This randomized phase II trial studies how well fulvestrant works with or without bortezomib in treating patients with estrogen receptor positive breast cancer that has spread to other places in the body and cannot be removed by surgery. Estrogen can cause the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by lowering the amount of estrogen the body makes. Bortezomib may stop the growth of breast cancer cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. It is not yet known whether fulvestrant is more effective with or without bortezomib in treating breast cancer.
PRIMARY OBJECTIVES: I. To determine if the addition of bortezomib to fulvestrant improves median progression free survival (PFS) compared with fulvestrant alone in postmenopausal women with estrogen receptor (ER)-positive locally advanced inoperable or metastatic breast cancer who have disease that is resistant to aromatase inhibitor therapy (Arms A versus \[vs.\] B). SECONDARY OBJECTIVES: I. To determine if the addition of bortezomib to fulvestrant improves the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day +1). II. To determine the percent of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remain progression-free 24 weeks from day +1 (Arms A vs. B). III. To determine the overall survival of patients treated with fulvestrant alone and fulvestrant plus bortezomib (Arms A, B, C). IV. To determine the adverse event profile in patients treated with fulvestrant alone and fulvestrant plus bortezomib (Arms A, B, C). V. To determine the clinical benefit rate at 12 and 24 weeks of fulvestrant plus bortezomib in patients who have progressed on the fulvestrant alone arm and crossover to receive the combination (Arm C). TERTIARY OBJECTIVES: I. To perform an exploratory analysis of the effects of bortezomib (plus fulvestrant) in intratumoral nuclear/cytoplasmic ER ratio, unfolded protein response (BiP), apoptosis (cleaved caspase 3), B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (Bcl-2) phospho c-Jun N-terminal kinase (JNK) in patients with tumors accessible to biopsy who consent to optional post-treatment biopsy. II. To determine with cyclin D1 expression in pretreatment tumor specimens (from metastatic disease or the primary tumor if the former is not available) is predictive of clinical benefit with fulvestrant-bortezomib. OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arms A or B). ARM A: Patients receive fulvestrant intramuscularly (IM) 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 C. ARM B: Patients receive fulvestrant as in arm A and bortezomib intravenously (IV) on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive fulvestrant IM on day 1 and bortezomib IV on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up every 3 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
118
University of Connecticut
Farmington, Connecticut, United States
Yale University
New Haven, Connecticut, United States
Cleveland Clinic-Weston
Weston, Florida, United States
Washington University School of Medicine
St Louis, Missouri, United States
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States
Maimonides Medical Center
Brooklyn, New York, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Mount Sinai Union Square
New York, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, United States
Mount Sinai West
New York, New York, United States
...and 11 more locations
Number of Participants With Progression Free Survival (PFS) at 12 Months
The number of patients, treated with fulvestrant alone and fulvestrant plus bortezomib, who remained progression-free (Arms A vs. B). Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: At 12 months
Number of Participants With Progression Free Survival (PFS) at 6 Months
Time frame: At 6 months
Clinical Benefit Rate (CBR) of Adding Bortezomib to Fulvestrant in Arm C
This outcome measure determined if the addition of bortezomib to fulvestrant improved the clinical benefit rate (defined as objective response plus stable disease for at least 24 weeks from day+1). Clinical Benefit Rate (CBR) is defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.
Time frame: Up to 24 weeks
Number of Participants Who Survived Until Study End (up to 7 Years)
Tabulation of the number of participants who survived from the date of first treatment until study end (up to 7 years).
Time frame: From first treatment day until study end, assessed up to 7 years
Progression Free Survival at 24 Weeks (Arm C)
Time frame: At 24 weeks
Frequency of Most Common Toxicities
Most common toxicities in the fulvestrant arm alone (Arm A) and the fulvestrant/bortezomib combination arm (Arm B). Most common toxicities are defined as adverse events having occurred in \>10% of the participants within either (or both) Arm A or Arm B.
Time frame: Up to 7 years
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