Conditions: Early Breast Cancer
Keywords: Neoadjuvant Therapy, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 NEGATIVE Breast Cancer, BRCA Positive
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 61
Healthy volunteers: no

Brief summary:
A PHASE 2, NON RANDOMIZED, OPEN LABEL, SINGLE ARM, MULTI CENTER STUDY OF TALAZOPARIB FOR NEOADJUVANT TREATMENT OF GERMLINE BRCA1/2 MUTATION PATIENTS WITH EARLY HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 NEGATIVE BREAST CANCER

Detailed description:
TALAZOPARIB (PARP INHIBITOR) FOR NEOADJUVANT TREATMENT OF GERMLINE BRCA1/2 MUTATION PATIENTS WITH EARLY HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 NEGATIVE BREAST CANCER. THIS IS A MONOTHERAPY TREATMENT FOR 24 WKS FOLLOWED BY SURGERY TO EVALUATE PATHOLOGICAL COMPLETE RESPONSE.

Arms:
arm 1: SINGLE ARM, NON-RANDOMIZED

Interventions: intervention 1: TALAZOPARIB
Intervention descriptions: intervention 1: Talazoparib 1mg/day

Protocol document:
Prot_000.pdf: 
Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
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A P H A S E 2, N O N -R A N D O MI Z E D, O P E N L A B E L, SI N G L E A R M, M U L T I-C E N T E R 
S T U D Y O F T A L A Z O P A RI B F O R N E O A D J U V A N T T R E A T M E N T O F G E R M LI N E 
B R C A 1/ 2 M U T A TI O N P A T I E N T S WI T H E A R L Y H U MA N E PI D E R M A L 
G R O W T H F A C T O R R E C E P T O R 2 N E G A TI V E B R E A S T C A N C E R 
I n vesti g ati o n al Pr o d uct N u mber:
P F -0 6 9 4 4 0 7 6
I n vesti g ati o n al Pr o d uct N a me:
T al az o p ari b 
U nite d St ates ( U S) I n vesti g ati o n al Ne w 
Dr u g (I N D) N u m ber:
Pr ot oc ol N u m ber:
C 3 4 4 1 0 2 0
P h ase:
2 b
T his d oc u me nt a n d acc o m pa n yi n g materials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o P fizer.  E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nts, y o u a gree t o h ol d t his i nf or mati o n i n 
c o nfi de nce a n d n ot c o p y or discl ose it t o ot hers (e xce pt w here re q uire d b y a p plica ble la w ) or use it f or 
u na ut h orize d p ur p ose s.  I n t he e ve nt of a n y act ual or s us pecte d breac h of t his o bli gati o n, Pfizer m ust be 
pr o m ptl y n otifie d.
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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
20-December-2017
Not applicable (N/A)
Amendment 1
12-February-2018 
Added clarification to the Schedule of 
Activities to footnotes q-u, Radiologic 
Assessments.
Removed inflammatory breast 
carcinoma (IBC) patients from 
Section 4.1. (Inclusion Criteria) and 
added them to Section 4.2. (Exclusion 
Criteria) in response to the following 
feedback from the FDA: “Revise the 
eligibility criteria such that patients with 
IBC are NOT eligible.  Patients with 
IBC should receive neoadjuvant therapy 
with an anthracycline and taxane 
combination.” 
Removed paragraphs from Section 8.1, 
which referred to an external endpoint 
adjudication committee; this study will 
not require one. 
Header 8.4. Changed to Special 
Situations per CT-02 Template.
Added wording: This amendment 
incorporates all revisions to date, 
including amendments made at the 
request of country health authorities and 
institutional review boards (IRBs)/ethics 
committees (ECs). 
Amendment 2
27-February-2018
Added to the Schedule of Activities, 
footnote f, and Section 7.9.2, Physical 
Examinations: A clinical exam of breast
and axilla should be included in each 
physical exam.  If the patient has 
evidence of clinical disease progression, 
treatment on study should be 
discontinued.  These patients should 
either switch to alternate systemic 


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therapy or go straight to surgery so as 
not to preclude potentially curative 
surgery. 
Added to Protocol Summary (Study 
Design), Section 9.1 (Sample Size 
Determination) and Section 9.7, 
(Interim Analysis): If at interim 
analysis, 7 patients or less achieve pCR 
among the first 28 patients in the 
evaluable population, the study may be 
stopped for futility.
Removed text pertaining to medical 
devices from Section 8.2.3 (Serious 
Adverse Events), and 8.5.1 (Medication 
Errors), since it is not applicable to this 
study.
Removed from Protocol Summary 
(Study Design), and Section 9.7 (Interim 
Analysis): Predefined IA futility criteria 
are not binding and the totality of 
evidence (efficacy and safety) will be 
considered.
Removed from Section 9.7 (Interim 
Analysis): However, enrollment in the 
study will not be interrupted for the 
assessment of futility at the interim 
analysis, as the futility boundary is not 
binding. 
Amendment 3
16-November-2018
Throughout: minor editorial edits have 
been made to enhance the readability of 
the protocol.
Throughout: term “fresh” updated to 
more correct term of “new at 
screening”.
Introduction: updated latest version of 
Talazoparib IB to August 2018.
Introduction, Protocol Summary 
(Background and Rationale), and 
Section 1.4 (Rationale for Study): added 


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t w o refere nces re gar di n g talaz o pari b’s 
e n ha nce me nt of t he c yt ot o xic effects of 
c he m ot hera p y.
Pr ot oc ol S u m mar y  ( Bac k gr o u n d a n d 
Rati o nale): A d de d safet y data f or A Es 
a n d p C R f or T N B C c o h ort.
Pr ot oc ol S u m mar y  ( Bac k gr o u n d a n d 
Rati o nale), Secti o n 1. 3. 1, a n d 
Secti o n 1. 4 u p date d wit h c u rre nt A S C O 
data a n d 2 0 1 8 N EJ M p u blicati o n 
refere nce.
Pr ot oc ol S u m mar y  ( Pri mar y E n d p oi nt), 
Ta ble 2 ( S u m mar y  of O bjecti ves a n d 
E n d p oi nts), Secti o n 1. 2. 5 ( p C R as a n 
E n d p oi nt i n Ne o A dj u va nt Trials), a n d 
Secti o n 9. 3. 3 ( p C R i n breast b y  
I n de pe n de nt Ce ntral Re view a n d 
I n vesti gat or); defi niti o n of p C R 
a me n de d as f oll o ws (te xt a d de d i n b ol d, 
te xt re m o ve d i n italics): p C R b y IC R 
after c o m pleti o n of 2 4 wee ks of 
ne oa dj u va nt talaz o pari b f oll o we d b y  
s ur ger y defi ne d as y p T 0/ Tis y p N 0 (t he 
a bse nce of resi d ual i n vasi ve a n d i n sit u
ca ncer i n t he bre ast a n d t he a xill ar y 
l y m p h n o des o n e val uati o n of t he 
c o m plete resecte d breast s peci me n a n d 
all sa m ple d re gi o nal l y m p h n o des 
f oll o wi n g c o m pleti o n of ne oa dj u va nt 
s yste mic t hera p y). 
 
 
 
Pr ot oc ol S u m mar y  ( Statistical 
Met h o ds): a n d Secti o n
9: clarifie d 
defi niti o n of a nal ys is p o p ulati o ns.
Pr ot oc ol S u m mar y  ( St u d y Sc he mata, 
Fi g ure 1): u p dat e d t u m or size fr o m 
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>1.5 cm to T1.
SOA (Table 1) and Section 7.1 
(Pregnancy Testing) clarified as 
pregnancy testing being performed by a 
serum or urine test. 
SOA footnote q: the second sentence, 
“Perform post-baseline assessments 
every 4 weeks through Week 25, or 
locally determined disease progression, 
whichever is earlier; and at end of 
treatment when study results are 
determined” was removed.
SOA footnote u: Added clarification 
that USS have a window of 3 days.
Section 1.2.2 updated for FDA approval 
of olaparib.
Section 1.3 updated with latest 
Development Safety Update Report 
information.
Section 1.3.1 updated with most current 
IB information for PRP-001 and 
ABRAZO studies.
Section 3 updated to clarify that biopsy 
can be performed using institutional 
procedures such as dual blue dye or 
radioisotope tracers (since not all the 
sites use both methods). 
Section 4.1 (Inclusion Criteria), Item 2 
updated to specify that patients must be 
willing and able to provide informed 
consent.  Also, Item 6 updated (tumor 
size changed from >1.5 cm to T1).
Sections 4.1, 4.2, and 4.3.1 (Inclusion 
Criteria, Exclusion Criteria, and 
Contraception, respectively): 
contraception requirements updated to 
7 months after the last dose of 
talazoparib for females and 4 months 


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after t he last d ose of talaz o pari b f or 
males ( A u g ust 2 0 1 8 Talaz o pari b I B).
Secti o n 5. 4. 1, Ta ble 4 u p date d t o 
i ncl u de la n g ua ge f or d ose re d ucti o n a n d 
disc o nti n uati o n.
Secti o n 5. 5 (I n vesti gati o nal Pr o d uct 
St ora ge) re na me d I n vesti gati o nal 
Pr o d uct St ora ge a n d Ha n dli n g; ha n dli n g 
i nstr ucti o ns were a d de d.
Secti o n 7. 1 ( Pre g na nc y  Testi n g) 
c orrecte d t o at scree ni n g, a n d o n Da y 1 
of C y cles 1- 6 a n d as per t he S O A.
Secti o n 8. 2. 3 ( Seri o us A d verse E ve nts) 
u p date d t o clarif y  t hat Sec o n dar y 
Pri mar y  Mali g na ncies s h o ul d be 
re p orte d as S A Es.
Secti o n 8. 5. 1 ( Me dicati o n Err ors) 
u p date d t o be i n li ne wit h Pfizer 
pr occeses.
S u bsecti o n 8. 5. 2 ( O ver d ose) a d de d t o 
Secti o n 8. 5 ( Me dicati o n Err ors a n d 
Lac k of Efficac y ) t o i nc or p orate 
la n g ua ge c o nsiste nt wit h u p date d I B 
re gar di n g o ver d ose ma na ge me nt 
( A u g ust 2 0 1 8 Talaz o pari b I B).
 
 
A me n d me nt 4
1 4- A u g -- 2 0 1 9 
T hr o u g h o ut d oc u me nt: + a n d 
– re place d wit h p ositi ve a n d ne gati ve, 
res pecti vely, f or clarit y.
Title pa ge: St u d y  title u p date d (tri ple 
ne gati ve breast ca ncer c ha n ge d t o 
h u ma n e pi der mal gr o wt h fact or rece pt or 
2 ne gati ve breast ca ncer).  W or di n g als o 
u p date d i n Pr ot oc ol S u m mar y  a n d 
Secti o n 3, St u d y  Desi g n a n d else w here 
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in the protocol as appropriate.
Summary (Background and Rationale): 
Added wording and references 1-4 and
8-9 for further background information 
on breast cancer.  Renumbered 
references accordingly.
Schedule of Activities: removed need 
for urinalysis at ‘post surgical follow 
up’ visit.
Section 1.2.5 (Neoadjuvant Therapy for 
ER positive Germline Breast Cancer 
Susceptibility Gene Positive Breast 
Cancer) added to provide background 
information on germline BRCA 1/2 
mutations in HR positive breast cancer.
Section 3 (Study Design): Patient 
numbers and study design updated to 
address lower than expected enrollment.
Section 4.1 (Inclusion Criteria): 

Criterion #1 updated to indicate that 
testing for gBRCA mutations may 
be performed at a local laboratory.  
Updated language in the Protocol 
Summary (Study Design), SoA 
(Footnote ee), and Section 3 (Study 
Design) accordingly.  This change 
was made to allow more flexibility 
for enrollment.

Criterion #5 updated to remove the 
requirement for patients to have 
triple negative invasive breast 
cancer.  Patients with hormone 
receptor positive disease will be 
permitted.  This change was made to 
allow more flexibility in enrollment.

Criterion #6 updated to Tumor ≥T1, 
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
Criterion #11 updated for methods 
of contraception; changed from 
2 highly effective methods to 
1 highly effective method, as per the 
August 2018 Talazoparib IB. 
Section 4.2 (Exclusion Criteria): 

Criterion #7: modified language in 
first bullet to allow patients to enter 
the study if they have stage 
1 melanoma which does not require 
any further treatment after adequate 
surgical excision.  This change was 
made to allow more flexibility for 
enrollment.

Criterion #1 updated for methods of 
contraception; changed from 
2 adequate methods to 1 highly 
effective method (highly effective 
methods are detailed in 
Section 4.3.1), as per the August 
2018 Talazoparib IB.
Section 4.1, Inclusion Criteria: Criteria 
adjusted clarify that both early and 
locally advanced disease are permitted.
Section 4.3.1, Contraception: language 
updated for methods of contraception;
changed from 2 highly effective
methods to 1 highly effective method, as 
per the August 2018 Talazoparib IB.  
Section 4.3.2 (Women of Childbearing 
Potential) added to align with the 
updated Pfizer protocol template.  
Section 6.1.1 (Screening for gBRCA 
Mutations) added to capture changes in 
Inclusion Criteria #1 for gBRCA 
screening requirements.
Section 9.1, Sample Size Determination: 
Background information added for HR 


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p ositi ve breast ca ncer.
Secti o n 9. 1, Sa m ple Size Deter mi nati o n: 
w or di n g u p date d t o reflect a re d ucti o n 
i n sa m ple size f or t he st u d y.  U p date d 
la n g ua ge i n t he Pr ot oc ol S u m mar y 
( St u d y Desi g n), Secti o n 3 ( St u d y 
Desi g n), a n d Secti o n 9. 9 ( I nteri m 
A nal y sis) acc or di n gl y.  T his c ha n ge was 
ma de d ue t o u ne x pecte d l o w e nr oll me nt 
rates.
Secti o n 7. 9. 4: a d de d Uri nal y sis c ol u m n 
a n d tests t o Ta ble 7.
 
 
Sec ti o n 9.9 , Interi m A nal y sis: W or di n g 
u p date d t o reflect a re d ucti o n i n sa m ple 
size f or t he st u d y.
Refere nces: 
Refere nces a d de d a n d refere nce 
n u m bers a d de d/li n ke d t o rele va nt 
secti o ns ( S u m mar y, Secti o ns 1. 2 5 a n d 
9. 1.  Ot her refere nces were re-n u m bere d 
acc ordi n gl y.
T his a me n d me nt i nc or p orates all re visi o ns t o date, i ncl u di n g a me n d me nts ma de at t he 
re q uest of c o u ntr y healt h a ut h orities a n d i nstit uti o nal re vie w b oar ds (IR Bs)/et hics c o m mittees 
( E Cs).  
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
LIST OF FIGURES .................................................................................................................14
APPENDICES .........................................................................................................................14
PROTOCOL SUMMARY.......................................................................................................16
1. INTRODUCTION ...............................................................................................................34
1.1. Mechanism of Action/Indication.............................................................................34
1.2. Background and Rationale ......................................................................................35
1.2.1. Breast Cancer..............................................................................................35
1.2.2. Triple Negative and Germline Breast Cancer Susceptibility Gene 1 
or 2 Positive Breast Cancer..............................................................................35
1.2.3. Neoadjuvant Therapy For Breast Cancer ...................................................36
1.2.4. Neoadjuvant Therapy For Triple Negative And Germline Breast 
Cancer Susceptibility Gene Positive Breast Cancer ........................................37
1.2.5. Neoadjuvant Therapy for ER Positive Germline Breast Cancer 
Susceptibility Gene Positive Breast Cancer.....................................................37
1.2.6. Pathological Complete Response as an Endpoint in Neoadjuvant 
Trials ................................................................................................................38
1.2.7. Poly(ADP Ribose) Polymerase Inhibition..................................................39
1.2.8. Poly (ADP Ribose) Polymerase Inhibitors as a Potential Targeted 
Therapeutic in Triple Negative Breast Cancer with Germline Breast 
Cancer Susceptibility Gene Mutations.............................................................40
1.3. Summary of Relevant Clinical Experience with Talazoparib.................................41
1.3.1. Efficacy.......................................................................................................42
1.3.2. Pharmacokinetics and Metabolism.............................................................45
1.3.3. Rationale for Talazoparib Dose..................................................................46
1.4. Rationale for Study..................................................................................................46
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................49
3. STUDY DESIGN.................................................................................................................50
4. PATIENT ELIGIBILITY CRITERIA.................................................................................52
4.1. Inclusion Criteria.....................................................................................................53
4.2. Exclusion Criteria....................................................................................................54
4.3. Lifestyle Requirements ...........................................................................................57


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4. 3. 1. C o ntrace pti o n ..............................................................................................5 7
4. 3. 2. W o me n of C hil d beari n g P ote ntial ( W C B P) Defi niti o n .............................. 5 8
4. 4. S p o ns or’s Q ualifie d Me dical Pers o n nel .................................................................. 5 9
5. S T U D Y T R E A T M E N T S ..................................................................................................... 5 9
5. 1. All ocati o n t o Treat me nt .......................................................................................... 5 9
5. 2. Patie nt C o m plia nce .................................................................................................6 0
5. 3. I n vesti gati o nal Pr o d uct S u p plies ............................................................................. 6 0
5. 3. 1. D osa ge F or m(s) a n d Pac ka gi n g .................................................................. 6 0
5. 3. 2. Pre parati o n a n d Dis pe nsi n g ........................................................................ 6 0
5. 4. A d mi nistrati o n ......................................................................................................... 6 0
5. 4. 1. D ose M o dificati o ns f or Talaz o p ari b D ue t o A d verse E ve nts ..................... 6 1
5. 4. 2. Talaz o pari b D ose Re -Escalati o n ................................................................. 6 3
5. 4. 3. M o dificati o ns D ue t o A b n or mal L i ver Tests ( All Treat ments) .................. 6 3
5. 5. I n vesti gati o nal Pr o d uct St ora ge a n d Ha n dli n g ........................................................ 6 6
5. 6. I n vesti gati o nal Pr o d uct Acc o u nta bilit y ................................................................... 6 7
5. 6. 1. Destr ucti o n of I n vesti gati o nal Pr o d uct S u p plies ........................................ 6 7
5. 7. C o nc o mita nt Treat me nt(s) ....................................................................................... 6 7
6. S T U D Y P R O C E D U R E S..................................................................................................... 6 8
6. 1. Scree ni n g ................................................................................................................. 6 8
6. 2. Treat me nt Peri o d ..................................................................................................... 6 8
6. 3. Sa fety F oll o w -u p..................................................................................................... 6 8
6. 4. L o n g Ter m F oll o w -u p ............................................................................................. 6 8
6. 5. Patie nt Wit h dra wal .................................................................................................. 6 9
7. A S S E S S M E N T S .................................................................................................................. 7 0
7. 1. Pre g na nc y  Testi n g................................................................................................... 7 1
7. 2. C o m pa ni o n Dia g n ostics f or Eli gi bilit y ................................................................... 7 1
7. 3. Efficac y  Assess me nts..............................................................................................7 2
7. 3. 1. Pri mar y  Efficac y E n d p oi nt: Pat h ol o gical C o m plete Res p o nse ..................7 2
7. 3. 2. Asses s me nt of Sec o n dar y Efficac y E n d p oi nts ...........................................7 2
7. 4. Patie nt Re p orte d O utc o mes Assess me nts ...............................................................7 2
7. 5. P har mac o ki netic Assess me nts ................................................................................. 7 3
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7. 8. Rater Q ualificati o ns................................................................................................. 7 5
7. 9. Safet y Assess me nts ................................................................................................. 7 6
7. 9. 1. A d verse E ve nts ........................................................................................... 7 6
7. 9. 2. P h y sical E xa mi nati o ns ................................................................................ 7 6
7. 9. 3. Vital Si g ns .................................................................................................. 7 6
7. 9. 4. Cli nical L a b orat or y Assess me nts ...............................................................7 6
8. A D V E R S E E V E N T R E P O R TI N G ...................................................................................... 7 7
8. 1. Re q uire me nts ........................................................................................................... 7 7
8. 1. 1. A d diti o nal Details o n Rec or di n g A d verse E ve nts o n t he C R F ................... 7 9
8. 1. 2. Eliciti n g A d verse E ve nt I nf or mati o n .......................................................... 7 9
8. 1. 3. Wit h dra wal fr o m t he St u d y  D ue t o A d verse E ve nts (see als o t he 
Patie nt Wit h dra wal secti o n) ............................................................................. 7 9
8. 1. 4. Ti me Peri o d f or C ollecti n g A d verse E ve nt/ Seri o us A d verse E ve nt 
I nf or mati o n ...................................................................................................... 7 9
8. 1. 4. 1. Re p orti n g Seri o us A d verse E ve nts t o Pfizer Safet y .................. 7 9
8. 1. 4. 2. Rec or di n g N o n -seri o us A d verse E ve nts a n d Seri o us 
A d verse E ve nts o n t he C ase Re p ort F or m ......................................... 8 0
8. 1. 5. Ca usalit y  Assess me nt ................................................................................. 8 0
8. 1. 6. S p o ns or’s Re p orti n g Re q uire me nts t o Re g ulat or y  A ut h orities.................. 8 0
8. 2. Defi niti o ns ............................................................................................................... 8 1
8. 2. 1. A d verse E ve nts ........................................................................................... 8 1
8. 2. 2. A b n or mal Test Fi n di n gs ............................................................................. 8 2
8. 2. 3. Seri o us A d verse E ve nts .............................................................................. 8 2
8. 2. 4. H os pitalizati o n ............................................................................................ 8 3
8. 3. Se verit y  Assess me nt................................................................................................ 8 4
8. 4. S pecial Sit uati o ns .................................................................................................... 8 4
8. 4. 1. Pr ot oc ol - S pecifie d Seri o us A d verse E ve nts............................................... 8 4
8. 4. 2. P ote ntial Cases of Dr u g -I n d uce d Li ver I nj ur y............................................ 8 5
8. 4. 3. E x p os ure t o t he I n vesti gati o nal Pr o d uct d uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure ..................................................... 8 6
8. 4. 4. E x p os ure d uri n g Pre g na nc y ........................................................................ 8 6
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8. 4. 4. 1. E x p os ure d uri n g Breastfee di n g................................................. 8 8
8. 4. 4. 2. Occ u pati o nal E x p os ure ............................................................. 8 8
8. 5. Me dicati o n Err ors a n d L ac k of Efficac y ................................................................. 8 8
8. 5. 1. Me dicati o n Err ors ....................................................................................... 8 8
8. 5. 2. O ver d ose ..................................................................................................... 8 9
8. 5. 3. L ac k of Efficac y ......................................................................................... 8 9
9. D A T A A N A L Y SI S/ S T A TI S TI C A L  M E T H O D S...............................................................9 0
9. 1. Sa m ple Size Deter mi nati o n ..................................................................................... 9 1
9. 2. A nal y sis of t he Pri mar y E n d p oi nt........................................................................... 9 2
9 . 3. A nal ysis of Sec o n dar y E n d p oi nts ...........................................................................9 2
9. 3. 1. Pat h ol o gical C o m plete Res p o nse b y I n vesti gat or Re vie w ......................... 9 3
9. 4. Et hical C o n d uct of t he S t u d y .................................................................................. 9 3
9. 4. 1. Resi d ual Ca ncer B ur de n ............................................................................. 9 4
9. 4. 2. Pat h ol o gical C o m plete Res p o nse i n Breast b y I n de pe n de nt Ce ntral 
Re vie w a n d I n vesti ga t or .................................................................................. 9 4
9. 4. 3. E ve nt -free S ur vi val a n d E ve nt-free S ur vi val at 3 Years ............................9 4
9. 4. 4. O verall S ur vi val a n d O verall S ur vi val at 3 Years ...................................... 9 5
9. 4. 5. Ti me t o Defi niti ve Deteri orati o n I n Gl o bal Healt h Stat us/ Q ol Per 
E ur o pea n Or ga nizati o n F or Researc h A n d Treat me nt Of Ca ncer Q ualit y  
Of L ife Q uesti o n naire ( E O R T C Q LQ -C 3 0) .................................................... 9 5
9. 4. 6. Ti me t o Defi niti ve Deteri orati o n I n Na usea A n d V o miti n g 
S y m pt o ms Per E O R T C Q L Q -C 3 0 ................................................................... 9 5
9. 4. 7. C ha n ge Fr o m Baseli ne I n Gl o bal Healt h Stat us/ Q o l, F u ncti o ni n g, 
A n d S y m pt o ms Per E O R T C Q L Q- C 3 0 a n d E O R T C Q L Q B R -2 3, A n d 
9. 4. 8. C ha n ge Fr o m Baseli ne I n Pr o p orti o n Of Patie nts Wit h Misse d 
E x pecte d Me nstr ual Peri o d Vers us Baseli ne A n d Pr o p orti o n Of Patie nts 
Wit h Deteri orati o n I n Na usea A n d V o miti n g S y m pt o ms ................................ 9 6
9. 5. P har mac o ki netic A nal y sis ....................................................................................... 9 6
9. 7. E x pl orat or y  A nalys is...............................................................................................9 7
9. 8. Safet y A nal ys is........................................................................................................ 9 7
9. 9. I nteri m A nal ys is...................................................................................................... 9 7
9. 1 0. Data M o nit ori n g C o m mittee ................................................................................. 9 8
C CI
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10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................98
11. DATA HANDLING AND RECORD KEEPING .............................................................99
11.1. Case Report Forms/Electronic Data Record .........................................................99
11.2. Record Retention...................................................................................................99
12. ETHICS............................................................................................................................100
12.1. Institutional Review Board/Ethics Committee....................................................100
12.2. Patient Information and Consent.........................................................................100
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................101
13. DEFINITION OF END OF TRIAL.................................................................................101
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................101
15. PUBLICATION OF STUDY RESULTS........................................................................102
15.1. Communication of Results by Pfizer ..................................................................102
15.2. Publications by Investigators ..............................................................................102
16. REFERENCES ................................................................................................................104
LIST OF TABLES
Table 1.
Study Schedule of Activities ....................................................................29
Table 2.
Objectives and Endpoints .........................................................................49
Table 3.
Dose Modifications for Talazoparib Toxicities........................................61
Table 4.
Dose Modification of Talazoparib Due to Adverse Events......................62
Table 5.
Criteria for Temporary Withholding of Study Drug in Association 
With Liver Test Abnormalities.................................................................64
Table 6.
Monitoring of Liver Tests for Potential Drug Induced Liver Injury ........65
Table 7.
Required Laboratory Tests .......................................................................77
LIST OF FIGURES
Figure 1.
Study Schematic: Single Agent Talazoparib ............................................28
Figure 2.
Dual Cytotoxic Mechanisms of PARP Inhibitors.....................................34
APPENDICES
Appendix 1. Abbreviations....................................................................................................110


