                                  |                                               |            |       |     |       |     |    |    |
| 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). |                                                                                  |                                               |            |       |     |       |     |    |    |
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per r e ci s

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 dise ase 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.
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1 0. 2. 1 cli

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 .
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1 0 . 2.2 p

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.
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1 0 . 2.3 s

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 .
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1 0. 3. 1 o

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 m e 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.
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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.
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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.
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1 1 . 1 i

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.
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1 1 . 2 d

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, 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.
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1 1 . 3 d

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 o c 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 ur e 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.
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1 2. 1. 1 pri

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.
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1 2. 1. 2 sec

T o deter mi ne t he cli nical be nefit rate, defi n e 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.
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1 2. 1. 3 c

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 vari a ble s u c 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 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.
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1 2 . 2 a

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.
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1 2 . 3 s

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
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1 2 . 4 accr

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.  
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Li vi n gst o n; 2 0 0 8.

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of cli nical o nc ol o g y : offi cial j o ur nal of t he A m eri ca n S ociet y of Cli nical O nc ol o g y

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as a t hera pe utic strate g y. Nat ure 2 0 0 5; 4 3 4: 9 1 7 -2 1.

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2 0 1 2; 4 8 1: 2 8 7 -9 4.

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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.

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t he basal-li ke s u bt y pe of i n vasi ve breast c arci 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 c a 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 ur e 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

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a n d B R C A 1/ 2 m utati o n -ass ociate d breast c a ncer ( B C). Sa n A nt o ni o Breast Ca ncer  
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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 pl ati 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 pl ati 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 c a 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 Me eti 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

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table of contents
a p p e n

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