Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in Her-positive, Her2-positive Metastatic Breast

Inclusion Criteria:

- Women with metastatic breast cancer, measurable or evaluable disease including bone
metastasis only (as per the Response Evaluation Criteria in Solid Tumors [RECIST]
v1.1)

- No prior systemic treatment for metastatic breast cancer

- Pathologic confirmation of metastatic breast cancer diagnosed by core needle biopsy

- Metastatic breast cancer with any evidence of ER or PR positivity in ≥ 1% cells in
biopsy specimens from either a primary or metastatic site

- Evidence of HER2 positive metastatic breast cancer in either a primary or metastatic
site, if 3+ by an IHC method defined as uniform membrane staining for HER2 in 10% or
more of tumor cells or demonstrate HER2 gene amplification by an ISH method (single
probe, average HER2 copy number ≥6.0 signals/cell; dual probe HER2/CEP17 ratio ≥2.0
with an average HER2 copy number ≥4.0 signals/cell; dual probe HER2/chromosome
enumeration probe (CEP) 17 ratio ≥2.0 with an average HER2 cop number <4.0
signals/cell; and HER2/CEP17 ratio <2.0 with an average HER2 copy number ≥6.0
signals/cell) or amplified by FISH > 2.0. High average copy number of HER2 (≥6.0
signals/cell) is considered positive regardless of the HER2/CEP17 ratio.

- Women 18 years and older

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Stable brain metastasis allowed (>2 weeks, clinically stable post treatment with
surgery +/- radiation or radiation alone and off steroids)

- Transthoracic echocardiogram with ejection fraction > 50%

- Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as
goserelin or leuprolide. Postmenopausal status is defined by any one of the following
criteria:

- Prior bilateral oophorectomy.

- Prior ovarian radiation for the purpose of ablation.

- Age ≥ 60 years.

- Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
tamoxifen, or ovarian suppression) and FSH, LH, and estradiol in the
postmenopausal range per local normal.

Laboratory values (≤ 28 days prior to registration)

- Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

- Platelet Count ≥ 75,000/ mm3

- Hg >9 g/dL

- Total Bilirubin ≤1.5 x upper limits of normal (ULN)

- Serum ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastasis)

- Creatinine ≤ 1.5 x ULN

- Written informed consent prior to beginning specific protocol procedures,
including expected cooperation of the patients for the treatment and follow-up,
must be obtained and documented according to the local regulatory requirements

- A baseline CT chest/abdomen/pelvis and bone scan or PET/CT

- Negative serum or urine pregnancy test within 7 days prior to starting treatment

- Women of child-bearing potential and men must agree to use adequate contraception
prior to study entry, for the duration of study participation, and for 90 days
following completion of therapy. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating
physician immediately.

Note: Recommended methods of birth control are: The consistent use of an intrauterine
device (IUD), double barrier methods (diaphragm with spermicidal gel or condoms with
contraceptive foam), sexual abstinence (no sexual intercourse) or sterilization.

Men must agree to use a condom and not father a child for the duration of the study and for
90 days after completion of therapy

Exclusion Criteria:

- HER2 negative metastatic breast carcinoma defined as 0 or 1+ by IHC or with a FISH
ratio (HER2 gene copy/ chromosome 17) <2 if IHC 2+ by local institution standard
protocol

- Any prior treatment for metastatic breast cancer. (excluding radiation therapy for the
purpose of ovarian ablation). Note: Prior adjuvant therapy with trastuzumab and
pertuzumab is permitted after a 6 month window following completion of adjuvant
therapy has passed.

- Patients currently receiving anticancer therapies or who have received anticancer
therapies within 2 weeks of the start of study drug (including chemotherapy, radiation
therapy, and biologics). Patients who have received prior endocrine therapy for
fertility purposes will be eligible.

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior treatment with any investigational drug within the preceding 2 weeks

- Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin,
carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, and
nafcillin), strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole,
ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir,
saquinavir, telaprevir, telithromycin, verapamil, and voriconazole), and CYP3A4
substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus,
fentanyl, pimozide, quinidine, sirolimus and tacrolimus). For a current table of
Substrates, Inhibitors and Inducers please access the following
website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/" See Appendix C.

- Uncontrolled brain metastases

- Leptomeningeal metastases

- Other malignancies within the past 3 years except for adequately treated carcinoma of
the cervix or basal or squamous cell carcinomas of the skin.

- Patients who have any severe and/or uncontrolled medical conditions or other
conditions that could affect their participation in the study such as:

- Symptomatic congestive heart failure of New York heart Association Class III or
IV

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction within 6 months of start of study drug, serious uncontrolled cardiac
arrhythmia or any other clinically significant cardiac disease

- Severely impaired lung function as defined as spirometry and DLCO that is 50% of
the normal predicted value and/or 02 saturation that is 89% or less at rest on
room air

- Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

- Active (acute or chronic) or uncontrolled severe infections

- Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
hepatitis

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of palbociclib (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection)

- Patients with an active, bleeding diathesis

- History of noncompliance to medical regimens

- Patients unwilling to or unable to comply with the protocol

- Ongoing alcohol or drug addiction

- Female patients who are pregnant or breast feeding, or adults of reproductive
potential who are not using effective birth control methods. If barrier contraceptives
are being used, these must be continued throughout the trial by both sexes. Hormonal
contraceptives are not acceptable as a method of contraception. (Women of childbearing
potential must have a negative urine or serum pregnancy test within 7 days prior to
starting treatment)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to palbociclib, anastrozole, trastuzumab or pertuzumab.