Vorinostat in Treating Patients With Stage IV Breast Cancer Receiving Hormone Therapy

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01720602
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 86
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This pilot clinical trial studies vorinostat in treating patients with stage IV breast cancer receiving hormone therapy. Vorinostat may help hormone therapy work better by making tumor cells more sensitive to the drug.

Condition or Disease	Intervention/Treatment	Phase
Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer	Drug: vorinostat; Drug: anastrozole; Drug: letrozole; Drug: exemestane; Procedure: positron emission tomography; Radiation: F-18 16 alpha-fluoroestradiol; Radiation: fludeoxyglucose F 18; Other: laboratory biomarker analysis	N/A

Detailed Description

PRIMARY OBJECTIVES:

1. Estimate the rate of clinical benefit (objective response plus stable disease) for patients treated with 28-day cycles of vorinostat (first 5 consecutive days each week for day 1-21) concurrent with daily aromatase inhibitor (AI) therapy (all 28 days).

SECONDARY OBJECTIVES:

1. Assess the safety and tolerability of vorinostat and AI combination therapy in patients with metastatic breast cancer.

2. Assess the change in estrogen receptor (ER) expression, measured as the change in F-18 16 alpha-fluoroestradiol (FES) standardized uptake value (SUV) using FES positron emission tomography (PET) completed per protocol 7184 after two weeks of vorinostat and AI therapy and after 8 weeks of therapy.

3. Assess tumor metabolic response, measured as the change in fludeoxyglucose F 18 (FDG) SUV using FDG PET completed per protocol 7184 after two weeks of vorinostat and AI therapy and after 8 weeks of therapy.

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

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

6. Assess the time to progression and the overall survival of patients treated with 28-day cycles of vorinostat (first 5 consecutive days each week for day 1-21) concurrent with daily AI therapy (all 28 days).

OUTLINE:

Patients receive vorinostat orally (PO) 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Vorinostat to Restore Sensitivity to Aromatase Inhibitor Therapy Part B
• Study Start Date: Nov 1, 2012
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (vorinostat, AI therapy) Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity.

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

Outcome Measures

Primary Outcome Measures

1. Rate of Clinical Benefit of Patients Receiving Vorinostat/AI Combination Therapy According to RECIST [8 weeks]

   A 90% score (Wilson) confidence interval will be computed for the rate of clinical benefit. Clinical benefit according to Recist score is defined as: Stable Disease, Partial Remission or Complete Remission. Lack of clinical benefit is defined as Progressive Disease (increase in target lesion size by 20% or more).

2. Response Rate According to RECIST [8 weeks]

   A 90% score (Wilson) confidence interval will be computed for the response rate. Clinical benefit according to Recist score is defined as: Stable Disease, Partial Remission or Complete Remission. Lack of clinical benefit is defined as Progressive Disease (increase in target lesion size by 20% or more).

Secondary Outcome Measures

1. Duration of Response [Up to 5 years]

   Duration of response will be summarized for responders.

2. Progression-free Survival (PFS) [From the time of start of study therapy to documented progression - up to 5 years]

   Progression-free survival is assessed relative to the start of the study therapy. Progression can be determined by RECIST 1.1, elevated tumor markers, worsening clinical symptoms or new lesions identified by FDG-PET or bone scan.

3. Overall Survival [From the time of start of study therapy to date of documented death]

   Overall survival is assessed relative to the start of the study therapy to the date of death, from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• 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 [B-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 >= 50,000/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 (K) levels normal limits

• Magnesium (Mg) levels normal limits

• Calculated creatinine clearance >= 30 mL/min

• Creatinine clearance should be calculated per institutional standard

• Serum total bilirubin =< 1.5 x ULN

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvate 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 or downregulating selective estrogen receptor modulator [SERM] or selective estrogen receptor degrader [SERD] i.e. tamoxifen or fulvestrant) within the past 6 weeks

