ER Reactivation Therapy for Breast Cancer (POLLY)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
ClinicalTrials.gov Identifier: NCT02188745 |
Recruitment Status :
Active, not recruiting
First Posted : July 14, 2014
Last Update Posted : March 17, 2022
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Condition or disease | Intervention/treatment | Phase |
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Metastatic Breast Cancer | Drug: 17B-estradiol Drug: Letrozole Drug: Anastrozole Drug: Exemestane | Phase 2 |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 19 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Phase II Pre-emptive OsciLLation of ER activitY Levels Through Alternation of Estradiol/Anti-estrogen Therapies Prior to Disease Progression in ER+/HER2- Metastatic or Advanced Breast Cancer |
Actual Study Start Date : | March 11, 2016 |
Estimated Primary Completion Date : | June 2022 |
Estimated Study Completion Date : | September 2022 |

Arm | Intervention/treatment |
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Experimental: Alternating Therapy
Study will use an 8-week/16-week alternating regimen of 17B-estradiol/AI (aromatase inhibitor) therapy. Use of only one Aromatase inhibitor throughout the study is preferred. 17B-estradiol: One tablet containing 2 mg 17B-estradiol will be taken orally three times daily, for a total dose of 6 mg/day. Letrozole: One tablet containing 2.5 mg letrozole will be taken orally once per day. Anastrozole: One tablet containing 1 mg anastrozole will be taken orally once per day. Exemestane: One tablet containing 25 mg exemestane will be taken orally once per day. |
Drug: 17B-estradiol
Anti-estrogen
Other Name: aromatase inhibitor Drug: Letrozole Aromatase inhibitors work by blocking estrogen receptors; they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Name: Letrozole (Aromatase inhibitor) Drug: Anastrozole Aromatase inhibitors work differently from tamoxifen and raloxifene. Instead of blocking the estrogen receptors, they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Name: Aromatase inhibitor Drug: Exemestane Aromatase inhibitors work differently from tamoxifen and raloxifene. Instead of blocking the estrogen receptors, they stop a key enzyme (called aromatase) from changing other hormones into estrogen. This lowers estrogen levels in the body, taking away the fuel that estrogen receptor-positive breast cancers need to grow.
Other Name: Aromatase inhibitor |
- Clinical benefit [ Time Frame: 12 Months ]Determine the rate of clinical benefit from alternating 17B-estradiol/aromatase. Clinical benefit is defined as complete response, partial response or stable disease at 24 weeks per RECIST criteria.
- Objective response rate [ Time Frame: 8 weeks ]Determine the objective response rate of patients treated with 17B-estradiol therapy for 8 weeks. Objective Response is defined as complete response + partial response as per RECIST criteria; the proportion of patients experiencing objective response on 17B-estradiol will be calculated to determine objective response rate.
- Progression-free survival [ Time Frame: 12 Months ]Determine the progression-free survival from alternating 17B-estradiol/aromatase inhibitor therapy in patients with advanced ER+ breast cancer. Progression-free survival is defined as the time period from the start of a treatment until the time of cancer progression or death from any cause. Cancer progression will be determined as per RECIST criteria.
- Adverse event profiles [ Time Frame: 12 Months ]Determine the adverse event profiles of 17B-estradiol and aromatase inhibitors in this patient population. Adverse events will be recorded as Grade 1, 2, 3, or 4. Incidences will be compared within patients over time.
- Predictive tumor genetic lesions [ Time Frame: 12 Months ]Determine whether specific tumor genetic lesions in ESR1 are predictive of response to 17B-estradiol and/or subsequent aromatase inhibitor therapies. The rates of clinical benefit from 17B-estradiol and/or subsequent AI therapy will be compared between patients with tumors with vs. without genetic lesions in ESR1.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | Female |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Women ≥18 years of age with clinical stage IV ER+/HER2- breast cancer, or with locally recurrent ER+/HER2- disease not amenable to therapy for curative intent.
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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.
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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 (except as noted below in c/d/e).
- 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 FISH ratio of <2 if IHC is 2+ or if IHC has not been done (as per ASCO/CAP definitions). In cases of borderline or equivocal HER2 status, eligibility will be determined by the PI.
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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 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 17B-estradiol and an aromatase inhibitor.
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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).
- 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, including specifically either PET/CT, or CT (CAP) and bone scan.
- Patient must be capable and willing to provide informed written consent for study participation.
- The following laboratory values must be confirmed for eligibility within 28 days prior to initiation of study therapy:
Hematology panel
- hemoglobin > 9 g/dL
- white blood cell (WBC) count (≥ 2,000/uL)
- platelet count ≥ 75,000/uL Serum biochemistry/metabolic panel
- creatinine ≤ 1.5 x upper limits of normal (ULN)
- total bilirubin ≤ 1.5 x upper limits of normal (ULN)
- ALT and AST ≤ 3.0 x upper limits of normal (ULN) For patients with liver metastasis: < 5 x upper limits of normal (ULN)
Exclusion Criteria:
- Treatment with fulvestrant within 16 weeks prior to study enrollment.
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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 CNS disease, unless clinically stable for ≥ 3 months.
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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%

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02188745
United States, Massachusetts | |
Baystate Medical Center | |
Springfield, Massachusetts, United States, 01199 | |
United States, Minnesota | |
Mayo Clinic Cancer Center | |
Rochester, Minnesota, United States, 55905 | |
United States, New Hampshire | |
Dartmouth Hitchcock Medical Center | |
Lebanon, New Hampshire, United States, 03756 |
Principal Investigator: | Gary N Schwartz, MD | Dartmouth-Hitchcock Medical Center |
Responsible Party: | Gary Schwartz, Associate Professor of Medicine, Dartmouth-Hitchcock Medical Center |
ClinicalTrials.gov Identifier: | NCT02188745 |
Other Study ID Numbers: |
D14122 |
First Posted: | July 14, 2014 Key Record Dates |
Last Update Posted: | March 17, 2022 |
Last Verified: | March 2022 |
metastatic locally advanced ER+ Estrogen therapy Estradiol therapy |
Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Letrozole Anastrozole Exemestane Estradiol Aromatase Inhibitors Estrogens |
Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs Antineoplastic Agents Steroid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Estrogen Antagonists Hormone Antagonists Antineoplastic Agents, Hormonal |