Fulvestrant With or Without Bortezomib in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01142401
First received: June 10, 2010
Last updated: September 16, 2014
Last verified: August 2014
  Purpose

This phase II trial is studying giving fulvestrant and bortezomib together to see how well they work compared to fulvestrant alone in treating postmenopausal women with locally advanced or metastatic breast cancer. 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.


Condition Intervention Phase
Estrogen Receptor-positive Breast Cancer
Recurrent Breast Cancer
Stage III Breast Cancer
Stage IIIB Breast Cancer
Stage IIIC Breast Cancer
Stage IV Breast Cancer
Drug: fulvestrant
Drug: bortezomib
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study of Fulvestrant vs. Fulvestrant in Combination With Bortezomib in Women With ER Positive Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • PFS [ Time Frame: From first treatment day until objective or disease progression or death from any cause, assessed up to 4 years ] [ Designated as safety issue: No ]
    The PFS distributions of the two treatment arms will be estimated by Kaplan-Meier. PFS distributions will be compared by an unstratified log-rank test. Ninety-five percent confidence intervals for the Kaplan-Meier PFS estimates will be calculated using Greenwood's formulae.


Secondary Outcome Measures:
  • Clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD]), evaluated according to RECIST [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Ninety-five percent confidence intervals will be calculated for the clinical benefit response proportion in each arm via binomial proportions. Comparison of the clinical benefit rate between the treatment arms will be performed by the chi-square test or Fisher's exact test, as appropriate.

  • Percentage progression-free [ Time Frame: At 24 weeks ] [ Designated as safety issue: No ]
    Ninety-five percent confidence intervals will be calculated for the percent progression-free at 24 weeks in each arm via binomial proportions. Comparison of the percent progression-free at 24 weeks between the treatment arms will be performed by the chi-square test or Fisher's exact test, as appropriate.

  • Overall survival [ Time Frame: The time from first treatment day until death, assessed up to 4 years ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method. The comparison of the overall survival distributions between the treatment arms will be performed by the log-rank test.

  • Toxicity as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    The frequency of subjects experiencing toxicities will be tabulated.


Enrollment: 118
Study Start Date: May 2010
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (fulvestrant)
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.
Drug: fulvestrant
Given IM
Other Names:
  • Faslodex
  • ICI 182,780
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (fulvestrant, bortezomib)
Patients receive fulvestrant as in arm A 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.
Drug: fulvestrant
Given IM
Other Names:
  • Faslodex
  • ICI 182,780
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm C (fulvestrant, bortezomib)
Patients receive fulvestrant IM 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.
Drug: fulvestrant
Given IM
Other Names:
  • Faslodex
  • ICI 182,780
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

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 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 (beginning in course 2). 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 IM 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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
  • 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, CT scan of chest/abdomen/pelvis) within 4 weeks of registration to arm C
  • Normal organ and marrow function as defined below (within 2 weeks of registration on arm C):

    • Leukocytes >= 3,000/mcL
    • Absolute neutrophil count >= 1,500/mcL
    • Platelets >= 100,000/mcL
    • Total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(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

Exclusion Criteria:

  • EXCLUSION CRITERIA FOR ARM A AND ARM B
  • 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
  • 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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01142401

Locations
United States, Connecticut
University of Connecticut
Farmington, Connecticut, United States, 06030
Yale University
New Haven, Connecticut, United States, 06520
United States, Florida
Cleveland Clinic Florida - Weston
Weston, Florida, United States, 33331
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New Jersey
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, United States, 08903
United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Eastchester Center for Cancer Care
Bronx, New York, United States, 10469
Montefiore Medical Center-Einstein Campus
Bronx, New York, United States, 10461
Maimonides Medical Center
Brooklyn, New York, United States, 11219
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Beth Israel Medical Center
New York, New York, United States, 10003
New York University Langone Medical Center
New York, New York, United States, 10016
New York University Clinical Cancer Center
New York, New York, United States, 10016-4760
Columbia University Medical Center
New York, New York, United States, 10032
Mount Sinai Medical Center
New York, New York, United States, 10029
Saint Luke's Roosevelt Hospital Center - Roosevelt Division
New York, New York, United States, 10019
Saint Luke's Roosevelt Hospital Center - Saint Luke's Division
New York, New York, United States, 10025
Weill Medical College of Cornell University
New York, New York, United States, 10065
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States, 44195
University Hospitals Case Medical Center
Cleveland, Ohio, United States, 44106
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
Sponsors and Collaborators
Investigators
Principal Investigator: Kerin Adelson Montefiore Medical Center - Moses Campus
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01142401     History of Changes
Other Study ID Numbers: NCI-2012-03000, NCI-2012-03000, CDR0000674542, AECM-000248, 10-03-055, 8457, N01CM00070, P30CA013330, N01CM00099, N01CM62207, U01CA076576, N01CM62204
Study First Received: June 10, 2010
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Bortezomib
Fulvestrant
Estradiol
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Estrogen Antagonists
Estrogen Receptor Modulators
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Estrogens
Hormones

ClinicalTrials.gov processed this record on September 18, 2014