• Patient had prior treatment with an histone deacetylase (HDAC) inhibitor (e.g., romidepsin [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, 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 laboratory (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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Hannah Linden, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Washington
• ClinicalTrials.gov Identifier: NCT01720602
• Other Study ID Numbers: 7841; NCI-2012-02004; P30CA015704
• First Posted: Nov 2, 2012
• Last Update Posted: Jan 7, 2020
• Last Verified: Jan 1, 2020

• Additional relevant MeSH terms: Breast Neoplasms; Breast Neoplasms, Male; Letrozole; Vorinostat; Anastrozole; Exemestane; Fluorodeoxyglucose F18

Study Results

Participant Flow

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Period Title: Overall Study
STARTED	15
COMPLETED	10
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Overall Participants	15
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 46.7%
>=65 years	8 53.3%
Sex: Female, Male (Count of Participants)
Female	15 100%
Male	0 0%

Outcome Measures

1. Primary Outcome

Title	Rate of Clinical Benefit of Patients Receiving Vorinostat/AI Combination Therapy According to RECIST
Description	A 90% score (Wilson) confidence interval will be computed for the rate of clinical benefit. Clinical benefit according to Recist score is defined as: Stable Disease, Partial Remission or Complete Remission. Lack of clinical benefit is defined as Progressive Disease (increase in target lesion size by 20% or more).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	10
Number (90% Confidence Interval) [percentage of patients]	60

2. Primary Outcome

Title	Response Rate According to RECIST
Description	A 90% score (Wilson) confidence interval will be computed for the response rate. Clinical benefit according to Recist score is defined as: Stable Disease, Partial Remission or Complete Remission. Lack of clinical benefit is defined as Progressive Disease (increase in target lesion size by 20% or more).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	10
Number (90% Confidence Interval) [percentage of patients]	60

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response will be summarized for responders.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	6
Median (Full Range) [weeks]	29.6

4. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival is assessed relative to the start of the study therapy. Progression can be determined by RECIST 1.1, elevated tumor markers, worsening clinical symptoms or new lesions identified by FDG-PET or bone scan.
Time Frame	From the time of start of study therapy to documented progression - up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	15
Median (Full Range) [months]	2

5. Secondary Outcome

Title	Overall Survival
Description	Overall survival is assessed relative to the start of the study therapy to the date of death, from any cause.
Time Frame	From the time of start of study therapy to date of documented death

Outcome Measure Data

Analysis Population Description

OS includes one patient still alive 55 months after starting study therapy

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
Measure Participants	15
Median (Full Range) [months]	19

Adverse Events

Arm/Group Title	Treatment (Vorinostat, AI Therapy)
Arm/Group Description	Patients receive vorinostat PO 5 days a week for 3 weeks. Patients also receive AI therapy comprising either anastrozole PO daily, letrozole PO daily, or exemestane PO daily for 4 weeks. Courses repeat every 28 days in the absence of disease progression and unacceptable toxicity. vorinostat: Given PO anastrozole: Given PO letrozole: Given PO exemestane: Given PO positron emission tomography: Correlative studies F-18 16 alpha-fluoroestradiol: Correlative studies fludeoxyglucose F 18: Correlative studies laboratory biomarker analysis: Correlative studies
All Cause Mortality
	Treatment (Vorinostat, AI Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Vorinostat, AI Therapy)
	Affected / at Risk (%)	# Events
Total	2/15 (13.3%)
Hepatobiliary disorders
Liver failure	1/15 (6.7%)
Infections and infestations
Fever	1/15 (6.7%)
Other (Not Including Serious) Adverse Events
	Treatment (Vorinostat, AI Therapy)
	Affected / at Risk (%)	# Events
Total	8/15 (53.3%)
Blood and lymphatic system disorders
Thrombocytopenia	2/15 (13.3%)
neutropenia	1/15 (6.7%)
Gastrointestinal disorders
vomiting	2/15 (13.3%)
diarrhea	1/15 (6.7%)
nausea	2/15 (13.3%)
General disorders
Rigors / chills	1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Muscle cramps	1/15 (6.7%)
Nervous system disorders
Dizziness	1/15 (6.7%)
Renal and urinary disorders
decrease in glomerular filtration	1/15 (6.7%)
creatinine increase	2/15 (13.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.