Neoadjuvant Talazoparib for Patients With a BRCA Deleterious Mutation

Main Study:

Study Drug Administration:

Each study cycle is 28 days.

If you are found to be eligible to take part in this study, you will take talazoparib
capsules by mouth 1 time each day at about the same time every morning. While it is not
required, if you have a caregiver, you should advise them to wear gloves when handling the
talazoparib capsules.

You will be given a study drug diary to write down what time you take talazoparib and if you
miss or vomit any doses. You will return your completed study drug diary and study drug
bottles with any unused study drug to each study visit. While it is not required, if you have
a caregiver, you should advise them to wear gloves when handling the talazoparib capsules.

If you have side effects, the study doctor may decide to lower your study drug dose or have
you stop taking the drug. You may be able to restart the study drug at the same or a lower
dose. The study doctor will discuss this with you.

On the days that you have study visits, you will take your dose of study drug at the clinic.
Do not take your dose of study drug at home on these days.

Study Visits:

On Day 1 of all cycles:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

Every week, blood (about 1 tablespoon) will be drawn for routine tests. If the study doctor
approves it, you may not have to return to the clinic on Days 8 and 15 of Cycle 2. You may
have these blood draws done at a local laboratory and have the results sent to the study
doctor. Your study doctor will discuss this with you.

On Days 1, 8, and 22 of Cycle 1, blood (about 1-2 tablespoons) will be drawn for biomarker,
PGt, and proteomic testing. Biomarkers are found in the blood and tissue and may be related
to your reaction to the study drug.

On Day 1 of Cycle 2,you will have an ultrasound of your breast(s) to check the status of the
disease.

Within 7 days before completing treatment with talazoparib:

- Blood (about 1-2 tablespoons) will be drawn for biomarker, PGt, and proteomic testing.

- You will have a core biopsy and an image-guided FNA to check the status of the disease
and for biomarker, PGt, and proteomic testing.

After your last dose of Cycle 2:

- You will have a physical exam.

- Blood (about 1 tablespoon) will be drawn for routine tests.

- You will have an ultrasound of your breast(s) to check the status of the disease.

After Cycle 2, you will receive chemotherapy and/or have surgery to remove the tumor as part
of the standard of care for the disease. You will be given a separate consent form that
describes this procedure and its risks. During the surgery, some of the tissue that is
removed will be collected to check the status of the disease and for biomarker, PGt, and
proteomic testing. After the surgery, you may be called by the study doctor to ask how you
are doing. This call should last about 10 minutes.

Cell lines will be created using your collected tissue. Cell lines are blood or tissue cells
that are grown in a laboratory or in research animals.

Xenograft models will be created using your collected tissue. A xenograft is taking a graft
of tissue from one donor and transplanting it into another. For this study, we will take a
graft of your tissue and transplant it into a mouse to help us better understand BRCA
mutations.

After surgery, you will receive chemotherapy as part of the standard of care for the disease.

Length of Treatment:

You will receive up to 2 cycles of study drug.You will no longer be able to take the study
drug if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

If you stop taking the study drug because the disease got worse, you will have an
image-guided core biopsy and FNA performed for biomarker testing, including genetic
biomarkers, proteomic testing, and PGt testing. This will be performed before you start any
new chemotherapy treatments as part of your standard care.

Your participation on the study will be over after the surgery.

Expansion Cohort:

Study Visits:

Each study cycle is 28 days.

If you are found to be eligible to take part in this study, you will take talazoparib
capsules by mouth 1 time each day at about the same time every morning. While it is not
required, if you have a caregiver, you should advise them to wear gloves when handling the
talazoparib capsules.

You will be given a study drug diary to write down what time you take talazoparib and if you
miss or vomit any doses. You will return your completed study drug diary and study drug
bottles with any unused study drug to each study visit.

If you have side effects, the study doctor may decide to lower your study drug dose or have
you stop taking the drug. You may be able to restart the study drug at the same or a lower
dose. The study doctor will discuss this with you.

On the days that you have study visits, you will take your dose of study drug at the clinic.
Do not take your dose of study drug at home on these days.

Study Visits:

On Day 1 of all cycles:

- You will have a physical exam

- Blood (about 1 tablespoon) will be drawn for routine tests.

On Days 1 and 15 of Cycle 1 only, blood (about 1 tablespoon) will be drawn for routine tests.
You may have these blood draws done at a local laboratory and have the results sent to the
study doctor. Your study doctor will discuss this with you.

On Day 1 of Cycle 1 and Cycle 3 only, blood (about 1-2 tablespoons) will be drawn for
biomarker, PGt, and proteomic testing. Biomarkers are found in the blood and tissue and may
be related to your reaction to the study drug.

On Day 1 of Cycle 3 and Day 1 of Cycle 5, you will have an ultrasound of your breast(s) to
check the status of the disease.

After receiving study drug for up to 6 cycles, you will have surgery to remove the tumor as
part of the standard of care for the disease. You will be given a separate consent form that
describes this procedure and its risks. During the surgery, some of the tissue that is
removed will be collected to check the status of the disease and for biomarker, PGt, and
proteomic testing. After the surgery, you may be called by the study doctor to ask how you
are doing. This call should last about 10 minutes.

Cell lines will be created using your collected tissue. Cell lines are blood or tissue cells
that are grown in a laboratory or in research animals.

Xenograft models will be created using your collected tissue. A xenograft is taking a graft
of tissue from one donor and transplanting it into another. For this study, we will take a
graft of your tissue and transplant it into a mouse to help us better understand BRCA
mutations.

After surgery, you will receive chemotherapy as part of the standard of care for the disease.

Length of Treatment:

You will receive up to 6 cycles of study drug.You will no longer be able to take the study
drug if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

If you stop taking the study drug because the disease got worse, you will have an
image-guided core biopsy and FNA performed for biomarker testing, including genetic
biomarkers, proteomic testing, and PGt testing. This will be performed before you start any
new chemotherapy treatments as part of your standard care.

Your participation on the study will be over after the surgery.

Inclusion Criteria:

1. Signed written informed consent

2. Histologically confirmed primary invasive adenocarcinoma of the breast with the size
of the primary tumor being at least 1 cm on imaging by either mammography, ultrasound
or breast MRI

3. Negative HER-2/neu- disease defined as patients with FISH ratio <2.0 or <6.0 HER2 gene
copies per nucleus, and IHC staining scores of 0, 1+, or 2+.

4. No treatment for current primary invasive adenocarcinoma of the breast such as
irradiation, chemotherapy, immunotherapy, investigational therapy or surgery. Previous
treatment for breast an/or ovarian cancer with chemotherapy, endocrine therapy,
surgery and radiation are allowed if >/=3 years prior to current diagnosis and there
is no clinical evidence of metastatic disease.

5. ECOG performance status of 0-1

6. Baseline MUGA or echocardiogram scans with LVEF of > 50%.

7. Patient must have adequate organ function as determined by the following laboratory
values: a. ANC>/=1,500 /uL b. Platelets >/=100,000 / uL c. Hgb >/= 9 g/dL d.
Creatinine clearance >50 ml/min e. Total bilirubin X ULN

8. Men or women 18 years of age or older.

9. Negative serum or urine pregnancy test for women within 7 days of receiving the first
dose of the study medication for women of childbearing potential. Women will be
considered not of childbearing potential and exempt from pregnancy testing if they are
either a) older than 50 and amenorrheic for at least 12 consecutive months following
cessation of all exogenous hormonal treatments, or b) have documentation of
irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or
bilateral salpingectomy, but not tubal ligation.

10. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for up to 8 weeks after the
last dose of investigational product. Men on study also must be using contraception.

11. Identified deleterious mutation in BRCA 1 or 2 genes ( this does not include variants
of uncertain significance).

12. Eligible to receive standard of care chemotherapy and/or surgery based upon standard
practices or institutional guidelines.

Exclusion Criteria:

1. Women who are pregnant (including positive pregnancy test at enrollment or prior to
study drug administration) or breast-feeding.

2. Disease free of prior malignancy for < 3 years with the exception of curatively
treated basal carcinoma of the skin or carcinoma in situ of the cervix.

3. Any other previous antitumor therapies for the current cancer event.

4. Has had major surgery within 21 days before Cycle 1 Day 1

5. Gastrointestinal tract disease or defect with associated malabsorption syndrome

6. Uncontrolled inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)

7. Myocardial infarction within 6 months before starting therapy, symptomatic congestive
heart failure (New York Heart Association > class II), unstable angina, or unstable
cardiac arrhythmia requiring medication

8. Serious intercurrent infections or non-malignant medical illness that are uncontrolled
or the control of which may be jeopardized by this therapy

9. Psychiatric disorders or other conditions rendering the subject incapable of complying
with the requirements of the protocols

10. Unable to take oral medications

11. Known to be human immunodeficiency virus positive

12. Known active hepatitis C virus, or known active hepatitis B virus

13. Concurrent disease or condition that would interfere with study participation or
safety, such as any of the following: • Active, clinically significant infection
either grade > 2 by National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) v4.03 or requiring the use of parenteral anti-microbial agents
within 14 days before Day 1 of study drug • Clinically significant bleeding diathesis
or coagulopathy, including known platelet function disorders • Non-healing wound,
ulcer, or bone fracture

14. Known hypersensitivity to any of the components of talazoparib