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S1222 Trial (Everolimus, Anastrozole and Fulvestrant) in Post-Menopausal Stage IV Breast Cancer

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ClinicalTrials.gov Identifier: NCT02137837
Recruitment Status : Terminated (lack of accrual)
First Posted : May 14, 2014
Results First Posted : January 28, 2021
Last Update Posted : January 28, 2021
Sponsor:
Collaborators:
AstraZeneca
Novartis
Information provided by (Responsible Party):
Southwest Oncology Group

Tracking Information
First Submitted Date  ICMJE May 12, 2014
First Posted Date  ICMJE May 14, 2014
Results First Submitted Date  ICMJE January 5, 2021
Results First Posted Date  ICMJE January 28, 2021
Last Update Posted Date January 28, 2021
Study Start Date  ICMJE May 2014
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 5, 2021)
  • Progression-Free Survival (Fulvestrant vs Fulvestrant + Everolimus ) [ Time Frame: up to 5 years ]
    From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive are censored at date of last contact.
  • Progression-free Survival (Fulvestrant Versus Fulvestrant + Everolimus + Anastrozole) [ Time Frame: up to 5 years ]
    From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.
Original Primary Outcome Measures  ICMJE
 (submitted: May 13, 2014)
progression-free survival [ Time Frame: up to 5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 5, 2021)
  • Progression Free Survival (Fulvestrant + Everolimus vs Fulvestrant + Everolimus + Anastrozole) [ Time Frame: up to 5 years ]
    From date of registration to date of first documentation of progression or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.
  • Overall Survival [ Time Frame: up to 5 years ]
    From date of registration to date of death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact.
  • Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [ Time Frame: Duration of treatment and follow up until death or 5 years post registration ]
    Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
  • Response Rate [ Time Frame: assessed every 12 weeks, up to 5 years ]
    Proportion of participants who have confirmed or unconfirmed partial or complete response to therapy
  • Clinical Benefit Rate [ Time Frame: assessed every 12 weeks, up to 5 years ]
    Proportion of participants who have confirmed and unconfirmed partial response, complete response or stable disease.
  • Molecular Determinants of Response in Circulating Tumor Cells: CTC-ETI [ Time Frame: Day 1, Day 29, time of progression (Day 29 to be collected only if Day 1 CTC was elevated.) ]
    CTC-Endocrine Therapy Index (CTC-ETI) on the CellSearch® platform. Based on enumeration of CTC/7.5 mL of whole blood, with >= 5 being elevated. (Due to limited samples collected, full analysis was not able to be performed as planned, so outcome measure reported here is number with elevated Day 1 CTC.)
Original Secondary Outcome Measures  ICMJE
 (submitted: May 13, 2014)
  • overall survival [ Time Frame: up to 5 years ]
  • Number of Participants with Serious and Non-Serious Adverse Events [ Time Frame: up to 5 years ]
  • response rate [ Time Frame: assessed every 12 weeks, up to 5 years ]
  • clinical benefit rate [ Time Frame: assessed every 12 weeks, up to 5 years ]
  • molecular determinants of response in circulating tumor cells [ Time Frame: Day 1, Day 29, time of progression ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE S1222 Trial (Everolimus, Anastrozole and Fulvestrant) in Post-Menopausal Stage IV Breast Cancer
Official Title  ICMJE Fulvestrant Alone Versus Fulvestrant and Everolimus Versus Fulvestrant, Everolimus and Anastrozole: A Phase III Randomized Placebo-Controlled Trial in Postmenopausal Patients
Brief Summary This randomized Phase III trial studies how well the combination of fulvestrant and everolimus together or the combination of anastrozole, fulvestrant and everolimus together, improve progression-free survival (PFS) versus fulvestrant alone.
Detailed Description

OBJECTIVES:

Primary

  • 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).
  • To test the benefit of adding the non-steroidal aromatase inhibitor anastrozole to optimal dose fulvestrant and everolimus (Arm 3) in order to improve progression free survival over optimal dose fulvestrant (Arm 1).

Secondary

  • To compare progression-free survival among those receiving fulvestrant + everolimus + anastrozole (Arm 3) versus fulvestrant + everolimus (Arm 2).
  • To compare overall survival among the treatment arms in post-menopausal patients with hormone-receptor positive (HR+) Stage IV breast cancer.
  • To assess and compare toxicities, feasibility and compliance among the study regimens.
  • To compare response rates and clinical benefit rates among the study regimens.
  • To test molecular determinants of response to endocrine therapy and everolimus in circulating tumor cells:

    1. CTC-Endocrine Therapy Index (CTC ETI) on the CellSearch® platform.
    2. CTC-Next Generation Sequencing Analysis (CTC-NGS) of single cells captured on the HD-CTC® platform.

OUTLINE:

This is a multicenter study. Patients will be stratified according to the following factors:

  • Measurable versus evaluable non-measurable disease
  • Prior adjuvant hormonal therapy completed more than 5 years ago vs. prior adjuvant hormonal therapy completed 1-5 years ago vs. de novo presentation of metastatic disease or no prior adjuvant hormonal therapy.

ARMS:

  • Arm 1: fulvestrant + placebo (everolimus) + placebo (anastrozole)
  • Arm 2: fulvestrant + everolimus + placebo (anastrozole)
  • Arm 3: fulvestrant + everolimus + anastrozole

Blood and tissue samples are collected for correlative science studies.

After completion of study treatment, patients are followed up every 6 months for 2 years and then yearly thereafter for 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Fulvestrant
    Other Names:
    • Faslodex
    • NSC-719276
  • Drug: Anastrozole
    Other Names:
    • Arimidex
    • NSC-719344
  • Drug: Everolimus
    Other Names:
    • Afinitor
    • Zortress
    • NSC-733504
  • Drug: Placebo - Anastrozole
  • Drug: Placebo - Everolimus
Study Arms  ICMJE
  • Placebo Comparator: Arm 1: fulvestrant + everolimus placebo + anastrozole placebo
    Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive an oral placebo daily for both everolimus and anastrozole. This treatment regimen will continue until disease progression or toxicity.
    Interventions:
    • Drug: Fulvestrant
    • Drug: Placebo - Anastrozole
    • Drug: Placebo - Everolimus
  • Experimental: Arm 2: fulvestrant + everolimus + anastrozole placebo
    Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive an oral everolimus and an oral placebo for anastrozole daily. This treatment regimen will continue until disease progression or toxicity.
    Interventions:
    • Drug: Fulvestrant
    • Drug: Everolimus
    • Drug: Placebo - Anastrozole
  • Experimental: Arm 3: fulvestrant + everolimus + anastrozole
    Patients receive an injection of fulvestrant in each buttock on Days 1 &15 for Cycle 1 and then Day 1 only for subsequent cycles. Patients also receive everolimus and anastrozole by mouth daily. This treatment regimen will continue until disease progression or toxicity.
    Interventions:
    • Drug: Fulvestrant
    • Drug: Anastrozole
    • Drug: Everolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 31, 2020)
37
Original Estimated Enrollment  ICMJE
 (submitted: May 13, 2014)
825
Actual Study Completion Date  ICMJE December 31, 2019
Actual Primary Completion Date December 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • Patients must have a histologically confirmed diagnosis of invasive breast carcinoma with positive estrogen and/or progesterone receptor status, and negative human epidermal growth factor receptor (HER-2), for whom endocrine therapy is planned.
  • 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:

    • Immunohistochemistries (IHC) 1+ negative or IHC 0 negative or
    • in situ hybridization (ISH) negative using a single probe ISH or dual probe ISH.
  • Estrogen receptor (ER) and progesterone receptor (PgR) positivity must be assessed according to American Society of Clinial Oncology (ASCO)/College of American Physicians (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.
  • Patients must be post-menopausal women with a confirmed diagnosis of metastatic breast cancer (M1). 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 one of the following criteria as per National Comprehensive Cancer Network (NCCN) guidelines Version 3. 2013:

    • Prior bilateral oophorectomy and/or hysterectomy
    • Patients ≥ 60 years of age
    • Patients < 60 years of age and amenorrheic for ≥ 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the post-menopausal range
    • Patients < 60 years of age taking tamoxifen or toremifene must have FSH and plasma estradiol levels within post-menopausal ranges
  • Patients must have measurable or evaluable disease. Patients must have a chest and abdominal computerized tomography (CT) 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. Evaluable disease must be assessed within 28 days prior to registration
  • 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.
  • 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.
  • 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.
  • Patients must have an International Normalized Ratio (INR) ≤ 1.6 within 28 days prior to registration.
  • 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.
  • 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)
    • alanine aminotransferase (ALT) (SGPT) and aspartate aminotransferase (AST) (SGOT) ≤ 2.5 x Institutional Upper Limit of Normal (IULN), or ≤ 5 x IULN if hepatic metastases are present.
  • Patients must have adequate renal function with serum creatinine level ≤ IULN within 28 days prior to registration.
  • 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.
  • Patients must have a complete history and physical examination within 28 days prior to registration.
  • 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.
  • Patients with presence of life-threatening metastatic visceral disease, defined as extensive hepatic involvement, or any degree of brain or leptomeningeal involvement (past or present), or symptomatic pulmonary lymphangitic spread are not eligible. Patients with discrete pulmonary parenchymal metastases are eligible, provided their respiratory function is not significantly compromised as a result of disease in the opinion of the investigator.
  • 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 must not have uncontrolled diabetes (defined as an Hg A1C >7% within 28 days prior to registration).
  • 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 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 chronic or active hepatitis are not eligible. Patients must not have any known uncontrolled underlying pulmonary disease.
  • 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 everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection).
  • 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.
  • 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.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02137837
Other Study ID Numbers  ICMJE S1222
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Southwest Oncology Group
Study Sponsor  ICMJE Southwest Oncology Group
Collaborators  ICMJE
  • AstraZeneca
  • Novartis
Investigators  ICMJE
Study Chair: Halle Moore, M.D. The Cleveland Clinic
PRS Account Southwest Oncology Group
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP