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


Phase 2
18 Years
N/A
Open (Enrolling)
Female
Estrogen Receptor-positive Breast Cancer, Stage III Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

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Trial Information

A Randomized Phase II Study of Fulvestrant vs. Fulvestrant in Combination With Bortezomib in Women With ER Positive Metastatic 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 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), apoptotis
(cleaved caspase 3, Bcl-2 phospho 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.

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.

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.

After completion of study therapy, patients are followed up every 3 months.


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 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 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
(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

- 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

- 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

- 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

- The effects of bortezomib on the developing human fetus at the recommended
therapeutic dose are unknown; for this reason and because other therapeutic agents
used in this trial are known to be teratogenic, 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
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

- 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 because of
the potential for pharmacokinetic interactions with bortezomib; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated

- 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 SERM or an AI; the GnRH analog may continue but the
SERM or AI must be discontinued

- Grade 2 or more peripheral neuropathy because the dose limiting toxicity of
bortezomib is neuropathy

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

PFS

Outcome Description:

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.

Outcome Time Frame:

From first treatment day until objective or disease progression or death from any cause, assessed up to 4 years

Safety Issue:

No

Principal Investigator

Kerin Adelson

Investigator Role:

Principal Investigator

Investigator Affiliation:

Montefiore Medical Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03000

NCT ID:

NCT01142401

Start Date:

May 2010

Completion Date:

Related Keywords:

  • Estrogen Receptor-positive Breast Cancer
  • Stage III Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms

Name

Location

Cleveland Clinic FoundationCleveland, Ohio  44195
Roswell Park Cancer InstituteBuffalo, New York  14263
Washington University School of MedicineSaint Louis, Missouri  63110
Beth Israel Medical CenterNew York, New York  10003
Cancer Institute of New JerseyNew Brunswick, New Jersey  08901
Weill Medical College of Cornell UniversityNew York, New York  10021
Maimonides Medical CenterBrooklyn, New York  11219
Mount Sinai Medical CenterNew York, New York  10029
University of ConnecticutFarmington, Connecticut  06032
Case Western Reserve UniversityCleveland, Ohio  44106
Yale UniversityNew Haven, Connecticut  06520
Ohio State University Medical CenterColumbus, Ohio  43210
New York University Clinical Cancer CenterNew York, New York  10016
Eastchester Center for Cancer CareBronx, New York  10469
The North Division of Montefiore Medical CenterBronx, New York  10466
New York University Langone Medical CenterNew York, New York  10016
Columbia University Medical CenterNew York, New York  10032
Montefiore Medical Center-Weiler DivisionBronx, New York  10461
Maimonides Cancer Center-Breast Cancer ProgramBrooklyn, New York  11220
Saint Luke's Roosevelt Hospital Center - Roosevelt DivisionNew York, New York  10019