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

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ClinicalTrials.gov Identifier: NCT03941730
Recruitment Status : Recruiting
First Posted : May 8, 2019
Last Update Posted : August 30, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE May 6, 2019
First Posted Date  ICMJE May 8, 2019
Last Update Posted Date August 30, 2019
Actual Study Start Date  ICMJE August 28, 2019
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03941730 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
  • 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.
  • Tumor response rate [ 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.
  • 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.
  • 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.
  • 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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 6, 2019)
Changes in serum cystatin levels in response to treatment [ Time Frame: 3 years ]
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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Estradiol in Treating Patients With ER Beta Positive, Triple Negative Locally Advanced or Metastatic Breast Cancer
Official Title  ICMJE Therapeutic Targeting of ER Beta in Triple Negative Breast Cancer
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE Biological: Therapeutic Estradiol
Given PO
Other Names:
  • 17 Beta-Estradiol
  • Aquadiol
  • Dimenformon
  • Diogyn
  • Diogynets
  • Estrace
  • ESTRADIOL
  • Estraldine
  • Oestradiol
  • Ovocylin
  • Progynon
  • Vagifem
Study Arms  ICMJE 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.
Intervention: Biological: Therapeutic Estradiol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 6, 2019)
38
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 30, 2022
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03941730
Other Study ID Numbers  ICMJE MC1831
NCI-2019-02285 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1831 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Matthew P Goetz Mayo Clinic
PRS Account Mayo Clinic
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP