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

Phase 2

Completed

Conditions: Stage II Breast Cancer
Stage III Breast Cancer
Breast Cancer
Stage I Breast Cancer

Interventions: Drug: vorinostat
Other: conventional surgery

Registration Number: NCT00262834

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 54

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.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Arm I	vorinostat	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.
Arm I	conventional surgery	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.

Primary Outcome Measures

Name	Time	Method
Change in Tissue Proliferation After 3 Days of Treatment	After 3 days of vorinostat	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.
Change in Tissue Apoptosis After 3 Days of Treatment	Baseline and after 3 day of vorinostat	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).
Number of Participants With Adverse Events	After 3 days of vorinostat	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.

Secondary Outcome Measures

Name	Time	Method
Change in Tissue Histone Acetylation After 3 Days of Treatment	Baseline and after 3 day of Vorinostat	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.
Change in Blood (Peripheral Blood Mononuclear Cells) Histone Acetylation After 3 Days of Treatment	Baseline and after 3 day of Vorinostat	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.