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


CC 13-640

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

Phase Phase 3

Disease Breast

Drug Everolimus



  1. 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.
  1. 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.
  2. 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.
  3. 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.
  4. To evaluate adherence to 1-year treatment of everolimus in comparison to placebo in addition to standard adjuvant endocrine therapy in this patient population.
  5. To collect specimens in order to evaluate biomarkers of therapeutic efficacy.
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 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.
  2. 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.))
  3. Patients must be high risk by belonging to one of the following risk groups:
    • 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
  1. 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.
  2. 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).
  3. Patients must have completed standard neoadjuvant or adjuvant taxane and/or anthracycline based chemotherapy prior to randomization. Completion of chemotherapy will be determined by the treating oncologist, but should include a minimum of 4 cycles (a cycle of weekly paclitaxel is considered 3 doses). Patients must be registered within 42 weeks after the last dose of chemotherapy. Patients may have started endocrine therapy at any time after the diagnosis of the current breast cancer.
  4. Patients must not be receiving or planning to receive trastuzumab. Concurrent bisphosphonate therapy is allowed. Patients must not have prior exposure to mTOR inhibitors (rapamycin, everolimus, temsirolimus, deforolimus). Patients must not have prior treatment with any investigational drug within the preceding 28 days and must not be planning to receive any other investigational drug for the duration of the study.
  5. Patients must have adequate bone marrow function, as defined by ANC of ≥ 1,500/mL, hemoglobin ≥ 9 g/dL and a platelet count ≥ 100,000/ mL within 28 days prior to registration.
  6. 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 Gilberts Syndrome)
    • ALT and AST ≤ 1.5 x Institutional Upper Limit of Normal (IULN)
    • Alkaline phosphatase ≤ 1.5 x IULN
  7. Patients must have adequate renal function with serum creatinine level ≤ IULN within 28 days prior to registration.
  8. 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.
  9. Patients must have a complete history and physical examination within 28 days prior to registration.
  10. Patients must have a performance status of 0-2 by Zubrod criteria (see Section 10.7).
  11. Patients must not have any Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia (see Appendix 18.2).
  12. Patients must not have uncontrolled diabetes (defined as an Hg A1C >7% within 28 days prior to registration).
  13. Patients must not have an organ allograft or other history of immune compromise. Patients must not be receiving chronic, systemic treatment with corticosteroids or other immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
  14. Patients known to be HIV positive may be enrolled if baseline CD4 count is > 500 cells/mm3 AND not taking anti-retroviral therapy. Patients with known hepatitis are not eligible unless there is a known negative hepatitis panel. Patients must not have any known uncontrolled underlying pulmonary disease.
  15. Patients must be able to take oral medications. Patient may not have any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of blinded drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
  16. Patients must not have received immunization with an attenuated live vaccine (e.g. intranasal influenza, MMR, oral polio, varicella, zoster, yellow fever and BCG vaccines) within seven days prior to registration nor have plans to receive such vaccination while on protocol treatment.
  17. Patients must not have taken within 14 days prior to registration , be taking, nor plan to take while on protocol treatment, strong CYP3A4 inhibitors, and/or CYP3A4 inducers. (See Section 7.3 and Appendix 18.4.)
  18. No other prior malignancy is allowed except for adequately treated basal cell (or squamous cell) skin cancer, in situ cervical cancer or other cancer for which the patient has been disease-free for 5 years.
  19. Patients must not be pregnant or nursing due to the potential for congenital abnormalities, and the potential of his regimen to harm nursing infants. Women/men of reproductive potential must have agreed to use an effective non-hormonal contraceptive method. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. Corresponding procedures for men include castration, vasectomy and barrier contractive devices. However, if at any point a previously celibate patient chooses to become heterosexually active during the protocol therapy, he/she is responsible for beginning contraceptive measures.
Translational Medicine Criteria
  1. 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.
  2. 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.
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 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.
Exclusion Criteria

Exclusion Criteria

Exclusion Criteria Not Available