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Alternating Estradiol and Aromatase Inhibitor Therapies for the Treatment of ER+ / HER2- Advanced or Metastatic Breast Cancer, POLLY Study

Trial Status: Active

This phase II trial studies how well alternating estradiol with an aromatase inhibitor (anti-estrogen therapy) works for the treatment of estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer that has spread to other places in the body (advanced or metastatic). Estradiol is an estrogen hormone that naturally occurs in humans. Estradiol is used for the treatment of symptoms of breast and prostate cancers. Aromatase inhibitors, such as letrozole, anastrozole, or exemestane, prevent the formation of estradiol by interfering with the aromatase enzyme. Aromatase inhibitors are often used as a type of therapy for post-menopausal women who have ER+ breast cancer. Alternating estradiol and with an aromatase inhibitors may work better than existing methods in treating patients with breast cancer.

Inclusion Criteria

  • Women with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent
  • Patient must have been treated with an anti-estrogen at any time in their disease history. Combination regimens that include an anti-estrogen and any biologic, or targeted therapy, are permitted (e.g., any CDK inhibitor, everolimus, or any other novel biologics), and are considered to be a single hormonal therapy based regimen. * Any number of prior lines of anti-estrogen (i.e., hormonal) therapy is permissible. * One line of prior chemotherapy for advanced/metastatic disease is permissible
  • Histologic documentation of ER strongly+/HER2- breast cancer by core needle biopsy, fine needle aspiration, incisional biopsy, or surgical biopsy of >= 1 site(s) of metastatic or locally advanced disease performed as standard of care within the past 4 months for assessment of eligibility for study participation * ER strongly+ status defined as ER staining by immunohistochemistry in >= 50% of malignant cell nuclei with an intensity >= 2+ on a scale of 0-3+. These criteria are equivalent to an Allred score >= 6 * HER2-negative status is defined as immunohistochemistry score of 0-1+, or with a fluorescence in situ hybridization (FISH) ratio of < 2 if immunohistochemistry (IHC) is 2+ or if IHC has not been done (as per American Society of Clinical Oncology/College of American Pathologists [ASCO/CAP] definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the principal investigator (PI) * Archived tumor specimens: Excess tumor tissue must be available for research purposes. This will include tumor tissue sufficient to make >= 10 five-micron sections; more tumor tissue is preferred. Freshly acquired tumor specimens: As part of a clinically indicated biopsy procedure, an additional 1-3 cores or tissue fragments will be obtained by core needle or surgical biopsy for research purposes and formalin-fixed-paraffin-embedded (FFPE) * Patients with bone-only metastatic disease with a history of ER+/HER2- breast cancer are eligible, and bone biopsy is not required, providing their primary cancer is consistent with the above-described ER and HER2 criteria * Patients with non-bone metastatic disease in whom a safe and accurate biopsy of recurrent/metastatic disease cannot be readily obtained are also eligible, providing their primary cancer is consistent with the above-described ER and HER2 criteria
  • Patient must be a candidate for treatment with 17 beta-estradiol and an aromatase inhibitor
  • If the most recent therapy was in the adjuvant setting, the recurrence-free interval (time from initiation of adjuvant anti-estrogen therapy to clinical evidence of disease recurrence) must have been >= 2 years. If the most recent therapy was in the advanced/metastatic setting, the progression-free interval must have been >= 3 months (except in the case of investigational hormonal therapies, or investigational combinations that include an endocrine agent)
  • Patient must be post-menopausal based on either a history of an oophorectomy, or >=1 year of amenorrhea. An elevated serum gonadotropin level and estradiol level in the postmenopausal range (as locally defined) can be used to confirm menopausal status in a subject with < 1 year of amenorrhea
  • Baseline radiographic staging performed as standard of care, including specifically either positron emission tomography (PET)/computed tomography (CT), or CT chest abdomen pelvis (CAP) and bone scan
  • Patient must be capable and willing to provide informed written consent for study participation
  • Hemoglobin > 9 g/dL (within 28 days prior to initiation of study therapy)
  • White blood cell (WBC) count >= 2,000/uL (within 28 days prior to initiation of study therapy)
  • Platelet count >= 75,000/uL (within 28 days prior to initiation of study therapy)
  • Creatinine =< 1.5 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy)
  • Total bilirubin =< 1.5 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy)
  • Alanine aminotransferase (AST) and aspartate aminotransferase (AST) =< 3.0 x upper limits of normal (ULN) (within 28 days prior to initiation of study therapy). For patients with liver metastasis: < 5 x upper limits of normal (ULN)

