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Palbociclib and Fulvestrant in Treating Patients with Hormone Receptor-Positive, HER2-Negative Metastatic or Locally Advanced Breast Cancer

Trial Status: Active

This phase II trial studies how well palbociclib and fulvestrant work in treating patients with hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other places in the body (metastatic) or that has only spread to nearby tissue or lymph nodes (locally advanced). Palbociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hormone therapy such as fulvestrant may block the use of estrogen and progesterone by tumor cells. Giving palbociclib with fulvestrant may work better in treating patients with hormone receptor positive, HER2-negative breast cancer.

Inclusion Criteria

  • Women may be premenopausal or postmenopausal; however, premenopausal women and men must be treated with concurrent luteinizing hormone-releasing hormone (LHRH) agonist (goserelin preferred) initiated at least 4 weeks prior to enrollment; NOTE: Postmenopausal status is defined by at least one of the following criteria: * Age >= 60 years * Age < 60 and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and follicle stimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females * Documented bilateral oophorectomy; or, * Medically confirmed ovarian failure
  • Histologically or cytologically confirmed adenocarcinoma of the breast with evidence of metastatic disease (stage IV) or locally advanced disease, not amenable to surgery or radiation with curative intent
  • Documentation of the following receptors based on local testing from most recent assessment: * ER-positive and/or PR-positive tumor (>= 1% positive stained cells) * HER2-negative tumor; NOTE: HER2-negative is determined as immunohistochemistry score 0/1+ or negative by in situ hybridization (FISH/CISH/SISH) defined as a HER2/CEP17 ratio < 2, for single probe assessment a HER2 copy number < 6 or per current American Society Clinical Oncologists (ASCO)-College of American Pathologists (CAP) or National Comprehensive Cancer Network (NCCN) guidelines
  • Patients must satisfy the following criteria for prior therapy: * Progressed on and following at least 6 months of combined treatment with palbociclib and AI therapy for advanced/metastatic breast cancer, and be able and willing to receive additional palbociclib treatment; palbociclib and AI must be the most recently received treatment prior to enrollment; up to one (1) prior line of chemotherapy for advanced/metastatic disease is allowed in addition to any number of prior lines of endocrine therapy * No prior treatment with fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway in the metastatic setting; use of these agents in the neoadjuvant and/or adjuvant settings is permitted * Patients receiving bisphosphonate therapy prior to registration may continue at the same intervals used prior to study registration
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Evaluable or measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1); NOTE: Enrollment of patients with bone-only disease may be limited if we find we are not able to get adequate tissue for research correlates from bone biopsies
  • Patients must have disease that is amenable to biopsy and be willing to provide the same; NOTE: Patients in whom a baseline biopsy is attempted, but is not successful, will still be considered eligible for the study; in addition, if the primary oncologist has a concern regarding the feasibility of a biopsy, it may be omitted after consulting with the protocol chair
  • Absolute neutrophil count (ANC) >= 1,000/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated creatinine clearance >= 60 ml/min per modified Cockcroft-Gault formula
  • Total bilirubin =< 1.5 x upper limit of normal (< 3 x ULN if Gilbert’s disease)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x upper limit of normal (=< 5 x ULN if lever metastases present)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x upper limit of normal (=< 5 x ULN if liver metastases present)
  • Alkaline phosphatase =< 2.5 x ULN (=< 5 x ULN if bone or liver metastases present)
  • Patients with a history of central nervous system metastasis are allowed provided they have been treated (i.e., surgery, radiation, and/or radiosurgery) at least 4 weeks prior to registration and have stable neurologic function, including no requirement for medication(s) to control symptoms for at least 2 weeks; patients with known leptomeningeal disease are not eligible; NOTE: Stable low dose dexamethasone allowed at discretion of protocol chair
  • Patients who have received prior radiation therapy must have recovered from toxicity of the prior radiation therapy prior to registration, and must have disease evaluable for response outside of the radiation fields or have evidence of post-radiation progression of previously irradiated sites of disease
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria

  • Women who are pregnant or breast-feeding; NOTE: Premenopausal women on ovarian suppression therapy are still considered of childbearing potential; women of childbearing potential and men must be strongly advised to use an accepted and effective method of non-hormonal contraception; acceptable contraception includes barrier methods (e.g., condoms or diaphragm) or intrauterine devices (IUDs) (these may include low-dose hormones at the discretion of the study chair)
  • Concurrent use of any of the following medications during study participation: * Inhibitors or inducers of CYP3A4 that may affect serum concentrations of palbociclib * Medications which prolong the QTc interval and may predispose to torsades de pointes
  • Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 2 weeks before registration; patients who received prior radiotherapy to >= 25% of bone marrow are not eligible independent of when it was received * NOTE: Patients taking Palbociclib must hold treatment for a minimum of 1 week prior to initiating study treatment. Patients are not required to hold treatment for aromatase inhibitors prior to initiating study treatment
  • Any other malignancy within 3 years prior to registration, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
  • Any of the following within 6 months of registration: myocardial infarction, severe/unstable angina, ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade >= 2, atrial fibrillation of any grade, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary embolism; no QTc interval > 480 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or torsade de pointes
  • Prior hematopoietic stem cell or bone marrow transplantation
  • Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of fulvestrant or goserelin (if applicable)
  • Known or possible hypersensitivity to palbociclib, fulvestrant, goserelin (if applicable) or to any of their excipients
  • Known human immunodeficiency virus infection
  • Other severe acute or chronic medical or psychiatric condition, including recent or active suicidal ideation or behavior, or laboratory abnormality 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

District of Columbia

Sibley Memorial Hospital
Status: ACTIVE
Contact: Maria Raquel Nunes


Anne Arundel Medical Center
Status: ACTIVE
Contact: Jeanine Lori Werner
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Vered Stearns
Phone: 443-287-6489
Johns Hopkins at Green Spring Station
Status: ACTIVE
Contact: Vered Stearns


Penn State Milton S Hershey Medical Center
Status: ACTIVE
Contact: Cristina I. Truica
Allegheny General Hospital
Status: ACTIVE
Contact: Antonios Christou
West Reading
Reading Hospital
Status: ACTIVE
Contact: Terrence Paul Cescon


I. To estimate progression-free survival (PFS) of palbociclib and fulvestrant in women and men with estrogen receptor (ER)/progesterone receptor (PR)-positive, HER2-negative metastatic breast cancer (MBC) who progressed on a palbociclib and an aromatase inhibitor (AI).

II. To determine the prevalence of ESR1 and PI3K mutations in tissue and in plasma tumor deoxyribonucleic acid (ptDNA) in women and men with ER/PR-positive, HER2-negative MBC who progressed on a palbociclib and an AI.


I. To evaluate the PFS in individuals with or without ESR1 mutations when treated with palbociclib and fulvestrant.

II. To evaluate the PFS in individuals with or without P13K mutations when treated with palbociclib and fulvestrant.

III. To correlate mutation burden, characterized by the number of exome mutations and ptDNA, with PFS and overall survival (OS).

IV. To describe measures of disease control, including response rate (RR) and clinical benefit rate (CBR).

V. To assess the safety and tolerability of palbociclib and fulvestrant in individuals who progressed on prior palbociclib and an AI.

VI. To determine change in circulating tumor cell (CTC) enumeration, CTC-ER status, and CTC-Ki67 in individuals when treated with palbociclib and fulvestrant.

VII. To correlate CTC enumeration, CTC-ER status and CTC-Ki67 with PFS, RR, CBR, and OS.

VIII. To determine if baseline CTC-ESR1 and CTC-other ER-related genes are mutated in individuals progressing on AI and palbociclib therapy.

IX. To compare CTC-ESR1 and cell free circulating plasma tumor ESR1 mutations.


I. To describe alterations in genes and gene products relevant to cell cycle, drug targets, tumor sensitivity and resistance.

II. To systematically identify novel protein kinases activated in biopsies.

III. To conduct additional correlative studies to determine associations between specific kinases identified and response.


Patients receive palbociclib orally (PO) on days 1-21. Patients also receive fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1 and then on day 1 only in subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Vered Stearns

  • Primary ID J15212
  • Secondary IDs NCI-2017-00071, CRMS-62948, IRB00086616
  • ID NCT02738866