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Drug Interventions

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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/15/2021.

Estradiol in Treating Patients With ER Beta Positive, Triple Negative Locally Advanced or Metastatic Breast Cancer

Clinicaltrials.gov identifier NCT03941730

Recruitment Status Recruiting

First Posted May 8, 2019

Last update posted October 1, 2020

Study Description

Brief summary:

This phase II trial studies how well estradiol works in treating patients with estrogen receptor beta (ER beta) positive, triple negative breast cancer that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Hormone receptors like ER beta allow the body to respond appropriately to hormones. Triple negative means that the breast cancer does not express other hormone receptors called ER alpha, progesterone, and HER2. In some people with triple negative breast cancer, ER beta is overexpressed. Tumor cells that overexpress ER beta grow slower in the laboratory and this growth is slowed in the presence of estrogen. Estradiol is a form of estrogen. This study may help doctors determine whether tumor cells that overexpress ER beta shrink in the presence of estradiol.

  • Condition or Disease:Anatomic Stage III Breast Cancer AJCC v8
    Anatomic Stage IIIA Breast Cancer AJCC v8
    Anatomic Stage IIIB Breast Cancer AJCC v8
    Anatomic Stage IV Breast Cancer AJCC v8
    Metastatic Triple-Negative Breast Carcinoma
    Prognostic Stage III Breast Cancer AJCC v8
    Prognostic Stage IIIA Breast Cancer AJCC v8
    Prognostic Stage IIIB Breast Cancer AJCC v8
    Prognostic Stage IIIC Breast Cancer AJCC v8
    Prognostic Stage IV Breast Cancer AJCC v8
    Recurrent Breast Carcinoma
    Anatomic Stage IIIC Breast Cancer AJCC v8
  • Intervention/Treatment: Biological: Therapeutic Estradiol
  • Phase: Phase 2
Detailed Description

PRIMARY OBJECTIVE: I. To assess the anti-tumor activity of estradiol in patients with locally advanced or metastatic triple negative breast cancer (TNBC) that expresses ERbeta (> 25% moderate or strong nuclear staining) and who have prior receipt of taxane and anthracycline based chemotherapy. SECONDARY OBJECTIVES: I. To examine the safety profile of estradiol when administered at a dose of 2 mg three times daily (tid) to women with locally advanced or metastatic TNBC that expresses ERbeta. II. To examine the changes in phosphorylated (phospho)-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67 in tumor biopsies taken before and after the first cycle of treatment. EXPLORATORY OBJECTIVES: I. To examine changes in plasma estradiol, serum cytokine and cystatin levels before/after 1 cycle of estradiol. II. Analyze the global gene expression profiles of paired biopsies prior to and following 1 cycle of therapy. III. To develop patient derived xenografts (PDX) that are ERalpha negative, HER2 negative and ERbeta positive (Mayo only). OUTLINE: Patients receive estradiol orally (PO) TID for days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up annually for 5 years from study registration.

Study Design
  • Study Type: Interventional
  • Estimated Enrollment: 38 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: Therapeutic Targeting of ER Beta in Triple Negative Breast Cancer
  • Actual Study Start Date: August 2019
  • Estimated Primary Completion Date: April 2022
  • Estimated Study Completion Date: April 2022
Arms and interventions
Arm Intervention/treatment
Experimental: Treatment (estradiol)
Patients receive estradiol PO TID for days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Biological: Therapeutic Estradiol
Given PO
Outcome Measures
  • Primary Outcome Measures: 1. Clinical benefit rate [ Time Frame: 6 months ]
    Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria for complete response (CR), partial response (PR), or stable disease (SD) for > 6 months following initiation of treatment. The 6 month clinical benefit rate is the percentage of patients who are found to meet the criteria for clinical benefit at least 6 months among all the patients who have started estradiol treatment.
  • Secondary Outcome Measures: 1. Incidence of adverse events [ Time Frame: 5 years ]
    An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. All grade 2, 3, 4 or 5 adverse events will be documented and assigned an attribute by treating clinician as to its relationship to treatment. For a given AE, the proportion of patients who report developing a grade 2-5 of this AE are determined. The number of dose reductions per patient and the reasons for the dose reduction are summarized.
  • 2. Tumor response rate among those patients with measurable disease [ Time Frame: 5 years ]
    The tumor response rate is defined as the 100% time the number of patients with a CR or PR (as defined by the RECIST criteria) on 2 consecutive evaluations at least 8 weeks apart divided by the total number of eligible patients who began study treatment. A 90% binomial confidence interval is constructed for the true response rate.
  • 3. Progression free survival (PFS) distribution [ Time Frame: From randomization to the first of the following events: local, regional, or distant recurrence, second primary disease of death due to any cause, assessed up to 5 years ]
    The distribution of PFS times will be estimated using the method of Kaplan-Meier.
  • 4. Overall survival distribution [ Time Frame: From randomization to death due to any cause, assessed up to 5 years ]
    The distribution of survival times are estimated using the method of Kaplan-Meier.
  • 5. Changes in phospho-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67 [ Time Frame: 5 years ]
    Patients undergo tumor biopsies prior to the start of treatment and at completion of cycle 1 treatment. These specimens will be undergoing immunohistochemistry (IHC) staining with the following antibodies: phosphorylated (phospho)-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67. For each of these biomarkers, a times series plot are constructed so that an individual patient's data will be represented using the same color for each of the five graphs. These graphs are visually inspected for trends within each of the graphs (variation between individuals) as well as across the five graphs (profile of biomarker changes within an individual).
  • Other Outcome Measures: 1. Changes in serum cystatin levels in response to treatment [ Time Frame: At the end of Cycle 1 (each cycle is 28 days +/- 3 days) ]
    Change in cystatin levels following one cycle of treatment are examined using signed rank tests and the difference in the percent change in its level following one cycle of treatment between patients who derived clinical benefit and those who did not will be examined using a two sample Wilcoxon rank sum test.
Eligibility Criteria
  • Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
  • Sexes Eligible for Study: Female
  • Accepts Healthy Volunteers: No
Criteria

