Fulvestrant With or Without Bortezomib in Patients With Inoperable Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer

<p>DISEASE CHARACTERISTICS:</p><ul><li><p>Histologically or cytologically confirmed breast cancer</p><ul><li>Estrogen-receptor positive disease</li><li>Stage IV disease or inoperable locally advanced disease</li><li><p>Disease resistant to aromatase inhibitor (AI) (i.e.,anastrazole, letrozole, or exemestane) in the adjuvant setting, and&#x2F;or disease progression after 1 or more AIs for metastatic disease</p><ul><li>Prior exposure to ≥ 1 AI regimen allowed</li><li>Prior tamoxifen allowed but not required</li></ul></li></ul></li><li>Measurable or non-measurable disease, or both</li><li>No known brain metastases</li><li><p>No rapidly progressive life-threatening metastases, including any of the following:</p><ul><li>Extensive hepatic involvement (&gt; 50% of the liver)</li><li>Symptomatic lymphangitic metastases</li><li>Brain or leptomeningeal involvement</li></ul></li></ul><p>PATIENT CHARACTERISTICS:</p><ul><li><p>Postmenopausal, meeting 1 of the following:</p><ul><li>At least 12 months without spontaneous menstrual bleeding</li><li>Prior bilateral salpingo-oophorectomy with or without hysterectomy</li><li>Age ≥ 55 years with a prior hysterectomy with or without oophorectomy</li><li>Age &lt; 55 years with a prior hysterectomy without oophorectomy or unknown status with a documented follicle-stimulating hormone level in postmenopausal range within the past 4 weeks</li><li>Undergoing treatment with a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (e.g., goserelin 3.6 mg every 4 weeks)</li></ul></li><li>ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)</li><li>Life expectancy &gt; 3 months</li><li>WBC ≥ 3,000&#x2F;mm^3</li><li>ANC ≥ 1,500&#x2F;mm^3</li><li>Platelet count ≥ 100,000&#x2F;mm^3</li><li>Total bilirubin normal</li><li>AST and ALT ≤ 2.5 times upper limit of normal</li><li>Creatinine normal OR creatinine clearance ≥ 60 mL&#x2F;min</li><li>More than 5 years since prior invasive malignancy except curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix</li><li>No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or fulvestrant</li><li><p>No uncontrolled intercurrent illness including, but not limited to, any of the following:</p><ul><li>Ongoing or active infection</li><li>Symptomatic congestive heart failure</li><li>Unstable angina pectoris</li><li>Cardiac arrhythmia</li><li>Psychiatric illness and&#x2F;or social situations that would limit compliance with study requirements</li></ul></li><li>No peripheral neuropathy ≥ grade 2</li></ul><p>PRIOR CONCURRENT THERAPY:</p><ul><li>See Disease Characteristics</li><li>One prior chemotherapy regimen for metastatic disease allowed</li><li>Prior bevacizumab allowed</li><li><p>At least 4 weeks since up to 2 doses of prior fulvestrant</p><ul><li>The interval between the first fulvestrant dose and registration must be ≤ 6 weeks</li></ul></li><li>More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C)</li><li>No prior bortezomib</li><li>No other concurrent investigational agents</li><li>No concurrent combination antiretroviral therapy for HIV-positive patients</li><li><p>No concurrent anticancer treatment except for the following:</p><ul><li>Bisphosphonates for bone metastases</li><li><p>GnRH analog allowed provided patient had progressive disease on a GnRH analog plus a selective estrogen-receptor modulator (SERM) or an AI</p><ul><li>SERM or AI must be discontinued</li></ul></li></ul></li><li>No concurrent over-the-counter remedy or herbal supplement (for patients randomized to bortezomib arm)</li><li>No other concurrent anticancer agents or therapies</li></ul>

