This is a non-randomized, open-label, single-arm, multicenter, phase II study of palbociclib in combination with tamoxifen in women with HR(+)/HER2(-) advanced breast cancer who have not received prior systemic anticancer therapies for their advanced/metastatic disease.

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

• Adequate hepatic function within 14 days prior to registration for protocol therapy defined as meeting all of the following criteria:

  • aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases and
  • alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases and
  • total serum bilirubin ≤ 1.5 × ULN

• Adequate renal function within 14 days prior to registration for protocol therapy defined by either of the following criteria:

  • serum creatinine ≤ 1.5 × ULN
  • OR if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

• Adequate hematologic function within 14 days prior to registration for protocol therapy defined as meeting all of the following criteria:

  • hemoglobin ≥ 9 g/dL
  • and absolute neutrophil count (ANC) ≥ 1.5 × 109/L
  • and platelet count ≥ 100 × 109/L

• 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.

Open-Label