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

NCT00324259 | Completed Phase 2 Results

• 1 other identifier: 04-0412 / 201108392
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 7

Brief 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 recommended and through the early identification of non-responders to avoid drug exposure in patients who are unlikely to benefit to estrogen treatment.

Conditions

Breast Neoplasms

Outcome Measures

Primary Outcomes (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.

  24 weeks after start of treatment

Secondary Outcomes (6)

• Progression-free Survival (PFS)

  Up to 48 weeks

• Quality of Life

  Baseline and Day 28

• Quality of Life (FACT-B Mean Score)

  Day 28

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

  12 weeks post-treatment termination

• 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.

  Every 3 months

Study Arms (2)

Arm 1 (6 mg estradiol)

ACTIVE COMPARATOR

6 mg of estradiol daily (2 mg tid).

Drug: Estradiol

Arm 2 (30 mg estradiol)

ACTIVE COMPARATOR

30 mg of estradiol. (10 mg tid)

Drug: Estradiol

Interventions

Estradiol DRUG

Arm 1 (6 mg estradiol); Arm 2 (30 mg estradiol)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• 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
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (7)

University of Chicago

Chicago, Illinois, 60637, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10021, United States

Location

University of North Carolina Breast Clinic

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Case Western University

Cleveland, Ohio, 44106, United States

Location

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

Cleveland, Ohio, 44195, United States

Location

Related Publications (1)

• 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.

  PMID: 19690310 DERIVED

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Estradiol

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Limitations and Caveats

The slight imbalance in numbers assigned to the 2 groups was a because of yearly data and safety monitoring, which led to early closure of the 30mg group for toxicity concerns after 32 patients had been enrolled.

Results Point of Contact

• Title: Dr. Matthew Ellis
• Organization: Washington University School of Medicine

mjellis@bcm.edu

314-362-8866

Study Officials

• Matthew Ellis, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 8, 2006
• First Posted: May 10, 2006
• Study Start: August 1, 2004
• Primary Completion: March 1, 2011
• Study Completion: August 1, 2014
• Last Updated: February 16, 2015
• Results First Posted: February 16, 2015

Record last verified: 2015-01

Locations

US (7)