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 5
A p pe n di x 2. E u r o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y -of -Life C ore Q uesti o n naire Q L Q C 3 0 ....................................... 1 1 5
A p pe n di x 3. E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer 
Q ualit y -of -Life B reast Ca ncer M o d ule Q L Q-B R 2 3 ............................... 1 1 7
A p pe n di x 5. Patie nt -Re p orte d O u tc o mes versi o n of t he C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ................................................................................. 1 2 1
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PROTOCOL SUMMARY 
Overview
Talazoparib (also known as PF-06944076, MDV3800, BMN 673) is being investigated for 
the treatment of germline breast cancer susceptibility gene 1/2, (gBRCA1/2), 
mutation-positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.
Background and Rationale
Breast cancer is a biologically diverse and genetically heterogeneous disease.1,2 Breast 
cancer susceptibility gene 1(BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are 
key components in the repair pathway for deoxyribose nucleic acid (DNA) double strand 
breaks,3 and mutations in these genes account for 20% to 25% of hereditary breast cancers 
and 5% of all breast cancers.4  A substantial portion of patients with gBRCA mutated breast 
cancer have hormone receptor-positive disease, including 20 30% of gBRCA1 carriers and 
45 72% of gBRCA2 carriers.5
Approximately 15% of all breast cancers are triple negative.  They can be defined by the lack 
of estrogen, progesterone, and HER2 receptors.  They are more commonly associated with 
younger women, pre-menopausal women of African American race and BRCA1 mutation 
carriers.  Triple-negative breast cancers (TNBCs) are generally more aggressive in nature and 
associated with visceral and soft tissue disease.  The incidence of BRCA 1 and 2 mutations in 
patients with TNBC has been reported to be between 9.6 to 10.6%.6,7  In a study of 
469 TNBC patients, gBRCA1/2 mutation prevalence was also shown to vary by race: 
Ashkenazi Jewish (50 %), Caucasian (33.3 %), Asian (28.5 %), African Americans 
(20.4 %), and Hispanic (20 %).  The prevalence of genetic mutations also differed by age at 
diagnosis, with most patients <40 years (43.8 %) of age.  Various studies have demonstrated 
that TNBCs are associated with a poorer prognosis than luminal breast cancers.  A Canadian 
series, including approximately 1600 triple negative cancers conducted by Dent, R et al8
demonstrated worse long term outcomes in terms of distant recurrence and death in triple 
negative tumors compared to non-triple negative tumors. 
The standard of treatment for neoadjuvant treatment is variable, but mostly focuses on the 
use of anthracycline- taxane regimens.  Other regimens used include adriamycin plus 
cyclophosphamide (AC).  Cyclophosphamide methotrexate, and fluorouracil (CMF) is 
another option which offers less toxicity; however, it has a longer duration of therapy.  
Platinum therapies have also shown efficacy in HER2 negative breast cancer, in particular 
germline breast cancer susceptibility gene (gBRCA) mutant tumors, as these tumors have 
defects in homologous recombination (hR), rendering them more susceptible to deoxyribose 
nucleic acid (DNA) cross linking agents such as platinums.  Retrospective neoadjuvant 
subject series have suggested that primary breast cancer in BRCA1 carriers is platinum-
sensitive and relatively unresponsive to anthracyclines and/or taxanes9 while other studies 
have found that BRCA1 is relatively responsive to anthracyclines and/or taxanes while 
BRCA2 disease is less responsive than sporadic primary breast cancer to these drug classes.10


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The GeparSixto (NCT01426880) and CALGB (NCT00632853) trials examined the efficacy 
of adding platinum to neoadjuvant regimens in triple negative breast cancer.  In GeparSixto, 
the pathological complete response (pCR) rates (breast/axilla) increased from 36.9% to 
53.2%; in the BRCA subgroup, an increase in pCR by 25% (probability value [p]=0.008) was 
observed.  The CALGB/Alliance trial showed an increase in pCR with the addition of 
carboplatin for breast/axilla (54% vs 41%; p=0.0029).  Since these studies were 
underpowered for long term outcome, it is difficult to assess long term benefit.  Therefore, 
the role for platinum therapy in TNBC still remains unclear and warrants further 
investigation in larger trials with examination of long term outcomes.  There have been 
studies resulting in improved disease-free survival (DFS) in patients who achieved pCR with 
platinum agents and BRCA mutation.  Frasci et al11 reported that in TNBC patients treated 
with eight cisplatin-epirubicin-paclitaxel weekly cycles, 62% showed pCR in both breast and 
axilla, and the projected 5-year DFS was 90% and 56% in pCRs and non-pCRs, respectively.  
The BRCA1 gene is expressed in several tissues, such as breast and ovarian tissue.  
Currently, more than 1600 mutations have been identified in the BRCA1 gene, and the 
majority of them promote frameshifts resulting in missense or non-functional protein.  
Women with BRCA1 mutations have an increased risk of developing breast and ovarian 
cancer, while men have a higher risk, to a lesser extent, of developing prostate cancer.12
BRCA2 does not share a high degree of sequence homology with other known genes, and the 
generated protein is comprised of regions with domains that are undefined.13  Currently, 
more than 1800 mutations have been identified in BRCA2, that include frameshift deletions, 
insertions, or nonsense mutations that lead to premature truncation of proteins. 
It has been demonstrated that BRCA1 and BRCA2 tumor suppressor genes perform a critical 
role in the response to cellular damage through activation of specific DNA repair processes 
and play an important part in DNA repair and as transcriptional regulators.14
Inhibition of poly (ADP-ribose) polymerase (PARP) catalytic activity contributes to the 
process of synthetic lethality-defined as a combination of two DNA repair pathway defects 
which may be lethal to the cell-resulting in single-strand breaks that require homologous 
recombination DNA repair for survival.  PARP inhibitors (PARPi) induce synthetic lethality 
in tumor cells containing mutations and/or deletions in genes involved in homologous 
replication or other DNA pathways, including BRCA1 and BRCA2.
Clinical trials have shown that PARPi are beneficial in the treatment of patients with breast 
cancer that are carriers of germline BRCA mutations.  In a phase 1 trial, olaparib 
(NCT00516373; 10 to 600 mg twice a day) treatment of solid tumors of patients with breast 
cancer with no gBRCA mutations vs. patients with breast cancer with gBRCA mutations, 
resulted in an objective response rate (ORR) of 15% and 33%, respectively15 in a phase 2 
trial (NCT00494234) of single-agent olaparib in patients with breast cancer with BRCA1/2 
mutation and advanced disease, investigated two dose levels (cohort 1: 400 mg twice daily 
[bd] and cohort 2: 100 mg bd) and demonstrated an ORR of 42% and 25%, respectively.  
Progression-free survival (PFS) was 5.7 and 3.8 months for cohorts 1 and 2, respectively.  A 
phase I study of niraparib (NCT00749502; 30 to 400 mg once a day) for treatment of solid 


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tumors resulted in an ORR of 40% in patients with gBRCA mutations vs. 18% in the general 
breast cancer population.16  Lastly, a first-in-human trial of oral talazoparib (NCT01286987; 
25 to1100 ug/day) resulted in an ORR of 65% and 33% in solid tumors of gBRCA patients 
with ovarian or breast cancer, respectively.17
Talazoparib is a potent, orally bioavailable, small molecule PARPi in development for the 
treatment of a variety of human cancers.  Single agent talazoparib treatment demonstrates 
potent antitumor effects in tissue culture studies, mouse tumor xenograft models, and in 
Phase 1 studies in patients with solid tumors.  Talazoparib has also been shown to enhance 
the cytotoxic effects of DNA damaging chemotherapy.18,19
Despite advances in the understanding of the biology of gBRCA associated TNBC, treatment 
options remain limited.  PARPi, as well as platinum-based combination therapies, have 
emerged as regimens of potential interest and in particular, therapy with single agent PARPi 
could present significant advantages over chemotherapy regimens through potentially 
improved tolerability.  
The PARP inhibitor olaparib, which was first approved by the Food and Drug Adminstration 
(FDA) in 2014 for patients with advanced ovarian cancer with gBRCA mutations, was 
assessed during a Phase 3 study (OlympiAD; NCT02000622) in metastatic gBRCA mutated 
breast cancer.  This trial included patients with HER2 negative, metastatic breast cancer that 
were either hormone receptor (HR) positive or triple negative; a subgroup of the patient 
population (approximately 50%) were defined as TNBC.  PFS was 7 months in the olaparib 
group vs. 4.2 months in the chemotherapy group (observed hazard ratio=0.58; 95% CI, 
0.43 to 0.80; p=0.009).  The objective response rate was 59.9% in the olaparib arm vs. 
28.8% in the chemotherapy arm.  Olaparib was determined to be effective against 
triple-negative breast cancers that arise in women with inherited, germline BRCA mutations 
(observed hazard ratio in the TNBC subgroup=0.43).20
The Phase 2 ABRAZO study, presented at ASCO 2017, demonstrated clinical activity of 
single agent talazoparib in advanced triple negative, gBRCA mutant breast cancer.  
ABRAZO (673-201; NCT02034916) is an open-label Phase 2, single arm study investigating 
the clinical efficacy and safety of single-agent talazoparib in 83 heavily pre-treated patients 
with gBRCA positive advanced breast cancer.  The primary endpoint was ORR by 
independent radiology review.  Cohort 1 consisted of 49 patients who previously responded
to platinum-based chemotherapy and subsequently developed disease progression.  A 
21% ORR (95% confidence interval [CI]: 10 to 35) was observed in this group of patients.  
Cohort 2 consisted of 35 patients who developed disease progression following at least three 
lines of non-platinum-based therapy.  This group of patients had a 37% ORR (95% CI: 22 
to 55).  


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Another study in the advanced breast cancer setting conducted by Litton et al. was recently 
published in the New England Journal of Medicine.21,22  This study (EMBRACA, 
NCT01945775) was a randomized, open-label, Phase 3 trial in which patients with advanced 
breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive 
talazoparib (1 mg once daily) or standard single-agent therapy of the physician’s choice 
(capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles).  The 
primary endpoint was progression-free survival.  Of the 431 patients who underwent 
randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive 
standard therapy.  Progression-free survival was significantly longer in the talazoparib group 
than in the standard-therapy group (hazard ratio for disease progression or death, 0.54; 
95% CI, 0.41 to 0.71; p<0.001; medians 8.6 months vs. 5.6 months).  The hazard ratio for 
overall survival based on interim analysis at the time of the final progression-free survival 
analysis was 0.76 (95% CI, 0.55 to 1.06; p=0.11 [57% of projected events]; medians 
22.3 months vs. 19.5 months).  The objective response rate was higher in the talazoparib 
group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 
8.8; p<0.001).  In all clinically-relevant subgroups, a consistent PFS benefit in favor of 
talazoparib was observed in comparison with physician’s choice of treatment (PCT), 
regardless of hormone-receptor status (hormone receptor positive [HR positive]: hazard ratio 
0.47, 95% CI, 0.32 to 0.70; or TNBC: hazard ratio 0.60, 95% CI, 0.41 to 0.87) BRCA 
mutation subtype, history of central nervous system (CNS) metastasis, visceral/non-visceral 
disease, or number of prior cytotoxic chemotherapies for advanced disease.  Complete 
response was seen in 5.5% of patients with talazoparib therapy vs zero patients receiving 
PCT and partial response was seen in 57.1% vs 27.2%, respectively.  In an exploratory 
analysis, time to end of first post-study therapy was longer with talzapari (hazard ratio 0.68; 
95% CI; 0.51 to 0.91).  Talazoparib was approved in October 2018 by the US FDA for the 
treatment of adult patients with deleterious or suspected deleterious germline 
BRCA- mutated (gBRCAm), HER2 negative locally advanced or metastatic breast cancer.
Talazoparib was generally well tolerated, and few adverse events (excluding progressive 
disease) led to permanent treatment discontinuation (5.9% in talazoparib arm vs 8.7% in 
PCT).  Most non-hematologic toxicities were lower-grade, and the more common 
hematologic toxicities were managed by dose interruption or dose reduction and supportive 
care as needed.  
An investigator-initiated research (IIR) study at MD Anderson Cancer Center titled 
“Neoadjuvant Talazoparib for Patients With a BRCA Deleterious Mutation” explored the 
feasibility of neoadjuvant talazoparib in a two part study (NCT02282345).  Part 1, which 
evaluated a lead-in of 2 months of talazoparib single agent followed by standard 
chemotherapy and surgery, is complete and was accepted for publication in NPJ Breast 
Cancer.23  Decreases in tumor volume (as assessed by the investigator) occurred in 13 out of 
13 patients following 2 months of talazoparib monotherapy (1 mg).  The median tumor 
volume decrease after two months of treatment with talazoparib was 88% (range of 30 to 
98%).  Notably, all TNBC patients achieved either residual cancer burden (RCB)-0 or RCB-1 
following completion of the protocol assigned therapy and surgery.  In this pilot study, 
talazoparib was well tolerated with no Grade 4 or 5 toxicities observed, and only one patient 
required dose reduction due to Grade 3 neutropenia.  Following these data on efficacy and 


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 0
t olera bilit y, part 2 of t he st u d y  was o pe ne d a n d e val uate d 2 4 wee ks of talaz o pari b 
m o n ot hera p y f oll o we d b y s ur ger y wit h n o a d diti o nal c he m ot hera p y.  T his part of t he st u d y 
e nr olle d 2 0 patie nts t otal, w h o recei ve d talaz o pari b m o n ot hera p y f or 6 m o nt hs f oll o we d b y  
s ur ger y a n d assess me nt of p C R.  All patie nts were B R C A p ositi ve a n d t he maj orit y was 
sta ge 2 or 3; m ost patie nts ha d tri ple ne gati ve breast ca ncer.  p C R t o si n gle a ge nt talaz o pari b 
was 1 0/ 1 9 = 5 3 %, ( 9 5 % CI  = 3 2 %, 7 3 %).  Resi d ual Ca ncer B ur de n was als o e val uate d: 
R C B 0 ( n o R C B) + R C B 1 ( mi ni mal resi d ual disease) was 1 2/ 1 9 = 6 3 % , 9 5 % CI = 4 1 %, 
8 1 %.  T here were 1 4 patie nts i n t he T N B C c o h ort.  Of t h ose patie nts, 7 ( 5 0 %) patie nts ha d 
R C B - 0, 1 ( 7. 4 %) patie nt ha d R C B-1, 4 ( 2 8. 5 %) patie nts ha d R C B -2 a n d 2 ( 1 4. 2 %) patie nts 
ha d R C B -3.  T heref ore, t he p C R rate was 5 0 % a n d p C R + R C B- 1 was 5 7. 1 %.   Of n ote, p C R 
occ urre d i n b ot h meta plastic carci n o ma a n d l o b ular carci n o ma.  Talaz o pari b was well 
t olerate d wit h acce pta ble a d here nce a n d ma na gea ble t o xicities.  
I n ter ms of he mat ol o gic t o xicities, 8 of 2 0 ( 4 0 %) patie nts ha d Gra de 3 a ne mia.   T here were 
n o patie nts wit h Gra de 4 a ne mia.  T here was o ne case of Gra de 4 t hr o m b oc y t o pe nia.  
Ne utr o pe nia occ urre d i n 4 patie nts at Gra de 2 ( 2 0 %) a n d Gra de 3 i n 3 ( 1 5 %) patie nts. 
F or n o n -he mat ol o gic t o xicities, m ost were Gra de 1 a n d 2.  T he m ost c o m m o n t o xicities 
occ urri n g i n > 5 0 % of patie nts were na usea, fati g ue, a n d al o pecia.  Ni netee n ( 1 9) of 
2 0 patie nts c o m plete d 6 m o nt hs of t hera p y;  o ne patie nt c o m plete d 5 m o nt hs a n d t he n 
recei ve d c he m ot hera py pri or t o s ur ger y.  T w o patie nts ha d d ose re d ucti o ns t o 0 . 7 5 m g, 
6 patie nts re d uce d t o 0. 5 m g, a n d o ne patie nt ha d a d ose re d ucti o n t o 0. 2 5 m g.  All d ose 
re d ucti o ns were d ue t o he mat ol o gic t o xicities.
T he fi n di n gs fr o m t his st u d y  de m o nstrate pr o misi n g efficac y f or talaz o pari b i n t he 
ne o -a dj u va nt g B R C A p ositi ve e arl y breast ca ncer setti n g.  Talaz o pari b is t he first si n gle 
tar gete d t hera py t o ac hie ve p C R i n B R C A p ositi ve patie nts, i ncl u di n g T N B C.  T his st u d y  
warra nts t he lar ger c o nfir mat or y  trial ( C 3 4 4 1 0 2 0).
T he prese nt st u d y is a n o n -ra n d o mize d, P hase 2 st u d y i n gB R C A 1/ 2 p ositi ve earl y H E R 2 
ne gati ve breast ca ncer, w hic h will e val uate t he safet y  a n d efficac y of talaz o pari b i n t he 
ne oa dj u va nt setti n g.  It will als o e val uate patie nt re p orte d o utc o mes
 
 
i n t his patie nt p o p ulati o n.
O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve 

T o e val uate t he p C R t o talaz o pari b after 2 4 wee ks of ne oa dj u va nt talaz o pari b t hera p y  
f oll o we d by s ur ger y.   p C R ( breast a n d a xilla) will be assesse d b y  i n de pe n de nt ce ntral 
re vie w (IC R). 
Sec o n d ar y O bjecti ves

T o e val uate p C R ( breast a n d a xilla) b y  i n vesti gat or. 
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 1

p C R i n breast o nl y  ( by I C R).

Resi d ual ca ncer b ur de n b y  IC R.

T o e val uate l o n g ter m o utc o me b y  assess me nt of 3 -ye ar E F S (e ve nt free s ur vi val) a n d 
o verall s ur vi val ( O S).

T o e val uate t he safet y a n d t olera bilit y of talaz o pari b.

T o descri be t he stea d y- state p har mac o ki netics ( P K) of talaz o pari b i n patie nts wit h 
g B R C A m utati o n -p ositi ve, H E R 2 ne gati ve breast ca nc er.

T o e val uate t he f oll o wi n g patie nt -re p orte d o utc o mes ( P R O):

Gl o bal healt h stat us/ Q ualit y  of Life ( Q o L), f u ncti o ni n g, a n d sy m pt o ms (i ncl u di n g 
na usea a n d v o miti n g);

Misse d e x pecte d me nstr ual peri o d; t his o bjecti ve ca pt ures t he c o nce pt of fertilit y  
preser v ati o n t hr o u g h P R O, si nce t here is a p ossi ble fertilit y  s pari n g effect of 
talaz o pari b vers us c he m ot hera py.
 
 
 
 
Pri m ar y E n d p oi nt

p C R b y  IC R after c o m pleti o n of 2 4 wee ks of ne oa dj u va nt talaz o pari b f oll o we d b y  
s ur ger y defi ne d as y p T 0/ Tis y p N 0 (t he a bse nce of resi d ual i n vasi ve ca ncer i n t he 
breast a n d t he a xillar y  ly m p h n o des o n e val uati o n of t he c o m plete resecte d breast 
s peci me n a n d all sa m ple d re gi o nal l ym p h n o des f oll o wi n g c o m pleti o n of ne oa dj u va nt 
s yste mic t hera p y). 
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 2
Sec o n d ar y E n d p oi nts

p C R b y  i n vesti gat or. 

R C B b y  IC R.

p C R (i n breast) b y I C R.

E F S (esti mate d at 3 ye ars).

O S (esti mate d at 3 years).

T y pe, i nci de nce, se verit y (as gra de d b y  Nati o nal Ca ncer I nstit ute [ N CI] C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts [ C T C A E] v 4. 0 3), seri o us ness a n d 
relati o ns hi p of st u d y me dicati o ns t o a d verse e ve nts ( A E) a n d a n y la b orat or y 
a b n or malities.

Ti me t o defi niti ve deteri orati o n i n gl o bal healt h stat us/ Q o L  per E O R T C ( E ur o pea n 
Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer) Q L Q ( Q ualit y of Life 
Q uesti o n naire) -C 3 0.

Ti me t o defi niti ve deteri orati o n i n na usea a n d v o miti n g s y m pt o ms per E O R T C 
Q L Q -C 3 0.

C ha n ge fr o m baseli ne i n gl o bal healt h stat us/ Q o L , f u ncti o ni n g, a n d sy m pt o ms per 
E O R T C Q L Q- C 3 0 a n d E O R T C Q L Q B R - 2 3.

Pr o p orti o n of patie nts wit h dete ri orati o n, i m pr o ve me nt a n d n o c ha n ge i n na usea a n d 
v o miti n g s y m pt o ms.

C ha n ge fr o m baseli ne i n pr o p orti o n of patie nts wit h misse d e x pecte d me nstr ual 
peri o d per P R O -C T C A E .

P K of talaz o pari b usi n g s parse sa m pli n g (tr o u g h c o nce ntrati o ns [ C tr o u g h] at li mite d 
time p oi nts).
 
 
  
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 3
 
St u d y Desi g n
T his is a n o n-ra n d o mize d, P hase 2, si n gle -ar m, o pe n -la bel, m ulti-ce nter st u d y e nr olli n g 
patie nts wit h g B R C A 1/ 2 H E R 2 ne gati ve breast ca ncer.  A p pr o xi matel y  si xt y patie nts will be 
e nr olle d i n t he st u d y a n d treate d wit h talaz o pari b 1 m g o nce dail y ( Q D ) f or 2 4 wee ks 
f ollo we d b y s ur ger y. Wit h
a sa m ple size of 6 0 patie nts, t he t w o -si de d 8 0 % e xact Bla ker 
c o nfi de nce i nter val ( CI) f or t he p C R rate w o ul d be at m ost 1 7 % wi de. If a p C R = 5 0 % is 
o bser ve d, t he l o wer b o u n d of t he e xact 8 0 % CI w o ul d e xcl u de 4 1 %.
A n i nteri m f utilit y anal ys is, desi g ne d base d o n Ba yesia n pre dicti ve pr o ba bilit y  ( P P), will be 
c o n d ucte d o nce 2 8 e val ua ble patie nts are assesse d f or p C R. T he P P is t he pr o ba bilit y  of 
c o ncl u di n g a p ositi ve res ult b y  t he e n d of t he trial base d o n t he c u m ulati ve i nf or mati o n i n t he 
c urre nt sta ge.  T he trial will be c o nsi dere d a s uccess if t he p osteri or pr o ba bilit y  t hat t he tr ue 
p C R rate e xcee ds 4 5 % is ≥8 0 %.  Pre dicti ve pr o ba bilit y  < 1 0 % was set as t he f utilit y b o u n dar y 
a n d ass u me d a n o n -i nf or mati ve beta ( 1, 1) pri or. O nce 2 8 e val ua ble patie nts are assesse d f or 
p C R, if 1 1 res p o nses or less are o bser ve d, t he pre dicti ve pr o ba bi lit y of t he trial bei n g 
s uccessf ul at t he f ull sa m ple size is less t ha n 1 0 %, at w hic h p oi nt t he S p o ns or w o ul d 
rec o m me n d st o p pi n g t he st u d y d ue t o f utilit y. If ≥1 2 res p o nses are o bser ve d i n t he first 
2 8 e val ua ble patie nts, t he st u d y will c o nti n ue e nr olli n g t o 6 0 e val ua ble patie nts.  
T he e val ua ble p o p ulati o n is t he pri mar y  a nalys is p o p ulati o n at t he i nteri m a n d fi nal a nalys is.  
Patie nts t hat d o n ot c o m plete talaz o pari b treat me nt f or 2 4 wee ks , d o n ot ha ve s ur ger y, or f or 
w h o m t he I CR assess me nt of t he p ost s ur ger y  s peci me n is n ot a vaila ble, will be e xcl u de d 
fr o m t he e val ua ble p o p ulati o n ( u nless t he y pr o gress e d or die d bef ore p C R c o ul d be assesse d ).
Patie nts w h o die or pr o gress bef ore p C R c o ul d be assesse d will be i ncl u de d as 
n o n- res p o n ders i n t he a nal yses. T he i nte nt-t o-treat (I TT ) p o p ulati o n will i ncl u de all patie nts 
w h o recei ve d at least 1 d ose of talaz o pari b, re gar dless of w het her or n ot t he y are c o nsi dere d 
e val ua ble.
A patie nt will partici pate i n u p t o 4 peri o ds: scree ni n g, talaz o pari b treat me nt p hase, s afet y 
f oll o w-u p, a n d l o n g -ter m f oll o w- u p.  Patie nts will be e val uate d at scree ni n g f or t he prese nce 
of a deleteri o us, s us pecte d deleteri o us, or pat h o ge nic ger mli ne B R C A 1 or B R C A 2 m utati o n 
as c o nfir me d b y a l ocal Cli ncal L a b orat or y Im pr o ve me nt A me n d me nts ( C LI A ) certifie d test.  
Patie nts m ust als o c o nse nt t o a bl o o d sa m ple f or ce ntral ge n o mic assess me nt usi n g t he 
B R A C A nal ys is C o m pa ni o n Dia g n ostics ( C D x ) test b y Myria d Ge netics, e xce pt f or patie nts 
w h o alrea d y ha ve e vi de nce of B R C A 1/ 2 m utati o n b y  M Y RI A D B R C A nal ysis C D x p ost 
2 0 1 6.  L o n g -ter m f oll o w u p peri o d is at least 5 years, w hic h starts fr o m t he date of s ur ger y 
f or E F S a n d after first d ose of dr u g f or O S.  Fi g ure 1 pr o vi des a st u d y sc he matic. 
C
C
I


Talazoparib (PF-06944076; MDV3800)
C3441020
Final Protocol Amendment 4, 14 August 2019
PFIZER CONFIDENTIAL
Page 24
Safety follow-up (end of treatment visit) will occur 28 days after the last dose of study drug 
or before initiation of a new antineoplastic or investigational therapy, whichever occurs first.  
There will also be an additional post- surgical safety follow up, 4 weeks after surgery for 
assessment of wound healing.  Long term follow-up will begin after date of surgery for EFS 
and OS after first dose of talazoparib.  
Study Treatments
Patients will receive talazoparib 1 mg daily for 24 weeks, followed by breast surgery, which 
should occur within 4 to 6 weeks (no longer than 6 weeks) of the last dose.  If hematological 
toxicity is present (ie, neutropenia/thrombocytopenia), the investigator will decide whether 
surgery will proceed according to schedule; a washout period is not needed.
Statistical Methods
Analysis populations:
Evaluable population is defined as all patients enrolled in the study who receive 24 weeks of 
talazoparib treatment 1 mg once daily (QD), undergo breast surgery and pCR assessment, as 
well as those patients who progress or die before pCR can be assessed.  The evaluable 
population is the primary analysis population for all efficacy endpoints at the interim analysis 
as well as the final analysis.  Patients who progress or die before pCR can be assessed
(regardless of whether or not they received 80% of study treatment) by investigator and by 
ICR will be considered as non-responders in the evaluable population. If a patient receives 
less than 80% of the protocol required treatment, undergoes surgery and achieves pCR by 
ICR, the patient will be counted as a responder in the ITT population, but will not be 
included in the evaluable population.
The intent to treat (ITT) analysis population is defined as all patients enrolled in the study 
who received at least one dose of talazoparib.  All efficacy analyses will also be reported in 
the ITT analysis population.  The safety population is defined as all patients enrolled in the 
study who received at least one dose of talazoparib (which is the same as the ITT population 
in this study).  All safety analyses will be reported using the safety population.
The PRO analysis population is defined as all patients who completed a baseline and at least 
one post baseline quality-of-life assessment prior to the end of study treatment.
The PK analysis population is defined as all patients treated with talazoparib for whom drug 
plasma concentration results (from at least 1 visit) are available.  For the PK analysis 
population, talazoparib concentrations will be summarized descriptively by nominal time and 
talazoparib dose strength.  Additionally, a subgroup of PK samples which meet pre-defined 
steady-state acceptance criteria (as detailed in the study statistical analysis plan [SAP]) will 
be summarized by nominal time and a within-patient average talazoparib steady state trough 
concentration will be listed by patient from this population.


