Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

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

Protocol: ALLIANCE-A011106

Full Title

ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A Phase III Study

Purpose

This randomized phase III trial studies fulvestrant to see how well it works compared to anastrozole or fulvestrant and anastrozole in treating postmenopausal patients with stage II-III breast cancer undergoing surgery. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant and anastrozole may fight breast cancer by blocking the use of estrogen by the tumor cells. It is not yet known whether giving fulvestrant alone, anastrozole alone, or fulvestrant and anastrozole together is more effective in treating patients with breast cancer.

Study Objective

PRIMARY OBJECTIVES:

I. To determine whether fulvestrant administered for 24 weeks as neoadjuvant endocrine treatment increases the proportion of endocrine sensitive tumors relative to patients treated with anastrozole.

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

III. If both of the fulvestrant containing arms are found to have an endocrine sensitive disease rate at least 10% higher than that of the anastrozole arm, we will assess whether the endocrine sensitive disease rate is greater with the combination of anastrozole and fulvestrant than with fulvestrant alone.

IV. To assess whether the 5-year recurrence free survival (RFS) rate among women treated with anastrozole with a modified preoperative endocrine prognostic index (PEPI) score 0 following 24 weeks of neoaduvant therapy is at most 90%.

V. For the fulvestrant containing regimens, a point and interval estimate of the 5 year RFS will be obtained.

SECONDARY OBJECTIVES:

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

II. 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.

III. 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).

IV. 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 cyclophosphamide, methotrexate, fluorouracil (CMF).

V. To summarize the frequency of severe (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] grade > 3) adverse events encountered with administration of paclitaxel in the neoadjuvant setting.

VI. To assess time to breast cancer recurrence for patients with endocrine resistant tumors defined by tumor marker of proliferation Ki-67 (Ki67) > 10% at week 4, Ki67 > 10% at week 12 and modified PEPI score of non-zero on neoadjuvant endocrine therapy, with all three groups combined or separated.

TERTIARY OBJECTIVES:

I. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant and those randomized to anastrozole.

II. To assess whether the degree of tumor Ki67 suppression at week 4 and surgery differs between patients randomized to fulvestrant in combination with anastrozole and those randomized to anastrozole.

III. To examine the impact of tumor estrogen receptor (ER) expression level post-neoadjuvant endocrine therapy on RFS in each treatment arm separately.

IV. To examine whether RFS differs with respect to pathologic tumor stage (T1 vs. T2) post-neoadjuvant endocrine therapy in the subgroup of women with a modified PEPI score of 0.

V. To examine whether rate of endocrine resistant tumors or RFS differs with respect to the degree of week 4 Ki67 suppression.

VI. To examine whether the rate of week 4 Ki67 level > 10%, the rate of endocrine resistant tumors or RFS differs with respect to pre-treatment gene expression profile.

VII. To examine whether gene expression profiles at week 4 can further refine the patient population who have modified PEPI score non-0 or shorter RFS.

VIII. To assess the pCR/residual cancer burden (RCB)-1 rate in each of the following cohorts: a. Those who chose to switch to paclitaxel after finding their week 4 Ki67 was > 10%; b. Those who chose to switch to paclitaxel after finding their week 12 Ki67 was > 10%; c. Those patients who chose to switch to a standard neoadjuvant taxane and/or anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 4 Ki67 was > 10%; d. Those patients who chose to switch to a standard neoadjuvant taxane and/or anthracycline containing regimen or CMF (rather than paclitaxel) after finding their week 12 Ki67 was > 10%.

IX. To evaluate cycle 1, day 2 tumor biopsy following the initiation of paclitaxel to develop early molecular markers of tumor response to paclitaxel.

X. To evaluate tumor tissue, serum, and plasma specimens collected at baseline, on-therapy, and at surgery for biomarker discovery (through methods such as gene expression profiling, patterns of gains or losses of deoxyribonucleic acid [DNA], tumor whole genome and targeted DNA and ribonucleic acid [RNA] sequencing and proteomics) in studies that aim to understand signaling pathways associated with endocrine therapy and taxane therapy sensitivity and resistance.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive anastrozole orally (PO) once daily (QD) on days 1-28. Treatment repeats every 4 weeks for 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery between days 7-28 of course 6.

ARM II: Patients receive fulvestrant intramuscularly (IM) on days 1 and 15 (course 1) and day 1 (courses 2-6). Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery between days 7-28 of course 6.

ARM III: Patients receive anastrozole as in Arm I and fulvestrant IM as in Arm II and undergo surgery between days 7-28 of course 6.

MODIFIED PEPI 0 VALIDATION PHASE: Patients with endocrine therapy resistant disease, defined by Ki67 > 10% at the 4-week or the 12-week biopsy receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, 15, and 22. Beginning 3-6 weeks later, patients undergo surgery. Treatment repeats every 4 weeks for 3 courses at the discretion of the treating physician.

After completion of study treatment, patients are followed up for 10 years.

Are you eligible?

Inclusion Criteria:

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

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

Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy

Clinical T2-T4c, any N, M0 invasive breast cancer, by American Joint Committee on Cancer (AJCC) 7th edition clinical staging, with the goal being surgery to complete excision of the tumor in the breast and the lymph node

Primary tumor must be:

Palpable

Its largest tumor diameter is > 2.0 cm by physical examination or by radiological assessment

Bi-dimensional measurement by tape, ruler or caliper technique must be provided

  • Note:

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

*** Patients with multi-focal breast cancer (defined as more than one lesion of invasive breast cancer in the same breast separated from the dominant breast lesion by less than 5 cm of radiologically normal breast tissue) are eligible; if the other lesions have been biopsied (biopsy not required) they must meet the estrogen receptor/human epidermal growth factor receptor 2 (ER/HER2) eligibility requirements; research biopsies and Ki67 assessment and radiological measures are to be performed on the dominant breast lesion

Invasive breast cancer is estrogen receptor (ER) 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

Invasive breast cancer is human epidermal growth factor receptor 2 (HER2) negative; a patient is considered to have HER2 negative breast cancer if one of the following if one of the following applies:

0 or 1+ by immunohistochemistry (IHC) and in situ hybridization (ISH) not done

0 or 1+ by IHC or ISH ratio (HER2 gene copy/chromosome 17) < 2

2+ by IHC and ISH ratio (HER2 gene copy/chromosome 17) < 2

Documentation of mammogram and ultrasound (including ductal carcinoma in situ [DCIS] and invasive cancer) of the diseased breast performed within 56 days prior to registration; mammogram for the unaffected contralateral breast is required within 12 months prior to registration

Absolute neutrophil count (ANC) > 1,000/mm^3

Platelet count > 100,000/mm^3

Total bilirubin < 1.5 x upper limits of normal (ULN)

Creatinine < 1.5 x ULN

Serum alanine aminotransferase (ALT) < 2.5 x ULN

Tissue acquisition: patient must agree to provide the required research biopsies at baseline, week 4 and at surgery for integral and integrated biomarker and correlative studies

Exclusion Criteria:

Premenopausal status

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)

An excisional biopsy of this breast cancer

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

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

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

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

Breast implants are contraindicated only if the implant precludes the required research biopsies or interferes with palpating the breast lesion

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

History of invasive breast cancer or contralateral DCIS

Breast Cancer