Vorinostat in Treating Women Who Are Undergoing Surgery For Newly Diagnosed Stage I -III Breast Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well vorinostat works in treating women who are undergoing surgery for newly diagnosed stage I, stage II, or stage III breast cancer. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat before surgery may shrink the tumor so that it can be removed.

Detailed Description
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PRIMARY OBJECTIVE: I. Determine the safety and tolerability of vorinostat in women undergoing conventional surgery for newly diagnosed stage I-III breast cancer. OULINE: This is a multicenter, pilot study. Patients receive oral vorinostat twice daily on days -3 to 0. Approximately 2 hours after the final dose of vorinostat, patients undergo surgical resection of the tumor on day 0. After completion of study treatment, patients are followed for 30 days.

Official Title
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A Pilot Study Evaluating Surrogates of Response to Short Term Oral Suberoylanilide Hydroxamic Acid (SAHA) in Women With Newly Diagnosed Breast Cancer

Conditions
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Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer

Intervention / Treatment
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* Drug: vorinostat
* Other: conventional surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: No prior or concurrent hormonal therapy for breast cancer Histologically confirmed breast cancer, stage I-III disease, scheduled to undergo definitive surgery or other primary treatment (e.g., preoperative/neoadjuvant systemic treatment) for breast cancer ECOG 0-2 OR Karnofsky 60-100% Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal PT ≤ 14 seconds Creatinine normal No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other uncontrolled intercurrent illness No history of allergic reaction attributed to compounds of similar chemical or biologic composition to vorinostat At least 30 days since prior hormone replacement therapy (e.g., estrogen and/or progestin) Concurrent vaginal hormone preparations (e.g., vagifem or estring) allowed No concurrent birth control pills No prior radiotherapy to the ipsilateral breast No prior or concurrent radiotherapy for breast cancer No prior or concurrent novel therapy for breast cancer At least 14 days since prior valproic acid or another histone deacetylase inhibitor No other concurrent investigational agents No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent therapy for this cancer WBC ≥ 3,000/mm^3 Exclusion criteria: Patients must not be recieving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to SAHA. Patients may not be taking valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to initiating SAHA. Women who are pregnant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Interventional Model Description: Patients receive oral vorinostat twice daily on days -3 to 0. Approximately 2 hours after the final dose of vorinostat, patients undergo conventional surgical resection of the tumor on day 0. After completion of study treatment, patients are followed for 30 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive oral vorinostat twice daily on days -3 to 0. Approximately 2 hours after the final dose of vorinostat, patients undergo conventional surgery of the tumor on day 0. After completion of study treatment, patients are followed for 30 days. | Drug: vorinostat<br>* Given orally, conventional surgery to follow.<br>* Other names: Zolinza;Other: conventional surgery<br>* Undergo conventional surgery<br>* Other names: surgery, conventional;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Participants were evaluated for adverse events due to vorinostat to assess if it was safe to give the drug prior to surgery. 17 of 25 participants who received vorinostat experienced at least 1 adverse event believed to be related to the study drug; no adverse events were severe, and the treatment was considered safe. | After 3 days of vorinostat | 
| Change in Tissue Proliferation After 3 Days of Treatment | Change in Ki-67 (a marker of tissue proliferation) by IHC compared to baseline in the treated (22 evaluable samples) or untreated patients (15 evaluable samples) were analyzed between groups. Ki-67 is a protein in cells that increases as cellsprepare to divide into new cells. A staining process can measure the percentage of tumor cells that are positive for Ki-67. The more positive cells there are, the more quickly they are dividing and forming new cells. | After 3 days of vorinostat | 
| Change in Tissue Apoptosis After 3 Days of Treatment | Change in cleaved caspase-3 (a marker of tissue apoptosis) by IHC compared to baseline in the treated (19 evaluable samples) or untreated patients (12 evaluable samples) were analyzed between groups. Cleaved caspase-3 is a protein in cells involved in apoptosis (cell death). | Baseline and after 3 day of vorinostat | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tissue Histone Acetylation After 3 Days of Treatment | To evaluate change from baseline in tissue histone acetylation in patients with primary breast cancer who received three days of Short Term Oral Suberoylanilide Hydroxamic Acid (SAHA) 300 mg PO bid immediately prior to definitive breast surgery or other primary treatment. This is measured by Cumulative Methylation Index, which is reported as the sum of all %M for all genes. %M= (methylated copies divided by methylated + unmethylated copies) x 100. | Baseline and after 3 day of Vorinostat | 
| Change in Blood (Peripheral Blood Mononuclear Cells) Histone Acetylation After 3 Days of Treatment | To evaluate baseline and change in histone acetylation in polymononuclear cells in patients with primary breast cancer who received three days of SAHA 300 mg PO bid immediately prior to definitive breast surgery or other primary treatment. | Baseline and after 3 day of Vorinostat |