Exclusion Criteria

  • Treatment with fulvestrant within 16 weeks prior to study enrollment
  • Any other concurrent systemic anti-cancer treatments, including conventional chemotherapeutic agents and biological agents, during the study period. Anti-resorptive bone therapies (e.g., bisphosphonates, denosumab) are permitted
  • Any investigational cancer therapy in the last 3 weeks
  • Known central nervous system (CNS) disease, unless clinically stable for >= 3 months
  • History of any of the following: * Deep venous thrombosis * Pulmonary embolism * Stroke * Acute myocardial infarction * Congestive heart failure * Previous malignancy not treated with curative intent, or with an estimated recurrence risk >= 30%

New Hampshire

Lebanon
Dartmouth Hitchcock Medical Center
Status: ACTIVE
Contact: Gary N. Schwartz
Phone: 603-650-4628

PRIMARY OBJECTIVE:

I. Determine the rate of clinical benefit from alternating estradiol (17 beta-estradiol)/aromatase inhibitor therapy in patients with advanced ER+ breast cancer.

SECONDARY OBJECTIVES:

I. Determine the objective response rate of patients treated with 17 beta-estradiol therapy for 8 weeks.

II. Determine the progression-free survival from alternating 17 beta-estradiol/aromatase inhibitor therapy in patients with advanced ER+ breast cancer.

III. Determine the adverse event profiles of 17 beta-estradiol and aromatase inhibitors in this patient population.

IV. Determine whether specific tumor genetic lesions in ESR1 are predictive of response to 17 beta-estradiol and/or subsequent aromatase inhibitor therapies.

EXPLORATORY OBJECTIVES:

I. Determine the rate of clinical benefit and interval of progression-free survival from continuous aromatase inhibitor therapy in patients with advanced ER+ breast cancer who had received alternating 17 beta-estradiol/aromatase inhibitor as the prior line of therapy.

II. Determine the rate of clinical benefit and interval of progression-free survival from continuous 17 beta-estradiol therapy in patients with advanced ER+ breast cancer who had received alternating 17 beta-estradiol/aromatase inhibitor as the prior line of therapy.

III. Identify molecular biomarkers predictive of response to 17 beta-estradiol and/or alternating 17 beta estradiol/aromatase inhibitor therapies.

IV. Determine whether genetic lesions in ESR1 become detectable in circulating deoxyribonucleic acid (DNA) in plasma at the time of disease progression on alternating 17 beta-estradiol/aromatase inhibitor therapies.

V. Identify molecular changes that occur in response to 17 beta-estradiol therapy in ER+/HER2- breast tumors.

OUTLINE:

Patients receive estradiol orally (PO) three times daily (TID) during 28-day treatment cycles, and an aromatase inhibitor (either letrozole, anastrozole, or exemestane) PO once daily (QD) during 28-day treatment cycles. Treatment alternates between 2 cycles of estradiol followed by 4 cycles of an aromatase inhibitor in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dartmouth Hitchcock Medical Center

Principal Investigator
Gary N. Schwartz

  • Primary ID D14122
  • Secondary IDs NCI-2020-02087, D-HH eIRB: STUDY00028110
  • Clinicaltrials.gov ID NCT02188745