Clinical Trials /

Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

NCT01953588

Description:

The study is being conducted to determine whether neoadjuvant endocrine therapy with fulvestrant or the combination of anastrozole and fulvestrant, is better than anastrozole when given before surgery to shrink the cancer and stop it from growing. Anastrozole inhibits tumor growth by reducing the levels of estrogen and has been approved by the Food and Drug Administration (FDA) of the United States for use after surgery for postmenopausal women with estrogen receptor positive breast cancer. It is also considered a standard of care to give anastrozole for a few months before surgery to shrink the tumor. Fulvestrant inhibits tumor cell growth by reducing the levels of estrogen receptor in the tumor cell. It is not approved by the FDA for use in women with early stage breast cancer before or after surgery, but is approved by the FDA for patients with advanced (Stage 4) estrogen receptor positive breast cancer that has spread to other parts of the body.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Fulvestrant</span> and/or <span class="go-doc-concept go-doc-intervention">Anastrozole</span> in Treating Postmenopausal Patients With Stage II-III <span class="go-doc-concept go-doc-disease">Breast Cancer</span> Undergoing Surgery

Title

  • Brief Title: Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery
  • Official Title: Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment (ALTERNATE) in Postmenopausal Women: A Phase III Study
  • Clinical Trial IDs

    NCT ID: NCT01953588

    ORG ID: A011106

    NCI ID: NCI-2013-01340

    Trial Conditions

    Estrogen Receptor-positive Breast Cancer

    HER2-negative Breast Cancer

    Invasive Ductal Breast Carcinoma

    Invasive Lobular Breast Carcinoma

    Recurrent Breast Cancer

    Stage II Breast Cancer

    Stage IIIA Breast Cancer

    Stage IIIB Breast Cancer

    Stage IIIC Breast Cancer

    Trial Interventions

    Drug Synonyms Arms
    fulvestrant Faslodex Arm II (fulvestrant), Arm III (anastrozole and fulvestrant)
    anastrozole Arimidex Arm I (anastrozole), Arm III (anastrozole and fulvestrant)

    Trial Purpose

    This randomized phase III trial has several primary objectives. One primary objective is to
    compare the efficacy of 3 different endocrine therapies, the estrogen receptor down
    regulator fulvestrant and the aromatase inhibitor anastrozole, either alone or in
    combination, in reducing cancer growth before surgery (neoadjuvant) in postmenopausal women
    with clinical stage II-III estrogen receptor positive and HER2 negative breast cancer.
    Another primary objective is to evaluate whether patients who achieved a modified PEPI
    (Preoperative Endocrine Prognostic Index) score of 0, defined by tumor size <5 cm, N0,
    Ki67<2.7% (by central testing), at surgery post 6 months of neoadjuvant endocrine therapy
    predict excellent long term outcome, for whom chemotherapy is unnecessary.

    Detailed Description

    Patients will be randomized to one of three treatment groups: anastrozole, fulvestrant or
    the combination of anastrozole and fulvestrant. Each cycle is 28 days for a total of 6
    cycles. Surgery must be performed between days 15-28 of Cycle 6 in each treatment arm.
    Patients who are determined to have an endocrine resistant tumor at week 4 or week 12 will
    discontinue endocrine protocol therapy. It is recommended that patients be switched to
    neoadjuvant treatment.

    After completion of surgery, those with a modified preoperative endocrine prognostic index
    (PEPI) score of 0 will continue assigned endocrine treatment for 4.5 years and those with a
    non-zero PEPI score will receive adjuvant chemotherapy +/- endocrine therapy chosen by
    treating physician.

    The primary and secondary objectives for the study are described below.

    Primary Objectives:

    1. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine
    treatment decreases the proportion of endocrine resistant tumors** relative to patients
    treated with anastrozole.

    2. To determine whether fulvestrant in combination with anastrozole, administered for 24
    weeks as neoadjuvant endocrine treatment, decreases the proportion of endocrine
    resistant tumors relative to patients treated with anastrozole.

    3. To assess whether the 5 year RFS rate among women with a modified preoperative
    endocrine prognostic index (PEPI) score of 0 following 24 weeks of neoadjuvant
    anastrozole treatment is at least 95%.

    4. To assess whether the 5 year RFS rate among women with a modified PEPI score of 0
    following 24 weeks of neoadjuvant fulvestrant, or fulvestrant in combination with
    anastrozole, is at least 95%. Note that this objective will only be tested if the
    selected fulvestrant arm was shown to be superior to anastrozole in objective 1 or 2.

    Endocrine resistant tumor is defined by any one of the following criteria**:

    - Ki67> 10% after 4 weeks on neoadjuvant endocrine therapy

    - Ki67> 10% after 12 weeks on neoadjuvant endocrine therapy

    - Progressive disease is documented anytime during neoadjuvant endocrine therapy

    - Surgical findings at 22-24 weeks post neoadjuvant endocrine therapy are such that:

    - pT stage is 3/4

    - positive lymph nodes are present or Ki67 > 2.7% (ie modified PEPI score of not
    being 0)

    - Discontinued neoadjuvant endocrine treatment for any reason

    Secondary Objectives:

    1. To assess whether the 5 year RFS rate among women with a preoperative endocrine
    prognostic index PEPI score of 0 following 24 weeks of neoadjuvant anastrozole
    treatment is at least 95%.

    2. To examine the differences in surgical outcome, clinical and radiological response
    rates, and safety profile between the fulvestrant arm and the anastrozole arm.

    3. To examine the differences in surgical outcome, clinical and radiological response
    rates, and safety profile between patients randomized to fulvestrant in combination
    with anastrozole and those randomized to anastrozole.

    4. To examine the rate of pathologic complete response (pCR) of 12 weeks of neoadjuvant
    paclitaxel in patients with endocrine resistant disease following 4 weeks or 12 weeks
    of neoadjuvant endocrine therapy with either fulvestrant or anastrozole or the
    combination of fulvestrant and anastrozole.

    5. To examine the rate of pathologic complete response (pCR) among those patients with
    endocrine resistant disease, following 4 weeks or 12 weeks of neoadjuvant endocrine
    therapy (with either fulvestrant or anastrozole or the combination of fulvestrant and
    anastrozole), who choose not to receive neoadjuvant paclitaxel, but another standard
    neoadjuvant taxane and/or anthracycline containing regimen or CMF.

    6. To summarize the frequency of severe (NCI CTCAE grade > 3) adverse events encountered
    with administration of paclitaxel in the neoadjuvant setting.

    7. To assess RFS for patients with endocrine resistant tumors defined as: 1) Ki67 > 10% at
    week 4, 2) Ki67 > 10% at week 12 and 3) modified PEPI score of non-zero on neoadjuvant
    endocrine therapy, with all three groups combined or separated.

    Trial Arms

    Name Type Description Interventions
    Arm I (anastrozole) Active Comparator Patients receive anastrozole 1 mg daily by mouth, Days 1-28, every 4 weeks for 6 cycles anastrozole
    Arm II (fulvestrant) Active Comparator Patients receive fulvestrant 500 mg IM, Days 1 and 15 of Cycle 1 and Day 1 of Cycles 2-6, every 4 weeks for 6 cycles fulvestrant
    Arm III (anastrozole and fulvestrant) Active Comparator Patients receive anastrozole 1 mg daily by mouth, Days 1-28, every 4 weeks for 6 cycles and fulvestrant 500 mg IM, Days 1 and 15 of Cycle 1 and Day 1 of Cycles 2-6, every 4 weeks for 6 cycles. fulvestrant, anastrozole

    Eligibility Criteria

    Inclusion Criteria:

    1. Female 18 years of age

    2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

    3. Postmenopausal, verified by:

    - post bilateral surgical oophorectomy or

    - no spontaneous menses 1 year or

    - no menses for < 1 year with follicle-stimulating hormone (FSH) and estradiol
    levels in postmenopausal range, according to institutional standards

    4. Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy

    5. Clinical T2-T4c, any N, M0 invasive breast cancer, by AJCC 7th edition clinical
    staging, with the goal being surgery to complete excision of the tumor in the breast
    and the lymph node. The extent of disease is a solitary lesion where the lesion is:

    - palpable

    - its size can be measured bidimensional by tape, ruler or caliper technique and

    - its largest tumor diameter is at least 2.0 cm (that is considered measurable
    by the WHO criteria)

    Note:

    - Patients with contralateral ductal carcinoma in situ and/or invasive breast
    cancer are not eligible.

    - Patients with multifocal/multi-lesional breast cancer are not eligible if more
    than one lesion is invasive breast cancer in the same breast.

    6. Invasive breast cancer is estrogen receptor positive with an Allred score of 6, 7 or
    8 by local institution standard protocol. If an Allred Score is not reported on the
    diagnostic pathology report, ER positivity in > 66% cells is eligible. If ER
    positivity is < 66%, the staining intensity (weak, intermediate, strong) is needed to
    calculate the Allred Score to determine eligibility.

    7. Invasive breast cancer is Human Epidermal Growth Factor Receptor 2 (HER2) negative
    defined as 0 or 1+ by immunohistochemistry (IHC) or with a fluorescence in situ
    hybridization (FISH) ratio (HER2 gene copy/chromosome 17) < 2 if IHC 2+ by local
    institution standard protocol.

    8. Documentation of mammogram and ultrasound (including ductal carcinoma in situ (DCIS)
    and invasive cancer) of the diseased breast performed within 42 days prior to
    registration. Mammogram for the unaffected contralateral breast is required within 12
    months prior to registration.

    9. Laboratory values 14 days prior to registration:

    1. Absolute Neutrophil Count (ANC) > 1000/mm^3

    2. Platelet Count > 100,000/mm^3

    3. Total Bilirubin < 1.5 x upper limits of normal (ULN)

    4. Creatinine < 1.5 x ULN

    5. Serum alanine transaminase (ALT) < 2.5 x ULN

    10. Tissue acquisition: Patient must agree to provide the required research biopsies at
    baseline, week 4 and at surgery for biomarker and correlative studies.

    Exclusion Criteria:

    1. Premenopausal status

    2. Inflammatory breast cancer defined as clinically significant erythema of the breast
    and/or documented dermal lymphatic invasion (not direct skin invasion by tumor or
    peau d' orange without erythema).

    3. An excisional biopsy of this breast cancer.

    4. Hormone replacement therapy of any type, megestrol acetate, or raloxifene within one
    week prior to registration.

    5. Tumor estrogen receptor (ER) Allred score between 0-5 or HER2 positive by IHC (3+) or
    amplified by FISH > 2.0.

    6. Surgical axillary staging procedure prior to study entry. Note: Fine needle
    aspiration (FNA) or core needle biopsy of axillary node is permitted.

    7. Clinical or radiographic evidence of metastatic disease. Metastatic workup is not
    required, but is recommended for patients with clinical stage III disease. Note:
    Isolated ipsilateral supraclavicular node involvement is permitted.

    8. Breast implants are contraindicated only if the implant precludes the required
    research biopsies. Patients who have previously had implants removed within 6 weeks
    prior to registration are eligible.

    9. Treatment for this cancer including surgery, radiation therapy, chemotherapy,
    biotherapy, hormonal therapy or investigational agent prior to study entry.

    10. History of invasive breast cancer or contralateral DCIS.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Female

    Primary Outcome Measures

    Rate of endocrine resistant disease - (Neo-adjuvant Phase)

    Recurrence-free survival (RFS) - (Post surgery Phase)

    Pathologic complete response rate - (pCR rate)

    Secondary Outcome Measures

    Trial Keywords