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

 -  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:

 1. Age greater than 50 years and amenorrhea for 1 year

 2. Bilateral Surgical ovariectomy

 3. Serum FSH and estradiol level in the postmenopausal range before the initiation
 of AI therapy.

 4. 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:

 1. Four or more lesions more than one cm, measurable on CT scan bone windows.

 2. At least one tumor marker that is elevated to at least two times the upper limit
 of normal.

 3. 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.

 Exclusion Criteria:

 -  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.