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

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ClinicalTrials.gov Identifier: NCT00324259
Recruitment Status : Completed
First Posted : May 10, 2006
Results First Posted : February 16, 2015
Last Update Posted : February 16, 2015
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Breast Neoplasms
Intervention Drug: Estradiol
Enrollment 66
Recruitment Details The study opened to participant enrollment on 08/03/2004 and closed to participant enrollment on 02/19/2008.
Pre-assignment Details  
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description 6 mg of estradiol daily (2 mg tid). 30 mg of estradiol. (10 mg tid)
Period Title: Overall Study
Started 34 32
Completed 34 32
Not Completed 0 0
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol) Total
Hide Arm/Group Description 6 mg of estradiol daily (2 mg tid). 30 mg of estradiol. (10 mg tid) Total of all reporting groups
Overall Number of Baseline Participants 34 32 66
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 34 participants 32 participants 66 participants
54.7
(36.3 to 83.8)
59.5
(39.4 to 77.7)
57.1
(36.3 to 83.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
Female
34
 100.0%
32
 100.0%
66
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 34 participants 32 participants 66 participants
34 32 66
Site  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
Bone/soft tissue 18 13 31
Visceral 5 5 10
Both 11 14 25
Estrogen receptor status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
Negative 1 0 1
Positive 33 32 65
Progesterone receptor status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 34 participants 32 participants 66 participants
Negative 8 6 14
Positive 26 26 52
1.Primary Outcome
Title Clinical Benefit Rate (CR Plus PR Plus SD)
Hide Description

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.

Time Frame 24 weeks after start of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 34 32
Measure Type: Number
Unit of Measure: participants
Complete response (CR) 0 0
Partial response (PR) 3 1
Stable disease (SD) 7 8
CR+PR+SD 10 9
2.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description

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.

Time Frame Up to 48 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 34 32
Measure Type: Number
Unit of Measure: participants
12 weeks (no progression) 30 20
24 weeks (no progression) 13 9
36 weeks (no progression) 7 6
48 weeks (no progression) 6 3
3.Secondary Outcome
Title Quality of Life
Hide Description

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.

Time Frame Baseline and Day 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
27 out of 34 participants in Arm 1 and 22 out of 32 participants in Arm 2 completed both the baseline and Day 28 (4 week) 6 item adverse effect questionnaire.
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 27 22
Mean (Standard Deviation)
Unit of Measure: units on a scale
Baseline 0.47  (0.48) 0.46  (0.59)
Day 28 0.70  (0.55) 0.92  (0.87)
4.Secondary Outcome
Title Quality of Life (FACT-B Mean Score)
Hide Description

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).

Time Frame Day 28
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
25 out of 34 participants in Arm 1 and 23 out of 32 participants completed the FACT-B questionnaire at Day 28 (4 weeks).
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 25 23
Mean (Standard Deviation)
Unit of Measure: units on a scale
109.5  (17.9) 106.9  (21.2)
5.Secondary Outcome
Title Frequency of Response to Re-treatment With the Same Aromatase Inhibitor That Immediately Preceded Treatment With Estradiol on Protocol.
Hide Description Best overall response
Time Frame 12 weeks post-treatment termination
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Only offered to patients experiencing clinical benefit on estradiol.
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 4 3
Measure Type: Number
Unit of Measure: participants
Partial response 1 1
Stable disease 1 0
Progressive disease 2 2
6.Secondary Outcome
Title 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.
Hide Description [Not Specified]
Time Frame Every 3 months
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
At the time that the study was powered there was not any information on any patients who were re-treated with estradiol after having a secondary response to a aromatase inhibitor after the first response to estradiol.
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Overall Survival (OS)
Hide Description [Not Specified]
Time Frame Until patient death
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
This outcome measure was not analyzed as the overall survival was not reported.
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:
6 mg of estradiol daily (2 mg tid).
30 mg of estradiol. (10 mg tid)
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
8.Post-Hoc Outcome
Title Metabolic Flare on FDG-PET/CT as Compared to Response
Hide Description [Not Specified]
Time Frame Baseline and 24 hours after administration of the first dose of estradiol
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description

The data was combined as the outcome was not based on comparison of the two groups but comparing the overall FDG-PET/CT metabolic flare to the overall responses.

