Clinical Trials /

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

NCT03941730

Description:

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 or other places in the body. 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Estradiol in Treating Patients With ER Beta Positive, Triple Negative Locally Advanced or Metastatic Breast Cancer
  • Official Title: Therapeutic Targeting of ER Beta in Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: MC1831
  • SECONDARY ID: NCI-2019-02285
  • SECONDARY ID: MC1831
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03941730

Conditions

  • Anatomic Stage III Breast Cancer AJCC v8
  • Anatomic Stage IIIA Breast Cancer AJCC v8
  • Anatomic Stage IIIB Breast Cancer AJCC v8
  • Anatomic Stage IIIC Breast Cancer AJCC v8
  • Anatomic Stage IV Breast Cancer AJCC v8
  • ESR2 Positive
  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Metastatic Triple-Negative Breast Carcinoma
  • Progesterone Receptor Negative
  • 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

Interventions

DrugSynonymsArms
Therapeutic Estradiol17 Beta-Estradiol, Aquadiol, Dimenformon, Diogyn, Diogynets, Estrace, ESTRADIOL, Estraldine, Oestradiol, Ovocylin, Progynon, VagifemTreatment (estradiol)

Purpose

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 or other places in the body. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      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) thrice daily (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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (estradiol)ExperimentalPatients receive estradiol PO TID for days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Therapeutic Estradiol

Eligibility Criteria

        Inclusion Criteria:

          -  Individuals of all races and ethnic groups are eligible for this trial.

          -  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): =< 2 prior chemotherapy regimens for treatment of
             metastatic breast cancer.

               -  Note: Prior use of monoclonal antibodies targeting PD1, PDL1 is allowed.

          -  PRE-SCREENING CRITERIA (STEP 0): Eastern Cooperative Oncology Group (ECOG) Performance
             status 0 or 1

          -  PRE-SCREENING CRITERIA (STEP 0): Willing to submit a biopsy specimen from locally
             recurrent or metastatic site (not primary) of breast cancer for ERbeta staining to
             Mayo Clinic Anatomic Pathology, if available. OR willing to undergo biopsy during
             pre-registration phase.

          -  PRE-REGISTRATION CRITERIA (STEP 1): For patients who submitted tissue for
             pre-screening (step 0) only: Presence of moderate or strong nuclear ERbeta staining in
             > 10% of cells.

          -  PRE-REGISTRATION CRITERIA (STEP 1): History of locally advanced or metastatic breast
             cancer that is ERalpha negative or low (< 10% nuclear staining), PR negative or low
             (<10% nuclear staining), and HER2 negative.

               -  Note: HER2 Negative Disease per 2013 ASCO/CAP guidelines, one of the following
                  must apply:

                    -  0 or 1+ by IHC and not amplified by 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-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.

          -  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): =< 2 prior chemotherapy regimens for treatment of
             metastatic breast cancer. (Note: Prior use of monoclonal antibodies targeting PD1,
             PDL1 is allowed.)

          -  PRE-REGISTRATION CRITERIA (STEP 1): Women must be postmenopausal.

               -  NOTE: Postmenopausal status is verified by:

                    -  Prior bilateral surgical oophorectomy, or

                    -  Age >= 60 years, or

                    -  Age < 60 years with no menses for > 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 (< 1% nuclear staining), and HER2 negative, and central lab
             confirmation that tumor is ERbeta positive (>= 25% moderate or strong nuclear
             staining).

          -  REGISTRATION CRITERIA (STEP 2): Hemoglobin >= 8 g/dL (=< 14 days prior to
             registration).

          -  REGISTRATION CRITERIA (STEP 2): Platelet count >= 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 =< 5 x ULN.

        Exclusion Criteria:

          -  PRE-REGISTRATION CRITERIA: Uncontrolled intercurrent illness including, but not
             limited to:

               -  Ongoing or active infection.

               -  Symptomatic congestive heart failure.

               -  Unstable angina pectoris.

               -  Uncontrolled symptomatic cardiac arrhythmia.

               -  Uncontrolled hypertension (defined as blood pressure > 160/90).

          -  PRE-REGISTRATION CRITERIA: Deep vein thrombosis / pulmonary embolism (DVT/PE) =< 12
             months prior to pre-registration.

               -  Note: Patients who are on anticoagulant therapy for maintenance are eligible as
                  long as the DVT and/or PE occurred > 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 =< 6 months prior to
             pre-registration

          -  PRE-REGISTRATION CRITERIA: History of coagulopathy.

          -  PRE-REGISTRATION CRITERIA: Other active second malignancy other than non-melanoma skin
             cancers within 3 years prior to pre-registration.

               -  NOTE: A second malignancy is not considered active if all treatment for that
                  malignancy is completed and the patient has been disease-free for >= 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, peripheral neuropathy).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical benefit rate
Time Frame:6 months
Safety Issue:
Description: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

Measure:Incidence of adverse events
Time Frame:5 years
Safety Issue:
Description: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.
Measure:Tumor response rate
Time Frame:5 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:The distribution of PFS times will be estimated using the method of Kaplan-Meier.
Measure:Overall survival distribution
Time Frame:From randomization to death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of survival times are estimated using the method of Kaplan-Meier.
Measure:Changes in phospho-ERbeta, cystatins 1, 2, 4 and 5, phospho-Smad2/3 and Ki-67
Time Frame:5 years
Safety Issue:
Description: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).

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

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