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Breast NeoplasmsPhase 2NCT00324259

Study of Physiological and High Dose Estradiol in the Treatment of Hormone Receptor Positive Metastatic Breast Cancer

A Phase 2 study testing Estradiol in people with Breast Neoplasms, run by Washington University School of Medicine at 7 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study aims to examine whether estradiol is an appropriate for future Phase 3 studies as second or third line endocrine treatment. In addition the protocol explores several approaches to enhance the safety of estrogen therapy, including the establishment of the efficacy of a lower dose than that currently… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Neoplasms
What is being tested?
Estradiol
Could I receive a placebo?
No, everyone receives an active treatment
How many people
66 participants
Where
7 sitesUnited States
Study dates
Aug 2004to Aug 2014
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Postmenopausal women with advanced hormone receptor positive (ER and or PgR) breast cancer, has received prior treatment with an aromatase inhibitor in the advanced disease setting, and experienced at least 24 weeks of progression free survival. As long as the patient experienced an aromatase inhibitor response as defined this way, she is still eligible even if she has received further lines of endocrine therapy, which may include other aromatase inhibitors or tamoxifen, even if these subsequent lines of treatment were unsuccessful (see below for permitted chemotherapy and trastuzumab therapy).
  • OR
  • Postmenopausal women with systemic or unresectable local relapse after taking at least two years of adjuvant aromatase inhibitor therapy.
  • Clinical diagnosis of postmenopausal status is defined as either:
  • Age greater than 50 years and amenorrhea for 1 year
  • Bilateral Surgical ovariectomy
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  • Serum FSH and estradiol level in the postmenopausal range before the initiation of AI therapy.
  • If the patient was receiving an LHRH agonist to maintain a postmenopausal state during AI therapy this should be continued since recovery of menses would lead to uncontrolled estrogen exposure and pregnancy during estrogen therapy is contraindicated.
  • Tumor cell expression of ER and/or PgR can be ascertained on either the primary or the metastatic site. However when both types of tissue are available, the metastatic site should be used to determine eligibility. ER and/or PgR positive are defined as at least 10% of malignant cells with positive nuclear staining.
  • The patients may have received adjuvant and/or neoadjuvant chemotherapy.
  • Prior radiotherapy is permitted as long as it was planned before the start of the study medication and is completed within 3 weeks of trial medication starting.
  • Prior tamoxifen therapy is also permitted as adjuvant or advanced disease therapy.
  • Patients with ER+ HER2+ disease are eligible even of they have received trastuzumab in the past (and even if it was administered in combination with endocrine treatment) as long as they meet all other eligibility criteria. Trastuzumab therapy must be held during estradiol treatment.
  • Use of prior experimental agents alone or in combination with endocrine therapy is also permissible, but a wash out of one month is required if the immediate prior therapy involved a study medication that had not been subject to regulatory approval.
  • Prior adjuvant chemotherapy is permitted as well as one line of chemotherapy for advanced disease.
  • Patient must have at least one measurable lesion defined by RECIST criteria. To be considered measurable, a baseline lesion must have a minimum diameter to compensate for measurement error: 1 cm for soft tissue lesions, 1 cm for lung lesions including pleural lesions measured by CT scan, 1 cm for liver lesions measured by CT scan.
  • Patients with bone only disease can also be enrolled if they meet the following criteria:
  • Four or more lesions more than one cm, measurable on CT scan bone windows.
  • At least one tumor marker that is elevated to at least two times the upper limit of normal.
  • All patients should have a baseline bone scan with X-ray evaluation of all hot spots, CT chest abdomen and pelvis (with bone windows), and tumor marker assessment. Also CT scan of the extremities should be done on suspicious areas seen on X-ray evaluation of all hot spots if these extremity lesions are to be followed for response.
  • The patient must have an ECOG performance status of 0-2
  • The patient should have a life expectancy of > 6 months.
  • The patient must have adequate hematologic function, defined as ANC >1000/mm3 and platelets > 75,000/mm3.
  • The patient must have adequate renal function, defined as serum creatinine less than or equal to 1.5 times the upper limit of normal.
  • The patient must have adequate liver function defined as serum bilirubin less than or equal to 1.5 times the upper limit of normal (three times the upper limit of normal for patients with hereditary benign hyperbilirubinaemia), transaminases (ALT, AST) less than or equal to 2.5 times the upper limit of normal in patients without liver metastasis or less than or equal to 5 times the upper limit of normal in patients with liver metastasis.
  • For patients with bone metastasis, treatment with i.v. bisphosphonates during the trial is mandatory because of the risk of hypercalcemia. Bisphosphonate therapy must be started before the patient begins protocol therapy.
  • Preexisting hypercalcemia should be treated and calcium normalized prior to study entry.
  • The patient must give written informed consent prior to initiation of any invasive study-related procedures that would otherwise not be performed, and must be able to comply with scheduled visits and evaluations.
  • Inclusion of Women and Minorities: Entry to this study is open to women of all racial and ethnic subgroups.
  • Patients with fasting blood glucose level ≤ 200 mg/dL. If greater, hyperglycemia must be treated before initiation of study investigations.