Talazoparib (PF-06944076; MDV3800)
C3441020
Final Protocol Amendment 4, 14 August 2019
PFIZER CONFIDENTIAL
Page 25
Analysis methods
pCR rate by ICR is defined as the number and percentage of patients achieving pCR by 
independent central review after talazoparib treatment for 24 weeks, followed by surgery, 
among all patients in the evaluable population.  Patients who progress or die before pCR can 
be assessed will be considered as non-responders.  pCR rate will be evaluated at the time of 
the interim and final analyses and will be summarized along with the exact 80% and 95% CI.  
pCR by ICR will also be summarized in the ITT population, along with the exact 80% and 
95% CI.  Patients who discontinue treatment or the study prematurely, are lost to follow-up, 
withdraw consent, progress or die before pCR can be assessed by central review will be 
considered as non-responders in the ITT population analysis. 
pCR rate by investigator is defined as the number and percentage of patients achieving pCR 
by investigator review after talazoparib treatment for 24 weeks, followed by surgery, among 
all patients in the evaluable population.  pCR rate by investigator will be evaluated at the 
time of the interim and final analyses and will be summarized along with the exact 95% CI.  
pCR by investigator will also be summarized in the ITT population, along with the exact 
95% CI.  Patients who discontinue treatment or study prematurely, are lost to follow-up, 
withdraw consent, progress or die before pCR can be assessed by investigator will be 
considered as non-responders in the ITT population analysis. 
Residual cancer burden by ICR will be reported as a categorical variable with four classes 
(categories) RCB 0 (pCR), I (minimal RCB), II (moderate RCB), and III (extensive RCB).  
Number and percentage of patients in each category will be reported along with exact 
95% CI.  The analysis of RCB by ICR will be conducted in the evaluable population. 
pCR rate in breast by ICR is defined as the number and percentage of patients achieving pCR 
in breast by independent central review after talazoparib treatment for 24 weeks, followed by 
surgery, among all patients in the evaluable population.  pCR in breast rate will be 
summarized using descriptive statistics along with the exact 95% CI.  pCR rate in breast by 
ICR will also be summarized in the ITT population along with 95% CI.  Patients who 
discontinue treatment or study prematurely, are lost to follow-up, withdraw consent, progress 
or die before pCR in breast can be assessed by central review will be considered as 
non-responders in the ITT population analysis.
EFS is defined as the time from surgery date to first documentation of local or distant 
recurrence, death, or initiation of antineoplastic therapy before documentation of first relapse.  
Patients discontinuing study before documentation of first relapse or death, but after surgery, 
will be censored observations for EFS.  EFS at 3 years is defined as the probability of being 
event-free at 3 years using Kaplan Meier methods.  The 95% CI for EFS at 3 years will be 
calculated using the Brookmeyer-Crowley method24 EFS at 3 years will be summarized in 
the evaluable population.


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 6
O S is defi ne d as t he ti me fr o m first d ose of talaz o pari b t o deat h d ue t o a n y ca use.  Patie nts 
n ot k n o w n t o ha ve die d at t he ti me of t he a nal ys is will be ri g ht ce ns ore d o n t he date t he y 
were last k n o w n t o be ali ve bef ore t he a nal ys is data c ut off date.  Details o n ce ns ori n g 
c o n ve nti o ns will be prese nte d i n t he statistical a nal ysis pla n.  O S at 3 ye ars is defi ne d as t he 
p r o ba bilit y of bei n g ali ve at 3 years after first d ose of talaz o pari b usi n g Ka pla n -Meier 
met h o ds.  T he 9 5 % CI  f or O S at 3 years will be calc ulate d usi n g t he Br o o k me y er-Cr o wle y  
met h o d.  O S will be s u m marize d i n t he e val ua ble a n d I T T p o p ulati o n.
Ti me t o defi n iti ve deteri orati o n of patie nt-re p orte d gl o bal healt h stat us/ Q o L ( defi ne d as 
1 0- p oi nt decrease fr o m baseli ne wit h o ut a n y s u bse q ue nt < 1 0 -p oi nt decrease) will be 
s u m marize d usi n g t he Ka pla n-Meier met h o d a n d will i ncl u de t he me dia n a n d 9 5 %
CI s.
Ti me t o defi n iti ve deteri orati o n of patie nt-re p orte d na usea a n d v o miti n g sy m pt o ms ( defi ne d 
as 1 0- p oi nt i ncrease fr o m baseli ne wit h o ut a n y  s u bse q ue nt < 1 0-p oi nt i ncrease) will be 
s u m marize d usi n g t he Ka pla n-Meier met h o d a n d will i ncl u de t he me dia n a n d 9 5 % CI s.  
L o n git u di nal mi xe d -effect -a nal ys es will be use d t o assess o ver ti me c ha n ge fr o m baseli ne i n 
na usea a n d v o miti n g s y m pt o ms, 
 f u ncti o ni n g, sy m pt o ms, a n d 
ge neral healt h stat us. 
T he pr o p orti o n of fe male patie nts wit h misse d e x pecte d me nstr ual peri o d p ost -baseli ne per 
Patie nt Re p orte d O utc o mes versi o n of t he C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts 
(P R O -C T C A E ; vs pr o p orti o n of patie nts wit h misse d e x pecte d me nstr ual peri o d at baseli ne); 
a n d pr o p orti o n of patie nts wit h deteri orati o n i n na u sea a n d v o miti n g sy m pt o ms ( vs n o 
deteri orati o n) will be c o m pare d. 
All safet y a nal ys es will be perf or me d usi n g t he safet y  p o p ulati o n. 
Dr u g e x p os ure i n t he safet y  a nalys is p o p ulati o n will be s u m marize d usi n g descri pti ve 
statistics. 
Treat me nt -e mer ge nt safe t y data will be c ollecte d fr o m t he first d ose of st u d y dr u g treat me nt 
t hr o u g h 2 8 da ys after t he date of per ma ne nt disc o nti n uati o n fr o m st u d y or bef ore i nitiati o n of 
ne w a nti ne o plastic or i n vesti gati o nal t hera p y, w hic he ver occ urs first. 
T he safet y of talaz o pari b will be e val uate d b y t he a nal ys is of i nci de nce of seri o us a n d 
n o n -seri o us a d verse e ve nts ( A Es), se verit y of a d verse e ve nts, i nci de nce of d ose 
m o dificati o ns a n d of per ma ne nt treat me nt disc o nti n uati o n d ue t o a d verse e ve nts, a n d 
i nci de nce of ne w cli nicall y si g nifica nt c ha n ges i n cli nical la b orat or y val ues a n d vital si g ns.
A d verse e ve nts will be c o de d t o preferre d ter m a n d s y ste m or ga n class usi n g t he Me dical 
Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A) a n d classifie d b y se verit y usi n g t he C T C A E, 
versi o n 4. 
T he n u m ber a n d perce nta ge of patie nts wit h a d verse e ve nts will be prese nte d b y  Me d D R A 
s yste m or ga n class a n d preferre d ter m, relati o ns hi p t o st u d y treat me nt, a n d se verity.  
Descri pti ve statistics will be use d. 
C CI


Talazoparib (PF-06944076; MDV3800)
C3441020
Final Protocol Amendment 4, 14 August 2019
PFIZER CONFIDENTIAL
Page 27
Laboratory values will be classified by severity using the CTCAE, version 4.  Laboratory 
shift tables of baseline to maximum post-baseline results to each subsequent visit will be 
produced as appropriate.


Talazoparib (PF-06944076; MDV3800)
C3441020
Final Protocol Amendment 4, 14 August 2019
PFIZER CONFIDENTIAL
Page 28
Figure 1.
Study Schematic: Single Agent Talazoparib
gBRCA positive HER2 negative early BC patients
Target Enrollment: n=60
Key Criteria:

Tumor T1, N0-3; 

No evidence of distant metastasis;

Early HER2 negative BC;

gBRCA mutation-positive;

No previous or concomitant anti- cancer therapies used for the treatment of cancer in the last 3 years;

Prior surgical treatment for contralateral DCIS allowed.
Abbreviations: gBRCA= germline mutation of breast cancer susceptibility gene; HER2 = human 
epidermal growth factor receptor 2; BC=breast cancer; mg=milligram; QD=once a day; FU=follow-up; 
pCR=pathological complete response; ICR=independent central review; DCIS=ductal in situ carcinoma.
0                4                 12                 20                24  
                                    (Weeks)                       
Biopsy                          Ultrasound                     End Treatment
and
Imaging
pCR by 
ICR
Within 4-6 
weeks
Adjuvant 
therapy per 
investigator 
choice
Talazoparib
1 mg QD
Survival FU
Every
12 wks
S 
U 
R 
G
E 
R 
Y


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 2 9
S C H E D U L E O F A C TI VI TI E S
T he sc he d ule of acti vities ta ble ( Ta ble 1 ) pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d pr oce d ures.  Refer t o t he S T U D Y 
P R O C E D U R E S a n d A S S E S S M E N T S secti o ns (Secti o n 6 a n d Secti o n 7 , res pecti vely) of t he pr ot oc ol f or detaile d i nf or mati o n o n eac h 
pr oce d ure a n d assess me nt re q uire d f or c o m plia nce wit h t he pr ot oc ol. 
T he i n vesti gat or ma y  sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d o n t he sc he d ule of acti vities ta ble, i n or der t o 
c o n d uct e val uati o ns or assess me n ts re q uire d t o pr otect t he well-bei n g of t he patie nt.
T a ble 1. 
St u d y Sc he d ule of Acti vities
Visit I de ntifier a
Scree ni n g
C 1 D 1 b
C 1 D 1 5
C 2 D 1
C 2 D 1 5
D 1 of 
C 3 -C 6
E n d of 
Tre a me nt 
Visit c
S ur ger y
P ost -
s ur gic al
F oll o w -u p d d
L o n g- Ter m 
F oll o w -u p d
Visit Wi n d o w
2 8 d a ys pri o r t o 
r a n d o miz ati o n
I nf or me d c o nse nt,e S SI D 
n u m ber
X
Me dical hist or y (i ncl u di n g 
t u m or hist or y)
X
Eli gi bilit y Criteria
X
Re gistrati o n
X
P h y sical e xa mi nati o n 
(i ncl udi n g vital si g ns) f
X
X  
X  
X  
X  
X  
X
E C O G Perf or ma nce stat us
X
X
X
X  
X
Baseli ne si g ns a n d s y m pt o ms
X
La b orat or y g
H e m at ol o g y
X
X  
X  
X  
X  
X  
X
X
Bl o o d c he mistr y
X
X  
X  
X  
X  
X  
X
X
Uri nal ysis
X
C oa g ulati o n
X
X
 
Ser u m or Uri ne Pre g na nc y 
test/c o ntrace pti o n c hec k 
X
X
X
X  
X
 
C CI
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 0
Visit I de ntifier a
Scree ni n g
C 1 D 1 b
C 1 D 1 5
C 2 D 1
C 2 D 1 5
D 1 of 
C 3 -C 6
E n d of 
Tre a me nt 
Visit c
S ur ger y
P ost -
s ur gic al
F oll o w -u p d d
L o n g- Ter m 
F oll o w -u p d
Visit Wi n d o w
2 8 d a ys pri o r t o 
r a n d o miz ati o n
 
 
Bl o o d sa m ple f or P Kl
X
X
( C 3 a n d 
C 4 o nl y)
 
Bl o o d sa m ple f or B R C A 
stat usee
X
 
E C G p
X
Ra di o gra p hic Assess me nts q
C T/ P E T/ M RI sca n C H E S T q
X
C T/ P E T/ M RI sca n 
A B D O M E N A N D P E L VI S r
X
B o ne Sca n s
X
Breast i ma gi n g 
( Ma m m o gra m/ U S S/ M RI)t
X
X
( U S S 
o nl y)
X
( U S S o nl y, 
C 4 a n d 
C 6 o nl y)
P R O Assess me nts u
A nt ie mesis me dicati o n l o gv
X  
X  
X  
X  
X
X
E O R T C Q L Q -C 3 0 w
X  
X  
X  
X  
X  
X
X
E O R T C Q L Q -B R 2 3 w
X  
X  
X  
X  
X  
X
X
P R O C T C A E w
X  
X  
X  
X  
X  
X
X
T u m or Tiss ue S peci me n 
( F F P E)x
X
Talaz o pari b y
→ 
→ 
→ 
→ 
→ 
→
C CI
C
C
I
C CI
C CI
C C
I
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 1
Visit I de ntifier a
Scree ni n g
C 1 D 1 b
C 1 D 1 5
C 2 D 1
C 2 D 1 5
D 1 of 
C 3 -C 6
E n d of 
Tre a me nt 
Visit c
S ur ger y
P ost -
s ur gic al
F oll o w -u p d d
L o n g- Ter m 
F oll o w -u p d
Visit Wi n d o w
2 8 d a ys pri o r t o 
r a n d o miz ati o n
C o nc o mita nt me dicati o n
X
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→
Seri o us a n d n o n -seri o us 
a d verse e ve nt m o nit ori n g z
X
→ 
→ 
→ 
→ 
→ 
→ 
→ 
→
N e w  a nti ne o plastic t hera p yaa
X
L ocal rec urre nce/ disease 
pr o gressi o n 
X
Dia g n osis of m yel o d ys plastic 
s y n dr o me or ac ute m yel oi d 
le u ke miab b
X
S ur vi val stat us cc
X
A b br e viati o ns: C = C ycle; C T C = Circ ulati n g T u m or Cells; 
; C T = C o m p ute d T o m o gra p h y; D = Da y ( of st u d y); 
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 O R T C Q L Q = E ur o pea n Or ga nisati o n f or Researc h a n d Trea t me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire; F F P E = F or mali n- fi xe d, paraffi n-e mbe d de d; H R Q L = healt h -relate d q ualit y of life; H R U = healt hcare res o urce utilizati o n; M RI = Ma g netic Res o na nce I ma gi n g; 
P K = P har mac o ki netics; P R O = Patie nt re p orte d o utc o mes; P R O C T C A E = Pa tie nt Re p orte d O utc o mes versi o n of t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; S SI D =s ocial 
sec urit y i de ntificati o n; U S S = Ultras o u n d sca n; 
a.
Da y relati ve t o start of st u d y treat me nt ( Da y 1).
b.
C y cles are 4 wee ks.  A 3- d a y  wi n d o w is all o we d f or all st u d y assess me nts, i ncl u di n g t he ti me bet wee n ra n d o mizati o n a n d first d ose.  St u d y Da y 1 is t he da y t hat t he patie nt 
recei ves t he first d ose of st u d y dr u g treat me nt.  Patie nts m ust n ot g o m ore t ha n 3 0 da ys bet wee n dr u g dis pe nsi n g visits.
c.
E O T visit is us uall y sc he d ule d f or 2 8 da ys p ost last d ose of st u d y me dicati o n or after per ma ne nt treat me nt disc o nti n uati o n or bef ore i nitiati o n of a ne w a nti ne o plastic or 
i n vesti gati o nal t hera p y, w hic he ver occ urs first.  P h o ne patie nts f or a d verse e ve nt f oll o w u p if t he y d o n ot c o me t o t he cli nic.  
d.
L o n g -ter m f oll o w-u p be gi ns after safet y f oll o w - u p a n d ma y be c o n d ucte d b y tele p h o ne e ver y 1 2 wee ks u ntil t he patie nt dies or wit h dra ws c o nse nt f or f oll o w -u p, or t he st u d y 
is ter mi nate d b y t he S p o ns or.
e.
O btai n a n y ti me bef ore a n y st u d y -s pecific pr oce d ures.  E ns ure c o nse nt is o n t he c urre nt versi o n of t he f or m a p pr o ve d b y t he et hics c o m mittee ( E C) a n d S p o ns or.   C o m plete, 
si g n, a n d fa x or e mail t he f or m wit h re q ueste d ite ms t o t he s p o ns or or desi g nee at least 2 b usi ness da ys bef ore e nr oll me nt.  Patie nt ma y pr ocee d t o Da y 1 visit or e nr oll me nt 
w he n s p o ns or or desi g nee a p pr o ves b y si g ne d f or m or e mail c orres p o n de nce.
f.
P h ysical E xa m: Assess s yste ms (e g, ge neral a p peara nce, hea d, e ye s, ears, n ose, m o ut h, t hr oat, s ki n, heart, l u n g, l y m p h n o des, gastr oi ntesti nal, ge nit o uri nar y, ne ur ol o gic, a n d 
s keletal) per sta n dar d of care at t he st u d y site or as cli nicall y i n dicate d b y s y m pt o ms.  A cli nical e xa m of breast a n d a xill a s h o ul d be i ncl u de d i n eac h p h ysical e xa m.  If t he 
patie nt has e vi de nce of cli nical disease pr o gressi o n, treat me nt o n st u d y s h o ul d be disc o nti n ue d.  T hese patie nts s h o ul d eit he r s witc h t o alter nate s yste mic t hera p y or g o strai g ht 
t o s ur ger y s o as n ot t o precl u de p ote ntiall y c urati ve s ur ger y. Vital si g n meas ure me nts ( bl o o d press ure, heart rate, a n d te m perat ure) a n d wei g ht will als o be assesse d. Hei g ht 
will als o be meas ure d at scree ni n g.   
g.
Patie nt t o c o m plete Q o L q uesti o n naires a n d ha ve bl o o d sa m ples c ollecte d bef ore t he firs t d ose of st u d y dr u g o n Da y 1.  If t he scree ni n g test is perf or me d > 7 da ys bef ore t he 
start of treat me nt, re peat t he test o n Da y 1.
C CI
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 3 2
 
 
 
 
 
l.
Bl o o d Sa m ple f or P har mac o ki netics: Plas ma P K sa m ples ( 4 m L ve n o us bl o o d sa m ples c ol lecte d i nt o a p pr o priatel y la bele d la ve n der-t o p K2E D T A [ di p otassi u m 
et h yle ne dia mi netetraacetic aci d] t u bes f or talaz o pari b deter mi nati o n) will be c ollecte d pre -d ose o n C 2 D 1, C 3 D 1, a n d C 4 D 1 o nl y.  Patie nts m ust be i nstr ucte d t o wit h h ol d t heir 
dail y d ose of t alaz o pari b o n P K sa m pli n g da ys u ntil t he pre -d ose P K sa m ple a n d safet y assess me nts (ie, he mat ol o g y, bl o o d c he mistr y, a n d E C Gs) ha ve bee n c o m plete d.  All 
patie nts: Rec or d t he d ose a m o u nts a n d ti me of d ose a d mi nistrati o n o n b ot h t he da y of a n d t he da y bef ore P K sa m pli n g.  Rec or d t he date a n d ti me of eac h P K sa m ple.  F or 
a d diti o nal details, see Secti o n 7. 5 a n d t he St u d y La b orat or y Ma n ual.
 
 
 
 
 
p.
Si n gle E C G, t o be d o ne l ocall y.
q.
If sca ns are d o ne wit hi n 6 wee ks pri or t o t he start of t he scree ni n g peri o d (i nf or me d c o nse nt fr o m si g ni n g date), t he y d o n ot nee d t o be re peate d.  A n y of t he i ma gi n g 
m o dalities ( C T/ P E T/ M RI) ca n be use d.
r.
Pel vis sca n ( C T/ P E T/ M RI) t o be d o ne as cli nicall y i n dicate d.
s.
B o ne sca n t o be d o ne as cli nicall y i n dicate d.
t.
Bre ast i ma gi n g ( Ma m m o gra m/ U S S/ M RI): a n y o ne of t he t hree i ma gi n g m o dalities ca n be use d; u nless i n dicate d ot her wise i n t he Sc he d ule of Acti vities .  U S S ha ve a wi n d o w 
of 3 da ys.
u.
As k t he patie nt t o c o m plete t he q uest i o n naires bef ore a n y ot her st u d y acti vities.  Q uesti o n naires s h o ul d be c o m plete d w hile al o ne i n t he sa me or der at eac h visit.
v.
A n electr o nic patie nt re p orte d -a ntie mesis me dicati o n l o g will be use d t o rec or d a ntie mesis me dicati o n ta ke n b y t he patie nts f or 7 c o nsec uti ve da ys pri or t o eac h cli nical visit.  
Si nce t here is n o patie nt visit sc he d ule d f or Da y 7, t he patie nt will be as ke d t o rec or d t his i nf or mati o n at h o me.
w.
Patie nt re p orte d o utc o mes will be assesse d electr o nicall y t o e val uate gl o bal healt h stat us/ Q o L, f u ncti o ns, a n d s y m pt o ms usi n g t he E O R T C Q L Q C 3 0 a n d Q L Q B R 2 3 
q uesti o n naires; 
  A d diti o nal patie nt re p orte d o utc o mes will be assesse d electr o nicall y t o e val uate t he 
pr o p orti o n of patie nts wit h misse d e x pecte d me nstr ual peri o d per P R O -C T C A E. 
x.
T u m or tiss ue fr o m t he s ur gical s peci me n will be re q uire d.  T his s h o ul d be se nt t o t he ce ntral la b as s o o n as p ossi ble f or e va l uati o n of t he pri mar y e n d p oi nt ( pat h ol o gical 
c o m plete res p o nse).
y.
Dr u g s u p pl y m ust be ta ke n i nt o acc o u nt w he n sc he d uli n g visits d uri n g wi n d o ws.  Visit pr oce d ures ma y be s plit acr oss t he wi n d o w t o all o w f or dr u g res u p pl y a n d c o m pleti o n 
of st u d y pr oce d ures.  I nstr uct patie nt t o self-a d mi nister st u d y dr u g treat me nts.  A d mi nister talaz o pari b i n t he cli nic o n st u d y da ys wit h P K assess me nts.
C
C
I
C
C
I
C
C
I
C CI
C
C
IC
C
I


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z.
Collect serious and non-serious adverse event information from the time of signed informed consent through and including a minimum of 28 calendar days after the last 
administration of the IP.  If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at the time the new treatment is started.
aa.
Record subsequent treatment information for patients starting a new antineoplastic or investigational therapy.
bb. Record any diagnosis of myelodysplastic syndrome or acute myeloid leukemia and report as a serious adverse event (SAE).  Provide tissue samples and other supporting data 
used to enable the diagnosis of myelodysplastic syndrome or acute myeloid leukemia for central review if requested.
cc.
Obtain survival status every 12 weeks by any means including telephone, clinic visit, chart review, or by communicating with an individual (eg, family, friend, referring 
health care provider) who is knowledgeable of the patient’s survival status.
dd. Post-surgical follow-up: a clinical examination of the post-surgical wound should be carried out and laboratory tests as indicated should be performed.
ee.
BRCA testing can be performed using a local, CLIA certified blood test. If local test is done (other than Myriad BRACAnalysisCDx post 2016), an additional sample will 
need to be sent for central testing to MYRIAD genetics. Patients must also consent to a blood sample for central genomic assessment using the BRACAnalysisCDx test by 
Myriad Genetics, except for patients who already have evidence of BRCA1/2 mutation by MYRIAD BRCAnalysisCDx post 2016. Blood samples for central BRCA status: 
collect two 10 mL samples of blood into appropriately labeled tubes at screening; send to Myriad Genetics for analysis.  See, Central Laboratory Manual and sample 
collection instructions contained in the provided kit. If positive gBRCA1/2 status has been confirmed by local test, patients may enroll and commence study treatment, 
provided all other inclusion/exclusion criteria are met and screening tests have been satisfactorily completed. In the event of discrepant results, where the local test is positive 
for gBRCA1/2 mutation and the central Myriad BRACAnalysis test is negative, the decision on further continuation on trial will be decided by the investigator and discussed 
with the sponsor based on a risk-benefit evaluation.


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1. INTRODUCTION
Talazoparib (also known as PF-06944076, MDV3800, BMN 673) is being investigated for 
the treatment of patients with gBRCA-positive, HER2 negative breast cancer.  A 
comprehensive review of talazoparib may be found in the single reference safety document 
(SRSD), which for this study is the Investigator’s Brochure (IB), provided by Pfizer and 
published August 2018.  Investigators are to review this document prior to initiating this 
study.
1.1. Mechanism of Action/Indication
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development 
for the treatment of a variety of human cancers.  PARP inhibitors, including talazoparib, 
exert cytotoxic effects via 2 mechanisms: (1) inhibition of PARP1 and PARP2 catalytic 
activity, and (2) PARP trapping, a process in which PARP protein bound to a PARP inhibitor 
does not readily dissociate from DNA (deoxyribonucleic acid), thereby preventing repair, 
replication, and transcription.25
Figure 2.
Dual Cytotoxic Mechanisms of PARP Inhibitors
Source: Adapted from Reference.25
PARP = poly (adenosine diphosphate-ribose) polymerase; DNA= deoxyribose nucleic acid; hR=homologous 
recombination.
Inhibition of PARP catalytic activity (upper pathway) interferes with the repair of single-strand breaks, 
leading to replication fork damage that requires homologous recombination DNA repair for cell survival.  
Trapping of PARP–DNA complexes with PARP inhibitor (lower pathway; PARP inhibitor represented by) 
also leads to replication fork damage with more DNA repair processes required for cell survival.  
Single agent talazoparib treatment has demonstrated potent antitumor effects in tissue culture 
studies, mouse tumor xenograft models, and in Phase 1 studies in patients with solid tumors.  
Talazoparib has also been shown to enhance the cytotoxic effects of DNA damaging 
chemotherapy,18,19 including temozolomide and irinotecan, in both in vitro and in vivo 
preclinical models.  


