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Eligibility
for people ages 18 years and up
Location
at San Francisco, California and other locations
Dates
study started
estimated completion:
Principal Investigator

Description

Summary

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen citrate, goserelin acetate, leuprolide acetate, anastrozole, letrozole, or exemestane, may fight breast cancer by lowering the amount of estrogen the body makes. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether hormone therapy is more effective when given with or without everolimus in treating breast cancer.

PURPOSE: This randomized phase III trial studies how well giving hormone therapy together with or without everolimus work in treating patients with breast cancer.

Official 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

Details

OBJECTIVES:

Primary

  • 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 human epidermal growth factor receptor (HER)2-negative breast cancer.

Secondary

  • 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 to 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. (exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to risk level (node-negative and recurrence score [RS]> 25 in the primary tumor, and a tumor measuring ≥ 2 cm in greatest diameter treated with adjuvant therapy vs 1-3 positive lymph nodes and RS> 25 treated with adjuvant therapy vs ≥ 4 positive lymph nodes [any RS value] treated with adjuvant therapy vs ≥ 4 positive lymph nodes [any RS value] prior to or after neoadjuvant chemotherapy). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive an approved endocrine therapy comprising tamoxifen citrate*, goserelin acetate** or leuprolide acetate**, or aromatase inhibitor (anastrozole, letrozole, or exemestane) for 2-5 years. Patients also receive a placebo orally (PO) daily for 1 year in the absence of disease progression or unacceptable toxicity.
  • Arm II: Patients receive an approved endocrine therapy regimen as in arm I. Patients also receive everolimus PO daily for 1 year in the absence of disease progression or unacceptable toxicity.

NOTE: *Men receive tamoxifen citrate PO for 5 years.

NOTE: **Goserelin acetate or leuprolide acetate is given if patient is or becomes postmenopausal.

Blood and tissue samples are collected for biomarker studies.

After completion of study treatment, patients are followed up every 6 months for 2 years and then yearly thereafter for 10 years.

Keywords

Breast Cancer estrogen receptor-positive breast cancer HER2-negative breast cancer stage IA breast cancer stage IB breast cancer stage II breast cancer stage IIIA breast cancer stage IIIB breast cancer stage IIIC breast cancer progesterone receptor-positive breast cancer male breast cancer Hormones Letrozole Exemestane Anastrozole Everolimus Sirolimus Tamoxifen Leuprolide Goserelin Citric Acid

Eligibility

For people ages 18 years and up

DISEASE CHARACTERISTICS:

  • Patients must have a histologically confirmed diagnosis of invasive breast carcinoma with positive estrogen (ER)- and/or progesterone-receptor (PR) status, and negative human epidermal growth factor receptor (HER)2, for whom standard adjuvant endocrine therapy is planned
  • ER and PR positivity must be assessed according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as either ER or PR ≥ 1% positive nuclear staining
  • HER2 test result negativity must be assessed as per ASCO/CAP 2013 guidelines using IHC, ISH or both.

HER2 is negative if a single test (or all tests) performed in a tumor specimen show:

  1. IHC negative (0 or 1+)
  2. ISH negative using single probe or dual probe. If 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+.

    HER2 equivocal is not eligible.

    • Patients must not have metastatic breast cancer (stage IV disease); patients with multifocal, multicentric, and 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 intramammary) in at least one breast, diagnosed within 30 days of each other
    • Patients must be high risk by belonging to one of the following risk groups:
    • Completion of adjuvant chemotherapy and pathologically negative axillary nodes,and a tumor measuring ≥ 2 cm in greatest diameter, and an Oncotype DX®recurrence score (RS)> 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 either an Oncotype DX® RS> 25 (screened via S1007 or otherwise) or tumor tissue with pathological Grade III following local practice. If Oncotype DX is done, then RS must be> 25. If the test is not done, but the patient has Grade III disease then the patient is eligible and Oncotype DX does not need to be performed.
    • Completion of adjuvant chemotherapy and pathologically 4 or more positive lymph nodes.
    • Completion of neoadjuvant chemotherapy and 1 or more positive nodes pathologically determined prior to or after chemotherapy
    • 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 ductal carcinoma in situ (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)

PATIENT CHARACTERISTICS:

  • Absolute Neutrophil Count ≥ 1,500/mL
  • Hemoglobin ≥ 9 g/dL
  • Platelet count ≥ 100,000/mL
  • Bilirubin ≤ 1.5 mg/dL (≤ 3.0 mg/dL if due to Gilbert syndrome)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 times institutional upper limit of normal (IULN)
  • Alkaline phosphatase ≤ 1.5 times IULN
  • Serum creatinine level ≤ IULN
  • Fasting cholesterol ≤ 300 mg/dL and triglycerides ≤ 2.5 times IULN; patients may be on lipid-lowering agents to reach these values
  • Patients must have a performance status of 0-2 by Zubrod criteria
  • 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
  • Patients previously diagnosed with diabetes must not have uncontrolled diabetes(defined as a hemoglobin [Hg] A1C> 7% within 28 days prior to registration)
  • Patients known to be human immunodeficiency virus (HIV) positive may be enrolled if baseline CD4 count is> 500 cells/mm³ and they are not taking anti-retroviral therapy
  • Patients with known hepatitis are not eligible
  • Patients must not have any known uncontrolled, underlying pulmonary disease
  • Patients must be able to take oral medications
  • Patients 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)
  • Patients must not be pregnant or nursing
  • Women/men of reproductive potential must have agreed to use an effective non-hormonal contraceptive method during and for 8 weeks after completion of study therapy
  • 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
  • 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
  • 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

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Patients must have completed standard neoadjuvant or adjuvant 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
  • 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
  • Patients must not be planning to receive any other anticancer drug for the duration of the study
  • 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
  • Patients must not have received immunization with an attenuated live vaccine (e.g.,intranasal influenza, measles, mumps, and rubella [MMR], oral polio, varicella,zoster, yellow fever, and Bacillus Calmette-Guérin [BCG] vaccines) within seven days prior to registration nor have plans to receive such vaccination while on protocol treatment
  • Patients must not have taken within 14 days prior to registration, be taking, nor plan to take while on protocol treatment, strong cytochrome P450 3A4 (CYP3A4)inhibitors and/or CYP3A4 inducers

