Study of Physiological and High Dose Estradiol in the Treatment of Hormone Receptor Positive Metastatic Breast Cancer
Condition: Breast Neoplasms
MeSH terms: Breast Neoplasms
Intervention: Estradiol
Intervention MeSH terms: Estradiol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 66.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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.