<p>DISEASE CHARACTERISTICS:</p><ul><li><p>Histologically or cytologically confirmed breast cancer</p><ul><li>Stage IV disease or inoperable locally advanced disease</li><li><p>Disease resistant to aromatase inhibitor (AI) (i.e., anastrazole, letrozole, or exemestane) in the adjuvant setting, and&#x2F;or disease progression after 1 or more AIs for metastatic disease</p><ul><li>Prior exposure to ≥ 1 AI regimen allowed</li><li>Prior tamoxifen allowed but not required</li></ul></li></ul></li><li>Measurable or non-measurable disease, or both</li><li>Estrogen receptor-positive disease</li><li>No known brain metastases</li><li><p>No rapidly progressive life-threatening metastases, including any of the following:</p><ul><li>Extensive hepatic involvement (&gt; 50% of the liver)</li><li>Symptomatic lymphangitic metastases</li><li>Brain or leptomeningeal involvement</li></ul></li></ul><p>PATIENT CHARACTERISTICS:</p><ul><li><p>Postmenopausal, meeting 1 of the following:</p><ul><li>At least 12 months without spontaneous menstrual bleeding</li><li>Prior bilateral salpingo-oophorectomy with or without hysterectomy</li><li>Age ≥ 55 years with a prior hysterectomy with or without oophorectomy</li><li>Age &lt; 55 years with a prior hysterectomy without oophorectomy or unknown status with a documented follicle-stimulating hormone level in postmenopausal range within the past 4 weeks</li><li>Undergoing treatment with a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (e.g., goserelin 3.6 mg every 4 weeks)</li></ul></li><li>ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)</li><li>Life expectancy &gt; 3 months</li><li>WBC ≥ 3,000&#x2F;mm^3</li><li>ANC ≥ 1,500&#x2F;mm^3</li><li>Platelet count ≥ 100,000&#x2F;mm^3</li><li>Total bilirubin normal</li><li>AST and ALT ≤ 2.5 times upper limit of normal</li><li>Creatinine normal OR creatinine clearance ≥ 60 mL&#x2F;min</li><li>More than 5 years since prior invasive malignancy except curatively treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix</li><li>No history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or fulvestrant</li><li><p>No uncontrolled intercurrent illness including, but not limited to, any of the following:</p><ul><li>Ongoing or active infection</li><li>Symptomatic congestive heart failure</li><li>Unstable angina pectoris</li><li>Cardiac arrhythmia</li><li>Psychiatric illness and&#x2F;or social situations that would limit compliance with study requirements</li></ul></li><li>No peripheral neuropathy ≥ grade 2</li></ul><p>PRIOR CONCURRENT THERAPY:</p><ul><li>See Disease Characteristics</li><li>One prior chemotherapy regimen for metastatic disease allowed</li><li>Prior bevacizumab allowed</li><li><p>At least 4 weeks since up to 2 doses of prior fulvestrant</p><ul><li>The interval between the first fulvestrant dose and registration must be ≤ 6 weeks</li></ul></li><li>More than 4 weeks since prior chemotherapy or radiotherapy (6 weeks for nitrosoureas or mitomycin C)</li><li>No prior bortezomib</li><li>No other concurrent investigational agents</li><li>No concurrent combination antiretroviral therapy for HIV-positive patients</li><li><p>No concurrent anticancer treatment except for the following:</p><ul><li>Bisphosphonates for bone metastases</li><li><p>GnRH analog allowed provided patient had progressive disease on a GnRH analog plus a selective estrogen-receptor modulator (SERM) or an AI</p><ul><li>SERM or AI must be discontinued</li></ul></li></ul></li><li>No concurrent over-the-counter remedy or herbal supplement (for patients randomized to bortezomib arm)</li><li>No other concurrent anticancer agents or therapies</li></ul>

