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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00262834
• Collaborator: (none)
• Enrollment: 54
• Location: 1
• Arm: 1
• Duration (Months): 91
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Stage I Breast Cancer; Stage II Breast Cancer; Stage III Breast Cancer	Drug: vorinostat; Other: conventional surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 54 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• 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.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)
• Primary Purpose: Treatment
• Official Title: A Pilot Study Evaluating Surrogates of Response to Short Term Oral Suberoylanilide Hydroxamic Acid (SAHA) in Women With Newly Diagnosed Breast Cancer
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I 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; Given orally, conventional surgery to follow.; Other Names: L-001079038 SAHA suberoylanilide hydroxamic acid Zolinza ; Other: conventional surgery; Undergo conventional surgery; Other Names: surgery, conventional

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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 Outcome Measures

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Vered Stearns, Johns Hopkins University/Sidney Kimmel Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00262834
• Other Study ID Numbers: NCI-2009-00098; NCI-2009-00098; CDR0000445404; SKCCC J0504; 6914; U01CA070095; P30CA006973
• First Posted: Dec 7, 2005
• Last Update Posted: Feb 19, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Breast Neoplasms; Vorinostat

Study Results

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 Detail	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.

Arm/Group Title	Vorinostat	Tissue Only
Arm/Group Description	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).	Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls.
Period Title: Overall Study
STARTED	25	29
COMPLETED	24	25
NOT COMPLETED	1	4

Baseline Characteristics

Arm/Group Title	Vorinostat	Tissue Only	Total
Arm/Group Description	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).	Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls.	Total of all reporting groups
Overall Participants	25	29	54
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	52	54
Age, Customized (years) [Number]
<=18 years	0	0	0
>18 years	25	29	54
Sex: Female, Male (Count of Participants)
Female	25 100%	29 100%	54 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%	29 100%	54 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of vorinostat.

Arm/Group Title	Vorinostat
Arm/Group Description	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).
Measure Participants	25
Number [participants]	17 68%

2. Primary Outcome

Title	Change in Tissue Proliferation After 3 Days of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Vorinostat	Tissue Only
Arm/Group Description	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).	Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls.
Measure Participants	25	29
Measure Evaluable tissue samples	22	15
Mean (Full Range) [percentage of change]	-3	-4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vorinostat, Tissue Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.42
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon rank-sum tests were used to compare the differences (post-pre) between groups.

3. Primary Outcome

Title	Change in Tissue Apoptosis After 3 Days of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Vorinostat	Tissue Only
Arm/Group Description	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).	Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls.
Measure Participants	25	29
Measure Evaluable tissue samples	19	12
Mean (Full Range) [percentage of change]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vorinostat, Tissue Only
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.50
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon rank-sum tests were used to compare the differences (post-pre) between groups.

4. Secondary Outcome

Title	Change in Tissue Histone Acetylation After 3 Days of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Arm I
Arm/Group Description	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. vorinostat: Given orally, conventional surgery to follow. conventional surgery: Undergo conventional surgery
Measure Participants	19
Number [Cumulative Methylation Index]	38.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Vorinostat
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change in Blood (Peripheral Blood Mononuclear Cells) Histone Acetylation After 3 Days of Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Vorinostat	Tissue Only
Arm/Group Description	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).	Women who declined vorinostat but agreed to donate tissues for biomarker assessment, signed a separate informed consent and were enrolled as controls.
Measure Participants	0	0

Adverse Events

Time Frame	Baseline and after 3 day of vorinostat
Adverse Event Reporting Description	Participants were assessed by study staff a specified time points per CTCAE 3.0.
Arm/Group Title	Vorinostat
Arm/Group Description	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). Only vortinostat group adverse events were reported or collected to assess association of events with the agent in question.
All Cause Mortality
	Vorinostat
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Vorinostat
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	Vorinostat
	Affected / at Risk (%)	# Events
Total	17/25 (68%)
Gastrointestinal disorders
Diarrhea	7/25 (28%)	7
Dysgeusia	4/25 (16%)	4
Anorexia	3/25 (12%)	3
Nausea	4/25 (16%)	4
General disorders
Fatigue	4/25 (16%)	4
Investigations
White blood cell decreased	6/25 (24%)	6
Nervous system disorders
Headache	1/25 (4%)	1

Limitations/Caveats

The main limitation of the trial is the unexpectedly low proportion of matched evaluable samples available for the biomarkers studied, ranging from 44% to 92%.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.