Locations

  • Kaiser Permanente-Deer Valley Medical Center accepting new patients
    Antioch, California, 94531, USA
  • Sutter Auburn Faith Hospital accepting new patients
    Auburn, California, 95602, USA
  • Sutter Cancer Centers Radiation Oncology Services-Auburn accepting new patients
    Auburn, California, 95603, USA
  • Alta Bates Summit Medical Center-Herrick Campus accepting new patients
    Berkeley, California, 94704, USA
  • Mills - Peninsula Hospitals accepting new patients
    Burlingame, California, 94010, USA
  • Sutter Cancer Centers Radiation Oncology Services-Cameron Park accepting new patients
    Cameron Park, California, 95682, USA
  • Mercy San Juan Medical Center accepting new patients
    Carmichael, California, 95608, USA
  • East Bay Radiation Oncology Center currently not accepting new patients, but might later
    Castro Valley, California, 94546, USA
  • Eden Hospital Medical Center accepting new patients
    Castro Valley, California, 94546, USA
  • Valley Medical Oncology Consultants-Castro Valley currently not accepting new patients, but might later
    Castro Valley, California, 94546, USA
  • John Muir Medical Center-Concord Campus withdrawn
    Concord, California, 94520, USA
  • Sutter Davis Hospital accepting new patients
    Davis, California, 95616, USA
  • Epic Care-Dublin accepting new patients
    Dublin, California, 94568, USA
  • Bay Area Breast Surgeons Inc accepting new patients
    Emeryville, California, 94608, USA
  • Epic Care Partners in Cancer Care accepting new patients
    Emeryville, California, 94608, USA
  • Kaiser Permanente-Fremont accepting new patients
    Fremont, California, 94538, USA
  • Valley Medical Oncology Consultants-Fremont currently not accepting new patients, but might later
    Fremont, California, 94538, USA
  • Contra Costa Regional Medical Center accepting new patients
    Martinez, California, 94553, USA
  • Fremont - Rideout Cancer Center accepting new patients
    Marysville, California, 95901, USA
  • Mercy UC Davis Cancer Center accepting new patients
    Merced, California, 95340, USA
  • Memorial Medical Center accepting new patients
    Modesto, California, 95355, USA
  • Kaiser Permanente-Modesto accepting new patients
    Modesto, California, 95356, USA
  • El Camino Hospital currently not accepting new patients, but might later
    Mountain View, California, 94040, USA
  • Palo Alto Medical Foundation-Camino Division accepting new patients
    Mountain View, California, 94040, USA
  • Palo Alto Medical Foundation-Gynecologic Oncology accepting new patients
    Mountain View, California, 94040, USA
  • Sutter Cancer Research Consortium accepting new patients
    Novato, California, 94945, USA
  • Highland General Hospital currently not accepting new patients, but might later
    Oakland, California, 94602, USA
  • Alta Bates Summit Medical Center - Summit Campus accepting new patients
    Oakland, California, 94609, USA
  • Bay Area Tumor Institute accepting new patients
    Oakland, California, 94609, USA
  • Hematology and Oncology Associates-Oakland currently not accepting new patients, but might later
    Oakland, California, 94609, USA
  • Tom K Lee Inc terminated
    Oakland, California, 94609, USA
  • Kaiser Permanente-Oakland accepting new patients
    Oakland, California, 94611, USA
  • Palo Alto Medical Foundation Health Care accepting new patients
    Palo Alto, California, 94301, USA
  • Stanford Cancer Institute currently not accepting new patients, but might later
    Palo Alto, California, 94304, USA
  • East Bay Medical Oncology Hematology Medical Associates Inc-Pleasant Hill terminated
    Pleasant Hill, California, 94523, USA
  • Valley Medical Oncology Consultants currently not accepting new patients, but might later
    Pleasanton, California, 94588, USA
  • Kaiser Permanente-Redwood City accepting new patients
    Redwood City, California, 94063, USA
  • Kaiser Permanente-Richmond accepting new patients
    Richmond, California, 94801, USA
  • Kaiser Permanente-Roseville accepting new patients
    Roseville, California, 95661, USA
  • Sutter Cancer Centers Radiation Oncology Services-Roseville accepting new patients
    Roseville, California, 95661, USA
  • Sutter Roseville Medical Center accepting new patients
    Roseville, California, 95661, USA
  • Mercy Medical Group accepting new patients
    Sacramento, California, 95816, USA
  • Sutter General Hospital accepting new patients
    Sacramento, California, 95816, USA
  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento, California, 95817, USA
  • Kaiser Permanente-South Sacramento accepting new patients
    Sacramento, California, 95823, USA
  • Kaiser Permanente - Sacramento accepting new patients
    Sacramento, California, 95825, USA
  • Saint Helena Hospital accepting new patients
    Saint Helena, California, 94574, USA
  • California Pacific Medical Center-Pacific Campus accepting new patients
    San Francisco, California, 94115, USA
  • Kaiser Permanente-San Francisco accepting new patients
    San Francisco, California, 94115, USA
  • Kaiser Permanente-Santa Teresa-San Jose accepting new patients
    San Jose, California, 95119, USA
  • Santa Clara Valley Medical Center currently not accepting new patients, but might later
    San Jose, California, 95128, USA
  • Kaiser Permanente San Leandro accepting new patients
    San Leandro, California, 94577, USA
  • Doctors Medical Center- JC Robinson Regional Cancer Center currently not accepting new patients, but might later
    San Pablo, California, 94806, USA
  • Kaiser Permanente-San Rafael accepting new patients
    San Rafael, California, 94903, USA
  • Kaiser Permanente Medical Center - Santa Clara accepting new patients
