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

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

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

Study Overview

• Status: Completed
• Conditions: Male Breast Cancer; Stage IV Breast Cancer; Recurrent Breast Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Procedure: positron emission tomography; Drug: letrozole; Procedure: biopsy; Genetic: gene expression analysis; Drug: anastrozole; Drug: vorinostat; Drug: exemestane; Radiation: F-18 16 alpha-fluoroestradiol

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (enzyme inhibitor therapy, AI sensitization therapy); 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.

Other: laboratory biomarker analysis; Correlative studies; Procedure: positron emission tomography; Correlative studies; Other Names: PET; FDG-PET; PET scan; tomography, emission computed; Drug: letrozole; Given PO; Other Names: CGS 20267; Femara; LTZ; Procedure: biopsy; Optional correlative studies; Other Names: biopsies; Genetic: gene expression analysis; Correlative studies; Drug: anastrozole; Given PO; Other Names: Arimidex; ICI-D1033; ANAS; Drug: vorinostat; Given PO; Other Names: SAHA; Zolinza; L-001079038; suberoylanilide hydroxamic acid; Drug: exemestane; Given PO; Other Names: Aromasin; FCE-24304; PNU 155971; Radiation: F-18 16 alpha-fluoroestradiol; Correlative studies; Other Names: F-18 FES; fluorine-18 16 alpha-fluoroestradiol

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): August 11, 2016

Study Registration Dates

• First Submitted: June 22, 2010
• First Submitted That Met QC Criteria: June 28, 2010
• First Posted (Estimate): June 30, 2010

Study Record Updates

• Last Update Posted (Actual): September 6, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Breast Neoplasms, Male; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Histone Deacetylase Inhibitors; Letrozole; Vorinostat; Anastrozole; Exemestane
• Other Study ID Numbers: 6856; NCI-2010-01289 (Registry Identifier: CTRP (Clinical Trial Reporting Program))