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Pilot Study Estradiol Followed by Exemestane Hormone Receptor + Metastatic Breast Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01385280
Recruitment Status : Completed
First Posted : June 30, 2011
Results First Posted : October 17, 2018
Last Update Posted : October 17, 2018
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Arizona

Brief Summary:

RATIONALE: Estrogen can cause the growth of tumor cells. Hormone therapy using therapeutic estradiol may fight breast cancer by lowering the amount of estrogen the body makes. Though estradiol initially produces stimulation of ER+ cancer cells, both laboratory and some clinical experience indicate that it may have the opposite effect on such cells, once they have become resistant to estrogen deprivation. In laboratory models, there is death of the "resistant" population after estradiol treatment, followed by restoration of sensitivity of the remaining cells to estrogen deprivation, as with an aromatase inhibitor. Exemestane may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving therapeutic estradiol together with exemestane may kill more tumor cells.

PURPOSE: This clinical trial studies therapeutic estradiol and exemestane in treating post-menopausal patients with hormone receptor-positive metastatic breast cancer

Condition or disease Intervention/treatment Phase
Estrogen Receptor-positive Breast Cancer Progesterone Receptor Positive Tumor Recurrent Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer Biological: therapeutic estradiol Drug: exemestane Other: laboratory biomarker analysis Other: enzyme-linked immunosorbent assay Not Applicable

Detailed Description:


I. To assess feasibility and toxicity associated with estradiol followed by exemestane in the treatment of estrogen receptor positive metastatic breast cancer patients failing prior aromatase inhibitor therapy.

II. Exploratory analysis of bio-correlates which will evaluate the mechanism of action of this treatment combination: changes in serum M-30, a marker of mitochondrial apoptosis; changes in number of circulating tumor cells (CTC); changes in CTC expression of ER, IGF1-R, and M-30.

III. Exploratory analysis of Progression Free Survival (PFS).

OUTLINE: Patients receive oral therapeutic estradiol once daily on days 1-3, twice daily on days 4-7, and thrice daily on days 8-90. Beginning on day 98, patients receive oral exemestane once daily in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Pilot Study Of Estradiol Followed By Exemestane For Post-Menopausal Hormone Receptor Positive Metastatic Breast Cancer After Prior Failed Endocrine Therapy: Reversing Endocrine Resistance
Study Start Date : February 2011
Actual Primary Completion Date : January 2013
Actual Study Completion Date : October 2013

Arm Intervention/treatment
Experimental: Arm I
Patients receive oral therapeutic estradiol once daily on days 1-3, twice daily on days 4-7, and thrice daily on days 8-90. Beginning on day 98, patients receive oral exemestane once daily in the absence of disease progression or unacceptable toxicity. Also laboratory biomarker analysis and enzyme-linked immunosorbent assay will be taken for correlative studies.
Biological: therapeutic estradiol
Given orally (PO)
Other Names:
  • Aquadiol
  • Dimenformon
  • Diogyn
  • Diogynets
  • ESDL

Drug: exemestane
Given PO
Other Names:
  • Aromasin
  • FCE-24304
  • PNU 155971

Other: laboratory biomarker analysis
Correlative studies

Other: enzyme-linked immunosorbent assay
Correlative studies
Other Name: ELISA

Primary Outcome Measures :
  1. Number of Participants With Grade 4 Toxicity [ Time Frame: By day 90 ]
    Such as deep vein thrombosis requiring hospitalization or pulmonary embolism

Secondary Outcome Measures :
  1. Patients With Change in Serum M-30 (a Marker of Mitochondrial Apoptosis) With Treatment [ Time Frame: At baseline and on days, 8, 30, 60, and 90 ]
  2. Patients With Change in Number of Circulating Tumor Cells (CTC) With Treatment [ Time Frame: At baseline and on days 8, 90, and 180 ]
  3. Patients With Change in Circulating Tumor Cells (CTC) Expression of M-30 With Treatment [ Time Frame: At baseline and on days 8, 90, and 180 ]
  4. Change in Circulating Tumor Cells (CTC) ER Expression With Treatment [ Time Frame: At baseline and on days 8, 90, and 180 ]
  5. Change in Circulating Tumor Cells (CTC) IGF1R Expression With Treatment [ Time Frame: At baseline and on days 8, 90, and 180 ]
  6. Median Time From Entry on Study to Progression of Disease [ Time Frame: Up to 1.5 years ]
    In weeks

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Post-menopausal women with metastatic carcinoma of the breast; post-menopausal, as defined by at least one of the following: at least 12 months without spontaneous menstrual bleeding, history of bilateral salpingo-oophorectomy with or without hysterectomy, age > 55 with hysterectomy with or without oophorectomy, serum Follicle-stimulating hormone (FSH) in post-menopausal range within 4 weeks of registration.
  • Positive for estrogen receptor (ER) or progesterone receptor (PgR) with positivity defined as immunohistochemical staining in >= 10% of cells
  • Either measurable disease by RECIST or non-measurable evaluable disease; tests to evaluate disease (measurable and non-measurable) must be completed within 28 days prior to registration; these will include a CT scan of the chest/abdomen/pelvis and a bone scan; patients with effusions or ascites as the only sites of disease are ineligible
  • Performance status of 0-2 by Zubrod criteria
  • Patients must have a baseline CA15-3 or CA 27.29 measurement for future comparison, but any baseline value is acceptable
  • Patients must have had prior aromatase inhibitor (AI) therapy in the metastatic setting (any number of prior AI is allowed, this may have been any of the AI's), or have developed metastatic disease on adjuvant AI therapy; prior treatment with tamoxifen and/or fulvestrant is also allowed; patients must not have been previously treated with estradiol for metastatic breast cancer
  • Patients must be able to take oral medications
  • Patients must be informed of the investigational nature of this study and give written informed consent in accordance with institutional and federal guidelines
  • Patients must consent to the serum and CTC blood specimen submissions

Exclusion Criteria:

  • Planning to receive concomitant chemotherapy, hormone therapy (including hormone replacement therapy), radiation therapy, or antibody therapy for malignancy while receiving protocol treatment, with the single exception of trastuzumab; concomitant trastuzumab will be allowed for Her-2 positive patients who were previously on trastuzumab; patients who have had previous radiotherapy must complete treatment within 4 weeks of registration, and have recovered from acute toxicity from radiation; patients with prior cytotoxic chemotherapy for metastatic disease will not be eligible
  • Known hypersensitivity or intolerance to estradiol, aromatase inhibitors, or aspirin; patients must not have a history of aspirin-induced GI bleeding within the past 3 years
  • Known untreated brain or CNS metastases due to the risk of bleeding on aspirin during estradiol
  • History of deep vein thrombosis, pulmonary embolism, or other clot requiring anticoagulation; patients must not have a known inherited hypercoagulable disorder
  • History of decompensated congestive heart failure, unstable angina, or uncontrolled psychiatric illness which would limit compliance with the protocol treatment
  • Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01385280

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United States, Arizona
University of Arizona Cancer Center
Tucson, Arizona, United States, 85724-5024
Sponsors and Collaborators
University of Arizona
National Cancer Institute (NCI)
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Principal Investigator: Robert Livingston University of Arizona

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: University of Arizona Identifier: NCT01385280     History of Changes
Other Study ID Numbers: 10-0906-04
NCI-2010-02366 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
3P30CA023074 ( U.S. NIH Grant/Contract )
First Posted: June 30, 2011    Key Record Dates
Results First Posted: October 17, 2018
Last Update Posted: October 17, 2018
Last Verified: September 2018
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Polyestradiol phosphate
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists