Trial of Anastrozole and Palbociclib in Metastatic HER2-Negative Breast Cancer

A total of 40 subjects will be enrolled over an enrollment period of 18-24 months. The study
is planned to enroll up to 25 patients in Cohort A (upfront) and 15 patients in Cohort B
(maintenance). Subjects will be recruited through Levine Cancer Institute locations and
through referrals. Women of any race or ethnic origin who meet the study criteria may
participate in this clinical trial. Males will not be eligible for this study. Breast cancer
in men is rare and the efficacy of aromatase inhibitors in males is limited. Children are not
included in this clinical trial because the effects of palbociclib are not known in the
pediatric population, but may be eligible for other pediatric trials.

Inclusion Criteria:

- Are 18 years of age or older, who are either:

- Postmenopausal, as defined by at least one of the following criteria:

- Age greater than or equal to 60 years;

- Age less than 60 years and cessation of regular menses for at least 12
consecutive months with no alternative pathological or physiological cause and
serum estradiol, FSH and LH level within the laboratory reference range for
postmenopausal females;

- Documented bilateral oophorectomy;

- Medically confirmed ovarian failure OR premenopausal or perimenopausal, i.e., not
meeting the criteria for being postmenopausal.

- Premenopausal or perimenopausal women can be enrolled if amenable to be treated with
an LHRH agonist. Patients must have commenced treatment with an LHRH agonist at least
4 weeks prior to start of study treatment.

- Histologically or cytological confirmed diagnosis of breast cancer with evidence of
metastatic disease. Locally advanced disease not amenable to resection is eligible.

- Documentation of ER-positive and, or PR-positive tumor based on most recent tumor
biopsy (unless bone-only disease). ER and PR assays are considered positive if there
is at least 1 percent positive in the tumor sample.

- Documentation of HER2-negative tumor based on most recent tumor biopsy. Tumor must not
demonstrate overexpression of HER2 by either IHC (immunohistochemistry) or in-situ
hybridization (ISH).

- No previous treatment for metastatic disease for Cohort A.

- For Cohort A: previous treatment with endocrine therapy in the adjuvant or
neoadjuvant setting is allowed

- For Cohort B: only first-line chemotherapy (can be single-agent or a combination
regimen) for metastatic disease with response (defined as a complete response or
partial response by RECIST version 1.1, or stable disease for six months or more
from this regimen) and chemotherapy discontinued for 21 days is allowed; patients
may have received prior systemic therapy in the adjuvant or neoadjuvant setting.

- For Cohort A, measurable disease as defined by RECIST version 1.1, or bone-only
disease prior to start of study treatment. Patients with bone-only metastatic cancer
must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by CT
or MRI. Patients with bone-only disease who have blastic-only metastasis are not
eligible. Tumor lesions previously irradiated or subjected to other loco regional
therapy will only be deemed measurable if progression at the treated site after
completion of therapy is clearly documented. For Cohort B, measurable disease as
defined by RECIST version 1.1, or evaluable disease.

- Patient has archival tumor tissue available that is formalin-fixed and
paraffin-embedded. Biopsy sample taken at the time of presentation with recurrent or
metastatic disease is recommended.For patients who do not have archival tissue, tissue
from a fresh biopsy should be obtained prior to study treatment initiation, if it can
be safely attained using local anesthesia only. One exception is those patients with
bone-only disease for whom provision of previous archival tissue would be acceptable.
Serial fresh tumor tissue samples will be collected in patients with lesions amenable
for a biopsy who consent to such a procedure.

- ECOG performance status 0, 1 or 2.

- Must have normal organ and marrow function as defined below:

- Hematologic: Absolute neutrophil count greater than or equal to 1,500/mcL;

- Platelets greater than or equal to 100,000/mcL; Hemoglobin greater than or equal
to 9 g/dL.

- Renal: Serum creatinine less than or equal to 1.5X ULN or Measured or calculated
creatinine clearance (CrCl) greater than or equal to 60 mL/min for subject with
creatinine levels > 1.5X ULN [CrCl should be calculated per institutional
standard; GFR can also be used in place of creatinine or CrCl]

- Hepatic: Total bilirubin less than or equal to 1.5X ULN; AST(SGOT)/ALT(SGPT) less
than or equal to 3X ULN (less than or equal to 5X ULN if liver metastases
present); Alkaline phosphatase less than or equal to 2.5X ULN (less than or equal
to 5X ULN if liver or bone metastases present)

- Able to swallow and retain oral medication per the Investigator.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Prior treatment with any CDK inhibitor

- Known active uncontrolled or symptomatic central nervous system (CNS) metastases,
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms,
cerebral edema, and/or progressive growth. Patients with treated brain metastases are
eligible if there is no evidence of progression for at least 4 weeks after
CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI
or CT) during the screening period.

- Use of food or drugs known to be potent CYP3A4 inhibitors and drugs known to be potent
CYP3A4 inducers (for examples, see the Prohibited Medications Section)

- Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 3 weeks
before treatment.

- Any of the following within 6 months prior to study consent: myocardial infarction,
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE Grade 2 or more,
atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident including transient ischemic
attack, or symptomatic pulmonary embolism.

- Impairment of gastro-intestinal function or GI disease that may significantly alter
the absorption of palbociclib, such as history of GI surgery which may result in
intestinal blind loops and patients with clinically significant gastroparesis, short
bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or
diarrhea of CTCAE Grade > 1.

- Prior hematopoietic stem cell or bone marrow transplantation.

- Known hypersensitivity to anastrozole.

- Known human immunodeficiency virus infection.

- Other severe acute or chronic medical or psychiatric condition, 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 patient inappropriate for entry into this study.

- Participation in other studies involving investigational drug(s) within 4 weeks before
treatment initiation in this study.