Metastatic Breast CarcinomaPhase 2NCT01142401

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

A Phase 2 study testing Bortezomib, Fulvestrant and Laboratory Biomarker Analysis in people with Metastatic Breast Carcinoma and Stage IIIB Breast Cancer AJCC v7, run by National Cancer Institute (NCI) at 21 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older, women only
Conditions the study is for: Metastatic Breast Carcinoma, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7
What is being tested?: Bortezomib, Fulvestrant and Laboratory Biomarker Analysis
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 118 participants
Where: 21 sitesUnited States
Study dates: 26 May 2010to 8 Jan 2021
Phase: Phase 2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
No healthy volunteers
Adult, Older adult

Who may be able to join

ELIGIBILITY CRITERIA FOR ARM A AND ARM B
Patients must have histologically or cytologically confirmed ER+ positive breast cancer
Patients must be postmenopausal, defined as: (1) a history of at least 12 months without spontaneous menstrual bleeding, (2) prior bilateral salpingo-oophorectomy, with or without hysterectomy, (3) age >= 55 years with a prior hysterectomy with or without oophorectomy, (4) age < 55 years with a prior hysterectomy without oophorectomy or unknown status, with a documented follicle-stimulating hormone (FSH) level in postmenopausal range within 4 week s of registration, (5) receiving a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (eg, goserelin 3.6 mg every [q] 4 weeks)
Patients must have stage IV disease or inoperable locally advanced disease
Patients may have measurable disease only, non-measurable disease only, or both (Response Evaluation Criteria in Solid Tumors [RECIST 1.1]); it is anticipated that at least 50% of patients will have only non-measurable disease
Patients are required to have disease that is resistant to aromatase inhibitor (AI), which is defined either as relapse while receiving adjuvant A.I. therapy (ie, anastrazole, letrozole, or exemestane), and/or disease progression after one or more A.I.s for metastatic disease; prior exposure to more than one AI is permitted

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Patient may have had prior tamoxifen but are not required to
Patients may have received up to one prior chemotherapy regimen for metastatic disease
Patients may have received prior bevacizumab
Patients who have received up to 2 doses of fulvestrant given within a 4 week period prior to registration are eligible; the interval between the first fulvestrant dose and registration must be 6 weeks or less; patients may have received EITHER 250 mg or 500 mg of fulvestrant previously; if the patient has received 250 mg, they will receive the 500 mg loading dose on study day -14; if they already received 500 mg, they will begin the study on day +1
Life expectancy of greater than 3 months
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Leukocytes >= 3,000/mcL
Absolute neutrophil count >= 1,500/mcL
Platelets >= 100,000/mcL
Total bilirubin within normal institutional limits
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
Creatinine within normal institutional limits OR
Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
Patients must be disease-free of prior invasive malignancies for >= 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix
Patients must have the ability to understand and the willingness to sign a written informed consent document
Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
ELIGIBILITY CRITERIA FOR ARM C
Previously met all eligibility criteria for arms A and B and registered on trial to arm A (fulvestrant alone)
Disease progression on arm A and agreeable to crossover to arm C
Has received no intervening therapy (ie, alternative endocrine therapy, chemotherapy, biologic therapy) between disease progression on arm A and registration an arm C
ECOG performance status 0-2
Tumor measurements (eg, computed tomography [CT] scan of chest/abdomen/pelvis) within 4 weeks of registration to arm C
Leukocytes >= 3,000/mcL, within 2 weeks of registration on arm C
Absolute neutrophil count >= 1,500/mcL, within 2 weeks of registration on arm C
Platelets >= 100,000/mcL, within 2 weeks of registration on arm C
Total bilirubin within normal institutional limits, within 2 weeks of registration on arm C
AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal, within 2 weeks of registration on arm C
Creatinine within normal institutional limits, within 2 weeks of registration on arm C OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal, within 2 weeks of registration on arm C

Who cannot join

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
Patients may not be receiving any other investigational agents
Patients with known brain metastases should be excluded from this clinical trial
Presence of rapidly progressive, life-threatening metastases; this includes patients with extensive hepatic involvement (> 50% of the liver involved), symptomatic lymphangitic metastases, or brain or leptomeningeal involvement
History of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib or fulvestrant
Patients who are concomitantly receiving bortezomib and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy

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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
Patients who have previously received fulvestrant
Patients who have previously received bortezomib
Concomitant anticancer treatment with the following exceptions: (1) bisphosphonates for bone metastases, (2) a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a selective estrogen receptor modulators (SERMs) or an AI; the GnRH analog may continue but the SERM or AI must be discontinued
Grade 2 or more peripheral neuropathy

Trial locations and contacts

21 sites in 1 country.

