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.