10 participants were not evaluable because early toxicity prevented response assessment and the PET data was not considered technically adequate or not available in 8 participants.

Arm/Group Title Arm 1 (6 mg Estradiol) and Arm 2 (30 mg Estradiol)
Hide Arm/Group Description:

Arm 1 = 6 mg of estradiol daily (2 mg tid).

Arm 2 = 30 mg of estradiol. (10 mg tid)

Overall Number of Participants Analyzed 46
Measure Type: Number
Unit of Measure: participants
Complete response 0
Partial response 3
Stable disease 9
Progressive disease 3
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Hide Arm/Group Description 6 mg of estradiol daily (2 mg tid). 30 mg of estradiol. (10 mg tid)
All-Cause Mortality
Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Affected / at Risk (%) Affected / at Risk (%)
Total   8/34 (23.53%)   8/32 (25.00%) 
Blood and lymphatic system disorders     
Hemoglobin  1  0/34 (0.00%)  1/32 (3.13%) 
Eye disorders     
Eye pain  1  0/34 (0.00%)  1/32 (3.13%) 
Vison loss  1  0/34 (0.00%)  1/32 (3.13%) 
Gastrointestinal disorders     
Abdominal pain  1  2/34 (5.88%)  1/32 (3.13%) 
Constipation  1  0/34 (0.00%)  2/32 (6.25%) 
Diarrhea  1  2/34 (5.88%)  1/32 (3.13%) 
GI hemorrhage  1  1/34 (2.94%)  0/32 (0.00%) 
Nausea  1  2/34 (5.88%)  3/32 (9.38%) 
Vomiting  1  2/34 (5.88%)  3/32 (9.38%) 
General disorders     
Fatigue  1  0/34 (0.00%)  1/32 (3.13%) 
Fever  1  2/34 (5.88%)  0/32 (0.00%) 
Pain  1  0/34 (0.00%)  1/32 (3.13%) 
Infections and infestations     
Pneumonia  1  1/34 (2.94%)  0/32 (0.00%) 
Investigations     
Neutropenia  1  0/34 (0.00%)  1/32 (3.13%) 
Metabolism and nutrition disorders     
Dehydration  1  0/34 (0.00%)  2/32 (6.25%) 
Hypercalcemia  1  0/34 (0.00%)  1/32 (3.13%) 
Hyponatremia  1  0/34 (0.00%)  1/32 (3.13%) 
Weight loss  1  0/34 (0.00%)  1/32 (3.13%) 
Musculoskeletal and connective tissue disorders     
Arm pain  1  0/34 (0.00%)  1/32 (3.13%) 
Neck pain  1  1/34 (2.94%)  0/32 (0.00%) 
Nervous system disorders     
CNS ischemia  1  1/34 (2.94%)  0/32 (0.00%) 
Cerebrovascular accident  1  0/34 (0.00%)  1/32 (3.13%) 
Headache  1  0/34 (0.00%)  2/32 (6.25%) 
Renal and urinary disorders     
Acute renal failure  1  0/34 (0.00%)  1/32 (3.13%) 
Hematuria  1  0/34 (0.00%)  1/32 (3.13%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  1/34 (2.94%)  0/32 (0.00%) 
Dyspnea  1  3/34 (8.82%)  1/32 (3.13%) 
Pleural effusion  1  1/34 (2.94%)  1/32 (3.13%) 
Surgical and medical procedures     
Perforated viscus  1  0/34 (0.00%)  1/32 (3.13%) 
Vascular disorders     
Thrombosis/embolism  1  1/34 (2.94%)  0/32 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm 1 (6 mg Estradiol) Arm 2 (30 mg Estradiol)