    Santa Clara, California, 95051, USA
  • Palo Alto Medical Foundation-Santa Cruz accepting new patients
    Santa Cruz, California, 95065, USA
  • Kaiser Permanente-Santa Rosa accepting new patients
    Santa Rosa, California, 95403, USA
  • Sutter Pacific Medical Foundation accepting new patients
    Santa Rosa, California, 95403, USA
  • Kaiser Permanente-South San Francisco accepting new patients
    South San Francisco, California, 94080, USA
  • Kaiser Permanente-Stockton accepting new patients
    Stockton, California, 95210, USA
  • Palo Alto Medical Foundation-Sunnyvale accepting new patients
    Sunnyvale, California, 94086, USA
  • Northbay Cancer Center accepting new patients
    Vacaville, California, 95687, USA
  • Sutter Cancer Centers Radiation Oncology Services-Vacaville accepting new patients
    Vacaville, California, 95687, USA
  • Kaiser Permanente Medical Center-Vacaville accepting new patients
    Vacaville, California, 95688, USA
  • Kaiser Permanente-Vallejo accepting new patients
    Vallejo, California, 94589, USA
  • Sutter Solano Medical Center/Cancer Center accepting new patients
    Vallejo, California, 94589, USA
  • Kaiser Permanente-Walnut Creek accepting new patients
    Walnut Creek, California, 94596, USA
  • John Muir Medical Center-Walnut Creek withdrawn
    Walnut Creek, California, 94598, USA
  • Woodland Memorial Hospital accepting new patients
    Woodland, California, 95695, USA
  • Kaiser Permanente-Anaheim accepting new patients
    Anaheim, California, 92807, USA
  • AIS Cancer Center at San Joaquin Community Hospital accepting new patients
    Bakersfield, California, 93301, USA
  • Kaiser Permanente-Baldwin Park accepting new patients
    Baldwin Park, California, 91706, USA
  • Kaiser Permanente-Bellflower accepting new patients
    Bellflower, California, 90706, USA
  • Providence Saint Joseph Medical Center/Disney Family Cancer Center currently not accepting new patients, but might later
    Burbank, California, 91505, USA
  • City of Hope Corona accepting new patients
    Corona, California, 92879, USA
  • UC Irvine Health Cancer Center-Newport accepting new patients
    Costa Mesa, California, 92627, USA
  • City of Hope Comprehensive Cancer Center accepting new patients
    Duarte, California, 91010, USA
  • Kaiser Permanente Hospital accepting new patients
    Fontana, California, 92335, USA
  • Kaiser Permanente accepting new patients
    Fresno, California, 93720, USA
  • Kaiser Permanente - Harbor City accepting new patients
    Harbor City, California, 90710, USA
  • Kaiser Permanente-Irvine accepting new patients
    Irvine, California, 92618, USA
  • UC San Diego Moores Cancer Center currently not accepting new patients, but might later
    La Jolla, California, 92093, USA
  • City of Hope Antelope Valley accepting new patients
    Lancaster, California, 93534, USA
  • Loma Linda University Medical Center accepting new patients
    Loma Linda, California, 92354, USA
  • Long Beach Memorial Medical Center-Todd Cancer Institute accepting new patients
    Long Beach, California, 90806, USA
  • Kaiser Permanente Los Angeles Medical Center accepting new patients
    Los Angeles, California, 90027, USA
  • Los Angeles County-USC Medical Center accepting new patients
    Los Angeles, California, 90033, USA
  • USC / Norris Comprehensive Cancer Center accepting new patients
    Los Angeles, California, 90033, USA
  • Kaiser Permanente-Cadillac accepting new patients
    Los Angeles, California, 90034, USA
  • Cedars-Sinai Medical Center accepting new patients
    Los Angeles, California, 90048, USA
  • Community Hospital of Monterey Peninsula currently not accepting new patients, but might later
    Monterey, California, 93940, USA
  • USC Norris Oncology/Hematology-Newport Beach accepting new patients
    Newport Beach, California, 92663, USA
  • Saint Joseph Hospital - Orange accepting new patients
    Orange, California, 92868, USA
  • UC Irvine Health/Chao Family Comprehensive Cancer Center accepting new patients
    Orange, California, 92868, USA
  • Kaiser Permanente - Panorama City accepting new patients
    Panorama City, California, 91402, USA
  • PCR Oncology accepting new patients
    Pismo Beach, California, 93449, USA
  • Pomona Valley Hospital Medical Center accepting new patients
    Pomona, California, 91767, USA
  • City of Hope Rancho Cucamonga accepting new patients
    Rancho Cucamonga, California, 91730, USA
  • Eisenhower Medical Center accepting new patients
    Rancho Mirage, California, 92270, USA
  • Kaiser Permanente-Riverside accepting new patients
    Riverside, California, 92505, USA
  • Salinas Valley Memorial accepting new patients
    Salinas, California, 93901, USA
  • Kaiser Permanente-San Diego Mission accepting new patients
    San Diego, California, 92108, USA
  • Kaiser Permanente-San Diego Zion accepting new patients
    San Diego, California, 92120, USA
  • Pacific Central Coast Health Center-San Luis Obispo accepting new patients
    San Luis Obispo, California, 93401, USA
  • Kaiser Permanente-San Marcos accepting new patients
    San Marcos, California, 92069, USA
  • Gene Upshaw Memorial Tahoe Forest Cancer Center accepting new patients
    Truckee, California, 96161, USA
  • Presbyterian Intercommunity Hospital accepting new patients
    Whittier, California, 90602, USA
  • Kaiser Permanente accepting new patients
    Woodland Hills, California, 91367, USA

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Southwest Oncology Group
ID
NCT01674140
Phase
Phase 3
Lead Scientist
Judith Luce
Study Type
Interventional
Last Updated
February 2017
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