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NCT01674140

S1207 Hormone Therapy With or Without Everolimus in Treating Patients With Breast Cancer

Last Updated: 2024-12-27

Study Results

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Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE3

Total Enrollment

1939 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-09-12

Study Completion Date

2030-01-31

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Breast Cancer

Keywords

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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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

DOUBLE

Participants Investigators

Intervention Type DRUG

Given subcutaneously or intramuscularly

tamoxifen citrate

Intervention Type DRUG

Given PO

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Inclusion Criteria

* 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

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Mariana Chavez-MacGregor, MD, MSc

Role: PRINCIPAL_INVESTIGATOR

M.D. Anderson Cancer Center

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United States Puerto Rico

References

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Pusztai L, Hoag JR, Albain KS, Barlow WE, Stemmer SM, Meisner A, Hortobagyi GN, Shak S, Rae JM, Baehner R, Sharma P, Kalinsky KM. Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor-Positive, Node-Positive Breast Cancer. J Clin Oncol. 2025 Mar 10;43(8):919-928. doi: 10.1200/JCO-24-01507. Epub 2024 Dec 2.

Reference Type DERIVED

PMID: 39621968 (View on PubMed)

Chavez-MacGregor M, Miao J, Pusztai L, Goetz MP, Rastogi P, Ganz PA, Mamounas EP, Paik S, Bandos H, Razaq W, O'Dea A, Kaklamani V, Silber ALM, Flaum LE, Andreopoulou E, Wendt AG, Carney JF, Sharma P, Gralow JR, Lew DL, Barlow WE, Hortobagyi GN. Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy +/- 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer. J Clin Oncol. 2024 Sep 1;42(25):3012-3021. doi: 10.1200/JCO.23.02344. Epub 2024 Jun 4.

Reference Type DERIVED

PMID: 38833643 (View on PubMed)

Provided Documents

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Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

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S1207

Identifier Type: OTHER

Identifier Source: secondary_id

U10CA032102

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2012-01995

Identifier Type: OTHER

Identifier Source: secondary_id

S1207

Identifier Type: -

Identifier Source: org_study_id

S1207 Hormone Therapy With or Without Everolimus in Treating Patients With Breast Cancer

Study Results

Basic Information

Brief Summary

Detailed Description

Conditions

Keywords

Study Design

Study Groups

Arm I

anastrozole

exemestane

goserelin acetate

letrozole

leuprolide acetate

tamoxifen citrate

placebo

Arm II

anastrozole

everolimus

exemestane

goserelin acetate

letrozole

leuprolide acetate

tamoxifen citrate

Interventions

anastrozole

everolimus

exemestane

goserelin acetate

letrozole

leuprolide acetate

tamoxifen citrate

placebo

Other Intervention Names

Eligibility Criteria

Inclusion Criteria

Sponsors

National Cancer Institute (NCI)

SWOG Cancer Research Network

Responsible Party

Principal Investigators

Mariana Chavez-MacGregor, MD, MSc

Locations

Southeast Cancer Center

University of Alabama at Birmingham Cancer Center

Anchorage Associates in Radiation Medicine

Anchorage Radiation Therapy Center

Alaska Breast Care and Surgery LLC

Alaska Oncology and Hematology LLC

Alaska Regional Hospital

Alaska Women's Cancer Care

Anchorage Oncology Centre

Katmai Oncology Group

Providence Alaska Medical Center

Fairbanks Memorial Hospital

Banner MD Anderson Cancer Center

University of Arizona Cancer Center at Saint Joseph's

University of Arizona Cancer Center-Orange Grove Campus

University of Arizona Cancer Center-North Campus

The University of Arizona Medical Center-University Campus

Yuma Cancer Center

CHI Saint Vincent Cancer Center Hot Springs

Baptist Memorial Hospital and Fowler Family Cancer Center - Jonesboro

University of Arkansas for Medical Sciences

Highlands Oncology Group-Rogers

Kaiser Permanente-Anaheim

Kaiser Permanente-Deer Valley Medical Center

PCR Oncology

Sutter Auburn Faith Hospital

Sutter Cancer Centers Radiation Oncology Services-Auburn

AIS Cancer Center at San Joaquin Community Hospital

Kaiser Permanente-Baldwin Park

Kaiser Permanente-Bellflower

Alta Bates Summit Medical Center-Herrick Campus

Providence Saint Joseph Medical Center/Disney Family Cancer Center

Mills-Peninsula Medical Center

Sutter Cancer Centers Radiation Oncology Services-Cameron Park

Mercy San Juan Medical Center

East Bay Radiation Oncology Center