Palbociclib in Combination With Tamoxifen as First Line Therapy for Metastatic Hormone Receptor Positive Breast Cancer

OUTLINE: This is a multi-center trial.

INVESTIGATIONAL TREATMENT:

- Palbociclib 125 mg will be administered orally once daily on days 1-21 (D1-D21) of each
28-day cycle. Subjects will not take palbociclib on D22-D28.

- Tamoxifen 20 mg will be administered orally once daily for every day of the 28-day cycle
(i.e., continuously).

Palbociclib should be taken with food in combination with tamoxifen. Subjects should take
their dose at approximately the same time each day.

It is encouraged, but not mandatory, that premenopausal subjects will also receive treatment
with goserelin or equivalent (e.g., Lupron) given as an injectable subcutaneous implant on D1
of every 28 days cycle or every 3 months.

Disease assessments will be performed at the completion of every 2 cycles.

Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or
subject death either from progression of disease, the therapy itself, or from other causes.
Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities
will be followed for a total of 24 months after discontinuation of study drug.

To demonstrate adequate organ function, all screening labs should be performed within 14 days
prior to registration for protocol therapy:

Hematological (must meet ALL of the following criteria):

- Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L

- Hemoglobin ≥ 9 g/dL

- Platelet count ≥ 100 × 10 9/L

Renal (must meet ONE of the following criteria):

- Serum creatinine ≤ 1.5 × ULN

- Serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic (must meet ALL of the following criteria):

- Aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known
hepatic metastases

- Alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic
metastases

- Total serum bilirubin ≤ 1.5 × ULN

Inclusion Criteria:

Subjects must meet all of the following applicable inclusion criteria to participate in
this study:

- Male or female ≥ 18 years of age at time of consent. NOTE: Both pre- and
post-menopausal women are eligible. Pre-menopausal status is defined as either:

- Last menstrual period within the last 12 months.

- In case of therapy-induced amenorrhea, plasma estradiol and /or FSH is in the
premenopausal range per local normal range.

- Locally advanced, locoregionally recurrent, or metastatic disease, not amenable to
curative therapy. NOTE: Although not required as a protocol procedure, a patient with
a new metastatic lesion should be considered for biopsy whenever possible to reassess
ER/PR/HER2 status if clinically indicated. If a biopsy is prospectively done as part
of standard of care, the study would like to store samples for correlative research.

- Histologically and/or cytologically confirmed diagnosis of ER positive and/or PR
positive (ER >1%, PR >1%), HER2 negative breast cancer. NOTE: Subject has
HER2-negative breast cancer (based on most recently analyzed biopsy) is defined as a
negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a
negative in situ hybridization (e.g. FISH, CISH, SISH, DISH, etc.) test is required by
local laboratory testing.

- Metastatic disease evaluable on imaging studies. Subjects may have measurable disease
as per RECIST 1.1 or bone-only disease. NOTE: Bone-only subjects are eligible if their
disease can be documented/ evaluated by bone scans, CT or MRI. Their disease will be
assessed using MDA criteria. NOTE: Previously irradiated lesions are eligible as a
target lesion only if there is documented progression of the lesion after irradiation.

- No prior systemic anti-cancer therapy for advanced HR+ disease. NOTE: Subjects
receiving adjuvant treatment with aromatase inhibitors at time of recurrence are
allowed to participate. There is no AI washout period required.

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

- Provided written informed consent and Health Insurance Portability and Accountability
Act of 1996 (HIPAA) authorization for release of personal health information, approved
by an Institutional Review Board/Independent Ethics Committee (IRB/IEC). NOTE: HIPAA
authorization may be included in the informed consent or obtained separately.

- Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A
negative serum or urine pregnancy test is required within 72 hours of study
registration from women of childbearing potential. If the urine test cannot be
confirmed as negative, a serum pregnancy test will be required.

- Women of childbearing potential (WOCP) must be willing to use two effective methods of
birth control such as use of a double barrier method (condoms, sponge, diaphragm, or
vaginal ring with spermicidal jellies or cream), or total abstinence for the course of
the study until 120 days after the last dose of study drug. The use of hormonal
contraceptives is discouraged. NOTE: Women are considered to be of childbearing
potential unless they are postmenopausal for at least 12 consecutive months or
surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or
hysterectomy).

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, and other study procedures.

- Male subjects capable of fathering a child must agree to use adequate contraception or
total abstinence for the course of the study until 120 days after the last dose of the
study drug.

NOTE: Male subjects will be considered as capable of fathering a child unless they have
azoospermia (whether due to having had a vasectomy or due to an underlying medical
condition).

- Co-enrollment in an imaging biomarker study or other non-therapeutic study is allowed.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

- Prior treatment with any CDK 4/6 inhibitor.

- Confirmed diagnosis of HER2 positive disease.

- Known uncontrolled or symptomatic CNS metastases. Subjects with known brain metastasis
will only be eligible after their tumors have been treated with definitive resection
and /or radiotherapy and they are neurologically stable for at least 1 month off
steroids.

- Advanced, symptomatic, visceral spread with a life expectancy less than 4 months.

- Prior (neo)adjuvant treatment with tamoxifen within the 12 months before study entry.

- Prior history of blood clots, pulmonary embolism or deep vein thrombosis.

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

- Concurrent malignancy or malignancy within 3 years of randomization, with the
exception of adequately treated basal cell carcinoma, squamous cell skin carcinoma,
non-melanomatous skin cancer or curatively resected cervical cancer.

- Any other concurrent severe and/or uncontrolled medical condition that would, in the
investigator's judgment, contraindicate subject participation in the clinical study.

- Currently receiving any of the following substances and cannot be discontinued 7 days
prior to study registration:

- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pomelos, star-fruit, and Seville oranges.

- Medications that have a narrow therapeutic window and are predominantly
metabolized through CYP3A4/5.

- Known strong inducers or inhibitors of CYP2D6.

- Major surgery within 14 days prior to study registration or has not recovered from
major side effects of surgery.

- Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].

- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected) (testing not mandatory)

- Any clinically significant infection defined as any acute viral, bacterial, or fungal
infection that requires specific treatment. NOTE: Anti-infective treatment must be
completed ≥ 7 days prior to study registration.

- Known allergy to palbociclib or any of its excipients

- Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study
registration. NOTE: if fracture is at a metastatic site, is chronic, and no surgical
treatment is planned, the subject can be enrolled.

- Any condition that, in the opinion of the investigator, might jeopardize the safety of
the subject or interfere with protocol compliance.

- Any mental or medical condition that prevents the subject from giving informed consent
or participating in the trial.

- Treatment with any therapeutic investigational agent within 28 days prior to
registration for protocol therapy. The subject must have recovered from the acute
toxic effects of the regimen.