Affected / at Risk (%) Affected / at Risk (%)
Total   34/34 (100.00%)   32/32 (100.00%) 
Blood and lymphatic system disorders     
Edema  1  7/34 (20.59%)  10/32 (31.25%) 
Hemoglobin  1  5/34 (14.71%)  12/32 (37.50%) 
Cardiac disorders     
Chest pain  1  2/34 (5.88%)  3/32 (9.38%) 
Palpitations  1  1/34 (2.94%)  1/32 (3.13%) 
Sinus arrythmia  1  1/34 (2.94%)  1/32 (3.13%) 
Gastrointestinal disorders     
Abdominal pain  1  2/34 (5.88%)  3/32 (9.38%) 
Ascites  1  1/34 (2.94%)  0/32 (0.00%) 
Constipation  1  11/34 (32.35%)  8/32 (25.00%) 
Dental pain  1  0/34 (0.00%)  1/32 (3.13%) 
Diarrhea  1  6/34 (17.65%)  7/32 (21.88%) 
Dry mouth  1  2/34 (5.88%)  1/32 (3.13%) 
Dyspepsia/heartburn  1  9/34 (26.47%)  9/32 (28.13%) 
Dysphagia  1  1/34 (2.94%)  1/32 (3.13%) 
Nausea  1  19/34 (55.88%)  16/32 (50.00%) 
Taste alteration  1  1/34 (2.94%)  1/32 (3.13%) 
Vomiting  1  6/34 (17.65%)  10/32 (31.25%) 
General disorders     
Fatigue  1  22/34 (64.71%)  18/32 (56.25%) 
Fever  1  4/34 (11.76%)  2/32 (6.25%) 
Sweating  1  0/34 (0.00%)  1/32 (3.13%) 
Infections and infestations     
Infection without neutropenia  1  5/34 (14.71%)  10/32 (31.25%) 
Skin (cellulitis)  1  0/34 (0.00%)  1/32 (3.13%) 
Investigations     
Alkaline phosphtase  1  2/34 (5.88%)  2/32 (6.25%) 
Hypercholesterolemia  1  2/34 (5.88%)  2/32 (6.25%) 
Hypertriglyceridemia  1  6/34 (17.65%)  11/32 (34.38%) 
Leukocytes  1  2/34 (5.88%)  0/32 (0.00%) 
Lymphopenia  1  5/34 (14.71%)  7/32 (21.88%) 
Neutrophils  1  2/34 (5.88%)  0/32 (0.00%) 
SGOT (AST)  1  1/34 (2.94%)  1/32 (3.13%) 
Weight gain  1  7/34 (20.59%)  4/32 (12.50%) 
Weight loss  1  1/34 (2.94%)  0/32 (0.00%) 
Metabolism and nutrition disorders     
Anorexia  1  6/34 (17.65%)  8/32 (25.00%) 
Dehydration  1  0/34 (0.00%)  1/32 (3.13%) 
Hypercalcemia  1  1/34 (2.94%)  1/32 (3.13%) 
Hyperglycemia  1  2/34 (5.88%)  2/32 (6.25%) 
Hypermagnesemia  1  0/34 (0.00%)  1/32 (3.13%) 
Hypoalbuminemia  1  3/34 (8.82%)  6/32 (18.75%) 
Hypocalcemia  1  2/34 (5.88%)  3/32 (9.38%) 
Hypokalemia  1  1/34 (2.94%)  1/32 (3.13%) 
Hyponatremia  1  2/34 (5.88%)  4/32 (12.50%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  12/34 (35.29%)  14/32 (43.75%) 
Bone pain  1  18/34 (52.94%)  18/32 (56.25%) 
Buttock pain  1  1/34 (2.94%)  0/32 (0.00%) 
Leg pain  1  0/34 (0.00%)  1/32 (3.13%) 
Muscle pain  1  16/34 (47.06%)  9/32 (28.13%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumor flare  1  4/34 (11.76%)  4/32 (12.50%) 
Tumor flare - infiltrating tumor in the orbit  1  0/34 (0.00%)  1/32 (3.13%) 
Nervous system disorders     
Ataxia  1  1/34 (2.94%)  0/32 (0.00%) 
Dizziness  1  6/34 (17.65%)  8/32 (25.00%) 
