Palbociclib in Combination With Bicalutamide for the Treatment of AR(+) Metastatic Breast Cancer (MBC)

The study therapy is to be self administered on an outpatient basis. Patients who meet
eligibility criteria and sign informed consent to Step 2 may begin treatment on study.
Treatment consists of bicalutamide orally once daily and palbociclib will be given orally
daily for 3 weeks on followed by 1 week off. A treatment cycle is considered to be 4 weeks.
Eligible patients will be evaluated for toxicity every 2 weeks during Cycle #1 and 2,
followed by every 4 weeks in subsequent cycles. Toxicity assessment will include history,
physical examination including vital signs, and laboratories including complete blood count
and comprehensive metabolic panel. Patients will keep a drug diary to document adherence to
oral therapy. Radiographic response evaluation per RECIST will occur every 8 weeks (2 cycles)
for cycles 1-6 and then every 12 weeks thereafter with high-resolution CT scan. Patients with
suspected bone-only lesions must have bone lesions assessed by CT with bone windows or by
bone scan at screening.

Phase I: We will use a standard 3+3 design for the dose finding lead in to establish the
recommended phase II doses for the combination of palbociclib and bicalutamide. The doses for
Phase I will be determined based on the dose level to which the patient is accrued.

Phase II: Treatment consists of bicalutamide orally once daily and palbociclib will be given
orally daily for 3 weeks on followed by 1 week off at the doses determined in phase I.

Inclusion Criteria:

A patient will be eligible for androgen receptor expression testing (STEP 1) if the
following criteria are met:

- Female

- Pathologically confirmed invasive cancer of the breast

- ER/PR status (ER or PR defined as positive if ≥1%; ER/PR is defined as negative if
<1%):

- Phase I: Patients may have ER/PR(-) breast cancer.

- HER2 normal (IHC 0-1; FISH < 2.0)

- Non-measurable or measurable, metastatic disease

- Available tissue for AR testing for research purposes

A patient will be eligible for participation in the therapeutic trial (STEP 2) if the
following criteria are met:

- Androgen receptor expression testing confirms that the patient's tumor is AR (+). AR
is considered positive if ≥1% of cell nuclei are immunoreactive using the Dako
antibody (clone AR441). Receptor testing may be performed on either primary tumor
specimen or tissue from a metastatic site. Local testing permitted for eligibility but
will require confirmation at MSKCC.

- There is no limit to the number of prior chemotherapy or endocrine therapy regimens
allowed. Patients with ER(+) AR(+) breast cancer must have had at least 1 prior line
of endocrine therapy to be eligible for the phase I portion of the trial.

- At least 2 weeks since last cytotoxic chemotherapy, hormonal therapy, or radiotherapy.
Toxicities related to prior therapy must either have returned to grade 1, or baseline
(excluding alopecia)

- Patient may receive bisphosphonates/denosumab for the palliation of bone metastases

- If patient has a history of brain metastases or leptomeningeal disease, lesions must
be stable for at least 3 months (as documented by either head CT or brain MRI)

- Prior treatment with bicalutamide will not be allowed

- At least 3 weeks from major surgery with full recovery

- ECOG performance status 0-2

- Age 18 years or greater

- Postmenopausal. Use of LHRH agonist permitted.

- Patients must not have another, non-breast, active malignancy that requires treatment.

- The effects of palbociclib on the developing human fetus at the recommended
therapeutic dose are unknown. Women of child-bearing potential must agree to use
adequate contraception (barrier method of birth control; abstinence). Women must not
breast feed while on study.

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

- Ability to swallow intact palbociclib capsules and bicalutamide tablets.

- Adequate organ and marrow function as defined below (ULN indicates institutional upper
limit of normal):

- Absolute neutrophil count ≥ 1.5 10^9/

- Hemoglobin ≥ 9.0 g/dL

- WBC ≥ 3.0 10^9/L

- Platelets ≥ 100 10^9/L

- Total bilirubin ≤ 1.5 ULN except for patients with known Gilbert syndrome

- AST(SGOT)/ALT(SGPT) ≤ 3 institutional ULN

- Plasma creatinine ≤ 1.5 ULN or Creatinine Clearance > 50 mL/min (calculated by
Cockcroft-Gault method)

- QTc interval ≤ 470 msec

Exclusion Criteria:

- Patients who have not recovered from adverse events of prior therapy to ≤ NCI
CTCAEv4.0 Grade 1.

- Patients receiving any other investigational anti-cancer agents.

- Patients who have received prior treatment with a selective CDK4/6 inhibitor

- Patients who have received prior anti-androgen therapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to palbociclib.

- Uncontrolled intercurrent illness including, but not limited to, known ongoing or
active infection, including HIV, active hepatitis B or C, symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia (specifically, uncontrolled
atrial fibrillation or ventricular dysrhythmias except ventricular premature
contractions), or psychiatric illness/social situations that would limit compliance
with study requirements.

- Pregnant women and women who are breast-feeding.

- Patients with a history of long-QT syndrome or documented family history of long-QT
syndrome. Patients who must remain on drugs that prolong the QT interval.

- Palbociclib is a substrate of CYP3A. Caution should be exercised when dosing
palbociclib concurrently with CYP3A inducers or inhibitors. Furthermore, patients who
are taking concurrent medications that are strong inducers/inhibitors or substrates of
CYP3A4 should be switched to alternative medications to minimize any potential risk.