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The main nonclinical toxicology findings with talazoparib were early hematologic changes 
and subsequent bone marrow and lymphoid organ depletion; focal atrophy and degeneration 
of the testes, epididymis, and seminiferous tubules; and dose-dependent apoptosis/necrosis in 
the gastrointestinal (GI) tract, ovarian follicular atresia, and liver after repeat-dose 
administration of talazoparib.  These findings are consistent with the exaggerated 
pharmacology of talazoparib and its tissue exposure pattern.  The hetamaologic and male 
reproductive organ findings occurred at sub-therapeutic exposure whereas the GI, ovarian 
and liver-related changes occurred at higher therapeutic exposure margins.  The hematologic 
findings were generally reversible and the early hematologic changes represent sensitive and 
early markers of target organ toxicity.  Talazoparib is clastogenic in genetic toxicology 
evaluations.  Talazoparib caused fetal malformations, structural variations and death of 
fetuses in an embryo-fetal development study in rats, in line with its clastogenic profile.
Talazoparib is being investigated for the neoadjuvant treatment of early HER2 negative, 
gBRCA1/2 mutation positive breast cancers.  Talazoparib has previously been investigated in 
both a Phase 2 study (673-201; ABRAZO) and in a Phase 3 study (673-301; 
C3441009; EMBRACA) involving gBRCA mutation patients with locally advanced and/or 
metastatic breast cancer compared with physician’s choice of capecitabine, eribulin, 
gemcitabine, or vinorelbine.
1.2. Background and Rationale
1.2.1. Breast Cancer
Breast cancer is the second leading cause of cancer-related death in women, despite 
improvements in screening and treatment regimens.  The American Cancer Society estimates 
that in 2017, approximately 2470 men and 252,710 women will be diagnosed with breast 
cancer, and approximately 460 men and 40,610 women will die due to the disease.26
1.2.2. Triple Negative and Germline Breast Cancer Susceptibility Gene 1 or 2 Positive 
Breast Cancer
Twelve to twenty percent of breast cancers are categorized as triple-negative.  TNBC is 
defined by the lack of protein expression of both estrogen receptor (ER) and progesterone 
receptor (PR), combined with an absence of HER2 receptor over-expression.27  Six different 
molecular subtypes of breast carcinoma have been identified.  Basal-like breast cancer is 
defined by the molecular phenotype of the tumor, as measured by complementary DNA 
(cDNA) microarrays; approximately 75% of TNBCs are basal-like.28  The basal-like subtype 
is associated with a BRCA mutation in 11-42% of cases.29
Breast cancer is a biologically diverse and genetically heterogeneous disease.1,2  Breast 
cancer susceptibility gene 1(BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are 
key components in the repair pathway for DNA double strand breaks (Campeau et al, 2008),3
and mutations in these genes account for 20% to 25% of hereditary breast cancers and 5% of 
all breast cancers.4 A substantial portion of patients with gBRCA mutated breast cancer have 
hormone receptor-positive disease, including 20-30% of gBRCA1 carriers and 45-72% of 
gBRCA2 carriers.5  In the United States, women in the general population have a 
12% lifetime-risk of developing breast cancer.30 In contrast, 55% to 65% of women who 


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inherit a BRCA1 mutation and approximately 45% of women who inherit a BRCA2 mutation 
will develop breast cancer by age 70.31,32
Prognosis and best treatment practices in patients with breast cancer with germline BRCA1 
or BRCA2 mutations have largely been characterized in retrospective studies from single 
institutions.33 When compared to sporadic primary breast cancer, BRCA1 disease is more 
likely to be hormone receptor negative and BRCA2 disease is more likely to be hormone 
receptor positive.33,34 BRCA1 and BRCA2 breast cancers have been reported to be higher 
grade and higher stage and to have more extensive and extracapsular lymph node 
involvement compared to non-BRCA cancers.33,35 Well-known prognostic and predictive 
factors for breast cancer include HR and HER2 expression.36  ER negative, progesterone 
receptor negative, HER2 negative tumors, known as HER2 negative breast cancer, have a 
poor prognosis.  Metastatic TNBC has the worst prognosis of all breast cancer subtypes, with 
a median PFS of 3 to 5 months and a median overall survival of <12 months.37-40  
BRCA mutations can be present regardless of HR and HER2 status.  Women who have 
BRCA1 mutations are more likely to develop TNBC than those who have BRCA2 
mutations.41  The choice of treatment is informed by the tumor receptor status at the time of 
initiation as tumor characteristics can evolve over time.  Investigational treatments based on 
the BRCA mutation status are being explored.  The FDA granted approval to the PARP 
inhibitor olaparib for the treatment of germline BRCA mutated, HER2 negative metastatic 
breast cancer in January 2018.
TNBC is a current focus due to poor prognosis and limited treatment options.  In comparing 
the low dose cyclophosphamide, doxorubicin, fluorouracil (CAF) regimen from 
CALGB8541 to the dose dense regimen of doxorubicin, cyclophosphamide followed by 
paclitaxel (AC-T) in CALGB974110, the relative reduction in risk of recurrence was 55% for 
ER negative tumors, and 26% in ER positive tumors.  The absolute improvement in risk of 
recurrence at 5 years was 22.8% for ER negative tumors and only 7% for ER positive 
patients treated with tamoxifen.  However, the rate of recurrence remains high, with poor OS 
rates.  Thus, a significant unmet medical need remains for new therapeutic options for 
women with TNBC.  These patients, due to the loss of ER, PR, and HER2 target receptors, 
do not respond well to hormonal or trastuzumab-based therapy; traditionally, the options 
have been surgery or chemotherapy, individually or in combination. Retrospective 
neoadjuvant subject series have suggested that primary breast cancer in BRCA1 carriers is 
platinum-sensitive and relatively unresponsive to anthracyclines and/or taxanes9 while other 
studies have found that BRCA1 is relatively responsive to anthracyclines and/or taxanes 
while BRCA2 disease is less responsive than sporadic primary breast cancer to these drug 
classes.10
1.2.3. Neoadjuvant Therapy For Breast Cancer
Neoadjuvant therapy was traditionally used for inoperable cancers; however, in recent years 
there has been a paradigm shift, and neoadjuvant therapy is used more frequently in early 
breast cancer (EBC).  Large studies have demonstrated comparable response rates when 
compared with adjuvant systemic therapy.42  


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Neoadjuvant therapy offers a number of benefits, including down-staging of tumors to allow 
for breast conserving surgery (BCS) and rapid assessment of response to therapy.  This could 
potentially expedite development and treatments for EBC.
1.2.4. Neoadjuvant Therapy For Triple Negative And Germline Breast Cancer 
Susceptibility Gene Positive Breast Cancer
Neoadjuvant therapy with platinum agents has yielded promising results.  A Phase 2 study 
conducted by Garber et al.43 evaluated cisplatin given as a single agent for four cycles to 
TNBC patients with stage 3 or 4 progression.  The overall pCR was 22%.  Seven percent of 
the women in the study were BRCA1 carriers; all achieved a pCR.  There is consistent 
evidence to show that 10 to 20% of patients with TNBC who would not experience pCR 
following a taxane/anthracycline treatment regimen, will achieve pCR when platinum is 
added to the regimen.
The Geparsixto (NCT01426880) and CALBG (NCT00632853) trials were 2 randomized 
studies assessing the addition of platinum-based chemotherapy (CT) to neoadjuvant regimens 
in a TNBC patient population (n=400 to 600).  Treatment regimens included taxol and doxil 
+ platinum weekly in the Geparsixto trial, and taxol + carboplatinum 3 weekly followed by 
dose sense anthracyclines in the CALBG trial.  pCR rates were 53% vs. 37% and 54% vs. 
41% in TNBC.  The pCR rate in the gBRCA subset of the Geparsixto trial was 61.7% vs. 
50%.  However, since increased rates of toxicity were observed as carboplatinum was added 
to standard chemotherapy regimens, it is not a single agent option.
1.2.5. Neoadjuvant Therapy for ER Positive Germline Breast Cancer Susceptibility 
Gene Positive Breast Cancer
A substantial portion of patients with gBRCA mutated breast cancer have hormone 
receptor-positive disease, including 22% of gBRCA1 carriers and 77% of gBRCA2 carriers.5
There is an unmet need for more effective therapies for gBRCA mutated hormone receptor
positive breast cancer as such patients are considered to have a higher risk for recurrence 
than patients without gBRCA mutations as follows: Hormone receptor positive breast cancer 
is frequently characterized by a higher grade in gBRCA2 carriers than in noncarriers.5

The rate of high recurrence score (RS) Oncotype Diagnostics (DX; Genomic Health, 
http://www.oncotypedx.com/ recurrence score) was approximately 3-fold higher in 
patients with gBRCA mutated estrogen receptor positive tumors compared with the 
general breast cancer population.  This suggests that hormone positive breast cancer 
in BRCA carriers may differ molecularly from that in noncarriers.5
PARP inhibitors have demonstrated a clinical benefit in gBRCA mutated hormone receptor-
positive breast cancer in both early and advanced settings.44-46 After 6 months of 
neoadjuvant talazoparib monotherapy in neoadjuvant talazoparib expansion Study 
NCI02282345, patients with gBRCA mutated hormone receptor positive breast cancer had a 
pCR rate of 3/5 (60%) and a combined RCB 0+1 rate of 4/5 (80%).22 Although based on a 
limited sample size, this promising pCR rate is substantially higher than that reported for 


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patients with hormone receptor positive early breast cancer who received chemotherapy44-46
and is similar to the pCR rates obtained by adding PARP inhibitors or carboplatin to 
conventional chemotherapy for the treatment of patients with early TNBC.44-46  These results 
suggest talazoparib monotherapy may benefit the gBRCA mutated hormone receptor positive 
subgroup of patients with early breast cancer as well.
The clinical benefit of neoadjuvant PARP inhibitors seen in the small groups of patients with 
hormone receptor positive tumors in studies of gBRCA mutated early breast cancer is 
supported by the demonstrated clinical benefit in larger groups of patients in advanced 
settings.46,21
Data from the Phase 3 EMBRACA study and Phase 2 ABRAZO study demonstrated the 
benefit of talazoparib monotherapy in gBRCA mutated, hormone receptor positive HER2 
negative advanced breast cancer.  

EMBRACA: Patients with hormone receptor positive advanced breast cancer 
comprised approximately 60% of the randomized patients.  In the prespecified 
subgroup analyses of the primary PFS endpoint, the hormone receptor positive 
subgroup had a hazard ratio of 0.47 (95% CI: 0.32, 0.71), and the TNBC subgroup 
had an HR of 0.60 (95% CI: 0.41, 0.81). A significant improvement in ORR was also
observed in both subgroups.  For the hormone receptor positive subgroup, ORR was 
63.2% in the talazoparib arm versus 37.9% in the PCT arm, with an odds ratio of 
2.89 (95% CI: 1.43, 4.83) p=0.0012).  For TNBC, ORR was 61.8% in the talazoparib 
arm versus 12.5% in the PCT arm with an odds ratio of 11.89 (95% CI: 4.54, 41.37; 
p<0.0001). 

ABRAZO: For patients with hormone receptor positive advanced breast cancer, ORR 
was 26.3% (5/19 patients) in Cohort 1 (platinum pretreated patients) and 31% 
(9/29 patients) in Cohort 2 (patients with 3 or more prior non-platinum-containing 
cytotoxic regimens).  For patients with TNBC, the ORR was 17.2% (5/29 patients) in 
Cohort 1 and 66.7% in Cohort 2 (4/6 patients).
The gBRCA mutational status appears to be a stronger biomarker of efficacy for talazoparib 
than hormone-receptor status based on the consistency of the treatment effect between 
patients with hormone receptor positive breast cancer and those with TNBC in EMBRACA 
and ABRAZO.  Deleterious gBRCA mutations cause DNA damage repair deficiencies, 
making cells vulnerable to targeted therapy with PARP inhibitors, regardless of disease stage.  
1.2.6. Pathological Complete Response as an Endpoint in Neoadjuvant Trials
Von Minckwitz45 conducted a pooled analysis of 12 international neoadjuvant breast cancer 
trials.  One of the key objectives was to determine the association between pCR and 
long-term outcome in terms of EFS and OS.  In the TNBC patients, there was a 
76% reduction in events and an 84% reduction in mortality when patients achieved a pCR, 
further supporting pCR as an endpoint for TNBC.  The impact of molecular subtype on the 
pCR shows that more aggressive types of cancers, ie, TNBCs, achieve a higher percentage of 
pCR than HER positive breast cancers.  Perjeta (pertuzumab, NCT01855828), first approved 


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in 2012, utilized pCR as a primary endpoint.  Neoadjuvant pertuzumab and trastuzamab, 
administered concomitantly with weekly paclitaxel and followed by 
5-fluorouracil/epirubicin/cyclophosphamide, resulted in a 78% pCR rate in ER 
negative/HER2 positive cancers (the pCR rate was substantially lower in ER positive
cancers).  This pCR rate is among the highest reported in the literature.49
The FDA Guidance Document ‘Pathological Complete Response in Neoadjuvant Treatment 
of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated 
Approval’ published in October 201450 supports the use of pCR as an endpoint in the 
neoadjuvant setting.  Per the Guidance, pCR is defined as:
1. The absence of residual invasive cancer in the breast and axillary lymph nodes on 
hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(ie, ypT0/Tis ypN0 in the current AJCC staging system); or 
2. The absence of residual invasive and in situ cancer on hematoxylin and eosin 
evaluation of the complete resected breast specimen and all sampled regional lymph 
nodes following completion of neoadjuvant systemic therapy (ie, ypT0 ypN0) in the 
current AJCC staging system).
1.2.7. Poly(ADP Ribose) Polymerase Inhibition
PARP1 and PARP2 play important roles in DNA repair.51,52 Following DNA damage, 
PARP1 and PARP2 bind to single-stranded DNA breaks, cleave nicotinamide adenine 
dinucleotide, and attach multiple ADP-ribose units to the target protein, including itself.53-56
The outcome is a highly negatively charged protein, which leads to the unwinding of the 
DNA strands and recruitment of proteins to repair the damaged DNA through the 
base-excision repair process.  When PARP1 and PARP2 are inhibited, single-strand DNA 
breaks persist, resulting in stalled replication forks and conversion of single-strand breaks 
into double-strand breaks.  These breaks must be repaired by homologous recombination or 
non-homologous end joining or they may become lethal.  Thus, inhibition of PARP catalytic 
activity results in synthetic lethality as defects in homologous recombination DNA repair 
prevent double strand breaks from being repaired, thereby killing the cell, including cancer 
cells.  
In addition, PARP inhibitors bind to PARP-DNA complexes (ie, become trapped), thereby 
inhibiting DNA repair, replication, and transcription, which may also be cytotoxic to cancer 
cells. Although other PARP inhibitors possess both activities, in vitro studies demonstrated 
that talazoparib is a more potent PARP trapper than other PARP inhibitors in clinical 
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1.2.8. Poly (ADP Ribose) Polymerase Inhibitors as a Potential Targeted Therapeutic in 
Triple Negative Breast Cancer with Germline Breast Cancer Susceptibility Gene 
Mutations
There is mounting evidence that germline BRCA1/2 breast cancers, besides having increased 
sensitivity to platinum agents, are also sensitive to PARP inhibitors. 
In a phase 1 trial, the PARP inhibitor olaparib (NCT00516373; 10 to 600 mg twice a day) 
treatment of solid tumors of patients with breast cancer with no gBRCA mutations vs. those 
patients with gBRCA mutations, resulted in an objective response rate (ORR) of 15% and 
33%, respectively.1  Tutt et al,15 in a phase 2 trial (NCT00494234) of single agent olaparib in 
patients with breast cancer with BRCA1/2 mutation and advanced disease, investigated two 
dose levels (cohort 1: 400 mg twice daily [bd] and cohort 2: 100 mg bd) and demonstrated an 
ORR of 42% and 25%, respectively.  Progression free survival (PFS) was 5.7 and 3.8 months 
for Cohorts 1 and 2, respectively.  A phase I study of niraparib (NCT00749502; 30 400 mg 
once a day) for treatment of solid tumors resulted in an ORR of 40% in patients with breast 
cancer with gBRCA mutations vs. 18% in the general breast cancer population.16 Lastly, a 
first in human trial of oral talazoparib (NCT01286987; 25 1100 ug/day) resulted in an ORR 
of 65% and 33% in solid tumors of gBRCA patients with ovarian cancer or breast cancer, 
respectively.17
Olaparib, which was approved by the FDA in 2014 for patients with advanced ovarian cancer 
with gBRCA mutations, was also assessed during a Phase 3 study (OlympiAD) in metastatic 
gBRCA mutated breast cancer.  This trial included patients with HER2 negative, metastatic 
breast cancer that were either HR positive or triple negative; a subgroup of the patient 
population (approximately 50%) were defined as TNBC.  In the OlympiAD study, 
205 patients with gBRCA mutated breast cancer were treated with olaparib (300 mg orally 
twice daily), compared to 91 patients (6 were not treated) treated with physician’s choice of 
chemotherapy (capecitabine, vinorelbine, or eribulin).  Seventy-one percent had been 
previously treated with anthracycline and a taxane in either an adjuvant or metastatic setting.  
Eligible patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1; 
gBRCA1/2 mutations; and histologically or cytologically confirmed breast cancer with 
evidence of metastatic disease.  Prior exposure to platinum was allowed, as long as no breast 
cancer progression occurred on treatment or if given in an adjuvant or neoadjuvant setting at 
least 12 months before study commencement (28%).  The hazard ratio for PFS was 
0.58 (95% CI; range 0.43 to 0.80; p<0.001; median of 7 months in the olaparib group vs. 
4.2 months in the chemotherapy group).  The objective response rate was 59.9% in the 
olaparib arm vs. 28.8% in the treatment of physician’s choice (TPC) arm.  Grade 3 adverse 
events (AEs) occurred in 36.6% and 50.5% of the olaparib and TPC arms, respectively.  
Mean change from baseline in global health-related quality of life (HRQoL, 
EORTC-QLQ-C30) across all timepoints favored olaparib (difference vs TPC 7.5; 95% CI 
2.48, 12.44; p=0.0035).59  In summary, olaparib provided significant benefit over standard 
therapy among patients with gBRCA muatated breast cancer.
The data for talazoparib in TNBC patients with gBRCA positive mutations are detailed in 
Section 1.3.1.


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1.3. Summary of Relevant Clinical Experience with Talazoparib
Talazoparib is a potent and specific inhibitor of PARP1 and PARP2 that play important roles 
in DNA repair.60,61  PARP inhibitors exert cytotoxic effects by 2 mechanisms: inhibition of 
PARP catalytic activity and PARP trapping.  Inhibition of PARP catalytic activity results in 
persistent single strand DNA breaks that require homologous recombination mediated DNA 
repair for survival.  PARP trapping prevents a talazoparib bound PARP protein complex 
from readily dissociating from DNA, thereby inhibiting DNA repair, replication, and 
transcription, resulting in double strand DNA breaks and consequent cytotoxicity.62 PARP
inhibitors induce synthetic lethality in tumor cells that bear mutations and/or deletions in 
genes involved in homologous recombination or other DNA repair pathways.  In BRCA1 and 
BRCA2 deficient cells, treatment with a PARP inhibitor results in cell cycle arrest and 
apoptosis.63
Talazoparib is more potent at inducing single agent synthetic lethality of BRCA1 and 
BRCA2 deficient tumor cells in vitro than any other PARP inhibitors reported to date.64  
Talazoparib inhibited growth of MX 1 human breast cancer cells (BRCA1 deficient) and 
Capan 1 pancreatic cancer cells (BRCA2 deficient), with 50% inhibitory concentration 
(IC50) values of 0.3 nM and 5.0 nM, respectively.65  The talazoparib IC50 for growth 
inhibition of Capan 1 cells was 50 to >2000 fold lower than the other PARP inhibitors tested.  
This superior cytotoxicity profile is potentially linked to the robust PARP trapping activity of 
talazoparib.  Consistent with its cytotoxic effects in tissue culture studies, talazoparib 
demonstrated antitumor activity in xenograft tumor models.  Talazoparib administered at 
0.33 mg/kg/day inhibited the growth of BRCA1 mutant MX 1 breast cancer xenografts in 
mice, while the same model proved refractory to olaparib administered at 100 mg/kg/day.  
These in vitro and in vivo activities suggest that talazoparib may have clinical activity in 
patients with BRCA mutated breast cancer.
As of 30 Nov 2017, (the cutoff date for the most recent Development Safety Update 
Report),66 approximately 798 patients have received talazoparib in company sponsored 
studies in hematologic malignancies and solid tumors.  Studies in solid tumors include a 
Phase 1 study (PRP-001) in advanced or recurrent solid tumors, a Phase 1 study in advanced 
malignancies (PRP-002), a Phase 2 study (673-201, C3441008, ABRAZO) in locally 
advanced and/or metastatic patients with breast cancer with a germline BRCA defect, a 
Phase 3 study (673-301, EMBRACA) in locally advanced or metastatic breast cancer with a 
germline BRCA defect, a Phase 1 hepatic impairment study (MDV3800-02), a Phase 1 
absorption, distribution, metabolism and excretion (ADME) study (MDV3800-03), a Phase 1 
study on cardiac re-polarization (MDV3800-14), a Phase 1 renal impairment study 
(NCT02997163), and a Phase 2 response rate study in men with DNA repair defects and 
metastatic castration-resistant prostate cancer (TALAPRO-1).
In Study PRP-001, a Phase 1, first-in-human, single-arm, open-label dose-escalation study of 
once daily talazoparib (BMN 673) in patients with advanced or recurrent solid tumors with 
DNA repair deficiencies, a total of 110 patients were treated with talazoparib at doses 
ranging from 0.025 to 1.1 mg/day.  During the dose-escalation phase of the study, 2 of the 
6 patients enrolled in the talazoparib 1.1 mg/day dose level experienced a dose-limiting 
toxicity: one was Grade 4 thrombocytopenia, the other was Grade 3 thrombocytopenia 


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requiring >5 days off study treatment.  Therefore, 1 mg/day was considered the maximum 
tolerated dose and recommended Phase 2 dose.  Between the dose-escalation and 
dose-expansion portions of the study, a total of 77 patients were treated with talazoparib at 
the 1 mg/day dose level in Study PRP-001 which was generally well tolerated and warranted 
further evaluation in patients with solid tumors with DNA repair deficiencies.  As a result, 
talazoparib has been dosed at 1 mg/day in subsequent studies in patients with solid tumors, 
including the breast cancer studies ABRAZO, EMBRACA, and currently ongoing 
investigator-initiated research.
The first indication for talazoparib is expected to be in patients with deleterious germline 
BRCA1 or BRCA2 mutations and HER2 negative locally advanced and/or metastatic breast 
cancer, pending results of study (673-301, EMBRACA).  Studies include a phase 1 study 
(PRP-001) in advanced or recurrent solid tumors, a study (PRP-002) in patients with 
hematologic malignancies, a Phase 2 study (673-201, ABRAZO) in locally advanced and/or 
metastatic breast cancer, and a Phase 3 study (673-301, EMBRACA) in locally advanced 
and/or metastatic breast cancer.  Results from company-sponsored studies are summarized in 
the following sections.
1.3.1. Efficacy
A phase 1 clinical study supports the efficacy of talazoparib at 1 mg/day. 
PRP-001 is a phase 1, open-label, safety, pharmacokinetics, and dose-escalation 
(0.025-1.1 mg/day) and expansion (1 mg/day) study of talazoparib monotherapy 
in 110 patients with advanced or recurrent solid tumors with DNA repair deficiencies.  As of 
the data cutoff date of 31 Jan 2018, objective responses (complete response [CR] or partial 
response per revised response evaluation criteria in solid tumors (RECIST) 1.1 were 
observed in 7 of 14 patients (50%) with breast cancer and 5 of 12 patients (41.7%) with 
ovarian/primary peritoneal cancer with deleterious germline BRCA mutations; clinical 
benefit (CR, PR, or stable disease 24 weeks) was observed in 12 of 14 patients (85.7%) and 
8 of 12 patients (66.7%), respectively.  
Study 673-201 (ABRAZO) is a Phase 2, 2-stage, 2-cohort study of talazoparib in patients 
with germline BRCA mutation and locally advanced and/or metastatic breast cancer.  
ABRAZO is investigating the clinical efficacy and safety of single-agent talazoparib in 
83 heavily pre-treated gBRCA positive patients with advanced breast cancer.  The primary 
endpoint was ORR by independent radiology review.  Cohort 1 consisted of 49 patients who 
previously responded to platinum-based chemotherapy and subsequently developed disease 
progression.  A 21% ORR (95% confidence interval [CI]: 10-35) was observed in this group 
of patients.  Cohort 2 consisted of 35 patients who developed disease progression following 
at least three lines of non-platinum-based therapy.  This group of patients had a 37% ORR 
(95% CI: 22 to 55).  Safety data for talazoparib as monotherapy are available from Phase 1, 
2, and 3 studies in patients with advanced cancer.  As of 31 January 2018, the confirmed 
objective response rate (CRs and pRs) was 20.8% for cohort 1 (prior platinum treatment, 
95% confidence interval: 10.47, 34.99), including 2 CRs (4.2%), and 37.1% for Cohort 2 
(3+L, non-prior platinum treatment, 95% CI: 21.47, 55.08) per independent central radiology 
assessment.  The objective response rate across both cohorts was 27.7% (95% CI: 18.45, 


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38.62), demonstrating clinically meaningful responses in this population with a poor 
prognosis and a high unmet medical need.  TNBC/HR positive incidence in Cohorts 1 and 
2 was 59%/41% and 17%/83%, respectively; while ORR by IRF for TNBC/HR positive was 
26%/29%, respectively.47
Aggregate safety data from 502 patients treated with open-label 1 mg/day talazoparib 
monotherapy (PRP-001, 673-201, 673-301, MDV3800-13, and MDV3800-14); data as of 
31 January 2018) provide the basis for the most common treatment emergent AEs in patients 
with solid tumors.  The most common AEs associated with talazoparib (>20%) were 
myelosuppression (anemia, neutropenia), gastrointestinal toxicity (nausea, diarrhea, 
vomiting, constipation), fatigue, alopecia, headache, and decreased appetite.  The most 
common (>5%) Grade 3 or 4 AEs and SAEs were associated with myelosuppression.  A total 
of 23 of 502 patients had a AE that led to death (8 associated with malignancies [1 pancreatic 
carcinoma patient; the other 7 malignancies were due to disease progression: 3 ovarian 
cancer patients, 2 breast cancer patients, and 1 metastatic breast cancer patient with 
bronchopneumonia]; 2 dyspnea; 2 general physical health deterioration; 3 disease 
progression; and 1 each lung infection, cerebral hemmorage, cerebrovascular incident, 
fatigue, liver disorder, neurological symptoms, respiratory failure, and veno-occlusive liver 
disease).  Of these, only the latter (reported in one patient in study 673-301) was assessed as 
related to study drug by the investigator.  The permanent discontinuation rate was relatively 
low (20 of 502 patients, 4%) due to AEs of anemia, increased ALT and accidental overdose,
increased AST, bradycardia, metastatic breast cancer, cerebral hemorrage, dyspnea, 
glioblastoma multiforme, headache, metastases to meninges, muscular weakness, 
neutropenia, obstructive airways disorder, thrombocytopenia, transient ischemic attack, and 
vomiting.  
Another study in the advanced breast cancer setting conducted by Litton et al. was recently 
published in the New England Journal of Medicine.21,22  This study (EMBRACA, 
NCT01945775) was a randomized, open-label, Phase 3 trial in which patients with advanced 
breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive 
talazoparib (1 mg once daily) or standard single-agent therapy of the physician’s choice 
(capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles).  The 
primary endpoint was progression-free survival.  Of the 431 patients who underwent 
randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive 
standard therapy.  Progression-free survival was significantly longer in the talazoparib group 
than in the standard-therapy group (hazard ratio for disease progression or death, 0.54; 
95% CI, 0.41 to 0.71; p<0.001; medians 8.6 months vs. 5.6 months).  The hazard ratio for 
overall survival based on interim analysis at the time of the final progression-free survival 
analysis was 0.76 (95% CI, 0.55 to 1.06; p=0.11 [57% of projected events]; medians 
22.3 months vs. 19.5 months).  The objective response rate was higher in the talazoparib 
group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 
8.8; p<0.001).  In all clinically-relevant subgroups, a consistent PFS benefit in favor of 
talazoparib was observed in comparison with physician’s choice of treatment (PCT), 
regardless of hormone receptor status (hormone receptor positive [HR positive]: hazard ratio 
0.47, 95% CI, 0.32 to 0.70; or TNBC: hazard ratio 0.60, 95% CI, 0.41 to 0.87) BRCA 
mutation subtype, history of central nervous sytem (CNS) metastasis, visceral/non-visceral 


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disease, or number of prior cytotoxic chemotherapies for advanced disease.  Complete 
response was seen in 5.5% of patients with talazoparib therapy vs zero patients receiving 
PCT, and partial response was seen in 57.1% vs 27.2%, respectively.  In an exploratory 
analysis, time to end of first post-study therapy was longer with talazoparib (hazard ratio 
0.68; 95% CI; 0.51 to 0.91).
In terms of hematologic toxicities, 8 of 20 (40%) patients had Grade 3 anemia.  There were 
no patients with Grade 4 anemia.  There was one case of Grade 4 thrombocytopenia.  
Neutropenia occurred in 4 patients at Grade 2 (20%) and Grade 3 in 3 (15%) patients. 
Talazoparib was generally well tolerated, and few adverse events (excluding progressive 
disease) led to permanent treatment discontinuation (5.9% in talazoparib arm vs 8.7% in 
PCT).  Most non-hematologic toxicities were lower-grade, and the more common 
hematologic toxicities were managed by dose interruption or dose reduction and supportive 
care as needed.  
An investigator-initiated research (IIR) study at MD Anderson Cancer Center titled 
“Neoadjuvant Talazoparib for Patients With a BRCA Deleterious Mutation” explored the 
feasibility of neoadjuvant talazoparib in a two part study (NCT02282345).  Part 1, which 
evaluated a lead-in of 2 months of talazoparib single agent followed by standard 
chemotherapy and surgery, is complete and was accepted for publication in NPJ Breast 
Cancer.23  Decreases in tumor volume (as assessed by the Investigator) occurred in 13 out of 
13 patients following 2 months of talazoparib monotherapy (1 mg).  The median tumor 
volume decrease after 2 months of treatment with talazoparib was 88% (range of 30-98%).  
Notably, all TNBC patients achieved either RCB-0 or RCB-1 following completion of the 
protocol assigned therapy and surgery.  In this pilot study, talazoparib was well tolerated with 
no Grade 4 or 5 toxicities observed, and only one patient required dose reduction due to 
Grade 3 neutropenia.  Following these data on efficacy and tolerability, Part 2 of the study 
was opened and evaluated 24 weeks of talazoparib monotherapy followed by surgery with no 
additional chemotherapy.  This part of the study enrolled 20 patients total who received 
talazoparib monotherapy for 6 months followed by surgery and assessment of pCR.  All 
patients were BRCA positive and the majority was stage 2 or 3; most patients had triple 
negative breast cancer.  pCR to single agent talazoparib were 10/19 = 53%, 
(95% CI = 32%, 73%).  Residual Cancer Burden was also evaluated: RCB 0 (no RCB) + 
RCB 1 (minimal residual disease) was 12/19 = 63%, 95% CI = 41%, 81%.  TNBC/HR
positive incidence in Cohorts 1 and 2 was 59%/41% and 17%/83%, respectively; while ORR 
by IRF for TNBC/HR positive was 26%/29%, respectively.54  There were 14 patients in the 
TNBC cohort.  Of those patients, 7 (50%) patients had RCB-0, 1 (7.4%) patient had RCB-1, 
4 (28.5%) patients had RCB- 2 and 2 (14.2%) patients had RCB-3.  Of note, pCR occurred in 
both metaplastic carcinoma and lobular carcinoma.  Talazoparib was well tolerated with 
acceptable adherence and manageable toxicities.
For non-hematologic toxicities, most were Grade 1 and 2. The most common toxicities 
occurring in >50% of patients were nausea, fatigue, and alopecia. Nineteen (19) of 
20 patients completed 6 months of therapy; one patient completed 5 months and then 
received chemotherapy prior to surgery.  Two patients had dose reductions to 0.75 mg, 


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6 patients reduced to 0.5 mg, and one patient had a dose reduction to 0.25 mg.  All dose 
reductions were due to hematologic toxicities.
The findings from this study demonstrate promising efficacy for talazoparib in the 
neo-adjuvant gBRCA positive early breast cancer setting.  Talazoparib is the first single 
targeted therapy to achieve pCR in BRCA positive patients, including TNBC.  This study 
warrants the larger confirmatory trial (C3441020).
1.3.2. Pharmacokinetics and Metabolism
The PK of talazoparib as a single agent was evaluated in 142 adult patients with cancer, 
including 109 patients with solid tumors (PRP-001) and 33 with hematologic malignancies 
(PRP-002).  Doses of 0.025 mg to 2 mg were administered orally as a single dose or as 
once-daily doses.  This dose range bracketed the 1 mg/day dose used in ongoing safety and 
efficacy studies and provided a framework for assessing dose linearity.  As the PK of 
talazoparib was similar in patients with solid tumors and hematologic malignancies, and no 
differences were apparent between males and females, the results are summarized 
collectively.  
Oral absorption of talazoparib was rapid and independent of dose after administration of 
single or once-daily doses.  Peak talazoparib concentrations were generally reached 
approximately 1 to 8 hours post-dose.  Exposure increased approximately 
dose-proportionally with increasing doses.  At 1 mg/day, the mean half-life was 
approximately 2 days; the mean apparent volume of distribution (V/F) was 415 L, which may 
suggest extensive extravascular distribution.  Steady state was reached in approximately 2 to 
3 weeks with daily administration.  
Apparent oral clearance (CL/F) of talazoparib appeared to be dose linear, with a mean CL/F 
across doses of approximately 5 liters per hour (L/h).  Renal excretion was a major 
elimination pathway for unchanged parent talazoparib.  Following oral administration, 
44% to 90.6% of the dose was recovered in urine as unchanged parent drug over 24 hours at 
steady state for doses up to 1 mg/day.  Mean renal clearance ranged from 1.38 L/h to 
4.96 L/h independent of dose, suggesting linear urinary elimination kinetics.  
A preliminary population PK analysis using data from patients in studies PRP-001 and 
PRP-002 assessed the effects of renal function on the PK of talazoparib.  The talazoparib 
CL/F in patients with mild renal impairment (creatinine clearance [CLCR] 60-89 mL/min) 
was similar compared with patients with normal renal function (CLCR 90 mL/min). In 
patients with moderate renal impairment (CLCR 30-59 mL/min), the talazoparib CL/F was 
decreased by 44% from normal, resulting in higher talazoparib exposure.  
Talazoparib does not induce or inhibit cytochrome P450 (CYP) enzymes or transporters and 
is therefore unlikely to demonstrate drug drug interaction liabilities.  However, talazoparib is 
a substrate for P-gp and breast cancer resistance protein (BCRP).  In a clinical drug drug 
interaction study, coadministration of talazoparib with a strong P gp and BCRP inhibitor 
(itraconazole) resulted in a 50% increase in talazoparib exposure (AUC24), while 
coadministration of talazoparib with an inducer (rifampin) caused no change in exposure.  


