ER Reactivation Therapy for Breast Cancer

NCT02188745 | Completed Phase 2 DMC

• 1 other identifier: D14122
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 3

Brief 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 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.

Conditions

Metastatic Breast Cancer

Keywords

metastatic; locally advanced; ER+; Estrogen therapy; Estradiol therapy

Outcome Measures

Primary Outcomes (1)

• 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.

  12 Months

Secondary Outcomes (4)

• Objective response rate

  8 weeks

• Progression-free survival

  12 Months

• Adverse event profiles

  12 Months

• Predictive tumor genetic lesions

  12 Months

Study Arms (1)

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.

Drug: 17B-estradiol; Drug: Letrozole; Drug: Anastrozole; Drug: Exemestane

Interventions

17B-estradiol DRUG

Anti-estrogen

Also known as: aromatase inhibitor

Alternating Therapy

Letrozole DRUG

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.

Also known as: Letrozole (Aromatase inhibitor)

Alternating Therapy

Anastrozole DRUG

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.

Also known as: Aromatase inhibitor

Alternating Therapy

Exemestane DRUG

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.

Also known as: Aromatase inhibitor

Alternating Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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:
• 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%

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (3)

Baystate Medical Center

Springfield, Massachusetts, 01199, United States

Location

Mayo Clinic Cancer Center

Rochester, Minnesota, 55905, United States

Location

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

Aromatase Inhibitors; Letrozole; Anastrozole; exemestane

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Mary Chamberlin, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: June 24, 2014
• First Posted: July 14, 2014
• Study Start: March 11, 2016
• Primary Completion: January 5, 2024
• Study Completion: July 5, 2024
• Last Updated: July 17, 2024

Record last verified: 2024-07

Locations

US (3)