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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Pilot Study of Vorinostat to Restore Sensitivity to Aromatase Inhibitor Therapy

Conditions
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Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor therapy, AI sensitization therapy)<br>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. | Drug: vorinostat<br>* Given PO<br>* Other names: Zolinza;Other: laboratory biomarker analysis<br>* Correlative studies<br>Procedure: biopsy<br>* Optional correlative studies<br>* Other names: biopsies;Radiation: F-18 16 alpha-fluoroestradiol<br>* Correlative studies<br>* Other names: fluorine-18 16 alpha-fluoroestradiol;Procedure: positron emission tomography<br>* Correlative studies<br>* Other names: tomography, emission computed;Drug: anastrozole<br>* Given PO<br>* Other names: ICI-D1033;Drug: letrozole<br>* Given PO<br>* Other names: LTZ;Drug: exemestane<br>* Given PO<br>* Other names: PNU 155971;Genetic: gene expression analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | 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. | Time elapsed from the first day of study treatment, until disease progression or death, assessed up to approximately 5 years | 
| Overall Survival | 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. | Time elapsed from the first day of study treatment until death, assessed up to approximately 5 years | 
| 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 |