Details

Details

Title Fulvestrant Alone Versus Fulvestrant and Everolimus VersusFulvestrant, Everolimus and Anastrozole: A Phase III Randomized Placebo-Controlled Trial in Postmenopausal Patients with Hormone-Receptor PositiveStage IV Breast Cancer

IRB S1222

CC 14-991

Hospital Beachwood, Fairview, Florida Weston, Hillcrest, Independence, Main Campus, Mansfield, North Coast Cancer, South Pointe, Strongsville, Wooster

Phase Phase 3

Disease Breast

Drug Anastrozole , Everolimus, Fulvestrant

Description

Description

Primary Objectives
  1. To test the benefit of interfering with the function of the estrogen receptor (ER) and providing downstream target inhibition (PI3K/AKT/mTOR) with a combination of optimal dose fulvestrant and everolimus (Arm 2) to improve progression-free survival compared to the optimal dose fulvestrant alone (Arm 1).
  2. To test the benefit of adding the non-steroidal aromatase inhibitor anastrozole to optimal dose fulvestrant and everolimus (Arm 3) in order to improve progressionfree survival over optimal dose fulvestrant (Arm 1).
Secondary Objectives
  1. To compare progression-free survival among those receiving fulvestrant + everolimus + anastrozole (Arm 3) versus fulvestrant + everolimus (Arm 2).
  2. To compare overall survival among the treatment arms in post-menopausal patients with hormone-receptor positive (HR+) Stage IV breast cancer.
  3. To assess and compare toxicities, feasibility and compliance among the study regimens.
  4. To compare response rates and clinical benefit rates among the study regimens.
  5. To test molecular determinants of response to endocrine therapy and everolimus in circulating tumor cells:
    • CTC-Endocrine Therapy Index (CTC ETI) on the CellSearch® platform.
    • CTC-Next Generation Sequencing Analysis (CTC-NGS) of single cells captured on the HD-CTC® platform.
Tertiary Objectives
  1. To collect and bank the following specimens for future research:
    • Circulating Cell-Free DNA
    • Cancer Tissue
    • Germline DNA
Inclusion Criteria

Inclusion Criteria

Disease Related Criteria
  1. Patients must have a histologically confirmed diagnosis of invasive breast carcinoma with positive estrogen and/or progesterone receptor status, and negative HER-2, for whom endocrine therapy is planned. Cytology-based diagnosis is allowed only if morphology, hormone-receptor and HER2 status can be assessed on such specimen. The HER-2 test result is negative (and should be reported as such), if a single test (or all tests) performed in a tumor specimen show: a) IHC 1+ negative or IHC 0 negative or b) ISH negative using a single probe ISH or dual probe ISH. Estrogen receptor (ER) and progesterone receptor (PgR) positivity must be assessed according to ASCO/CAP guidelines as either ER or PR ≥ 1% positive nuclear staining. If HER2 IHC is 2+, an evaluation for gene amplification must be performed and the gene must not be amplified. Gene amplification evaluation is not required if evaluation by IHC is 0 or 1+ by institutional standards. NOTE: In cases where the HER2 status of metastases
  2. (particularly in bone) is inconclusive (i.e. HER2 testing is 2+ by immunohistochemistry) the primary tumor must be HER2 negative by ASCO/CAP guidelines.
  3. Patients must be post-menopausal women with a confirmed diagnosis of metastatic breast cancer (M1-see Section 4.0). Pathologic confirmation of histology is preferable. In the case of bone metastases only, biopsy-proven metastatic disease of solitary site, or multiple sites of involvement are required. Post-menopausal is defined by at least one of the following criteria:
    • Prior bilateral oophorectomy OR
    • Amenorrheic for ≥ 12 months (if ≤ 55 years of age and prior chemotherapy in the past 5 years and/or tamoxifen within the past year, then FSH and estradiol must be in the post-menopausal range and obtained within 28 days prior to registration) OR
    • Previous hysterectomy with one or both ovaries left in place (or previous hysterectomy in which documentation of bilateral oophorectomy is unavailable AND FSH values consistent with the institutional normal values for the post-menopausal state. FSH levels must be obtained within 28 days prior to registration.
Clinical/Laboratory Criteria
  1. Patients must have measurable or non-measurable disease (see Section 10.1). Patients must have a chest/abdominal CT scan (PET/CT of diagnostic quality, conventional or spiral) and bone scan within 28 days prior to registration. All scans needed for assessment of measurable disease must be performed within 28 days prior to registration. Non-measurable disease must be assessed within 42 days prior to registration. All disease must be assessed and documented on the Baseline Tumor Assessment Form. See Section 15.3 for guidelines and submission instructions for required central radiology review.
  2. Patients with a history of prior chemotherapy or hormone therapy or immunotherapy for recurrent or metastatic disease are NOT eligible. Prior adjuvant or neoadjuvant chemotherapy if completed more than 12 months prior to registration is acceptable. Any number of prior hormonal therapy regimens for the adjuvant setting but not for metastatic or recurrent disease is allowed; prior adjuvant or neoadjuvant treatment with an aromatase inhibitor (e.g. anastrozole, letrozole, exemestane) is allowed, if completed more than 12 months prior to randomization. Radiation therapy to any site must be completed at least 7 days prior to registration.
  3. Patients who have taken luteinizing hormone-releasing hormone (LHRH) analogue as adjuvant therapy are eligible provided they have a) discontinued such therapy at least 12 months prior to registration AND b) have not resumed their menstrual periods.
  4. Patients must not have had prior exposure to fulvestrant or mTOR inhibitors (e.g., rapamycin, everolimus, temsirolimus, deforolimus). Concurrent bisphosphonate therapy is allowed. Patients must not have prior treatment with any investigational drug within 28 days prior to registration and must not be planning to receive any other investigational drug for the duration of the study.
  5. Patients must have an International Normalized Ratio (INR) ≤ 1.6 within 28 days prior to registration.
  6. Patients must have adequate bone marrow function, as defined by Absolute Neutrophil Count (ANC) of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a peripheral platelet count ≥ 100,000/ mL, all within 28 days prior to registration.
  7. Patients must have adequate hepatic function obtained within 28 days prior to registration and documented by all of the following:
    • Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilbert's Syndrome)
    • ALT (SGPT) and AST (SGOT) ≤ 2.5 x Institutional Upper Limit of Normal (IULN), or ≤ 5 x IULN if hepatic metastases are present.
  8. Patients must have adequate renal function with serum creatinine level ≤ IULN within 28 days prior to registration.
  9. Patients must have a fasting cholesterol ≤ 300 mg/dL and triglycerides ≤ 2.5 x IULN obtained within 28 days prior to registration. Patients may be on lipid lowering agents to reach these values.
  10. Patients must have a complete history and physical examination within 28 days prior to registration.
  11. Patients with bleeding diathesis (i.e., disseminated intravascular coagulation [DIC], clotting factor deficiency) or long-term anti-coagulant therapy (other than antiplatelet therapy) are NOT eligible.
    12. Specimen Submission
    1. Patients must have consented to a baseline blood draw for analysis of CTC-ETI, CTC-NGS and germline DNA sequencing as outlined in Section 15.2.
    2. Patients must be offered participation in banking of specimens for future research. With the patient's consent, specimens (tissue from primary tumor and/or metastatic biopsy) must be submitted to the repository. Patient consent must be obtained before specimens are submitted. See Section 15.1 for further information, including specimen submission timepoints.
    Regulatory Criteria
    1. Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
    2. As a part of the registration process (see Section 13.4 for registration instructions), the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system.
Exclusion Criteria

Exclusion Criteria

Exclusion Criteria Not Available