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Talazoparib is eliminated via renal excretion with minimal metabolism.  Talazoparib does 
not cross the blood brain barrier, so neuropsychiatric adverse events are not expected.
Talazoparib is not mutagenic, but similar to other PARP inhibitors, is clastogenic in vitro in 
peripheral blood lymphocytes and in vivo in a rat bone marrow micronucleus assay.  The 
inhibition of the PARP catalytic activity is potentially linked to the clastogenic activity of 
talazoparib.  In line with its clastogenic property, talazoparib caused fetal malformations, 
structural variations, and death in an embryo fetal development study in rats.
The main nonclinical toxicology findings at subtherapeutic exposures of talazoparib were 
hematologic changes including pancytopenia, bone marrow hypocellularity, and lymphoid 
depletion.  Findings in reproductive organs were focal atrophy and degenerative changes in 
the testes, epididymis, and seminiferous tubules.  Additional changes included dose 
dependent apoptosis/necrosis in the gastrointestinal (GI) tract, ovarian follicular atresia, and 
liver after repeat dose administration of talazoparib.  The findings in the ovary were observed 
at greater than 5-fold clinical margin.  These findings are consistent with the exaggerated 
pharmacology of talazoparib and its tissue exposure pattern.  The hematologic findings were 
generally reversible and the early hematologic changes represent sensitive and early markers 
of target organ toxicity.  
1.3.3. Rationale for Talazoparib Dose
The doses of talazoparib in this protocol are supported by nonclinical studies and phase 1 
studies in patients with advanced malignancies.  Antitumor activity has been observed and 
warrants further exploration in a larger patient population.  The expected adverse events with 
talazoparib include myelosuppression, gastrointestinal toxicity, and fatigue. Hepatotoxicity, 
febrile neutropenia, and neutropenic sepsis are potential risks per the investigator brochure, 
Section 7.  The activity of talazoparib as monotherapy and in combination with other agents 
is being evaluated in multiple indications.
Talazoparib has demonstrated efficacy at a dose of 1 mg/day.  Talazoparib 1 mg/day orally 
will be administered until completion of protocol assigned therapy, unacceptable toxicity, 
withdrawal of consent, or death.  For patients with moderate renal impairment (estimated 
glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2) at screening, the starting dose will 
be 0.75 mg/day. The dose of 1 mg /day has been established as the recommended dose for 
adults with solid tumors in study PRP-001 (NCT01286987).  Subsequently this dose has been 
used as the starting dose in studies 673-201 (ABRAZO), MDV3800-14, and 
673-301 (EMBRACA) with a total number of approximately 403 patients having received 
talazoparib at 1 mg/ day.
1.4. Rationale for Study
Approximately 15% of all breast cancers are triple negative.  They can be defined by the lack 
of estrogen, progesterone, and HER2 receptors.  They are more commonly associated with 
younger women, pre-menopausal women of African American race and BRCA1 mutation 
carriers.  Triple negative cancers are generally more aggressive in nature and associated with 
visceral and soft tissue disease. 


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The incidence of BRCA 1 and 2 mutations in patients with TNBC has been reported to be 
between 9.6 to 10.6%.6,7  In a study of 469 TNBC patients, gBRCA1/2 mutation prevalence 
was also shown to vary by race: Ashkenazi Jewish (50%), Caucasian (33.3%), Asian 
(28.5%), African Americans (20.4%), and Hispanic (20%).  The prevalence of genetic 
mutations also differed by age at diagnosis, with most patients <40 years (43.8 %) of age.  
Various studies have demonstrated that triple negative breast cancers are associated with a 
poorer prognosis than luminal breast cancers.  A Canadian series, including approximately 
1600 triple negative cancers conducted by Dent, R et al.8 demonstrated worse long term 
outcomes in terms of distant recurrence and death in triple negative tumors compared to 
non-triple negative tumors. 
The standard of treatment for neoadjuvant treatment is variable, but mostly focuses on the 
use of anthracycline- taxane regimens.  Other regimens used include adriamycin plus 
cyclophosphamide (AC).  Cyclophosphamide methotrexate, and fluorouracil (CMF) is 
another option which offers less toxicity, however has a longer duration of therapy. 
Platinum therapies have also shown efficacy in HER2 negative breast cancer, in particular 
germline BRCA mutant tumors as these tumors have defects in homologous recombination 
rendering them more susceptible to DNA cross linking agents such as platinums.
The Geparsixto and CALGB trials examined the efficacy of adding platinum to neoadjuvant 
regimens in triple negative breast cancer.  In GeparSixto, the pCR rates (breast/axilla) 
increased from 36.9% to 53.2% and in the BRCA subgroup an increase in pCR by 
25% (p=0.005).  The CALGB/Alliance trial showed an increase in pCR with the addition of 
carboplatin for breast/axilla (54% vs 41%; p=0.0029).
Since these studies were underpowered for long term outcome, it is difficult to assess long 
term benefit.  Therefore, the role for platinum therapy in TNBC still remains unclear and 
warrants further investigation in larger trials with examination of long term outcomes.  There 
have been studies resulting in improved disease-free survival (DFS) in patients who achieved 
pCR with platinum agents and BRCA mutation.  Frasci et al.11 reported that in TNBC 
patients treated with eight cisplatin epirubicin paclitaxel weekly cycles, 62% showed pCR in 
both breast and axilla, and the projected 5 year DFS was 90% and 56% in pCRs and non 
pCRs, respectively.  
The BRCA1 gene is expressed in several tissues, such as breast and ovarian tissue.  
Currently, more than 1600 mutations have been identified in the BRCA1 gene, and the 
majority of them promote frameshifts resulting in missense or non-functional protein.  
Women with BRCA1 mutations have an increased risk of developing breast and ovarian 
cancer, while men have a higher risk, to a lesser extent, of developing prostate cancer.12
BRCA2 does not share a high degree of sequence homology with other known genes, and the 
generated protein is comprised of regions with domains that are undefined.13  Currently, 
more than 1800 mutations have been identified in BRCA2, that include frameshift deletions, 
insertions, or nonsense mutations that lead to premature truncation of proteins. 


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It has been demonstrated that BRCA1 and BRCA2 tumor suppressor genes perform a critical 
role in the response to cellular damage through activation of specific DNA repair processes 
and play an important part in DNA repair and as transcriptional regulators.14
Inhibition of PARP catalytic activity contributes to the process of synthetic lethality defined 
as a combination of two DNA repair pathway defects which may be lethal to the cell 
resulting in single-strand breaks that require homologous recombination DNA repair for 
survival.  PARP inhibitors induce synthetic lethality in tumor cells containing mutations 
and/or deletions in genes involved in homologous replication or other DNA pathways, 
including BRCA1 and BRCA2.
Clinical trials have shown that PARPi are beneficial in the treatment of patients that are 
carriers of germline BRCA mutations.
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development 
for the treatment of a variety of human cancers.  Single agent talazoparib treatment 
demonstrates potent antitumor effects in tissue culture studies, mouse tumor xenograft 
models, and in Phase 1 studies in patients with solid tumors.  Talazoparib has also been 
shown to enhance the cytotoxic effects of DNA damaging chemotherapy.18,19
Despite advances in the understanding of the biology of gBRCA associated TNBC, treatment 
options remain limited.  PARPi, as well as platinum-based combination therapies, have 
emerged as regimens of potential interest and in particular therapy with single agent PARPi 
could present significant advantages of chemotherapy regimens through potentially improved 
tolerability. 
The PARP inhibitor olaparib, which was approved by the FDA in 2014 for patients with 
advanced ovarian cancer with gBRCA mutations was assessed during a Phase 3 study 
(OlympiAD) in metastatic gBRCA mutated breast cancer.  PFS was 7 months in the olaparib 
group vs. 4.2 months in the chemotherapy group (observed hazard ratio=0.58; 95% CI, 
0.43 to 0.80; p=0.009).  The objective response rate was 59.9% in the olaparib arm vs. 
28.8% in the chemotherapy arm.  Olaparib was determined to be effective against 
triple-negative breast cancers that arise in women with inherited, germline BRCA mutations 
(observed hazard ratio in the TNBC subgroup = 0.43).  
The Phase 2 ABRAZO study21 (NCT02034916), presented at American Society of Clinical 
Oncology (ASCO) 2017, demonstrated clinical activity of single agent talazoparib in 
advanced triple negative, germline BRCA mutant breast cancer.  Talazoparib (1 mg/day) was 
administered following platinum-based therapy (Cohort 1) or 3 platinum-free 
cytotoxic-based regimens (Cohort 2) in TNBC, gBRCA1/2 mutation patients with locally 
advanced or metastatic breast cancer.  TNBC/HR positive incidence in Cohort 1 and 
Cohort 2 was 59%/41% and 17%/83%, respectively.  ORR by IRF for BRCA1/BRCA2 was 
24%/34%, and ORR by IRF for TNBC/HR positive was 26%/29%.  Talazoparib was 
well-tolerated in both cohorts.


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 4 9
T he prese nt st u d y is a n o n -ra n d o mize d P hase 2 st u d y i n g B R C A 1/ 2 positi ve earl y H E R 2
ne gati ve breast ca ncer w hic h will e val uate t he safet y  a n d efficac y of talaz o pari b i n t he 
ne oa dj u va nt setti n g.  It will als o e val uate patie nt relate d o utc o mes 
 
i n t his patie nt p o p ulati o n.
2. S T U D Y O B J E C TI V E S A N D E N D P OI N T S
T a ble 2.
O bjecti ves a n d E n d p oi nts
Pri m ar y O bjecti ve:
Pri m ar y E n d p oi nt:

T o e val uate t he p C R t o talaz o pari b after 
c o m pleti o n of 2 4 wee ks of ne oa dj u va nt t hera p y 
f oll o we d b y s ur ger y.  p C R will be assesse d b y 
I C R.

p C R b y I C R after c o m pleti o n of 2 4 w ee ks of 
talaz o pari b f oll o we d b y s ur ger y 
p ost -ne oa dj u va nt treat me nt defi ne d as y p T 0/ Tis 
y p N 0 (t he a bse nce of resi d ual i n vasi ve ca ncer 
i n t he breast a n d t he a xillar y l y m p h n o des o n 
e val uati o n of t he c o m plete resecte d breast 
s peci me n a n d all sa m ple d re gi o nal l y m p h n o des 
f oll o wi n g c o m pleti o n of ne oa dj u va nt s yste mic 
t hera p y).
Sec o n d ar y O bjecti ve(s):
Sec o n d ar y E n d p oi nt(s):

T o e val uate p C R ( breast a n d a xilla) b y 
i n vesti gat or a n d p C R i n breast o nl y.

R C B b y I C R .

T o e val uate l o n g ter m o utc o me b y assess me nt of 
3- year E F S a n d O S.

T o e val uate t he safet y a n d t olera bilit y of 
talaz o pari b.

T o descri be t he stea d y -state P K of talaz o pari b i n 
patie nts wit h g B R C A m utati o n -p ositi ve, H E R 2 
ne gati ve breast ca ncer.

T o e val uate t he f oll o wi n g P R O:

Gl o bal healt h stat us/ Q o L, f u ncti o ni n g, 
a n d s y m pt o ms (i ncl u di n g na usea a n d 
v o m iti n g);

Misse d e x pecte d me nstr ual peri o d; t his 
o bjecti ve ca pt ures t he c o nc e pt of 
fertilit y preser vati o n t hr o u g h P R O, 
si nce t here is a p ossi ble fertilit y s pari n g 
effect of talaz o pari b vers us 

p C R b y i n vesti gat or.

p C R (i n breast) b y I C R.

R C B b y I C R.

E F S (esti mate d at 3 years).

O S (esti mate d at 3 years).

T y pe, i nci de nce, se verit y (as gra de d b y t he 
N CI -C T C A E v 4. 0 3), seri o us ness a n d 
relati o ns hi p of st u d y me dicati o ns t o a d verse 
e ve nts ( A E) a n d a n y la b orat or y a b n or malities. 

P K of talaz o pari b usi n g s parse sa m pli n g 
( Ctr o u g h at li mite d ti me p oi nts).

Ti m e t o defi niti ve deteri orati o n i n gl o bal healt h 
stat us/ Q o L per E O R T C Q L Q-C 3 0.

Ti m e t o defi niti ve deteri orati o n i n na usea a n d 
v o m iti n g s y m pt o ms per E O R T C Q L Q-C 3 0.

C ha n ge fr o m baseli ne i n gl o bal healt h 
stat us/ Q o L, f u ncti o ni n g, a n d s y m pt o ms per 
E O R T C Q L Q -C 3 0 a n d E O R T C Q L Q B R -2 3.

Pr o p orti o n of patie nts wit h deteri orati o n, 
i mpr o ve me nt a n d n o c ha n ge i n na usea a n d 
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 0
c he m ot hera p y.  
v o m iti n g s y m pt o ms.

C ha n ge i n baseli ne i n pr o p orti o n of patie nts 
wit h misse d e x pecte d me nstr ual peri o d per 
P R O -C T C A E.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. S T U D Y D E SI G N 
T his is a n o n -ra n d o mize d, o pe n-la bel, m ulti-ce nter, si n gle-ar m, p hase 2 efficac y a n d safet y 
trial of talaz o pari b as ne oa dj uva nt t hera p y i n g B R C A 1/ 2 p ositi ve earl y H E R 2 ne gati ve breast 
ca ncer.  T he trial is bei n g c o n d ucte d i n t he U S o nl y . 
A p pr o xi matel y  si xt y t otal patie nts will be e nr olle d i n t he st u d y a n d treate d wit h talaz o pari b 
1 m g Q D f or 2 4 wee ks, f oll o we d b y  s ur ger y a n d a n assess me nt f or p C R b y  ce ntral re vie w.  
T he trial will be c o nsi dere d a s uccess if t he p osteri or pr o ba bilit y  t hat t he tr ue p C R rate 
e xceeds 4 5 % is ≥8 0 %.  O nce 2 8 e val ua ble patie nts are assesse d f or p C R, if 1 1 or less 
res p o nses are o bser ve d, t he predicti ve pr o ba bilit y  of t he trial bei n g s uccessf ul at t he f ull 
sa m ple size is less t ha n 1 0 %, at w hic h p oi nt t he S p o ns or w o ul d rec o m me n d st o p pi n g t he 
st u d y d ue t o f utilit y. If ≥1 2 res p o nses are o bser ve d i n t he first 2 8 e val ua ble patie nts, t he 
st u d y will c o nti nue e nr olli n g t o 6 0 patie nts.
Patie nts will recei ve talaz o pari b 1 m g dail y f or 2 4 wee ks, f oll o we d b y breast s ur ger y , w hic h 
s h o ul d occ ur wit hi n 4 t o 6 wee ks ( n o l o n ger t ha n 6 wee ks) of t he last d ose.  If he mat ol o gical 
t o xicit y is prese nt (ie, ne utr o pe nia/t hr o m b oc yt o pe nia), t he i n vesti gat or will deci de w het her 
s ur ger y will pr ocee d acc or di n g t o sc he d ule; a was h o ut peri o d is n ot nee de d.
Eli gi ble pati e nts i ncl u de me n a n d w o me n wit h hist ol o gicall y c o nfir me d dia g n osis of earl y 
i n vasi ve H E R 2 ne gati ve a de n ocarci n o ma of t he breast wit h ger mli ne B R C A 1/ 2 m utati o ns 
w h o are s uita ble f or ne oa dj u va nt t hera p y.
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A patient will participate in up to 4 periods: screening, talazoparib treatment phase, safety 
follow-up, and long-term follow-up.  The study schematic is provided in Figure 1.  
Patients will be evaluated at screening for the presence of a deleterious, suspected 
deleterious, or pathogenic germline BRCA1 or BRCA2 mutation. Long term follow-up 
period is at least 5 years, which starts from the date of surgery for EFS and after first dose of 
drug for OS.  Presence of germline BRCA1/2 mutation will confirmed by a local CLIA 
(Clinical Laboratory Improvement Amendments) certified test.  Germline DNA from blood 
will also be tested centrally for mutations in BRCA1 and BRCA2 using a 
BRACAnalysisCDx test (Myriad Genetics), except for those patients who already have 
evidence of gBRCA1/2 mutation by Myriad BRCAnalysisCDx post 2016.
For all patients, disease status will be assessed at screening by computed tomography (CT) 
scans (chest, abdomen, pelvis) or magnetic resonance imaging (MRI) for assessment of 
distant metastases.
For all patients, hematology and serum chemistry samples will be collected every 2 weeks on 
Cycles 1 and 2 and Day 1 of each cycle for cCycles 3 to 6.  Other general and laboratory 
assessments will be performed at regular intervals throughout the study according to the 
Schedule of Activities (Table 1). 
All patients entered on the trial will receive neoadjuvant talazoparib 1 mg/day PO for 
24 weeks, with the exception of patients with baseline moderate renal impairment (as defined 
by an eGFR 30 and <60 mL/min/1.73m2) who will receive a starting dose of 0.75 mg/day of 
talazoparib; followed by surgery and assessment of pCR. 
For all patients, study drug treatment should continue until completion of protocol assigned
therapy, followed by surgery unless the patient is no longer clinically benefitting in the 
opinion of the investigator, there is unacceptable toxicity, withdrawal of consent, or death.  
Dosing interruptions are permitted for a period of 28 days to allow recovery from drug 
related toxicities.  Patients who receive less than 80% of the prescribed talazoparib dose 
during the neoadjuvant treatment period will not be evaluable. 
Patients will undergo definitive breast surgery within 6 weeks of the last dose of talazoparib.  
Tumors must be removed by either lumpectomy or mastectomy with clinically appropriate 
axillary surgery.  Any involved axillary nodes should be marked with a metallic indicator or 
other standard approach before systemic therapy to ensure their removal at the time of 
definitive surgery as recommended by FDA guidances.50 For patients with clinically 
negative axillary lymph nodes, sentinel lymph node biopsy, using institutional procedures 
such as dual blue dye or radioisotope tracers, should be performed at the time of definitive 
surgery and include resection of at least two nodes whenever possible.15,67  The surgical 
specimens (breast and axillary lymph node tissue) will be sent to the central lab as soon as 
possible for evaluation of pCR (defined per protocol) by central Pathologists at M.D.  
Anderson Cancer Center.  Any further post-operative therapy, either local or systemic will be 
at the discretion of the treating physician.  A post-surgical follow up visit will take place after 
4 weeks of surgery.


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 2
Safet y  will be assesse d b y a d verse e ve nts, p h ysical e xa mi nati o ns, vital si g ns, a n d cli nical 
la b orat or y tests.  Assess me nt of a b n or mal li ver tests is descri be d i n Secti o n 5. 4. 3 .  
Patie nt re p orte d o utc o mes will be assesse d electr o nicall y  t o e val uate gl o bal healt h 
stat us/ Q o L, f u ncti o ns, a n d s ym pt o ms usi n g t he E O R T C Q L Q C 3 0 a n d Q L Q B R 2 3 
q uesti o n naires; 
  
A d diti o nal patie nt re p orte d o utc o mes will be assesse d electr o nicall y  t o e val uate t he 
pr o p orti o n of patie nts wit h misse d e x pecte d me nstr ual peri o d per P R O -C T C A E .  
Patie nt re p orte d o utc o mes will be assesse d electr o nicall y  d uri n g t he cli nical visit at t he 
f oll o wi n g ti me p oi nts: C 1 D 1 ( Baseli ne), C 1 D 1 5, C 2 D 1, C 2 D 1 5, D 1 of C 3-C 6, E n d of 
Treat me nt a n d F oll o w -u p. 
A n electr o nic patie nt re p orte d -a ntie mesis me dicati o n l o g will be use d t o rec or d a ntie mesis 
me dicati o n ta ke n b y t he patie nts f or 7 c o nsec uti ve da ys pri or t o eac h cli nical visit.
S u bjects w h o pr o gress w hile o n talaz o pari b will a ut o maticall y  be c o nsi dere d n o n-res p o n ders 
t o talaz o pari b a n d will pr ocee d t o t he sta ndar d of care t hera p y of t he treati n g p h ys icia n’s 
c h oice or pr ocee d t o s ur ger y if t he treati n g p hys icia n feels t hat is i n t he patie nt’s best i nterest.  
Safet y  f oll o w-u p will occ ur a p pr o xi matel y  2 8 d a y s after t he last d ose of st u d y dr u g or bef ore 
i nitiati o n of a ne w i n vesti gati o nal t hera p y, w hic he ver occ urs first.  T here will als o be a n 
a d diti o nal p ost -s ur gical safety f oll o w u p, 4 wee ks after s ur ger y , f or assess me nt of w o u n d 
heali n g.  L o n g ter m f oll o w -u p will be gi n after s ur ger y  f or E F S a n d after first d ose of 
talaz o pari b f or O S a n d will ta ke place e ver y 1 2 wee ks t hereafter u ntil deat h, wit h dra wal of 
c o nse nt f or f oll o w u p, or st u d y ter mi nati o n b y t he S p o ns or.  
Plas ma P K sa m ples f or deter mi nati o n of talaz o pari b c o nce ntrati o ns will be c ollecte d at 
defi ne d ti me p oi nts t o descri be t he stea d y -state P K of talaz o pari b i n patie nts wit h g B R C A 
m utati o n -p ositi ve H E R 2 ne gati ve breast ca ncer a n d t o s u p p ort e x pl orat or y a nal ys es t o 
c orrelate talaz o pari b e x p os ure a n d t u m or res p o nse (e g, p C R, E F S, etc.) a n d/ or select safet y 
fi ndi n gs.
4. P A TI E N T E LI GI BI LI T Y C RI T E RI A
T his st u d y  ca n f ulfill its o bjecti ves o nl y if a p pr o priate patie nts are e nr olle d.  T he f oll o wi n g 
eli gi bilit y criteria are desi g ne d t o select patie nts f or w h o m partici pati o n i n t he st u d y is 
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n deci di n g w het her a partic ular patie nt is s uita ble f or t his pr ot oc ol.
Patie nt eli gi bilit y  s h o ul d be re vie we d a n d d oc u me nte d b y a n a p pr o priate me m ber of t he 
i n vesti gat or’s st u dy tea m bef ore patie nts are i ncl u de d i n t he st u d y.  
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4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Presence of germline BRCA1/2 mutation as confirmed by a local CLIA (Clinical 
Laboratory Improvement Amendments) certified test.  Consent to a blood sample for 
genomic assessment by the BRACAnalysisCDx test at Myriad Genetics, except for 
patients who already have evidence of BRCA1/2 mutation by Myriad 
BRACAnlaysisCDx post 2016.
2. Patients must be willing and able to provide evidence of a personally signed and 
dated informed consent document indicating that they (or a legally acceptable 
representative) have been informed of all pertinent aspects of the study. 
3. Women and men at least 18 years of age or older.  
4. Documentation of histologically confirmed invasive adenocarcinoma of the breast. 
5. HER2 negative breast cancer:

HER2 negative or non-amplified as determined by the current American Society 
of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria 
which are as follows: HER2 testing by IHC as 0 or 1+.  If HER2 is 2+, ISH (in 
situ hybridization) must be performed.  HER2 is positive for gene amplification 
if: IHC 3+ based on circumferential membrane staining that is complete, intense, 
ISH positive based on: Single-probe average HER2 copy number 
>/= 6.0 signals/cell Dual-probe HER2/chromosome 17 polysomy (CEP17) ratio 
>/= 2.0;c,e with an average HER2 copy number >/=4.0 signals/cell Dual-probe 
HER2/CEP17 ratio >/= 2.0;c,e with an average HER2 copy number 
<4.0 signals/cell Dual-probe HER2/CEP17 ratio < 2.0;c,e with an average HER2 
copy number >/= 6.0 signals/cell.
6. Tumor T1, N0-3.
7. No evidence of distant metastasis. 
8. Adequate bone marrow, hepatic, and renal function as defined by the following:

Absolute neutrophil count (ANC) 1,500/mm3 (1.5 x 109 /L);

Platelets 100,000/mm3 (100 x 109 /L); 

Hemoglobin (Hb) 9 g/dL (may not have received growth factors or blood 
transfusions within 14 days before obtaining the hematology values at screening);


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 5 4

G F R 3 0 m L / mi n/ 1. 7 3 m 2 b y  t he m o dificati o n of diet i n re nal disease [ M D R D] 
calc ulati o n [a vaila ble via w w w. m dr d.c o m]; 

Ala ni ne a mi n otra nsferase ( A L T) a n d as partate a mi n otra nsferase ( A S T) 
< 2. 5 X U L N;

T otal ser u m bilir u bi n < 1. 5 X U L N.
9.
E C O G perf or ma nce stat us 0 or 1.
 
