Title Phase III Randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/- one year of everolimus in patients with high-risk hormone receptor-positive and HER2/NEU negative breast cancer. E^3 Breast Cancer Study- Evaluating Everolimus with Endocrine Therapy
IRB SWOG 1207
Hospital Beachwood, Fairview, Hillcrest, Independence, Main Campus, Mansfield, North Coast Cancer, South Pointe, Strongsville, Wooster
Phase Phase 3
- The primary objective of this study is to compare whether the addition of one year of everolimus (10 mg daily) to standard adjuvant endocrine therapy improves invasive disease-free survival (IDFS) in patients with high-risk, hormone-receptor (HR) positive and HER2-negative breast cancer.
- To compare whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves overall survival (OS) and distant recurrence-free survival (DRFS) in this patient population.
- To evaluate the safety, toxicities and tolerability of one year of everolimus in combination with standard adjuvant endocrine therapy and compare it with standard adjuvant endocrine therapy plus placebo in this patient population.
- To determine whether the benefit of one year of everolimus use in addition to standard adjuvant endocrine therapy varies by recurrence score (RS), nodal status, or other commonly used prognostic factors.
- To evaluate adherence to 1-year treatment of everolimus in comparison to placebo in addition to standard adjuvant endocrine therapy in this patient population.
- To collect specimens in order to evaluate biomarkers of therapeutic efficacy.
Inclusion CriteriaDisease Related Criteria
- 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 standard adjuvant endocrine therapy is planned. Estrogen and progesterone receptor positivity must be assessed according to ASCO/CAP guidelines as either ER or PR ≥ 1% positive nuclear staining. HER-2 test result negativity must be assessed as per ASCO/CAP 2013 guidelines using IHC, ISH or both. HER-2 is negative if a single test (or all tests) performed in a tumor specimen show: a) IHC negative (0 or 1+) or b) ISH negative using single probe or dual probe (average HER-2 copy number <: 4.0 signals per cell by single prove or HER-2/CEP ratio < 2.0 with an average copy number < 4.0 signals per cell by dual probe). If HER2 IHC is 2+, evaluation for gene amplification (ISH) must be performed and the ISH must be negative; ISH is not required if IHC is 0 or 1+. HER-2 equivocal is not eligible.
- Patients must not have metastatic breast cancer (Stage IV disease). Patients with multifocal, multicentric, synchronous bilateral and primary inflammatory breast cancers are allowed.
- Multifocal disease is defined as more than one invasive cancer < 2 cm from the largest lesion within the same breast quadrant.
- Multicentric disease is defined as more than one invasive cancer ≥ 2 cm from the largest lesion within the same breast quadrant or more than one lesion in different quadrants.
- Synchronous bilateral disease is defined as invasive breast cancer with positive lymph nodes (axillary or inflammatory) in at least one breast, diagnosed within 30 days of each other. )NOTE: The tumor with the highest recurrence score should be used.))
- Completion of adjuvant chemotherapy and pathologically negative lymph nodes, and a tumor measuring ≥ 2 cm in greatest diameter, and an Oncotype DX® Recurrence Score > 25 (completed as standard of care). Patients with micrometastases as the only nodal involvement (pN1mi) are eligible, and will be categorized as node-negative.
- Completion of adjuvant chemotherapy, and pathologically 1-3 positive lymph nodes, and an Oncotype DX® Recurrence Score > 25 (screened via S1007 or otherwise).
- Completion of adjuvant chemotherapy and pathologically 4 or more positive lymph nodes.
- Completion of neoadjuvant chemotherapy and 4 or more positive nodes pathologically determined prior to or after chemotherapy.
NOTE: In the lymph node positive groups, at least one metastasis ≥ 2.0 mm must be present. Patients with micrometastases as the only nodal involvement (pN1mi) are eligible and will be categorized as node-negative.Clinical/Laboratory Criteria
- Patients must have completed either breast-conserving surgery or total mastectomy, with negative margins and appropriate axillary staging. A negative margin is defined as no evidence of tumor or DCIS at the line of resection. Additional operative procedures may be performed to obtain clear margins.
- Patients who had breast-conserving surgery must have completed whole breast radiation. Use of regional nodal basin radiation will be at the discretion of the investigator according to institutional guidelines.
- Patients with ≥ 4 positive lymph nodes must have completed breast/chest wall and nodal basin radiation therapy according to standard of care guidelines before randomization. Omission of radiation therapy is not allowed in this high-risk population of patients.
- Patients must be registered no sooner than 21 days after completion of radiation therapy and must have recovered (≤ Grade 1) from any of the effects of radiation.
- Patients must have undergone axillary staging by sentinel node biopsy or axillary lymph node dissection (ALND).
- For patients with 1-3 positive lymph nodes, sentinel node biopsy alone is allowed provided that the patient completed either whole breast or chest wall radiation and the primary tumor is < 5 cm.
- All patients with ≥ 4 positive lymph nodes must have completed ALND (with or without prior sentinel node biopsy).
- Bilirubin ≤ 1.5 mg/dL (or ≤ 3.0 mg/dL if due to Gilberts Syndrome)
- ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN)
- Alkaline phosphatase ≤ 1.5 x IULN
- Patients must have pre-treatment blood and tissue specimens submitted for translational medicine as outlined in Sections 15.1a and 15.1b. With patient consent, residuals will be banked for future research.
- Patients (at NCORP Institutions only) must be offered the opportunity to participate in the S1207-E01 Behavioral and Health Outcomes study (BAHO) (see Sections 15.1c, 15.2 and Appendix 18.1). NOTE: Patients who have already started endocrine therapy are eligible for the BAHO study.
- 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.
- As a part of the OPEN registration process (see Section 13.4 for OPEN access 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.