Inclusion Criteria:

- PRE-SCREENING CRITERIA (STEP 0): History of locally advanced or metastatic breast
cancer that is ERalpha negative or low (< 10% nuclear staining) and HER2 negative. - Note: HER2 negative disease per 2013 American Society of Clinical Oncology/College of American of Pathologists (ASCO/CAP) guidelines, one of the following must apply: - 0 or 1+ by immunohistochemistry (IHC) and not amplified by in situ hybridization (ISH); - 0 or 1+ by IHC and ISH not done; - 2+ by IHC and not amplified by ISH or; - IHC not done and not amplified by ISH. - PRE-SCREENING CRITERIA (STEP 0): = 25% of cells in specimen submitted during Pre-Screening Step.

- PRE-REGISTRATION CRITERIA (STEP 1): Willing to undergo a standard of care biopsy of
locally recurrent or metastatic breast cancer for ERalpha, PR, and HER2 as well as
additional research cores.

- PRE-REGISTRATION CRITERIA (STEP 1): Measurable or non-measurable disease as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

- Note: The tumor lesion biopsied during the pre-registration period is not
considered measurable disease.

- PRE-REGISTRATION CRITERIA (STEP 1): If history of brain metastases must meet the
following criteria:

- Patients with a history of brain metastases are eligible only if they are
asymptomatic and have stable disease for >= 3 months, including < 28 days of prior to pre-registration. - Not receiving steroids for brain metastases. - PRE-REGISTRATION CRITERIA (STEP 1): ECOG performance status 0 or 1. - PRE-REGISTRATION CRITERIA (STEP 1): Prior treatment with paclitaxel and anthracycline (in combination or in separate regimens) either in the adjuvant or metastatic setting, - PRE-REGISTRATION CRITERIA (STEP 1): == 60 years, or

- Age 1 year with follicle stimulating hormone
(FSH) and estradiol levels within postmenopausal range, according to
institutional standard.

- PRE-REGISTRATION CRITERIA (STEP 1): Able to swallow oral medications.

- PRE-REGISTRATION CRITERIA (STEP 1): Willingness to stop use of strong inducers or
inhibitors of CYP3A4 prior to registration.

- NOTE: Use of strong inducers or inhibitors is allowed during pre-registration as
long as patient will complete course prior to registration.

- REGISTRATION CRITERIA (STEP 2): Histologic confirmation, from local lab that tumor is
ERalpha negative (= 8 g/dL (== 75,000/mm^3 (=< 14 days prior to registration). - REGISTRATION CRITERIA (STEP 2): Creatinine =< 1.5 x upper limit of normal (ULN) (=< 14 days prior to registration). - REGISTRATION CRITERIA (STEP 2): Total bilirubin =< 1.5 x ULN (=< 14 days prior to registration). - REGISTRATION CRITERIA (STEP 2): Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) 2.5 x ULN (=< 14 days prior to registration). - For patients with liver metastasis = 160/90).

- PRE-REGISTRATION CRITERIA: Deep vein thrombosis / pulmonary embolism (DVT/PE) = 6 months prior to pre-registration, and
there is no evidence for active thrombosis (either DVT or PE).

- PRE-REGISTRATION CRITERIA: Stroke =< 6 months prior to pre-registration. - PRE-REGISTRATION CRITERIA: Two or more episodes of DVT and/or PE =< 5 years prior to pre-registration. - PRE-REGISTRATION CRITERIA: Abnormal uterine bleeding == 3 years
prior to pre-registration.

- REGISTRATION CRITERIA: None of the following therapies are allowed =< 14 days prior to registration. - Chemotherapy. - Immunotherapy. - Biologic therapy. - Hormonal therapy. - Monoclonal antibodies. - Anti-HER2 or other "targeted" (e.g. mTOR) therapy. - Note: Any adverse events derived from these therapies must be =< grade 2 prior to starting study therapy (exceptions for alopecia).

Contacts and Locations
Contacts
Locations

United States, Florida
Mayo Clinic in Florida
Jacksonville

United States, Minnesota
Mayo Clinic
Rochester

Sponsors and Collaborators

Mayo Clinic

National Cancer Institute (NCI)

Investigators

Principal Investigator: Matthew P Goetz Mayo Clinic

More Information
  • Responsible Party: Mayo Clinic
  • ClinicalTrials.gov Identifier: NCT03941730 History of Changes
  • Other Study ID Numbers: MC1831, NCI-2019-02285, MC1831, P30CA015083
  • First Posted: May 8, 2019 Key Record Dates
  • Last Update Posted: October 1, 2020
  • Last Verified: April 2020
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Additional relevant MeSH terms: Carcinoma Breast Neoplasms