Who cannot join

  • Patients with CNS involvement with metastatic breast cancer or life threatening lymphangitic or large volume lung or liver disease that threatens organ function.
  • Patients with history of deep venous thrombosis, pulmonary embolism, stroke, acute myocardial infarction, congestive cardiac failure, untreated hypertension.
  • Ischemic changes on a baseline EKG or other evidence of ischemic heart disease.
  • Undiagnosed abnormal genital bleeding
  • Untreated cholelithiasis
  • Fasting serum triglycerides greater than 400. Patients should be treated and triglycerides controlled prior to study entry.
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  • Treatment with fulvestrant within 12 months of study initiation (fulvestrant has been shown to antagonize estradiol induced apoptosis in preclinical models (5).
  • The patient's only qualifying lesion (s) have been previously irradiated or are scheduled for irradiation following study entry.
  • Severe or uncontrolled concomitant disease from other causes.
  • EGOG Performance status 3 or 4.
  • The patient has previous malignancies other than breast cancer except a) adequately treated in situ carcinoma of the cervix, b) localized basal or squamous cell carcinoma of the skin c) any previous malignancy treated with curative intent with a recurrence risk of less than 30%.
  • The patient is unable to understand the informed consent or is unlikely to be compliant with the protocol.
  • More than one line of palliative chemotherapy for advanced disease.

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • University of North Carolina Breast Clinic

    Chapel Hill, North Carolina, 27599

  • University of Chicago

    Chicago, Illinois, 60637

  • Case Western University

    Cleveland, Ohio, 44106

  • Cleveland Clinic, Lerner College of Medicine, Case Western Reserve University

    Cleveland, Ohio, 44195

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Memorial Sloan-Kettering Cancer Center

    New York, New York, 10021

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

About this study

Official title: A Phase II Randomized Study of Physiological (6 mg Daily) and High Dose (30 mg Daily) Estradiol in the Treatment of Hormone Receptor Positive Metastatic Breast Cancer

This study aims to examine whether estradiol is an appropriate for future Phase 3 studies as second or third line endocrine treatment. In addition the protocol explores several approaches to enhance the safety of estrogen therapy, including the establishment of the efficacy of a lower dose than that currently recommended and through the early identification of non-responders to avoid drug exposure in patients who are unlikely to benefit to estrogen treatment.

Read the detailed description

The purpose of this study is to compare the effects of two doses (6 mg and 30 mg) of Estradiol, a type of estrogen. This and other forms of estrogen used at doses much higher than those used for postmenopausal hormone replacement therapy have been shown to cause tumor growth stabilization or shrinkage in patients with breast cancer.

Being tested
Estradiol
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EstradiolDrug

Study groups in NCT00324259
Study groupRoleWhat they receive
Arm 1 (6 mg estradiol)Active comparator6 mg of estradiol daily (2 mg tid).
Receives: Drug: Estradiol
Arm 2 (30 mg estradiol)Active comparator30 mg of estradiol. (10 mg tid)
Receives: Drug: Estradiol

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Clinical Benefit Rate (CR Plus PR Plus SD)

    Complete response (CR) + partial response (PR) + stable disease (SD) using RECIST 1.0

    CR = disappearance of all target lesions

    PR = at least a 30% decrease in the sum of the longest diameter of target lesions taking as reference the baseline sum longest diameter

    SD = neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for progressive disease

    SD is defined as lack of disease progression by 24 weeks.

    Measured: 24 weeks after start of treatment

Secondary outcomes (6)

  1. Progression-free Survival (PFS)

    Defined as the time from treatment initiation to disease progression or death.

    Time of last observation for patients remaining in the study and the time at which dose reductions, study drug termination, and withdrawal of consent occurred were treated as censored data.

    Indicated as number of participants who had not progressed at 12 weeks, 24 weeks, 36 weeks, and 48 weeks.

    Progression per RECIST 1.0 = at least a 20% increase in the sum of the longest diameter of target lesions taking as references the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions.

    Measured: Up to 48 weeks

  2. Quality of Life

    Surveyed using a 6 item estrogen adverse effect questionnaire (headaches, bloating, breast tenderness, retention of fluid, nausea, and vomiting).

    Used a 5-point scale ranging from 0 (not at all) to 4 (very much).

    The scores from the 6 estrogen adverse effect items were summed to produce a single score, ranging from 0-24, with higher scores indicating higher adverse effects.

    Measured: Baseline and Day 28

  3. Quality of Life (FACT-B Mean Score)

    Surveyed using the multidimensional Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire

    The FACT-B (version 4) questionnaire consists of 36 items with five-point scale, ranging from 0-4, where a total score ranges from 0-144 and higher scores indicate better QoL. The total FACT-B score is the sum of scores for five subscales including: physical well-being (7 items), social/family well-being (7 items), emotional well-being (6 items), functional well-being (7 items), and specific breast cancer concerns (9 items).

    Measured: Day 28

  4. Frequency of Response to Re-treatment With the Same Aromatase Inhibitor That Immediately Preceded Treatment With Estradiol on Protocol.

    Best overall response

    Measured: 12 weeks post-treatment termination

  5. Frequency of Response to Re-treatment With Estradiol for Patients Who Have a Secondary Response to an Aromatase Inhibitor After the First Response to Estradiol.

    Measured: Every 3 months

  6. Overall Survival (OS)

    Measured: Until patient death

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 May 2006 (estimated)
  2. Study startAug 2004
  3. Primary completionMar 2011
  4. Study completionAug 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
66 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00324259
Sponsor's protocol ID
04-0412 / 201108392
Status last verified
Jan 2015
First submitted
8 May 2006
Last updated
16 Feb 2015
Data monitoring committee
No

Publications

  • Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009 Aug 19;302(7):774-80. doi: 10.1001/jama.2009.1204.

    PubMed 19690310

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Estradiol in people with Breast Neoplasms, run by Washington University School of Medicine at 7 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 30 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 16 Feb 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Feb 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Clinical Benefit Rate (CR Plus PR Plus SD) (time frame: 24 weeks after start of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00324259, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2015.

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