  
1 1.
W o me n of c hil d beari n g p ote ntial ( W C B P) m ust ha ve a ne gati ve ser u m or uri ne 
pre g na nc y  test wit hi n 1 4 da ys pri or t o e nr oll me nt.  W C B P m ust be usi n g a hi g hly 
effecti ve met h o d of c o ntrace pti o n t o a v oi d pre g na nc y  t hr o u g h o ut t he st u d y a n d f or 
7 m o nt hs after t he last d ose of i n vesti gati o nal pr o d uct (I P).  Male patie nts wit h fe male 
part ners of re pr o d ucti ve p ote ntial a n d pre g na nt part ners m ust use a c o n d o m (e ve n 
after vasect o m y) d uri n g treat me nt wit h talaz o pari b a n d f or 4 m o nt hs af ter t he fi nal 
d ose. 
1 2. Willi n g a n d a ble t o c o m pl y  wit h sc he d ule d visits, treat me nt pla n, la b orat or y tests, a n d 
ot her st u d y  pr oce d ures.
1 3. Fe male patie nts of n o n -c hil d beari n g p ote ntial m ust meet at least 1 of t he f oll o wi n g 
criteria:
a.
Ac hie ve d p ost me n o pa usal stat u s, defi ne d as f oll o ws: cessati o n of re g ular me nses 
f or at least 1 2 c o nsec uti ve m o nt hs wit h n o alter nati ve pat h ol o gical or 
p h y si ol o gical ca use; stat us ma y be c o nfir me d wit h a ser u m f ollicle-sti m ulati n g 
h or m o ne ( F S H) le vel c o nfir mi n g t he p ost me n o pa usal state ;
b.
Ha ve u n der g o ne a d oc u me nte d h y sterect o m y a n d/ or bilateral o o p h orect o m y; 
c.
Ha ve me dicall y  c o nfir me d o varia n fail ure; 
d.
All ot her fe male patie nts (i ncl u di n g fe male s u bjects wit h t u bal li gati o ns) are 
c o nsi dere d t o be of c hil d beari n g p ote ntial. 
4. 2. E xcl usi o n Crit eri a
Patie nts wit h a n y  of t he f oll o wi n g c haracteristics/c o n diti o ns will n ot be i ncl u de d i n t he st u d y:
1.
I n vesti gat or site staff me m bers directly i n v ol ve d i n t he c o n d uct of t he st u d y a n d t heir 
fa mil y me m bers, site staff me m bers ot her wise s u per vise d b y t he i n vesti gat or, or 
patie nts w h o are Pfizer e m pl o y ees, i ncl u di n g t heir fa mil y me m bers, directl y i n v ol ve d 
i n t he c o n d uct of t he st u d y.
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2. Participation in other studies involving investigational drug(s) within 12 months prior 
to study entry and/or during study participation.
3. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
4. Any other previous antitumor therapies for the current cancer event.  Treatment for 
ductal carcinoma in situ (DCIS) is allowed; ie, surgery, hormonal therapy and 
radiation. 
5. Evidence of distant metastasis apparent prior to randomization.
6. Patients with inflammatory breast carcinoma.
7. Malignancy within the last 3 years, except: 

Stage 1 melanoma which does not require any further treatment after adequate 
surgical excision;

Adequately treated non-melanoma skin cancer;

Curatively treated in situ cancer of the cervix; 

Stage 1, Grade 1 endometrial carcinoma; or

Adequately treated contralateral breast carcinoma which has been disease free for 
a year;

Other solid tumors including lymphomas (without bone marrow involvement) 
curatively treated with no evidence of disease for 5 years.
8. Concomitant use strong of P-gp inhibitors or inducers or BCRP inhibitors (see 
Section 5.7).
9. Previous or concomitant systemic anti-cancer therapies used for the treatment of 
cancer in the last 3 years.
10. Prior treatment with a PARP inhibitor in any disease setting.


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11. Pregnant female subjects, breastfeeding female subjects, fertile male subjects, and 
female subjects of childbearing potential who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for at least 7 months for females, 4 months for males after the last dose of 
investigational product. 
12. Major surgery within 14 days prior to study entry; patients must have recovered from 
any effects of any major surgery.
13. No known history of cardiovascular disease, including any of the following:

Myocardial infarction or symptomatic cardiac ischemia within 24 weeks before 
screening;

Congestive heart failure New York Heart Association Class III or IV; 

History of clinically significant ventricular arrhythmias eg, history of sustained 
ventricular tachycardia, ventricular fibrillation, torsades de pointes) within one 
year prior to randomization;

History of Mobitz II second degree or third-degree heart block, unless a 
permanent pacemaker is in place;

Hypotension as indicated by systolic blood pressure <86 mm Hg (millimeters of 
mercury) at screening;

Bradycardia as indicated by heart rate (HR) <45 beats per minute on the screening 
electrocardiogram (ECG); 

Uncontrolled hypertension as indicated by systolic blood pressure >170 mm Hg 
or diastolic blood pressure >105 mm Hg at screening.  However, patients can be 
re-screened after adequate control of blood pressure is achieved.
14. Active clinically significant infection either Grade >2 by NCI-CTCAE v4.03, or 
requiring the use of parenteral anti-microbial agents within 14 days before day 1 of 
study drug.
15. Clinically significant bleeding diathesis or coagulopathy, including known platelet 
function disorders.
16. Non-healing wound, ulcer or bone fracture.
17. Known hypersensitivity to any of the components of talazoparib.
18. Patients with myelodysplastic syndrome/acute myeloid leukemia.
19. Patients with uncontrolled seizures.


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20. Any evidence of other disease or any concomitant medical or psychiatric problems 
which in the opinion of the Investigator would prevent completion of treatment or 
follow-up, such as:

Evidence of severe or uncontrolled cardiac disease, uncontrolled ventricular 
arrhythmia, myocardial infarction within 12 months prior to study entry, or active 
infection including hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV);

Patients unable to swallow orally administered medication, or patients with 
gastrointestinal disorders likely to interfere with absorption of the trial 
medication.
4.3. Lifestyle Requirements 
4.3.1. Contraception
In this study, fertile male patients and female patients who are of childbearing potential as 
applicable to the study will receive talazoparib, which has been associated with 
teratogenicity/fetotoxicity in preclinical studies.  Talazoparib is clastogenic in nonclinical 
genetic toxicological evaluations.  Talazoparib also caused fetal malformations, structural 
variations, and death in an embryo fetal development study in rats.  
Patients who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use a of highly effective method of contraception 
consistently and correctly for the duration of the active treatment period and for at least 7 or 
4 months for females and males, respectively, after the last dose of IP.  The investigator or 
his or her designee, in consultation with the patient, will confirm that the patient has selected 
a highly effective method of contraception for the individual patient (and his or her partner) 
from the permitted list of contraception methods (see below) and will confirm that the patient 
has been instructed in its consistent and correct use.  At time points indicated in the Schedule 
of Activities, the investigator or designee will inform the patient of the need to use a highly 
effective method of contraception consistently and correctly and document the conversation 
and the subject’s affirmation in the patient’s chart.  In addition, the investigator or designee 
will instruct the patient to call immediately if the selected contraception method is 
discontinued or if pregnancy is known or suspected in the patient or the partner.  Highly 
effective methods of contraception are those that, alone or in combination, result in a failure 
rate of less than 1% per year when used consistently and correctly (ie, perfect use).
All sexually active male subjects must agree to prevent potential transfer to and exposure of 
partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning 
with the first dose of IP and continuing for at least 4 months after the last dose of talazoparib.  
Contraception should be considered for a nonpregnant female partner of childbearing 
potential.


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4.3.2. Women of Childbearing Potential (WCBP) Definition
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WCBP:
1. Premenarchal.
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation for any of the above conditions can come from the site personnel’s 
review of the patient’s medical records, medical examination, or medical history interview.
The method of documentation should be recorded in the patient’s medical record for the 
study.
3. Postmenopausal female.
A postmenopausal state is defined as age 60 or older or no menses for 12 months without an 
alternative medical cause.
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT).
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.


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4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and IP identifiers, patient study numbers, contact information for the 
investigator site, and contact details for a contact center in the event that the investigator site 
staff cannot be reached to provide advice on a medical question or problem originating from 
another healthcare professional not involved in the patient’s participation in the study.  The 
contact number can also be used by investigator staff if they are seeking advice on medical 
questions or problems; however, it should be used only in the event that the established 
communication pathways between the investigator site and the study team are not available.  
It is therefore intended to augment, but not replace, the established communication pathways 
between the investigator site and the study team for advice on medical questions or problems 
that may arise during the study. The contact number is not intended for use by the patient
directly, and if a subject calls that number, he or she will be directed back to the investigator 
site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonisation (ICH) 
guidelines, IP is defined as a pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference/comparator in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH Harmonised Tripartite Guideline: Guideline 
for Good Clinical Practice E6 [ICH E6 1.33]).  For this study, the IP is talazoparib.
5.1. Allocation to Treatment
Allocation of patients to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, randomization number (although non-randomized, a randomization number 
is still required for all patients to reconcile and merge separated data files), and the patient 
number. The site personnel will then be provided with a treatment assignment and 
dispensable unit (DU) or container number when IP is being supplied via the IRT 
system.  The IRT system will provide a confirmation report containing the patient number 
and DU or container number assigned. The confirmation report must be stored in the site’s 
files.
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 


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5.2. Patient Compliance
For self-administration of talazoparib at home, compliance will be captured and completed 
by the patient using an electronic diary.  Patients will record the daily administration of the 
study drug (talazoparib).  Data entered in the diary will be compared with drug accountability 
done at the site prior to dispensing additional study drug.  In the event of unexplained 
discrepancies, drug accountability data will prevail in determining patients’ degree of 
compliance, which will be recorded in the case report form (CRF).  Patients will be 
considered out of compliance if >20% of monthly doses are missed.  
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
Talazoparib drug product will be supplied as 2 clinical dosage strengths of 0.25 mg or 1 mg, 
calculated relative to the talazoparib free base, for oral administration.  Depending on the 
prescribed dose, patients may take two 0.25 mg capsules for the 0.5 mg dose, or three 
0.25 mg capsules for the 0.75 mg dose.  The drug substance is a 4 methylbenzenesulfonate 
(tosylate) salt of talazoparib free base, the active moiety.  The drug product consists of 
talazoparib tosylate drug substance formulated with silicified microcrystalline cellulose 
(SMCC) filled into hydroxypropyl methylcellulose (HPMC) as immediate release capsules.  
The drug product should be stored at room temperature (15 to 30°C; 59 to 86°F).  The 
capsules are supplied in induction-sealed high-density polyethylene (HDPE) bottles.
5.3.2. Preparation and Dispensing
Talazoparib will be dispensed using an Interactive Web Response System (IWRS) drug 
management system every 4 weeks through week 24.  A qualified staff member will dispense 
the IP via unique container numbers in bottle(s) provided, in quantities appropriate for the 
study visit schedule.  The patient/caregiver should be instructed to maintain the product in 
the bottle(s) provided throughout the course of dosing and return the bottle to the site at the 
next study visit.  
5.4. Administration
Talazoparib will be self-administered by mouth at approximately the same time each day 
outside the clinic, except on days when PK is assessed; patients will withhold their dose until 
after the pre-dose PK blood sample is drawn.  Talazoparib can be administered with or 
without food.  Patients will swallow the IP whole, and will not manipulate or chew the IP 
prior to swallowing.  Patients should not make up missed or vomited doses; dosing should 
resume on the next calendar day unless otherwise instructed.  
Daily dosing of talazoparib can be interrupted for recovery from toxicity for up to 28 days.  
Thereafter, treatment at the same or a reduced dose can be considered based on a discussion 
between sponsor or designee and Investigator if the patient has not developed progressive 
disease.  Dose modifications should be made based on observed toxicity as follows:


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
Grade 1 or 2 toxicity: No requirement for dosing interruption or dose reduction.  If 
the toxicity persists at grade 2, a dose reduction to the next lower dose level (eg, from 
1 mg/day to 0.75 mg/day) may be implemented at the discretion of the Investigator;

Grade 3 toxicity: Daily dosing should be stopped.  Talazoparib dosing may resume at 
the next lower dose level (eg, from 1 mg/day to 0.75 mg/day, 0.75 mg/day to 
0.5 mg/day); 

Grade 4 toxicity: Daily dosing should be stopped.  Talazoparib may resume at a lower 
dose level (1-2 dose level decrease) with the approval of the medical monitor when 
toxicity resolves to grade 1 or returns to baseline.  See the following table (Table 3) 
for further details.  Also, refer to Section 5.4.1 and Table 4, Dose Modifications for 
Talazoparib Due to Adverse Events. 
Table 3.
Dose Modifications for Talazoparib Toxicities
Dose Level
Initial dose level
1 mg/daya
First dose level reduction
0.75 mg/day
Second dose level reduction
0.5 mg/day
a. Patients with baseline moderate renal impairment will have a starting dose of 0.75 mg/day.
Talazoparib will be permanently discontinued for individual patients as a result of any 
unresolved Grade 3 or Grade 4 toxicity or based on a decision by the patient or Investigator 
that continued treatment is not in the patient’s best interest.  Talazoparib must be 
permanently discontinued for unresolved Grade 3 toxicity lasting longer than 14 days or for 
Grade 4 toxicity lasting longer than 3 days.
5.4.1. Dose Modifications for Talazoparib Due to Adverse Events
The daily dose of talazoparib may be reduced sequentially in 0.25 mg per day increments 
depending on the degree of toxicity.  Dose modifications for talazoparib due to adverse 
events are described in Table 4.  Patients will receive a starting dose of 1 mg/day of 
talazoparib, with the exception of patients with baseline moderate renal impairment (as 
defined by an eGFR 30 and <60 mL/min/1.73 m2) who will receive a starting dose of 
0.75 mg/day of talazoparib.  


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Table 4.
Dose Modification of Talazoparib Due to Adverse Events
Toxicity
Management of Adverse Events
Grade 1 or 2
No requirement for dosing interruption or dose reduction 
Selected hematologic grade 3 
or 4 events
Anemia 
(hemoglobin <8.0 g/dL)
Hold talazoparib and implement supportive care as per local guidelines.  
Monitor weekly until hemoglobin returns to 9.0 g/dL or better, then 
resume talazoparib at a reduced dose at the initiation of the next cycle.  
Talazoparib may be reduced by 1 dose level as described in Section 5.4.  
If anemia with hgb <8.0 g/dL recurs after dose reduction, hold talazoparib 
and implement supportive care per local guidelines.  Monitor weekly until 
hemoglobin returns to 9.0 g/dL (Day 1), then resume talazoparib at a 
further reduced dose at the initiation of the next cycle.
If anemia persists for >4 weeks without recovery of hemoglobin to at least 
9.0 g/dL despite supportive care measures at any dose level, discontinue 
talazoparib and consider referral to a hematologist.
Transfusions and other supportive measures are permitted to support 
management of hematological toxicities at any occurrence.
Neutropenia 
(ANC <1000/L)
Hold talazoparib and implement supportive care per local guidelines.  
Monitor weekly until ANC 1500/µL, then resume talazoparib at a 
reduced dose at the initiation of the next cycle.
If neutropenia recurs after the dose reduction, hold talazoparib and 
implement supportive care per local guidelines.  Monitor weekly until 
ANC 1500/µL, then resume talazoparib at a further reduced dose at the 
initiation of the next cycle.
If neutropenia persists for >4 weeks without recovery to 1500/μL at any 
dose level despite supportive care measures, discontinue talazoparib and 
consider a referral to a hematologist.
G-CSF and GM-CSF may be used at investigators discretion for the 
supportive (including prophylactic) treatment of neutropenia at any 
occurence.
Thrombocytopenia (platelets 
<50,000/µL)
Hold talazoparib and implement supportive care per local guidelines.  
Monitor weekly until platelets 50,000/L, then resume talazoparib at a 
reduced dose at the initiation of the next cycle.
If thrombocytopenia (<50,000/μL) recurs after one dose reduction, hold 
talazoparib and implement supportive care per local guidelines.  Monitor 
weekly until platelets 75,000/L, then resume talazoparib a further 
reduced dose at the initiation of the next cycle.
If thrombocytopenia persists for >4 weeks without recovery to 50,000/L 
despite supportive care measures, discontinue talazoparib and consider a 
referral to a hematologist.
Thrombopoietin analogues and/or platelet transfusions may be used at 
investigators discretion for the supportive treatment of thrombocytopenia 
at any occurrence. 
Nonhematologic laboratory 
Grade 3 events, except 
abnormal liver tests
Hold talazoparib as follows:
For Grade 3 laboratory abnormalities, hold talazoparib until the laboratory
abnormality resolves to Grade 2 (to baseline grade for creatinine 
increases).  Resume talazoparib at the same dose or reduce of one dose 
level at the initiation of the next cycle.


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Toxicity
Management of Adverse Events
If Grade 3 laboratory abnormality recurs, hold talazoparib until the 
laboratory abnormality resolves to Grade 2 (to baseline grade for 
creatinine increases).  Reduce talazoparib of one dose level if the dose was 
not previously reduced, or to further reduced dose level if subject was 
previously dose reduced at the initiation of the next cycle.
For Grade 4 laboratory abnormalities, hold talazoparib until the laboratory 
abnormality resolves to Grade 2 (to baseline grade for creatinine 
increases).  Reduce talazoparib of one dose level at the initiation of the 
next cycle. 
Talazoparib must be discontinued if a Grade 4 adverse event recurs after 
treatment resumes.
Implement supportive care per local guidelines.
Contact medical monitor to discuss potential dose modification.
Talazoparib must be permanently discontinued for unresolved Grade 3 
toxicity lasting longer than 14 days or for Grade 4 toxicity lasting longer 
than 3 days.  Treatment may be resumed at a 1 dose level reduction if clear 
clinical benefit is observed, after discussion with the Sponsor. 
Grade 3 abnormal liver tests
Hold talazoparib for liver test abnormalities as specified in Section 5.4.3. 
Guidelines for follow-up for possible drug-induced liver injury and for 
resuming talazoparib after the liver test abnormalities resolve to baseline 
grade are provided in Section 5.4.3.  
The criteria for permanent discontinuation talazoparib/placebo are 
provided in Section 5.4.3.  
Nonlaboratory Grade 3 
events
Hold talazoparib as follows:
For Grade 3 adverse events, hold talazoparib until the adverse event 
resolves to Grade 1 or baseline.  Resume talazoparib at the same dose or 
reduce by 1 dose level as described in Section 5.4.  
For Grade 4 adverse events, permanently discontinue talazoparib. 
Implement supportive care per local guidelines.  
Contact medical monitor to discuss potential dose modification.  
Talazoparib must be permanently discontinued for unresolved Grade 3 
toxicity lasting longer than 14 days.  Treatment may be resumed at a 
1 dose level reduction if clear clinical benefit is observed, after discussion 
with the medical monitor.  
Talazoparib must be discontinued if a grade 4 adverse event recurs after 
treatment resumes.  
ANC=absolute neutrophil count.  
5.4.2. Talazoparib Dose Re-Escalation
Dose re-escalation of talazoparib is not allowed.  
5.4.3. Modifications Due to Abnormal Liver Tests (All Treatments)
Patients who develop abnormal liver tests (aspartate aminotransferase [AST], alanine 
aminotransferase, [ALT], total bilirubin [TBili]), abnormal international normalized ratio 
(INR) values, or signs or symptoms consistent with hepatitis during study treatment may 
meet the criteria for temporarily withholding or permanently discontinuing study drug.  


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Patients who have abnormal liver tests or meet the criteria for permanent discontinuation or 
temporary withholding of study drug will be followed up according to the recommendations 
in this section.  
Study drug should be withheld for any liver test abnormality listed in Table 6.  When 
withholding study drug, follow-up should continue for possible drug-induced liver injury 
(Table 5) until the liver test abnormalities resolve to baseline grade.  However, talazoparib 
should be permanently discontinued if any liver test elevation persists for more than 7 days.
Table 5.
Criteria for Temporary Withholding of Study Drug in Association With 
Liver Test Abnormalities
Screening AST or ALT Value
Elevationa
≤3 × ULN
>5 × ULN (ALT or AST 3 × ULN with the presence of signs 
and symptoms consistent with acute hepatitis and/or eosinophilia 
[500 eosinophils/µL])
>3 × ULN and ≤5 × ULN
>8 × ULN
Baseline Total Bilirubin Value
≤1.5 × ULN
>3 × ULN 
>1.5 × ULN and ≤3 × ULN
(Patients with Gilbert syndrome or 
for whom indirect bilirubin 
concentrations suggest an 
extrahepatic source of elevation) 
>5 × ULN
For re-challenge, dose modification may be required per Table 3.  
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.  
a.
Talazoparib should be permanently discontinued if any elevation persists for more than 7 days.
Re-challenge with talazoparib following liver test abnormalities is not permitted if these 
abnormalities are accompanied with signs or symptoms consistent with drug-induced liver 
toxicity or meet permanent discontinuation criteria.  Re-challenge with talazoparib may be 
considered at a 0.25 mg/day reduction if an alternative cause for the abnormal liver tests 
(ALT, AST, TBili) is discovered and the laboratory abnormalities resolve to normal or 
baseline values.  The investigator and sponsor should discuss and agree with any decision to 
rechallenge any of the assigned study drugs.  Following re-challenge, patients should be 
closely monitored for signs and symptoms of hepatitis and/or abnormal liver test results.  
Study drug treatment should be permanently discontinued permanently if any of the 
following criteria are met: 

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available (Note: in the presence of elevated alkaline phosphatase 
associated with bone metastases, gamma glutamyl transferase [GGT] should be tested 
and the results should be within the reference range);

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:


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
Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller);

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).

Patients with AST/ALT >5 × ULN that persists for more than 7 days (AST/ALT 
>8 × ULN for patients with hepatic involvement);

Patients with AST/ALT >20 × ULN that persists for longer than 3 days; 

Patients with TBili >3 × ULN that persists for longer than 7 days (>5 × ULN for 
patients with Gilbert’s disease);

No alternative cause explains the combination of the above laboratory abnormalities.
When study drug treatment is temporarily withheld or permanently discontinued due to a 
potential drug induced liver injury, a period of close observation is to commence until the 
liver test abnormalities return to baseline or normal values.  The evaluations listed in Table 6
should be performed. 
Table 6.
Monitoring of Liver Tests for Potential Drug Induced Liver Injury
Results
Frequency for Repeating Liver (AST, ALT, 
Bilirubin [Total and Direct]) and INR Tests
After the initial liver test abnormality 
Within 24 hours 
If AST or ALT 3 × ULN (>5 × ULN if 
baseline ALT/AST is >3 × ULN), and total 
bilirubin >2 × ULN or INR >1.5
Every 24 hours until laboratory abnormalities 
improve
If ALT or AST 3 × ULN (>5 × ULN if 
baseline ALT/AST is >3 × ULN) and total 
bilirubin or INR are normal 
Every 48 to 72 hours until laboratory abnormalities 
improve
If the liver test abnormalities improve AND the 
patient is asymptomatic
Frequency may decrease
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized 
ratio; ULN = upper limit of normal.  
As drug-induced liver injury is a diagnosis of exclusion, it is important to initiate 
investigation of alternative causes for abnormal liver tests, which may include consultation 
with a hepatologist.  Contact the medical monitor with questions regarding sufficient 
follow-up tests.  


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5.5. Investigational Product Storage and Handling
The investigator or an approved representative, eg, pharmacist, will ensure that talazoparib is 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
Talazoparib is considered a cytotoxic and clastogenic agent; precautions regarding 
appropriate secure storage and handling must be used by healthcare professionals, including 
personal protective clothing, disposable gloves, and equipment.  Patients should be advised 
that oral anticancer agents (ie, talazoparib) are toxic substances and that other caregivers 
should always use gloves when handling the capsules.
IPs should be stored in their original containers and in accordance with the labels.  
Any storage conditions stated in the talazoparib SRSD will be superseded by the storage 
conditions stated on the label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of IP receipt throughout the study.  Even for
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the IP must be quarantined and not used until Pfizer provides 
permission to use the IP.  It will not be considered a protocol deviation if Pfizer approves the 
use of the IP after the temperature excursion.  Use of the IP prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions. 
Site staff will instruct patients on the proper storage requirements for take home IPs. 


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Refer to the IP Manual for additional guidance on storage conditions and actions to be taken 
when conditions are outside of the pre-specified range.
5.6. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the IP supplies.  All IP will be accounted for using a drug accountability 
form/record.  All bottles of study drug must be returned to the investigator by the patient at 
every visit and at the end-of-treatment visit.  Patients who do not return bottles at the 
end-of-treatment visit will be reminded to bring them at their next visit.
5.6.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused IP (eg, at the 
site).  If destruction is authorized to take place at the investigator site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer, and all 
destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Patients must be instructed not to take any additional medications (over-the-counter or other 
products) during the study without prior consultation with the investigator.  Any medications 
including herbal supplements, vitamins, or treatment taken by the patient from 28 days prior 
to the start of study treatment and up to 28 days following the last dose of IP, including the 
start and end dates of treatment and the reason for their administration, must be recorded on 
the CRF.  
Use of the following treatments is prohibited prior to study entry (28 days prior to 
randomization), during the study, and for 30 days following the last dose of the IP, or as 
otherwise noted.

Prior or concurrent treatment with another PARP inhibitor.

Previous or concomitant systemic anti-cancer agents used for the treatment of cancer 
in the last 3 years.

Use of the following P-gp inhibitors (amiodarone, carvedilol, clarithromycin, 
cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, 
ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, 
saquinavir, telaprevir, tipranavir, verapamil, and valspodar), P-gp inducers 
(avasimibe, carbamazepine, phenytoin, rifampin, and St. John’s wort) or BCRP 
inhibitors (curcumin, cyclosporine, elacridar [GF120918], and eltrombopag) is 
prohibited.


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
While the following mediations are not prohibited from use during study conduct, 
caution should be used upon concomitant use of the following transporter inhibitors 
with talazoparib: atorvastatin, azithromycin, conivaptan, diltiazem, diosmin, 
eliglustat, felodipine, flibanserin, fluvoxamine, piperine, quercetin, and schisandra 
chinensis extract.
The start date, stop date, and indication for concomitant treatments and/or therapies and 
medications received from screening until end of treatment will be recorded on the CRF.
6. STUDY PROCEDURES 
6.1. Screening
See Table 1 for screening procedures.  Screening for gBRCA1/2 Mutations:

If positive gBRCA1/2 status has been confirmed by a local CLIA certified test, 
patients may enroll and commence study treatment, provided all other 
inclusion/exclusion criteria are met and screening tests have been satisfactorily 
completed. 

A blood sample must be sent to Myriad Genetics for central testing 
(BRACAnalysisCDx test), except for those patients who already have evidence of 
gBRCA1/2 mutation by Myriad BRACAnalysisCDx post 2016. 

In the event of discrepant results, where the local BRCA test is positive for 
gBRCA1/2 mutation and the central Myriad BRACAnalysis test is negative, the 
decision on further trial continuation will be decided by the investigator and discussed 
with the sponsor based on a risk-benefit evaluation.
6.2. Treatment Period
See Table 1 for treatment procedures.  
6.3. Safety Follow-up
For safety follow-up procedures after the treatment period, see Table 1.  Safety follow-up 
will occur a minimum of 28 calendar days after the last dose of study drug or before 
initiation of a new antineoplastic therapy (whichever occurs first) to capture any potential 
AEs (see the Time Period for Collecting Adverse Event/Serious Adverse Event Information
section).  Contact with the patient for AE follow-up may be done via phone call if the patient
does not come to the site.  There will be an additional post-surgical follow up 4 weeks after 
surgery.  
6.4. Long Term Follow-up
For long-term follow-up procedures after the treatment period, see Table 1.  This period 
begins after surgery for EFS and after first dose of talazoparib for OS.  Survival status can be 
obtained by any means including telephone, during a visit, chart review, or contact with 
someone who is knowledgeable of the patient’s survival status (eg, relative, friend, referring 


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healthcare provider).  If allowed by local laws and regulations, survival status may be 
obtained from public records for patients withdrawing consent from the study or for patients 
lost to follow-up.
6.5. Patient Withdrawal 
Withdrawal of consent:
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the subject to provide this information.  
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of IP or also from study procedures and/or posttreatment study follow-up, and 
entered on the appropriate CRF page.  In the event that vital status (whether the patient is 
alive or dead) is being measured, publicly available information should be used to determine 
vital status only as appropriately directed in accordance with local law.
Lost to follow-up: 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal from the Study Due to Adverse Events (see also the Patient Withdrawal section)
or behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given study site. 


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If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  This includes follow-up with persons authorized by the patient.  “Lost to follow-up” 
is defined by the inability to reach the patient after a minimum of 2 documented phone calls, 
faxes, or e-mails as well as lack of response by the patient to 1 registered mail letter.  All 
attempts to contact the patient and information received during contact attempts must be 
documented in the patient’s medical record and CRF.  If it is determined that the patient has 
died, the site will use locally permissible methods to obtain the date and cause of death.  If 
the investigator’s use of a third-party representative to assist in the follow-up portion of the 
study has been included in the patient’s informed consent, then the investigator may use a 
sponsor-retained third-party representative to assist site staff with obtaining the patient’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study.  The site staff and representative will consult publicly available sources, 
such as public health registries and databases, in order to obtain updated contact information.  
If, after all attempts, the patient remains lost to follow-up, then the contact date should be 
reported and documented in the patient’s medical records and CRF.  
In any circumstance, every effort should be made to document subject outcome, if possible.  
The investigator should inquire about the reason for withdrawal, request that the subject 
return all unused investigational product(s), request that the subject return for a final visit, if 
applicable, and follow up with the subject regarding any AEs.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.  Patients will be enrolled to account for a 10% drop-off 
rate.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.


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7. 1. Pre g n a nc y Testi n g
F or fe male patie nts of c hil d beari n g p ote ntial, a ser u m or uri ne pre g na nc y  test ( uri ne 
pre g na nc y  tests must ha ve a se nsiti vit y  of at least 2 5 mI U/ m L f or h u ma n c h ori o nic 
g o na d otr o pi n) will be perf or me d as per t he S O A . 
A ne gati ve pre g na nc y  test res ult is re q uire d bef ore t he patie nt ma y recei ve talaz o pari b.  
Pre g na nc y tests will als o be d o ne w he ne ver o ne me nstr ual c ycle is misse d d uri n g t he acti ve 
treat me nt peri o d ( or w he n p ote ntial pre g na nc y is ot her wise s us pecte d).  Pre g na nc y tests ma y 
als o be re peate d if re q ueste d b y  i nstit uti o nal re vie w b oar ds (I R Bs)/( E Cs) or if req uire d b y  
l ocal re g ulati o ns. 
Ser u m or uri ne pre g na nc y tests will be c o n d ucte d wit h t he test kit pr o vi de d b y  t he ce ntral 
la b orat or y i n acc or da nce wit h i nstr ucti o ns pr o vi de d i n its pac ka ge i nsert.  Patie nts w h o ha ve 
misse d a me nstr ual peri o d or w h o s h o w a n i n deter mi nate or p ositi ve res ult o n t he uri ne test 
ma y  n ot f urt her pr o gress i n t he st u d y u ntil pre g na nc y is r ule d o ut usi n g f urt her dia g n ostic 
testi n g (e g, a ne gati ve q ua ntitati ve ser u m pre g na nc y test c o n d ucte d at a certifie d la b orat or y).
I n t he case of a p ositi ve c o nfir me d pre g na nc y , t he patie nt will be wit h dra w n fr o m 
a d mi nistrati o n of IP a n d fr o m t he st u d y .
7. 2. C o m p a ni o n Di a g n ostics f or Eli gi bilit y
Patie nts are re q uire d t o ha ve H E R 2 ne gati ve breast ca ncer t hat is g B R C A p ositi ve.  T he 
bl o o d sa m ples will be se nt t o ce ntral la b f or a nal ysis wit h res ults ret ur ne d wit hi n 2 wee ks.
B R C A testi n g ca n be perf or me d usi n g a l ocal, C LI A certifie d bl o o d test. If l ocal test is d o ne 
( ot her t ha n Myria d B R A C A nal ysis C D x p ost 2 0 1 6), a n a d diti o nal sa m ple will nee d t o be se nt 
f or ce ntral testi n g t o M Y RIA D ge netics. Patie nts m ust als o c o nse nt t o a bl o o d sa m ple f or 
ce ntral ge n o mic assess me nt usi n g t he B R A C A nal y sis C D x test b y Myri a d Ge netics, e xce pt 
f or patie nts w h o alrea dy ha ve e vi de nce of B R C A 1/ 2 m utati o n b y  M Y RI AD 
B R C A nal ys is C D x p ost 2 0 1 6.
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7.3. Efficacy Assessments
7.3.1. Primary Efficacy Endpoint: Pathological Complete Response
The primary efficacy endpoint is the pathologic complete response to talazoparib after 
24 weeks of neoadjuvant therapy followed by surgery.  pCR will be assessed by histological 
examination of the post-surgical specimen by ICR.  The post-surgical specimen should be 
sent to the central lab as soon as possible.  Further details can be found in the laboratory 
manual. 
7.3.2. Assessment of Secondary Efficacy Endpoints
The secondary endpoints include pCR by investigator, RCB, pCR (in breast), EFS at 3 years 
and OS at 3 years.
The study assessments of efficacy for these endpoints (RCB by ICR and pCR by 
investigator) will be assessed by histological examination of the post-surgical specimen.  
EFS and OS will be collected by telephone follow up of patients every 12 weeks during the 
long term follow up period.  Follow up for EFS will start from date of surgery.  Follow up for 
OS will start from day of first dose of talazoparib. 
7.4. Patient Reported Outcomes Assessments
Global health status/quality of life, functioning, and symptoms data will be collected 
electronically using the EORTC QLQ-C30 and QLQ BR23 questionnaires.
The EORTC QLQ-C30 is a standardized instrument that assesses cancer-specific 
patient-reported global quality of life, functioning, and disease/treatment-related symptoms.  
Patients will self-rate their self-care, activity level, pain/discomfort, and mental health during 
the past week by choosing 1 of 4 possible responses that record the level of intensity (not at 
all, a little, quite a bit, and very much) within each dimension.  The questionnaire also asks 
the patient to rate their overall health and overall quality of life within the past week on a 
scale of 1 to 7, where 1 is “very poor” and 7 is “excellent.”  The QLQ-C30 questionnaire is 
provided in Appendix 2.
The EORTC QLQ-BR23 (Breast Cancer Quality of Life Questionnaire) is a breast 
cancer-specific module of the EORTC questionnaire that assesses the functioning and 
symptoms of patients with breast cancer.  The EORTC QLQ-BR23 functional scales consist 
of the 4 scales that assess body image, sexual functioning, sexual enjoyment, and future 
perspective.  The EORTC QLQ-BR23 symptom scales consist of the 4 scales that assess 
systemic therapy side effects, breast symptoms, arm symptoms, and upset by hair loss.  
Patients will choose 1 of 4 possible responses that record level of intensity (not at all, a little, 
quite a bit, very much) within each dimension.  The QLQ-BR23 module is provided in 
Appendix 3.
For the global health status/QoL, functional and symptom scores in EORTC QLQ-C30 and 
QLQ-BR23, a 10 point change from baseline will be used to indicate clinically meaningful 
change.68


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Misse d e x pecte d me nstr ual peri o d will be assesse d electr o nicall y usi n g t he P R O -C T C A E 
q uesti o n naire, a patie nt -re p orte d o utc o me meas ure de vel o pe d t o e val uate s ym pt o matic 
t o xicit y i n patie nts o n ca ncer cli nical trials.  T he P R O -C T C A E q uesti o n naire is pr o vi de d i n 
A p pe n di x 5 .  T here are n o g ui deli nes yet esta blis he d b y t he U S Nati o nal Ca ncer I nstit ute 
( de vel o per of P R O-C T A E) f or h o w best t o a nal ys e P R O-C T C A E data l o n git u di na ll y.6 9
Res ults fr o m P R O -C T A E will be re p orte d descri pti vel y .  
 
 
 
 
 
O n Da y  1, patie nts will c o m plete t hese q uesti o n naires bef ore t he first d ose of st u d y dr u g.  At 
s u bse q ue nt visits, patie nts will c o m plete t hese q uesti o n naires at t he site bef ore a ny ot her 
st u d y acti vities a n d i n t he sa me or der at eac h visit.  T hese q uesti o n naires will be c ollecte d 
acc or di n g t o t he sc he d ule of assess me nts i n Ta ble 1 .
7. 5. P h ar m ac o ki netic Assess me nts
Plas ma P K sa m ples f or deter mi nati o n of talaz o pari b c o nce ntrati o ns will be c ollecte d pri or t o 
d osi n g ( pre -d ose) o n Da y 1 of C y cles 2, 3, a n d 4.  Patie nts m ust be i nstr ucte d t o wit h h ol d 
t heir dail y d ose of talaz o pari b o n P K sa m pli n g da ys u ntil t he pre-d ose P K sa m ple a n d safet y  
assess me nts (ie, he mat ol o g y , bl o o d c he mistr y, a n d E C Gs) ha ve bee n c o m plete d.  T he date 
a n d e xact ti me of t he P K sa m ple c ollecti o n a n d t he m ost rece nt talaz o pari b d osi n g ti mes 
( bef ore a n d after P K sa m ple c ollecti o n) will be rec or de d o n t he C R F.  T he date of a ny 
missi n g d ose(s) s h o ul d als o be rec or de d i n t he C R F. 
T he act ual ti mes ma y  c ha n ge b ut t he n u m ber of sa m ples will re mai n t he sa me.  All eff orts 
will be ma de t o o btai n t he P K sa m ples at t he e xact n o mi nal ti me relati ve t o d osi n g.  
H o we ver, pre -d ose sa m ples o n Da y 1 of C ycles 2, 3 a n d 4 will n ot be ca pt ure d as a pr ot oc ol 
de viati o n, as l o n g as t he P K sa m ple is c ollecte d pri or t o talaz o pari b a d mi nistrati o n o n t hat 
cale n dar da y a n d t he e xact ti me of t he P K sa m ple c ollecti o n a n d t he e xact d osi n g ti me are 
n ote d o n t he s o urce d oc u me nt a n d data c ollecti o n t o ol (e g, C R F).  
O ne 4 m L  sa m ple of ve n ous bl o o d will be c ollecte d i n a p pr o priatel y la bele d la ve n der t o p 
K 3 E D T A c ollecti o n t u bes at t he pr ot oc ol -s pecifie d ti mes.  Sa m ples will be a nalyz e d usi n g 
vali date d a nal yt ical met h o ds i n c o m plia nce wit h Pfizer sta n dar d o perati n g pr oce d ures. 
Bl o o d sa m ples will be c ollecte d fr o m all partici pati n g patie nts f or P K assess me nts of 
talaz o pari b o n Da y 1 of C y cles 2, 3, a n d 4 bef ore a d mi nistrati o n of t he talaz o pari b d ose o n 
t hat da y.  I n t he e ve nt a pre-d ose sa m ple ca n n ot be/is n ot c ollecte d as sc he d ule d, e ver y  effort 
s h o ul d be ma de t o c ollect a ma ke u p pre-d ose sa m ple o n Da y  1 of a later c ycle be yo n d 
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C y cle 4 f oll o wi n g t he sa me r ules descri be d.  D oc u me nte d rati o nale is nee de d i n t he data base 
f or a ny missi n g a n d dela ye d sa m pli n g.
A d diti o nal bl o o d sa m ples ma y  be re q ueste d fr o m patie nts e x perie nci n g u ne x pecte d or seri o us 
a d verse e ve nts, or a d verse e ve nts t hat lea d t o disc o nti n uati o n.
 
 
Refer t o t he St u d y  La b orat or y Ma n ual f or detaile d c ollecti o n, pr ocessi n g a n d s hi p pi n g 
pr oce d ures.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. 8. R ater Q u alific ati o ns
Ra di ol o gists will be b oar d -certifie d i n t heir disci pli ne or carr y si milar cre de ntials as o utli ne d 
i n t he In de pe n de nt Ra di o gra p hic Re v ie w C harter.
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7.9. Safety Assessments
Safety endpoints include adverse events (graded according to the NCI CTCAE, version 4.0), 
physical examination (including blood pressure and pulse rate), and laboratory tests 
(hematology and chemistry).
7.9.1. Adverse Events
The procedures for the investigator assessment of adverse events are presented in Section 8.
7.9.2. Physical Examinations
Physical examinations will be conducted according to the Schedule of Activities.  At 
screening, this will constitute an assessment of systems (eg, general appearance, head, eyes, 
ears, nose, mouth, throat, skin, heart, lung, lymph nodes, gastrointestinal, genitourinary, 
neurologic, and skeletal).  During treatment, systems will be assessed per standard of care at 
the study site or as clinically indicated by symptoms.  A clinical exam of breast and axilla 
should be included in each physical exam.  If the patient has evidence of clinical disease 
progression, treatment on study should be discontinued.  These patients should either switch 
to alternate systemic therapy or go straight to surgery so as not to preclude potentially 
curative surgery. 
7.9.3. Vital Signs
Vital sign measurements (blood pressure, heart rate, and temperature) and weight will be 
assessed as shown in the Schedule of Activities.  Height will also be measured at screening.  
7.9.4. Clinical Laboratory Assessments
Blood samples for hematology and serum chemistry assessments will be collected as shown 
in Table 1 and analyzed at a central laboratory.  In addition to (but not in place of) these 
central laboratory assessments, the Investigator may also collect local laboratory assessments 
within 3 days prior to a scheduled visit to guide decision-making at regularly scheduled 
visits.  The required laboratory tests are listed in Table 7. 


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T a ble 7.
Re q uire d L a b or at or y Tests
H e m at ol o g y
Ser u m C he mistr y
Uri n al ysis ( di pstic k )
A d diti o n al tests
H e m at ocrit
Al b u mi n
C ol or
clarit y
S pecific gra vit y
p H
Pr otei n 
Gl uc ose 
Ket o nes
Bilir u bi n
ur o bili n
Bl o o d
Nitrite
Le u k oc yte esterase
M icr osc o p y
Cell ular ele me nts - R B C
 
H e m o gl o bi n
T otal pr otei n
Mea n c or p usc ular 
v ol u me
Al kali ne p h os p hatase
R B C
A L T
Platelets
A S T
T otal bilir u bi n a
W B C w it h differe ntial
B U N

A N C
Creati ni ne

L y m p h oc ytes
Gl uc ose ( n o n -fasti n g)

M o n oc ytes
Bicar b o n ate

E osi n o p hils
Calci u m

Bas o p hils
C hl ori de
Ma g nesi u m
P h os p hate
P otassi u m
S o di u m
L D H
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; 
B U N = bl o o d urea nitr o ge n; C R F = case re p ort f or m; I N R = i nter nati o nal n or malize d rati o; L D H = lactate 
de h y dr o ge nase; P T = pr ot hr o m bi n ti me; R B C = re d bl o o d cell; W B C = w hite bl o o d cell.
T he la b orat or y ma n ual f or t his st u d y pr o vi des details re gar di n g sa m ple c ollecti o n pr oce d ures, la b orat or y tests, a n d 
a d diti o nal tests t hat ma y be re q uire d.
a.
F or p ote ntial H y’s La w cases, i n a d diti o n t o re peati n g A S T a n d A L T, la b orat or y tests s h o ul d i ncl u de al b u mi n, 
creati ne ki nase, t otal bilir u bi n, direct a n d i n direct bilir u bi n, ga m ma -gl uta m yl tra nsferase, P T/I N R, a n d al kali ne 
p h os p hatase.
8. A D V E R S E E V E N T R E P O R T I N G
8. 1. Re q uire me nts
T he ta ble bel o w s u m marizes t he re q uire me nts f or rec or di n g safet y e ve nts o n t he C R F a n d f or 
re p orti n g safet y e ve nts o n t he Cli nical Trial ( C T) seri o us a d verse e ve nts ( S A Es) Re p ort F or m 
t o Pfizer Safet y.  T hese re q uire me nts are deli neate d f or 3 t y pes of e ve nts: ( 1) S A Es; 
( 2) n o n- seri o us a d verse e ve nts ( A Es); a n d ( 3) e x p os ure t o t he I P u n der st u d y d uri n g 
pre g na nc y  or breastfee di n g, a n d occ u pati o nal e x p os ure.  
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the IP under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy 
(EDP), exposure via 
breastfeeding, occupational 
exposure (regardless of 
whether associated with an 
AE)
All observed or volunteered events regardless of suspected causal relationship to the IP(s) 
will be reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an IP 
under study.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer 
Safety must be made immediately, irrespective of the extent of available event information.  
This time frame also applies to additional new (follow-up) information on previously 
forwarded reports.  In the rare situation that the investigator does not become immediately 
aware of the occurrence of an event, the investigator must report the event within 24 hours 
after learning of it and document the time of his/her first awareness of the event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.


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8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient /legally acceptable representative.  In addition, each study 
subject/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF.  
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting Adverse Event/Serious Adverse Event Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the subject provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving IP), through and including a minimum of 
28 calendar days after the last administration of the IP.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting Serious Adverse Events to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to IP must be 
reported to Pfizer Safety.


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Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious Adverse Events and Serious Adverse Events on the Case 
Report Form
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the IP caused or contributed to an AE; generally the facts (evidence) or 
arguments to suggest a causal relationship should be provided.  If the investigator does not 
know whether or not the IP caused the event, then the event will be handled as “related to IP” 
for reporting purposes, as defined by the sponsor.  If the investigator's causality assessment is 
“unknown but not related” to IP, this should be clearly documented on study records.  
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

EDP;

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs. 


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8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.


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Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Secondary primary malignancies should be reported as an SAE.  Hospitalization due 
to signs and symptoms of disease progression should not be reported as an SAE.  If the 
malignancy has a fatal outcome during the study or within the active collection period, then 
the event leading to death must be recorded as an AE on the CRF, and as an SAE with 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 5 (see the Severity 
Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);


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
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed below.
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 


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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the ULN should be 
monitored more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) TBili elevations (>2 × ULN) by several days or weeks.  The increase 
in TBili typically occurs while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT 
and TBili values will be elevated within the same lab sample).  In rare instances, by the time 
TBili elevations are detected, AST/ALT values might have decreased.  This occurrence is 
still regarded as a potential DILI.  Therefore, abnormal elevations in either AST OR ALT in 
addition to TBili that meet the criteria outlined below are considered potential DILI (assessed 
per Hy’s law criteria) cases and should always be considered important medical events, even 
before all other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 


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The patient should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, GGT, PT/INR, total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a co-formulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product during Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.4.4. Exposure during Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the IP; or the female 
becomes or is found to be pregnant after discontinuing and/or being exposed to the 
IP.  An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products);


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
A male has been exposed (eg, because of treatment or environmental exposure) to the 
IP prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy;

If a patient or patient’s partner becomes or is found to be pregnant during the 
subject’s treatment with the IP, the investigator must report this information to Pfizer 
Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must 
be done irrespective of whether an AE has occurred and within 24 hours of awareness 
of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the IP;


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
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, 
the investigator will provide the patient with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the 
source documents that the patient was given the Pregnant Partner Release of 
Information Form to provide to his partner.
8.4.4.1. Exposure during Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.4.2. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.5. Medication Errors and Lack of Efficacy
Other exposures to the IP under study may occur in clinical trial settings, such as medication 
errors and lack of efficacy.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors and lack of 
efficacy*
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
*For lack of efficacy (particularly for studies conducted with vaccines, contraceptives, and products used in the 
treatment of life-threatening diseases or conditions [eg, anti-infectives]), see the Lack of Efficacy section below.
8.5.1. Medication Errors
Medication errors may result from the administration or consumption of the IP by the wrong 
patient, or at the wrong time, or at the wrong dosage strength.  Medication errors include:

Medication errors involving patient exposure to the IP;


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
Lack of dose reduction as specified by the protocol;

Continuation of treatment after patient met disconintuation criteria;

Incorrect study drug dose (overdose or underdose) taken by patient;

Patient did not take study medication for 6 or more days within 4 weeks, unless dose 
was withheld due to an AE;

Patient did not receive treatment as assigned by IRT;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study patient are to be captured on the medication error 
page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5.2. Overdose
An overdose of talazoparib is defined as any dose over the prescribed dose; there is no 
specific treatment in the event of an overdose, and symptoms are not established.  In the 
event of overdose, treatment with talazoparib should be stopped, and physicians should both 
consider gastric decontamination and follow general supportive measures.  All overdose 
events are to be reported within 24 hours of awareness (as per the requirements dictated in 
Section 8.5.1, Medication Errors) by the study site whether or not the overdose is associated 
with an adverse event and the sponsor/medical monitor must be contacted.  Whether or not 
the overdose is accompanied by an AE, as determined by the investigator, the overdose is 
recorded on the adverse event page of the CRF and, if applicable, any associated AE(s), 
serious and non-serious, are also recorded on an AE page of the CRF. Overdose should also 
be reported to Pfizer Safety within 24 hours on a Common Terminology for Serious Adverse 
Events (CTSAE) Report Form.
8.5.3. Lack of Efficacy 
Lack of efficacy in an approved indication should be reported as an SAE to Pfizer Safety.


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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is described in a SAP, which will be maintained by the sponsor.  The SAP may modify what 
is outlined in the protocol where appropriate; however, any major modifications of the 
primary endpoint definitions or their analyses will also be reflected in a protocol amendment.
Two analyses are planned, including an interim and a final analysis.  The interim analysis 
will be performed to evaluate the safety as well as the primary endpoint (pCR) after 
28 evaluable patients receive talazoparib 1 mg QD for 24 weeks, followed by surgery and 
central assessment of pCR.  The final analysis of the primary endpoint will be performed 
when the last patient enrolled who does not discontinue treatment prematurely completes 
talazoparib treatment 1 mg QD for 24 weeks, followed by surgery and central assessment of 
pCR, withdraws consent, discontinues from the study, or dies, whichever occurs first.
Statistical Methods
Analysis populations:
Evaluable population is the primary analysis population for all efficacy endpoints at the 
interim analysis as well as the final analysis and is defined as all patients enrolled in the 
study who receive 24 weeks of talazoparib treatment 1 mg QD, undergo breast surgery and 
central pCR assessment or who otherwise progress or die prior to being evaluated for pCR.  
All efficacy analyses will be conducted in the evaluable population unless otherwise 
specified in the statistical analysis plan.
For all patients, study drug treatment should continue until completion of protocol assigned 
therapy, followed by surgery unless the patient is no longer clinically benefitting in the 
opinion of the investigator, there is unacceptable toxicity, withdrawal of consent, or death.  
Dosing interruptions are permitted for a period of 28 days (one period up to 28 days OR 
several interruptions that total a number of days <80% of the prescribed course of treatment 
of 24 weeks) to allow recovery from drug related toxicities.  Patients who receive less than 
80% of the prescribed talazoparib dose during the neoadjuvant treatment period will not be 
part of the evaluable population.  However, patients who progress or die before pCR can be 
assessed (regardless of whether or not they received 80% of study treatment) by investigator 
and by ICR will be considered non-responders in the evaluable population.
The intent to treat (ITT) analysis and safety populations are defined as all patients enrolled in 
the study who received at least one dose of talazoparib.  All efficacy analyses will also be 
reported in the ITT analysis population, unless otherwise specified.  All safety analyses will 
be reported using the safety population.  Drug exposure in the safety analysis population will 
be summarized using descriptive statistics.
PRO analysis population is defined as all patients who completed a baseline and at least one 
post baseline quality-of-life assessment prior to the end of study treatment.


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The PK analysis population is defined as all patients treated with talazoparib for whom drug 
plasma concentration results (from at least 1 visit) are available.  For the PK analysis 
population, talazoparib concentrations will be summarized descriptively by nominal time and 
talazoparib dose strength.  Additionally, a subgroup of PK samples which meet pre-defined 
steady-state acceptance criteria (as detailed in the study SAP) will be summarized by 
nominal time and a within-patient average talazoparib steady state trough concentration will 
be listed by patient from this population. 
9.1. Sample Size Determination
Current standard of care in TNBC consists of chemotherapy-based regimens.  Published pCR 
rates vary greatly from 20% to 50%.  Data is limited for neoadjuvant regimens in gBRCA
positive TNBC where mostly retrospective subgroup analysis are available54 with the best 
chemotherapy-based regimens showing ~50% pCR rates.  Also, the investigator-initiated 
research study23 in neoadjuvant gBRCA positive BC where patients were treated with 
talazoparib monotherapy shows ~50% pCR in a HER2 negative population.  Similarly, 
patients with gBRCA mutated hormone receptor positive breast cancer had a pCR rate of 
3/5 (60%) and a combined RCB 0+1 rate of 4/5 (80%).22  Although based on a limited 
sample size, this promising pCR rate is substantially higher than that reported for patients 
with hormone receptor positive early breast cancer who receive chemotherapy and is similar 
to the pCR rates obtained by adding PARP inhibitors or carboplatin to conventional 
chemotherapy for the treatment of patients with early TNBC.44-46 These results suggest 
talazoparib monotherapy may benefit the gBRCA mutated hormone receptor positive 
subgroup of patients with early breast cancer as well.
Approximately sixty patients will be enrolled in the study and treated with talazoparib 1 mg 
QD for 24 weeks followed by surgery. With a sample size of 60 patients, the two-sided 
80% exact Blaker CI for the pCR rate would be at most 17% wide. If a pCR=50% is 
observed, the lower bound of the exact 80% CI would exclude 41%. 
An interim futility analysis, designed based on Bayesian predictive probability (PP), will be 
conducted once 28 evaluable patients are assessed for pCR. The PP is the probability of 
concluding a positive result by the end of the trial based on the cumulative information in the 
current stage.  The trial will be considered a success if the posterior probability that the true 
pCR rate exceeds 45% is ≥80%.  Predictive probability <10% was set as the futility boundary 
and assumed a non-informative beta (1,1) prior. Once 28 evaluable patients are assessed for 
pCR, if 11 responses or less are observed, the predictive probability of the trial being 
successful at the full sample size is less than 10%, at which point the Sponsor would 
recommend stopping the study due to futility. If ≥12 responses are observed in the first 
28 evaluable patients, the study will continue enrolling to 60 evaluable patients.  
In the HR positive group after 6 evaluable patients have completed treatment and undergone 
surgery, the pCR rate will be assessed. If 2 patients achieve pCR out of the initial 6, then the 
posterior probability that the true pCR rate in the HR positive group is greater than 
45% would be 28.9%, assuming a non- informative Beta (0.5,0.5) prior. Therefore, if 2 or 
more pCRs are observed, the HR positive subgroup will continue to enroll. If 1 or no pCRs 
are observed, then closing of the HR positive subgroup will be considered. In the event that 


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enrollment in the HR positive group is stopped, enrollment in the TNBC group will continue
to a total of 60 patients.  The evaluable population is the primary analysis population at the 
interim and final analysis. The intent-to-treat (ITT) population will include all patients who 
received at least one1 dose of talazoparib, regardless of whether or not they are considered 
evaluable.
9.2. Analysis of the Primary Endpoint
The primary study objective is to evaluate the pCR rate by independent central review (ICR) 
in the evaluable population. 
pCR is defined as the absence of residual invasive cancer in the breast and axillary lymph 
nodes on hematoxylin and eosin evaluation of the complete resected breast specimen and all 
sampled regional lymph nodes following completion of neoadjuvant systemic therapy 
(ie, ypT0/Tis ypN0 in the current AJCC staging system). 
pCR rate by ICR is defined as the number and percentage of patients achieving pCR by 
independent central review after talazoparib treatment for 24 weeks, followed by surgery, 
among all patients in the evaluable population. 
pCR rate by ICR will be analyzed at the time of the interim and final analyses and will be 
summarized along with the exact 80% and 95% CI. 
pCR rate by ICR will also be summarized in the ITT population along with exact 80% and 
95% CI.  Patients who discontinue treatment or study prematurely, are lost to follow-up, 
withdraw consent, progress or die before pCR can be assessed by central review will be 
considered as non-responders in the ITT population analysis.
For all patients, study drug treatment should continue until completion of protocol assigned 
therapy, followed by surgery unless the patient is no longer clinically benefitting in the 
opinion of the investigator, there is unacceptable toxicity, withdrawal of consent, or death.  
Dosing interruptions are permitted for a period of 28 days to allow recovery from drug 
related toxicities.  Patients who receive less than 80% of the prescribed talazoparib dose 
during the neoadjuvant treatment period will not be part of the evaluable population.
If a patient receives less than 80% of the protocol required treatment, undergoes surgery and 
achieves pCR by ICR, the patient will be counted as a responder in the ITT population, but 
will not be included in the evaluable population.
9.3. Analysis of Secondary Endpoints
The following efficacy parameters will be evaluated as secondary endpoints.