2010-07-02

2010-08-03

2010-07-05

2010-08-04

<p>OBJECTIVES:</p><p>Primary</p><ul><li>To determine the median progression-free survival of postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer treated with fulvestrant with versus without bortezomib.</li></ul><p>Secondary</p><ul><li>To determine whether the addition of bortezomib to fulvestrant improves the clinical benefit rate of these patients for at least 24 weeks.</li><li>To determine the progression-free survival at 24 weeks of patients treated with these regimens.</li><li>To determine the overall survival of patients treated with these regimens.</li><li>To determine the adverse event profile of these regimens in these patients.</li><li>To determine the clinical benefit rate at 12 and 24 weeks of patients who progressed on fulvestrant alone and crossed over to the combination treatment.</li></ul><p>Tertiary</p><ul><li>To analyze the effects of bortezomib and fulvestrant in intratumoral nuclear&#x2F;cytoplasmic ER ratio, unfolded protein response (BiP), apoptosis (cleaved caspase 3, Bcl-2 phospho JNK) in tumors accessible to biopsy.
(exploratory)</li><li>To determine whether activation of NF-kB correlates with a poor response to fulvestrant alone and with low levels of the markers of apoptosis.
(exploratory)</li><li>To determine whether cyclin D1 expression in pretreatment tumor specimens (metastatic disease or the primary tumor) is predictive of clinical benefit with fulvestrant-bortezomib. (exploratory)</li></ul><p>OUTLINE: This is a multicenter study.
Patients are stratified according to ECOG performance status (0 vs 1-2), measurable disease (yes vs no), and prior chemotherapy for metastatic disease (yes vs no).
Patients are randomized to 1 or 2 treatment arms.</p><ul><li>Arm I: Patients receive fulvestrant intramuscularly on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm II.</li><li>Arm II: Patients receive fulvestrant as in arm I and bortezomib IV on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</li></ul><p>Some patients undergo blood and tumor tissue sample collection at baseline and during study for correlative studies.</p><p>After completion of study therapy, patients are followed up every 3 months.</p>

<p>OBJECTIVES:</p><p>Primary</p><ul><li>To determine the median progression-free survival of postmenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer treated with fulvestrant with versus without bortezomib.</li></ul><p>Secondary</p><ul><li>To determine whether the addition of bortezomib to fulvestrant improves the clinical benefit rate of these patients for at least 24 weeks.</li><li>To determine the progression-free survival at 24 weeks of patients treated with these regimens.</li><li>To determine the overall survival of patients treated with these regimens.</li><li>To determine the adverse event profile of these regimens in these patients.</li><li>To determine the clinical benefit rate at 12 and 24 weeks of patients who progressed on fulvestrant alone and crossed over to the combination treatment.</li></ul><p>Tertiary</p><ul><li>To analyze the effects of bortezomib and fulvestrant in intratumoral nuclear&#x2F;cytoplasmic ER ratio, unfolded protein response (BiP), apoptosis (cleaved caspase 3, Bcl-2 phospho JNK) in tumors accessible to biopsy.
(Exploratory)</li><li>To determine whether activation of NF-kB correlates with a poor response to fulvestrant alone and with low levels of the markers of apoptosis.
(Exploratory)</li><li>To determine whether cyclin D1 expression in pretreatment tumor specimens (metastatic disease or the primary tumor) is predictive of clinical benefit with fulvestrant-bortezomib. (Exploratory)</li></ul><p>OUTLINE: This is a multicenter study.
Patients are stratified according to ECOG performance status (0 vs 1-2), measurable disease (yes vs no), and prior chemotherapy for metastatic disease (yes vs no).
Patients are randomized to 1 of 2 treatment arms.</p><ul><li>Arm I: Patients receive fulvestrant intramuscularly on day 1 (days -14, 1, and 15 of course 1 only).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with progressive disease may crossover to arm II.</li><li>Arm II: Patients receive fulvestrant as in arm I and bortezomib IV on days 1, 8, and 15 (beginning in course 2).
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.</li></ul><p>Some patients undergo blood and tumor tissue sample collection at baseline and during study for correlative studies.</p><p>After completion of study therapy, patients are followed up every 3 months.</p>