Vorinostat and Trastuzumab in Treating Patients With Metastatic or Locally Recurrent Breast Cancer

Study Overview
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Brief Summary
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This phase I/II trial is studying the side effects and best dose of vorinostat when given together with trastuzumab and to see how well they work in treating patients with metastatic breast canceror breast cancer that has recurred in the chest wall. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Vorinostat and trastuzumab also may stop the growth of tumor cells by blocking blood flow to the tumor. Giving vorinostat together with trastuzumab may be a better way to block tumor growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of vorinostat in combination with trastuzumab (Herceptin) in patients with metastatic or local chest wall recurrent HER-2-amplified breast cancer. (Phase I) II. To determine the toxic effects of this regimen in these patients. (Phase I) III. To determine the response rate in patients treated with this regimen. (Phase II) SECONDARY OBJECTIVE: I. To determine the time to progression in patients treated with this regimen. (Phase II) OUTLINE: This is an open-label, multicenter, dose-escalation study of vorinostat. PHASE I: Patients receive oral vorinostat twice daily on days 1-14 and trastuzumab (Herceptin®) IV over 90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of vorinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose limiting toxicity. At least 6 patients are treated at the MTD. PHASE II: Patients receive vorinostat at the MTD and trastuzumab as in phase I. After completion of study treatment, patients are followed periodically for 3 years.

Official Title
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A Phase I/II Study of Suberoylanilide Hydroxamic Acid (SAHA) in Combination With Trastuzumab (Herceptin) in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Her-2 Amplified Breast Cancer

Conditions
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Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: vorinostat
* Drug: trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active or ongoing infection No history of allergic reaction to compounds of similar chemical or biologic composition to vorinostat or other agents used in study No psychiatric illness or social situation that would preclude study compliance No other uncontrolled illness More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin; 1 week for capecitabine) and recovered More than 3 weeks since prior radiotherapy and recovered Recovered from prior therapy At least 2 weeks since prior valproic acid More than 4 weeks since prior investigational agents More than 4 weeks since prior lapatinib ditosylate No concurrent combination antiretroviral therapy for HIV-positive patients Measurable disease, defined as >= 1 unidimensionally measurable lesion > 20 mm by conventional techniques or > 10 mm by spiral CT scan No other concurrent investigational agents Concurrent bisphosphonates allowed provided therapy was initiated prior to study treatment No other concurrent anticancer therapy Recurrent or progressive disease while receiving prior trastuzumab (Herceptin) (with or without chemotherapy) OR relapsed within 3 months of last dose of prior adjuvant trastuzumab for metastatic disease Histologically confirmed breast cancer Must overexpress HER-2 gene Metastatic or chest wall recurrent disease Site of measurable disease must not have been irradiated (except chest wall recurrence treated with adjuvant radiation therapy) No untreated brain metastases Previously treated brain metastasis responsive to radiotherapy and/or surgery allowed provided the brain is not the sole site of measurable disease ECOG 0-2 Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 9 g/dL AST and ALT =< 2 times upper limit of normal Bilirubin =< 1.5 mg/dL (3 mg/dL in the presence of Gilbert's disease provided direct bilirubin is normal) Creatinine =< 1.5 mg/dL LVEF normal by nuclear scan or echocardiogram No evidence of PR prolongation or AV block by EKG No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients will receive vorinostat by mouth twice a day for 2 weeks. They will also receive a 90-minute infusion of trastuzumab in week 1. | Drug: vorinostat<br>* Given orally<br>Drug: trastuzumab<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Response included complete response (CR) and partial response (PR). CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. | Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Tumor response is assessed by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. Disease progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s). Time to progression is defined as time from registration to disease progression. | Tumor assessment was obtained at baseline, after 6 weeks (week 6 = last week of Cycle 2), and after every 4 cycles of therapy | 
| Overall Survival | Overall survival is defined as time from registration to death from any cause. Patients who were alive were censored as the last date of known alive. | Survival was assessed every 3 months for first 2 years from protocol entry, then every 6 months until 3 years from study entry |