Fulvestrant With or Without Bortezomib in Patients With Inoperable Locally Advanced or Metastatic Estrogen Receptor Positive Breast Cancer
Condition: Metastatic Breast Carcinoma; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7
MeSH terms: Breast Neoplasms
Intervention: Bortezomib; Fulvestrant; Laboratory Biomarker Analysis
Intervention description: Given IV; Given IM; Correlative studies
Intervention MeSH terms: Bortezomib; Fulvestrant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 118.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility 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, 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

        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

          -  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