Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage III Breast Cancer
Conditions
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.
Interventions
DRUGvorinostat
Given orally, conventional surgery to follow.
OTHERconventional surgery
Undergo conventional surgery
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Women enrolled from two sites, Johns Hopkins Medical Institutes and Anne Arundel Medical Center. Informed consent was obtained from all participants in the vorinostat and control groups.
Pre-assignment details
Women must have adequate performance status and blood counts/organ function; no hormones within 30 days of diagnostic biopsy, prior or concomitant treatment for the current cancer, or uncontrolled intercurrent illness that could limit compliance were allowed.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat Women in the vorinostat group were scheduled to receive 6 doses of oral vorinostat at 300 mg twice daily (bid), with the last dose administered by study personnel approximately 2 hours before the scheduled breast surgery (or biopsy). | 25 |
| Tissue Only Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls. | 29 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Surgery delayed/tissue not collected | 1 | 4 |
Baseline characteristics
| Characteristic | Vorinostat | Tissue Only | Total |
|---|---|---|---|
| Age, Continuous | 55 years | 52 years | 54 years |
| Age, Customized <=18 years | 0 years | 0 years | 0 years |
| Age, Customized >18 years | 25 years | 29 years | 54 years |
| Region of Enrollment United States | 25 participants | 29 participants | 54 participants |
| Sex: Female, Male Female | 25 Participants | 29 Participants | 54 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
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).
Time frame: Baseline and after 3 day of vorinostat
Population: Matched samples (ie, diagnostic biopsy and surgical tissues) for cleaved caspase-3 by IHC were available from 19 (71%) treated and from 12 (48%) controls.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change in Tissue Apoptosis After 3 Days of Treatment | 0 percentage of change |
| Tissue Only | Change in Tissue Apoptosis After 3 Days of Treatment | 0 percentage of change |
p-value: 0.5Wilcoxon (Mann-Whitney)
Primary
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.
Time frame: After 3 days of vorinostat
Population: Matched samples (ie, diagnostic biopsy and surgical tissues) for Ki-67 by IHC were available from 22 (92%) treated and from 15 (60%) controls.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorinostat | Change in Tissue Proliferation After 3 Days of Treatment | -3 percentage of change |
| Tissue Only | Change in Tissue Proliferation After 3 Days of Treatment | -4 percentage of change |
p-value: 0.42Wilcoxon (Mann-Whitney)
Primary
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.
Time frame: After 3 days of vorinostat
Population: Participants who received at least one dose of vorinostat.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Number of Participants With Adverse Events | 17 participants |
Secondary
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.
Time frame: Baseline and after 3 day of Vorinostat
Population: No data was collected for this outcome. We were not able to successfully dissolve the pellet in lysis buffer, and the samples were not subjected to histone acetylation analyses.
Secondary
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.
Time frame: Baseline and after 3 day of Vorinostat
Population: 25 matched samples were collected; however, only 19 were available for analysis as there were 6 cases that were not evaluable for Cumulative Methylation Index.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vorinostat | Change in Tissue Histone Acetylation After 3 Days of Treatment | 38.3 Cumulative Methylation Index |
p-value: 0.24Wilcoxon (Mann-Whitney)