Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Southwest Oncology Group
Sponsor:
Collaborators:
AstraZeneca
Novartis
Information provided by (Responsible Party):
Southwest Oncology Group
ClinicalTrials.gov Identifier:
NCT02137837
First received: May 12, 2014
Last updated: August 19, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Drug: Fulvestrant
Drug: Anastrozole
Drug: Everolimus
Drug: Placebo - Anastrozole
Drug: Placebo - Everolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Fulvestrant Alone Versus Fulvestrant and Everolimus Versus Fulvestrant, Everolimus and Anastrozole: A Phase III Randomized Placebo-Controlled Trial in Postmenopausal Patients

Resource links provided by NLM:


Further study details as provided by Southwest Oncology Group:

Primary Outcome Measures:
  • progression-free survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • overall survival [ Time Frame: up to 5 years ] [ Designated as safety issue: No ]
  • Number of Participants with Serious and Non-Serious Adverse Events [ Time Frame: up to 5 years ] [ Designated as safety issue: Yes ]
  • response rate [ Time Frame: assessed every 12 weeks, up to 5 years ] [ Designated as safety issue: No ]
  • clinical benefit rate [ Time Frame: assessed every 12 weeks, up to 5 years ] [ Designated as safety issue: No ]
  • molecular determinants of response in circulating tumor cells [ Time Frame: Day 1, Day 29, time of progression ] [ Designated as safety issue: No ]

Estimated Enrollment: 825
Study Start Date: May 2014
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Fulvestrant
Other Names:
  • Faslodex
  • NSC-719276
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.
Drug: Fulvestrant
Other Names:
  • Faslodex
  • NSC-719276
Drug: Everolimus
Other Names:
  • Afinitor
  • Zortress
  • NSC-733504
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.
Drug: Fulvestrant
Other Names:
  • Faslodex
  • NSC-719276
Drug: Anastrozole
Other Names:
  • Arimidex
  • NSC-719344
Drug: Everolimus
Other Names:
  • Afinitor
  • Zortress
  • NSC-733504

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02137837

Contacts
Contact: Megan M Hardin 2106148808 ext 1014 mhardin@swog.org
Contact: Dana Sparks, MAT 2106148808 ext 1004 dsparks@swog.org

  Show 146 Study Locations
Sponsors and Collaborators
Southwest Oncology Group
AstraZeneca
Novartis
Investigators
Study Chair: George Somlo, M.D. City of Hope Cancer Center
  More Information

No publications provided

Responsible Party: Southwest Oncology Group
ClinicalTrials.gov Identifier: NCT02137837     History of Changes
Other Study ID Numbers: S1222
Study First Received: May 12, 2014
Last Updated: August 19, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Southwest Oncology Group:
Metastatic breast cancer
Invasive breast carcinoma
estrogen receptor-positive breast cancer
HER2-negative breast cancer
Stage IV breast cancer
progesterone receptor-positive breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Anastrozole
Estradiol
Everolimus
Fulvestrant
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Aromatase Inhibitors
Enzyme Inhibitors
Estrogen Antagonists
Estrogen Receptor Modulators
Estrogens
Hormone Antagonists
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014