Metastatic Breast CancerPhase 2POLLYNCT02188745
ER Reactivation Therapy for Breast Cancer
A Phase 2 study testing 17B-estradiol, Letrozole and Anastrozole in people with Metastatic Breast Cancer, run by Dartmouth-Hitchcock Medical Center at 3 sites in United States.
Trial summary
Before anti-estrogens such as tamoxifen were developed to treat estrogen receptor (ER)-positive breast cancer, high-dose estrogen therapies were used. This seems counterintuitive since anti-estrogens block ER function, while estrogens increase ER function, but these therapies are effective to similar extents for the… Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Metastatic Breast Cancer
- What is being tested?
- 17B-estradiol, Letrozole and Anastrozole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 3 sitesUnited States
- Study dates
- 11 Mar 2016to 5 Jul 2024
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
- 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 (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.
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- 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.
- 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.
- 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)
Who cannot join
- 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 CNS disease, unless clinically stable for ≥ 3 months.
- History of any of the following:
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- 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%
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
Mayo Clinic Cancer Center
Rochester, Minnesota, 55905
Baystate Medical Center
Springfield, Massachusetts, 01199
About this study
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
Before anti-estrogens such as tamoxifen were developed to treat estrogen receptor (ER)-positive breast cancer, high-dose estrogen therapies were used. This seems counterintuitive since anti-estrogens block ER function, while estrogens increase ER function, but these therapies are effective to similar extents for the treatment of metastatic ER+ breast cancer. Estrogen therapies are most effective against cancers that develop resistance to anti-estrogens, likely because such cancers have adapted to grow without ER function, and restoring ER function (with estrogen) is damaging to the cancer cells. In some patients with ER+ breast cancer that becomes resistant to anti-estrogens, treatment with the estrogen 17B-estradiol induces tumor response. Furthermore, when 17B-estradiol-sensitive tumors eventually become resistant to 17B-estradiol, switching back to anti-estrogen therapy is often effective. These observations suggest that cancers can alternate between anti-estrogen-sensitive and 17B-estradiol-sensitive states. The investigators hypothesize that treatment with alternating 17B-estradiol / anti-estrogen therapies on a defined 8-week / 16-week schedule will more effectively prevent cancer growth than continuous treatment with either type of therapy in patients with metastatic anti-estrogen-resistant ER+ breast cancer.
Read the detailed description
Metastatic breast cancer is rarely cured by current therapies. ER+ breast cancers ultimately become resistant to all available anti-estrogens. Response rates to estrogens are similar to those of anti-estrogens in the metastatic setting. Given that ER+ breast cancers are often responsive to anti-estrogens and estrogens, alternating anti-estrogen/estrogen therapies may be more effective than continuous treatment with either type of agent. Anecdotal evidence indicates that such a strategy of alternating therapies is effective in some patients. Preclinical evidence suggests that anti-estrogen-resistant ER+ breast cancers are sensitized to the anti-tumor effects of estrogens. Such cells harbor subpopulations that can ultimately regain the ability to grow in the presence of estrogens, and revert to their anti-estrogen-sensitive state. The investigators will formally test whether alternating 17B-estradiol/anti-estrogen therapies is effective for the management of anti-estrogen-resistant metastatic ER+/HER2- breast cancer, and to identify molecular biomarkers that predict tumor response to 1) 17B-estradiol and 2) alternating 17B-estradiol/anti-estrogen therapies. If successful, this study would present a novel strategy to manage metastatic ER+/HER2- breast cancer by pre-emptively switching therapies prior to disease progression.
- Conditions
- Metastatic Breast Cancer
- Being tested
- 17B-estradiol, Letrozole, Anastrozole, Exemestane
- Keywords
- metastatic, locally advanced, ER+, Estrogen therapy, Estradiol therapy
- Medical subject headings
- Breast Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
17B-estradiolDrug
Also called aromatase inhibitor
Anti-estrogen
LetrozoleDrug
Also called Letrozole (Aromatase inhibitor)
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.
AnastrozoleDrug
Also called Aromatase inhibitor
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.
ExemestaneDrug
Also called Aromatase inhibitor
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.
| Study group | Role | What they receive |
|---|---|---|
| Alternating Therapy | Experimental | 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. Receives: Drug: 17B-estradiol; Drug: Letrozole; Drug: Anastrozole; Drug: Exemestane |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Benefit
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.
Measured: 24 weeks
Secondary outcomes (4)
Objective Response Rate
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.
Measured: 8 weeks
Progression-free Survival
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.
Measured: 12 Months
Adverse Event Profiles
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.
Measured: 12 Months
Predictive Tumor Genetic Lesions
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 reported.
Measured: 12 Months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Jul 2014 (estimated)
- Study start11 Mar 2016
- Primary completion5 Jan 2024
- Study completion5 Jul 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Metastatic Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mary D Chamberlin, Dartmouth-Hitchcock Medical Center
- Investigators
- Mary Chamberlin, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02188745
- Sponsor's protocol ID
- D14122
- Other IDs
- NCI-2020-02087
- Acronym
- POLLY
- Status last verified
- Sep 2026
- First submitted
- 24 Jun 2014
- Last updated
- 25 Sep 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No