City, postcode or hospital

21 sites in 1 country

United States21 sites

Maimonides Medical Center
Brooklyn, New York, 11219
Roswell Park Cancer Institute
Buffalo, New York, 14263
Case Western Reserve University
Cleveland, Ohio, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, 44195
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, 44195
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, 43210
University of Connecticut
Farmington, Connecticut, 06030
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Yale University
New Haven, Connecticut, 06520
Mount Sinai Union Square
New York, New York, 10003
Laura and Isaac Perlmutter Cancer Center at NYU Langone
New York, New York, 10016
Mount Sinai West
New York, New York, 10019
Mount Sinai Saint Luke's
New York, New York, 10025
Mount Sinai Hospital
New York, New York, 10029
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, 10032
NYP/Weill Cornell Medical Center
New York, New York, 10065
Washington University School of Medicine
St Louis, Missouri, 63110
Montefiore Medical Center-Einstein Campus
The Bronx, New York, 10461
Montefiore Medical Center-Weiler Hospital
The Bronx, New York, 10461
Eastchester Center for Cancer Care
The Bronx, New York, 10469
Cleveland Clinic-Weston
Weston, Florida, 33331

Other trials in United States

About this study

Official title: A Randomized Phase II Study of Fulvestrant vs. Fulvestrant in Combination With Bortezomib in Women With ER Positive Metastatic Breast Cancer

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.

Read the detailed description

PRIMARY OBJECTIVES:

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:

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).

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:

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.

Conditions: Metastatic Breast Carcinoma, Stage IIIB Breast Cancer AJCC v7, Stage IIIC Breast Cancer AJCC v7, Stage IV Breast Cancer AJCC v6 and v7
Being tested: Bortezomib, Fulvestrant, Laboratory Biomarker Analysis
Medical subject headings: Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

BortezomibDrug
Also called [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341
Given IV
FulvestrantDrug
Also called Faslodex, Faslodex(ICI 182,780), ICI 182,780, ICI 182780
Given IM
Laboratory Biomarker AnalysisOther
Correlative studies

Study groups in NCT01142401
Study group	Role	What they receive
Arm A (fulvestrant)	Experimental	Patients receive fulvestrant 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. Receives: Drug: Fulvestrant; Other: Laboratory Biomarker Analysis
Arm B (fulvestrant, bortezomib)	Experimental	Patients receive fulvestrant as in arm A and bortezomib IV on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Receives: Drug: Bortezomib; Drug: Fulvestrant; Other: Laboratory Biomarker Analysis
Arm C (fulvestrant, bortezomib)	Experimental	Patients receive fulvestrant IV on day 1 and bortezomib IM on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Receives: Drug: Bortezomib; Drug: Fulvestrant; Other: Laboratory Biomarker Analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

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
Measured: At 12 months
Number of Participants With Progression Free Survival (PFS) at 6 Months
Measured: At 6 months

Secondary outcomes (4)

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.
Measured: 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).
Measured: From first treatment day until study end, assessed up to 7 years
Progression Free Survival at 24 Weeks (Arm C)
Measured: 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.
Measured: Up to 7 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

26 May 20108 Jan 2021

First posted11 Jun 2010 (estimated)
Study start26 May 2010
Primary completion30 Jul 2015
Study completion8 Jan 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Metastatic Breast CarcinomaStudies of the same condition, open and under way.
More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 118 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01142401
Sponsor's protocol ID: NCI-2012-03000
Other IDs: NCI-2012-03000, CDR0000674542, 10-01555, AECM-000248, 10-03-055, 8457, 8457, N01CM00070
Status last verified: Nov 2023
First submitted: 10 Jun 2010
Last updated: 27 Nov 2023
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No