Headache  1  7/34 (20.59%)  12/32 (37.50%) 
Migraine  1  0/34 (0.00%)  2/32 (6.25%) 
Motor neuropathy  1  0/34 (0.00%)  1/32 (3.13%) 
Sensory neuropathy  1  2/34 (5.88%)  6/32 (18.75%) 
Psychiatric disorders     
Insomnia  1  10/34 (29.41%)  11/32 (34.38%) 
Mood alteration - anxeity  1  11/34 (32.35%)  5/32 (15.63%) 
Mood alteration - depression  1  5/34 (14.71%)  3/32 (9.38%) 
Renal and urinary disorders     
Hematuria  1  1/34 (2.94%)  0/32 (0.00%) 
Proteinuria  1  1/34 (2.94%)  0/32 (0.00%) 
Ureter pain  1  1/34 (2.94%)  2/32 (6.25%) 
Urinary frequency/urgency  1  5/34 (14.71%)  1/32 (3.13%) 
Urinary retention  1  1/34 (2.94%)  0/32 (0.00%) 
Reproductive system and breast disorders     
Breast pain  1  7/34 (20.59%)  13/32 (40.63%) 
Change in libido  1  3/34 (8.82%)  1/32 (3.13%) 
Groin pain  1  0/34 (0.00%)  1/32 (3.13%) 
Pelvic pain  1  2/34 (5.88%)  0/32 (0.00%) 
Vaginal bleeding  1  7/34 (20.59%)  6/32 (18.75%) 
Vaginal discharge  1  7/34 (20.59%)  7/32 (21.88%) 
Vaginal dryness  1  2/34 (5.88%)  0/32 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Bronchospasm  1  1/34 (2.94%)  0/32 (0.00%) 
Chest congestion  1  1/34 (2.94%)  0/32 (0.00%) 
Cough  1  8/34 (23.53%)  7/32 (21.88%) 
Dyspnea  1  8/34 (23.53%)  9/32 (28.13%) 
Epistaxis  1  0/34 (0.00%)  2/32 (6.25%) 
Nasal congestion  1  1/34 (2.94%)  0/32 (0.00%) 
Pleural effusion  1  0/34 (0.00%)  3/32 (9.38%) 
Voice change  1  1/34 (2.94%)  1/32 (3.13%) 
Skin and subcutaneous tissue disorders     
Alopecia  1  1/34 (2.94%)  0/32 (0.00%) 
Dry skin  1  1/34 (2.94%)  0/32 (0.00%) 
Erythema multiforme  1  1/34 (2.94%)  1/32 (3.13%) 
Hirsuitism  1  2/34 (5.88%)  2/32 (6.25%) 
Hives  1  0/34 (0.00%)  1/32 (3.13%) 
Hyperpigmentation  1  0/34 (0.00%)  1/32 (3.13%) 
Pigmentation change  1  1/34 (2.94%)  1/32 (3.13%) 
Pruritis/itching  1  5/34 (14.71%)  2/32 (6.25%) 
Rash  1  2/34 (5.88%)  2/32 (6.25%) 
Skin bruising  1  1/34 (2.94%)  1/32 (3.13%) 
Vascular disorders     
Hot flashes  1  5/34 (14.71%)  7/32 (21.88%) 
Hypertension  1  2/34 (5.88%)  1/32 (3.13%) 
Thrombosis/embolism  1  0/34 (0.00%)  1/32 (3.13%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, CTCAE (3.0)
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.
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr. Matthew Ellis
Organization: Washington University School of Medicine
Phone: 314-362-8866
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00324259     History of Changes
Other Study ID Numbers: 04-0412 / 201108392
First Submitted: May 8, 2006
First Posted: May 10, 2006
Results First Submitted: October 8, 2014
Results First Posted: February 16, 2015
Last Update Posted: February 16, 2015