Vorinostat in Treating Patients With Stage IV Breast Cancer Receiving Aromatase Inhibitor Therapy

Not Applicable

Completed

Conditions: Recurrent Breast Cancer
Stage IV Breast Cancer
Male Breast Cancer

Interventions: Drug: vorinostat
Other: laboratory biomarker analysis
Procedure: biopsy
Radiation: F-18 16 alpha-fluoroestradiol
Procedure: positron emission tomography
Drug: anastrozole
Drug: letrozole
Drug: exemestane
Genetic: gene expression analysis

Registration Number: NCT01153672

Lead Sponsor: University of Washington

Brief Summary: This pilot clinical trial studies vorinostat in treating patients with stage IV breast cancer receiving aromatase inhibitor (AI) therapy. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vorinostat may also help AI therapy work better by making tumor cells more sensitive to the drug

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the rate of clinical benefit (objective response plus stable disease) for patients treated with cycles consisting of 2 weeks of vorinostat followed by 6 weeks of AI therapy.

SECONDARY OBJECTIVES:

I. Assess the safety and tolerability of vorinostat in patients with metastatic breast cancer.

II. Assess the change in estrogen receptor (ER) expression, measured as the change in fluoroestradiol standard uptake value (FES SUV) using fluoroestradiol-positron emission tomography (FES-PET) completed per protocol 7184 after two weeks of vorinostat therapy and after 8 weeks of therapy.

III. Assess tumor metabolic response, measured as the change in fluorodeoxyglucose (FDG) SUV using FDG PET completed per protocol 7184 after two weeks of vorinostat therapy and after 8 weeks of therapy.

IV. Assess the change in hormone levels (estradiol, estrone, follicle-stimulating hormone \[FSH\], sex binding globulin, testosterone, and free testosterone) after 8 weeks of therapy.

V. Assess the change in ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), epithelial growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) tumor expression after two weeks of vorinostat therapy in patients that consent to optional tissue biopsy procedure.

VI. Assess the time to progression and the overall survival of patients treated with cycles of 2 weeks of vorinostat followed by 6 weeks of AI.

OUTLINE:

Patients receive vorinostat orally (PO) once daily (QD) for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months until disease progression, and then annually thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 8

Inclusion Criteria

Histologically or cytologically proven diagnosis of breast cancer
Stage IV disease
Patient has previously derived clinical benefit from endocrine therapy, but is no longer deriving benefit to endocrine therapy in the opinion of the treating investigator; patients need to stop AI for at least one week prior to starting vorinostat treatment on this protocol
At least one site of measurable disease, as defined by the modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Female patient is post menopausal as defined by one of the following; free from menses for > 2 years, surgically sterilized ,FSH and Estradiol in post-menopausal range AND surgical absence of uterus OR chemotherapy induced amenorrhea lasting > 1 year OR currently on ovarian suppression
Female patient of childbearing potential has a negative urine or serum (beta-human chorionic gonadotropin [hCG]) pregnancy test within 14 days prior to receiving the first dose of vorinostat
Male patient agrees to use two barrier methods of contraception or abstain from intercourse for the duration of the study
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9 g/dL
Prothrombin Time or international normalized ratio (INR) =< 1.5 x upper limit of normal (ULN) unless receiving therapeutic anticoagulation
Partial thromboplastin time (PTT) =< 1.2 times the ULN unless the patient is receiving therapeutic anticoagulation
Potassium and magnesium levels within normal limits
Calculated creatinine clearance >= 30 mL/min
Serum total bilirubin =< 1.5 X ULN
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 X ULN
Alkaline Phosphatase =< 2.5 X ULN
Patient, or the patient's legal representative, has voluntarily agreed to participate by giving written informed consent
Patient has a life expectancy of at least 12 weeks in the opinion of the treating investigator
Patient is willing to continue on same AI therapy
Patient agrees to participate in imaging Protocol 7184 and is separately consented

Exclusion Criteria

Patient has not derived clinical benefit from prior endocrine therapy
Patient is currently participating or has participated in a study with an investigational compound or device within 30 days of initial dosing with study drug(s) other than the imaging protocol 7184
Patient has received an ER blocking therapy (selective estrogen receptor modulating [SERM] or downregulating [SERD] i.e. tamoxifen or fulvestrant) within the past 6 weeks
Patient had prior treatment with an histone deacetylase (HDAC) inhibitor (e.g., romidespin [Depsipeptide], NSC-630176, MS 275, LAQ-824, belinostat [PXD-101], LBH589, MGCD0103, CRA024781, etc); patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study; patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period
Patient is on any systemic steroids that have not been stabilized to the equivalent of =<10 mg/day prednisone during the 30 days prior to the start of the study drugs
Patient has known hypersensitivity to the components of study drug or its analogs
Patients with uncontrolled brain metastases
New York Heart Association (NYHA) Class III or IV congestive heart failure, myocardial infarction within the previous 6 months, corrected QT interval (QTc) > 0.47 seconds, or uncontrolled arrhythmia.
Type I Diabetes Mellitus; patients with Type II Diabetes Mellitus will be included as long as their glucose can be controlled to under 200 mg/dL
Patient is pregnant or breast feeding, or expecting to conceive or father children within the projected duration of the study
Patient with a "currently active" second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled; patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for > 5 years or are considered by their physician to be at less than 30% risk of relapse
Patients with known active viral hepatitis
Patient has a history or current evidence of any condition, therapy, or lab abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study or is not in the best interest of the patient to participate

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	laboratory biomarker analysis	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	F-18 16 alpha-fluoroestradiol	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	gene expression analysis	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	letrozole	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	biopsy	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	positron emission tomography	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	vorinostat	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	anastrozole	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (enzyme inhibitor therapy, AI sensitization therapy)	exemestane	Patients receive vorinostat PO QD for 2 weeks followed by AI therapy comprising anastrozole PO QD, letrozole PO QD, OR exemestane PO QD for 6 weeks. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Duration of Response	Up to approximately 5 years	Duration of response will be summarized for responders.
Rate of Clinical Benefit According to RECIST	Up to approximately 5 years	Conventional imaging (CT, bone scan) was performed at baseline and at week 8 and tumor response assessed by RECIST criteria

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Time elapsed from the first day of study treatment until death, assessed up to approximately 5 years	Kaplan-Meier survival curves will be used to describe overall survival. Overall survival time will be censored on the last date the patient was known to be alive.
Progression-free Survival	Time elapsed from the first day of study treatment, until disease progression or death, assessed up to approximately 5 years	Kaplan-Meier survival curves will be used to describe progression-free survival. For progression-free survival, patients without documented disease progression or death will be treated as censored observations on the date of the last tumor assessment.
Percentage of Patients That Experience Adverse Events as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0	Up to approximately 5 years