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9.3.1. Pathological Complete Response by Investigator Review
pCR rate by investigator is defined as the number and percentage of patients achieving pCR 
by investigator review after talazoparib treatment for 24 weeks, followed by surgery, among 
all patients in the evaluable population pCR rate by investigator in the evaluable population 
will be analyzed at the time of the interim and final analyses and will be summarized along 
with the exact 95% CI.
pCR by investigator will also be summarized in the ITT population, along with the exact 
95% CI.  Patients who discontinue treatment or study prematurely, are lost to follow-up, 
withdraw consent, progress, or die before pCR can be assessed by investigator will be 
considered non-respondersin the ITT population analysis.
If a patient receives less than 80% of the protocol required treatment, undergoes surgery and 
achieves pCR by ICR, the patient will be counted as a responder in the ITT population, but 
will not be included in the evaluable population.
9.4. Ethical Conduct of the Study
This study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the following:

International Ethical Guidelines for Biomedical Research Involving Human Patients 
(Council for International Organizations of Medical Sciences 2002);

ICH Guideline for Good Clinical Practice;

US Code of Federal Regulations (CFR) sections that address clinical research studies, 
and/or other national and local regulations, as applicable;

ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice (GGCP)
E6 (ICH E6);

The ethical principles established by the Declaration of Helsinki.
Specifically, this study is based on adequately performed laboratory and animal 
experimentation.  The study will be conducted under a protocol reviewed and approved by an 
IRB/EC/research ethics board (REB) and will be conducted by scientifically and medically 
qualified persons. The benefits of the study are in proportion to the risks.  The rights and 
welfare of the patients will be respected and subject participation continued as long as the 
Investigators conducting the study do not find the hazards to outweigh the potential benefits.  
Each patient, or his/her legally authorized representative will provide written, informed 
consent before any study-related tests or evaluations are performed.


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9.4.1. Residual Cancer Burden
The residual cancer burden is a continuous index derived from the following: primary tumor 
dimensions; cellularity of the tumor bed; axillary nodal burden.
Residual cancer burden by ICR will be reported as a categorical variable with four classes 
(categories) RCB 0 (pCR), I (minimal RCB), II (moderate RCB), III (extensive RCB).  
Number and percentage of patients for all 4 categories in the evaluable population will be 
reported along with exact 95% CI.  The analysis of RCB by ICR will be conducted in the 
evaluable population.
9.4.2. Pathological Complete Response in Breast by Independent Central Review and 
Investigator
pCR in breast is defined as the absence of residual invasive cancer in the breast and axillary 
lymph nodes on hematoxylin and eosin evaluation of the complete resected breast specimen 
following completion of neoadjuvant therapy with talazoparib. 
pCR rate in breast by ICR is defined as the number and percentage of patients achieving pCR 
in breast by independent central review after talazoparib treatment for 24 weeks, followed by 
surgery, among all patients in the evaluable population.  
pCR rate in breast by investigator review is defined as the number and percentage of patients 
achieving pCR in breast by investigator review after talazoparib treatment for 24 weeks, 
followed by surgery, among all patients in the evaluable population.  
pCR in breast rate will be summarized using descriptive statistics along with the exact 
95% CI. 
pCR in breast rate will also be summarized in the ITT population along with exact 95% CI 
Patients who discontinue treatment or study prematurely, are lost to follow-up, withdraw 
consent, progress or die before pCR in breast can be assessed, will be considered 
non-responders. 
If a patient receives less than 80% of the protocol required treatment, undergoes surgery and 
achieves pCR in breast, the patient will be counted as a responder in the ITT population, but 
will not be included in the evaluable population.
9.4.3. Event-free Survival and Event-free Survival at 3 Years
EFS is defined as the time from surgery date to first documentation of local or distant 
recurrence or death or initiation of antineoplastic therapy before documentation of first 
relapse.  Patients discontinuing study before documentation of first relapse or death, but after 
surgery will be censored observations for EFS.  Additional details regarding censoring rules 
will be presented in the statistical analysis plan.


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 5
E F S at 3 years is defi ne d as t he pr o ba bilit y of bei n g e ve nt -free at 3 years usi n g Ka pla n Meier 
met h o ds.  T he 9 5 % CI f or E F S at 3 ye ars will be calc ulate d usi n g t he Br o o k me y er-Cr o wle y  
met h o d.  T he a nal ys is of E F S at 3 years will be perf or me d i n t he e val ua ble p o p ulati o n.
9. 4. 4. O ver all S ur vi v al a n d O ver all S ur vi v al at 3 Ye ars
O S is defi ne d as t he ti me fr o m first d ose of talaz o pari b t o deat h d ue t o a n y ca use.  Patie nts 
n ot k n o w n t o ha ve die d at t he ti me of t he a nal ys is will be ri ght ce ns ore d o n t he date t he y  
were last k n o w n t o be ali ve bef ore t he a nal ys is data c ut off date.  Details o n ce ns ori n g 
c o n ve nti o ns will be prese nte d i n t he statistical a nal ysis pla n. 
O S at 3 y ears is defi ne d as t he pr o ba bilit y of bei n g ali ve at 3 years afte r first d ose of 
talaz o pari b usi n g Ka pla n-Meier met h o ds.  T he 9 5 % CI  f or O S at 3 years will be calc ulate d 
usi n g t he Br o o k me y er-Cr o wle y  met h o d.  T he a nal ysis of O S at 3 years will be perf or me d i n 
t he e val ua ble a n d I T T p o p ulati o n.
9. 4. 5. Ti me t o Defi niti ve Deteri or a ti o n I n Gl o b al He alt h St at us/ Q ol Per E ur o pe a n 
Or g a niz ati o n F or Rese arc h A n d Tre at me nt Of C a ncer Q u alit y Of Life Q uesti o n n aire 
( E O R T C Q L Q-C 3 0)
Ti me t o defi niti ve deteri orati o n of patie nt -re p orte d gl o bal healt h stat us/ Q o L ( defi ne d as 
> 1 0 - p oi nt decrease fr o m baseli ne wit h o ut a n y s u bse q ue nt < 1 0 p oi nt decrease) will be 
s u m marize d usi n g s ur vi val a nalys is met h o ds.  T his will i ncl u de Ka pla n-Meier esti mates of 
t he me dia n a n d 2 5t h a n d 7 5 t h perce ntiles, 9 5 % CI  (base d o n t he Br o o k me yer -Cr o wle y  
met h o d ), Ka pla n-Meier pl o ts will als o be pr o vi de d.
9. 4. 6. Ti me t o Defi niti ve Deteri or ati o n I n N a use a A n d V o miti n g S y m pt o ms Per E O R T C 
Q L Q -C 3 0
Ti me t o defi niti ve deteri orati o n of patie nt -re p orte d na usea a n d v o miti n g sy m pt o ms ( defi ne d 
as > 1 0-p oi nt i ncrease fr o m baseli ne wit h o ut a n y  s u bse q uent < 1 0 p oi nt i ncrease) will be 
s u m marize d usi n g s ur vi val a nalys is met h o ds.  T his will i ncl u de Ka pla n-Meier esti mates of 
t he me dia n a n d 2 5t h a n d 7 5 t h perce ntiles, a n d 9 5 % CI  (base d o n t he Br o o k me y er-Cr o wle y  
met h o d ).  Ka pla n-Meier pl ots will als o be pr o vi de d .  
9. 4. 7. C h a n ge Fr o m B aseli ne I n Gl o b al He alt h St at us/ Q ol, F u ncti o ni n g, A n d S y m pt o ms 
Per E O R T C Q L Q- C 3 0 a n d E O R T C Q L Q B R -2 3
 
 
A l o n git u di nal mi xe d -effect m o del a nal ys es will be use d t o assess c ha n ge fr o m baseli ne i n 
gl o bal healt h stat us/ Q O L, f u ncti o ni n g, a n d s y m pt o ms per E O R T C Q L Q -C 3 0, E O R T C Q L Q 
B R -2 3C CI
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 6
9. 4. 8. C h a n ge Fr o m B aseli ne I n Pr o p orti o n Of P atie nts Wit h Misse d E x pecte d 
Me nstr u al Peri o d Vers us B aseli ne A n d Pr o p orti o n Of P atie nts Wit h Deteri or ati o n I n 
N a use a A n d V o miti n g S y m pt o ms 
T he pr o p orti o n of fe male patie nts wit h misse d e x pecte d me nstr ual peri o d p ost baseli ne per 
P R O -C T C A E ( vs pr o p orti o n of patie nts wit h misse d e x pecte d me nstr ual peri o d at baseli ne); 
a n d pr o p orti o n of patie nts wit h deteri orati o n i n na usea a n d v o miti n g s y m pt o ms ( vs n o 
deteri orati o n) will be c o m pare d.
Deteri orati o n i n na usea a n d v o miti n g s y m pt o ms is defi ne d as a 1 0 p oi nt i ncrease fr o m 
baseli ne f or t hat s pecific ti me p oi nt. 
I m pr o ve me nt i n na usea a n d v o miti n g s ym pt o ms is defi ne d as a 1 0 p oi nt decrease fr o m 
baseli ne f or t hat s pecific ti me p oi nt.
N o c ha n ge i n na usea a n d v o miti n g s y m pt o ms w o ul d be defi ne d as sc ores t hat d o n ot satisf y  
b ot h cate g ories me nti o ne d a b o ve.
9. 5. P h ar m ac o ki netic A n al ysis
T he relati o ns hi p bet wee n stea d y -state talaz o pari b tr o u g h c o nce ntrati o ns wit h t u m or res p o nse 
a n d/ or safet y fi n di n gs after acc o u nti n g f or p ote ntial c o variates ma y be e val uate d.  T he res ults 
of a n y e x pl orat or y  p o p ulati o n P K/ P D a nal ysis ma y be re p orte d se parately fr o m t he cli nica l 
st u d y re p ort.
All patie nts treate d wit h talaz o pari b f or w h o m dr u g plas ma res ults (fr o m at least 1 visit) are 
a vaila ble w o ul d be i ncl u de d i n t he P K a nal ys is.  Talaz o pari b c o nce ntrati o ns will be 
s u m marize d descri pti vel y by n o mi nal ti me a n d talaz o pari b d ose stre n gt h.  A d diti o nall y, a 
s u b gr o u p of P K sa m ples w hic h meet pre-defi ne d stea d y -state acce pta nce criteria (as detaile d 
i n t he st u d y S A P) will be s u m marize d b y n o mi nal ti me a n d a wit hi n- patie nt a vera ge 
talaz o pari b stea dy- state tr o u g h c o nce ntrati o n will be liste d b y patie nt fr o m t his p o p ulati o n. 
 
 
 
 
 
 
 
 
 
 
 
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 9 7
 
9. 7. E x pl or at or y A n al ysis 
S u b gr o u p a nal ys es will be c o n d ucte d as a p pr o priate f or p C R a n d R C B f or t he h or m o ne 
rece pt or p ositi ve s u b gr o u p a n d t he T N B C s u b gr o u p.  T he s u b gr o u p a nal yses will re p ort e xact 
c o nfi dence i nter vals f or p C R b y  IC R a n d i n vesti gat or.  F or R C B, t he e xact CI s will be 
calc ulate d b y I CR o nl y.  
9. 8. S afet y A n al ysis
All safet y a nal ys es will be perf or me d usi n g t he safet y  p o p ulati o n, defi ne d as all patie nts w h o 
recei ve a ny a m o u nt of st u d y dr u g.  Dr u g e x p os ure will be s u m marize d usi n g descri pti ve 
statistics.  Treat me nt-e mer ge nt safety data will be c ollecte d fr o m t he first d ose of st u d y dr u g 
treat me nt t hr o u g h 2 8 da ys after t he date of per ma ne nt disc o nti n uati o n fr o m st u d y or bef ore 
i nitiati o n of ne w a nti ne o plastic or i n vesti gati o nal t hera p y, w hic he ver occ urs first. 
A d verse E ve nts
T he safet y of talaz o pari b will be e val uate d b y t he a nal ys is of i nci de nce of seri o us a n d 
n o n- seri o us a d verse e ve nts, se verit y of a d verse e ve nts, i nci de nce of d ose m o dificati o ns a nd 
of per ma ne nt treat me nt disc o nti n uati o n d ue t o a d verse e ve nts, a n d i nci de nce of ne w 
cli nicall y si g nifica nt c ha n ges i n cli nical la b orat or y val ues a n d vital si g ns.
A d verse e ve nts will be c o de d t o preferre d ter m a n d s y ste m or ga n class usi n g Me d D R A a n d 
classi fie d by se verit y usi n g t he C T C A E, versi o n 4.  T he n u m ber a n d perce nta ge of patie nts 
wit h a d verse e ve nts will be prese nte d b y Me d D R A s yste m or ga n class a n d preferre d ter m, 
relati o ns hi p t o st u d y treat me nt, a n d se verity.  Descri pti ve statistics will be use d. 
A n al ysis of L a b or at or y Res ults
La b orat or y  val ues will be classifie d b y se verity usi n g t he C T C A E, versi o n 4.  L a b orat or y 
s hift ta bles of baseli ne t o ma xi m u m p ost-baseli ne res ults t o eac h s u bse q ue nt visit will be 
pr o d uce d as a p pr o priate.
A n al ysis of Vit al S i g ns/ P h ysic al E x a mi n ati o n
Vital si g ns a n d p h ys ical e xa mi nati o n fi n di n gs will be s u m marize d b y visit usi n g descri pti ve 
statistics.
9. 9. I nteri m A n al ysis
O ne i nteri m a nal ys is will be perf or me d t o assess efficac y a n d safety after 2 8 e val ua ble
patie nts c o m plete tal az o pari b treat me nt 1 m g Q D f or 2 4 wee ks, f oll o we d b y s ur ger y  a n d 
assess me nt of p C R b y IC R.  T he trial will be c o nsi dere d a s uccess if t he p osteri or pr o ba bilit y  
t hat t he tr ue p C R rate e xcee ds 4 5 % is ≥8 0 %. At t he i nteri m, t he criteria f or f utilit y  are as 
f oll o ws: O nce 2 8 e val ua ble patie nts are assesse d f or p C R, if 1 1 res p o nses or less are 
o bser ve d, t he pre dicti ve pr o ba bilit y  of a s uccessf ul trial at t he f ull sa m ple size is less t ha n 
C CI


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10%, at which point the investigator would recommend stopping the study due to futility. If 
≥12 responses are observed in the first 28 evaluable patients, the study will continue 
enrolling to 60 patients. 
In the HR positive group after 6 evaluable patients have completed treatment and undergone 
surgery, the pCR rate will be assessed. If 2 patients achieve pCR out of the initial 6, then the 
posterior probability that the true pCR rate in the HR positive group is greater than 
45% would be 28.9%, assuming a non-informative Beta (0.5,0.5) prior. Therefore, if 2 or 
more pCRs are observed, the HR positive subgroup will continue to enroll. If 1 or no pCRs 
are observed, then closing of the HR positive subgroup will be considered.
Interim analysis results may be used for internal business decisions regarding future study 
planning.  Additional analysis details will be documented in an interim analysis SAP or final 
SAP.
9.10. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the patient’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician patient chart.  In these 
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Patient Information and Consent
All parties will ensure protection of subject personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients.  The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation.  


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Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, decisionally-impaired adult), how 
the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject, or the patient’s legally acceptable representative, before any 
study-specific activity is performed, unless a waiver of informed consent has been granted by 
an IRB/EC.  The investigator will retain the original of each patient’s signed consent 
document.
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the IP, Pfizer 
should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
End of trial is defined as the time at which it is deemed that a sufficient number of patients 
have been recruited and completed the study as stated in the regulatory application 
(ie, clinical trial application [CTA]) and ethics application.  Poor recruitment (recruiting less 
than the anticipated number in the CTA) is not a reason for premature termination but is 
considered a normal conclusion to the study.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or IP safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of talazoparib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) as quickly as practical.  As directed by Pfizer, all study materials must be 
collected and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 24 weeks of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the pre-specified protocol or was terminated.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.


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The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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16. REFERENCES
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Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 0
A p pe n di x 1. A b bre vi ati o n s 
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y  be use d i n t he pr ot oc ol. 
A b bre vi ati o n
Ter m
A B R A Z O
A P hase 2, 2 -Sta ge, 2 -C o h ort St u d y  of Talaz o pari b ( B M N 6 7 3), 
i n Locall y  A d va nce d a n d/ or Metastatic Breast Ca ncer Patie nts 
Wit h B R C A M utati o n ( A B R A Z O St u d y )
A C
c ycl o p h os p ha mi de
A D M E
a bs or pti o n, distri b uti o n, meta b olis m, a n d e xcreti o n
A E
a d verse e ve nt
AJ C C
A merica n J oi nt C o m mittee o n Ca ncer
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 C O -C A P
A merica n S ocie t y of Cli nical O nc ol o g y-C olle ge of A merica n 
Pat h ol o gists
A S T
as partate a mi n otra nsferase
Bcl - 2
B- cell l ym p h o ma 2
B C S
breast c o nser vi n g s ur ger y
B C R P
Breast ca ncer resista nce pr otei n
B C S R
breast c o nser vi n g s ur ger y  rate
b d
t wice daily
BI C R
bli n de d i n de pe n de nt ce ntral re vie w
Bi o Mari n
Bi o Mari n P har mace utical, I nc. ( Sa n Rafael, C A); ori gi nal h ol der 
of talaz o pari b I N D
B M N 6 7 3
Bi o Mari n P har mace utical, I nc. le gac y  c o m p o u n d n u m ber f or 
talaz o pari b (als o k n o w n as P F 0 6 9 4 4 0 7 6, M D V3 8 0 0)
B R C A
breast ca ncer s usce pti bilit y  ge ne
B R C A 1
breast ca ncer s usce pti bilit y  ge ne 1 
B R C A 2
breast ca ncer s usce pti bilit y ge ne 2
B R C A 1/ 2
breast ca ncer s usce pti bilit y  ge nes 1 a n d 2
B U N
bl o o d urea nitr o ge n
c D N A
c o m ple me ntar y D N A
C D x
C o m pa ni o n Dia g n os tics
C E P 1 7
c hr o m os o me 1 7 p ol ys o m y
C F R
c o de of fe deral re g ulati o ns
CI
c o nfi de nce i nter val
C N S
ce ntral ner v o us s ys te m
C K
creati ne ki nase
C L C R
creati ni ne cleara nce
C L / F
a p pare nt cleara nce
C L I A
Cli nical L a b orat or y Im pr o ve me nt A me n d me nts
C M F
c ycl o p h os p ha mi de, met h otre xate, a n d fl u or o uracil
C CI
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 1
A b bre vi ati o n
Ter m
C R
c o m plete res p o nse
C R F
case re p ort f or m
C R R
cli nical res p o nse rate
C R P R
C- reacti ve pr otei n test
C S A
cli nical st u d y a gree me nt
C S F
cere br os pi nal fl ui d
C S R
cli nical st u d y re p ort
C T
c o m p ute d t o m o gra p h y
C T A
cli nical trial a p plicati o n
C T C A E
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C T S A E
C o m m o n Ter mi n ol o g y  f or Seri o us A d verse E ve nts
Ctr o u g h
tr o u g h c o nce ntrati o ns
D CI S
d uctal i n sit u carci n o ma
D D R
D N A da ma ge r e pair
D F S
disease -free s ur vi val
DI LI
dr u g -i n d uce d li ver i nj ur y
D M C
data m o nit ori n g c o m mittee
D N A
de o x yri b o n ucleic aci d
D S B
d o u ble -stra n d brea k
D U
dis pe nsa ble u nit
D X
Dia g n ostics
E B C
earl y breast ca ncer
E C
et hics 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 C R F
electr o nic case re p ort f or m
e G F R
esti mate d gl o mer ular filtrati o n rate
E D P
e x p os ure d uri n g pre g na nc y
E F S
e ve nt-free s ur vi val
E M B R A C A
A St u d y  E val uati n g Talaz o pari b ( B M N 6 7 3), a P A R P In hi bit or, 
i n A d va nce d a n d/ or Metastatic Breast Ca ncer Patie nts Wit h 
B R C A M utati o n ( E M B R A C A St u d y )
E O R T C
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer
E O T 
E n d of Treat me nt
E R
estr o ge n rece pt or
E S M O
E ur o pea n S ociet y f or Me dical O nc ol o g y
E U
E ur o pea n U ni o n
E u dra C T
E ur o pea n Cli nical Trials Data base
F D A
F o o d a n d Dr u g A d mi nstrati o n
F S F V
first s u bject first visit
F S H
f ollicle-sti m ulati n g h or m o ne
C CI
C CI


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Abbreviation
Term
gBRCA
germline mutation of breast cancer susceptibility gene
GCP
Good Clinical Practice
GGCP
Guidelines for Good Clinical Practice
GGT
gamma-glutamyl transferase
GI 
gastrointestinal tract
Hb
hemoglobin
HBV
hepatitis B virus
HCV
hepatitis C virus
HDPE
high density polyethylene
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HPMC
hydroxypropyl methylcellulose 
hR
homologous recombination
hRD
homologous recombination defect
HR 
heart rate
HRQL
health-related quality of life
HRT
hormonal replacement therapy
HRU
healthcare resource utilization
IB
investigator’s brochure
ICH
International Council for Harmonisation
ICH E6
ICH Harmonised Tripartite Guideline: Guideline for Good 
Clinical Practice E6
ICR
independent central review
ID
identification
IIR
investigator-initiated research
IND
investigational new drug application
INR
international normalized ratio
IHC
immunohistochemistry
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISH
in situ hybridization
ITT 
intent to treat analysis population
IUD
intrauterine device
IWR
interactive web response
IWRS
interactive web response system
IXRS
interactive voice and Web response system
LDH
lactate dehydrogenase
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
L/h
liters per hour
LSLV
last subject last visit 


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Abbreviation
Term
MDRD
modification of diet in renal disease
MDV3800
Legacy-Medivation, Inc. compound number for talazoparib (also 
known as PF 06944076, formerly BMN 673)
Medivation
Medivation, Inc., a wholly owned subsidiary of Pfizer Inc as of 
28 September 2016 (in-licensed talazoparib from BioMarin on 
06 October 2015)
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MnB
meningitis serogroup B
MRI
magnetic resonance imaging
N/A
not applicable
NSABP
National Surgical Adjuvant Breast and Bowel Project
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
p
probability value
PARP
poly(ADP-ribose) polymerase
PARP1
poly(ADP-ribose) polymerase 1
PARP2
poly(ADP-ribose) polymerase 2
PARPi
poly(ADP-ribose) polymerase inhibitor
pCR
pathological complete response
PCD
primary completion date
PD
pharmacodynamic(s)
PCT
physician’s choice of treatment
PF-06944076
Pfizer Inc compound number for talazoparib (also known as 
MDV3800, formerly BMN 673)
PF-06944076-15
Pfizer Inc compound number for talazoparib tosylate
PFS
progression-free survival
PGx
pharmacogenomic(s)
PI
principal investigator
P-gp
permeability glycoprotein
PK
pharmacokinetic(s)
PP
predictive probability
PR
progesterone receptor
PRO
patient reported outcomes
PRO-CTCAE
Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events
PT
prothrombin time
QD
once a day
QLQ
quality of life questionnaire
QLQ-BR23
Breast Cancer-Specific Quality of Life Questionnaire 
QLQ-30
Quality of Life Questionnaire-Core 30
QoL
quality of life


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Abbreviation
Term
RBC
red blood cells
RCB
residual cancer burden
REB
research ethics board
RECIST v1.1
revised response evaluation criteria in solid tumors 
RNA
ribonucleic acid
RS
recurrence score
SAE
serious adverse event
SAP
statistical analysis plan
SMCC
with silicified microcrystalline cellulose 
SOP
standard operating procedure
SRSD
single reference safety document
SSB
single-strand break
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TNBC
triple-negative breast cancer
TPC
treatment of physician’s choice
ULN
upper limit of normal
US
United States
V/F
apparent volume of distribution
WBC
white blood cells
WCBP
women of childbearing potential
Definition of Terms: 
Investigational Product (IP): “A pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including a product with a marketing 
authorization when used or assembled (formulated or packaged) in a way different from the 
approved form, or when used for an unapproved indication, or when used to gain further 
information about an approved use” (from International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use Harmonised 
Tripartite Guideline: Guideline for Good Clinical Practice E6 [ICH E6]).  The terms “IP” and 
“study drug” may be used interchangeably in the protocol.


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Appendix 2. European Organisation for Research and Treatment of Cancer 
Quality-of-Life Core Questionnaire QLQ C30
We are interested in some things about you and your health.  Please answer all of the 
questions yourself by selecting the number that best applies to you.  There are no “right” or 
“wrong” answers.  The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year): 
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
1.
Do you have any trouble doing strenuous 
activities, like carrying a heavy shopping bag or a 
suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk 
outside of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the 
day?
1
2
3
4
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
6.
Were you limited in doing either your work or 
other daily activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or 
other leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4
Please go to the next page


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During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on 
things, like reading a newspaper or watching 
television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment 
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment 
interfered with your social activities?
1
2
3
4
28
Has your physical condition or medical treatment 
caused you financial difficulties?
1
2
3
4
For the following questions please select the number between 1 and 7 that 
best applies to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very Poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very Poor
Excellent
Copyright 1995 EORTC Quality of Life Group.  All rights reserved.  Version 3.0


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Appendix 3. European Organisation for Research and Treatment of Cancer 
Quality-of-Life Breast Cancer Module QLQ-BR23


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Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 1 9
C CI
C CI


Talaz o pari b ( P F -0 6 9 4 4 0 7 6; M D V 3 8 0 0)
C 3 4 4 1 0 2 0
Fi nal Pr ot oc ol A me n d me nt 4, 1 4 A u g ust 2 0 1 9
P FI Z E R C O N FI D E N TI A L
Pa ge 1 2 0
C CI


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Appendix 5. Patient-Reported Outcomes version of the Common Terminology Criteria 
for Adverse Events

SAP_001.pdf: