Trial for Locally Advanced Breast Cancer Using Vorinostat Plus Chemotherapy

Study Overview
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Brief Summary
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Vorinostat is a histone deacetylase (HDAC) inhibitor which is approved by the U.S. Food and Drug Administration for the treatment of a rare type of cancer involving the skin (cutaneous T cell lymphoma), but not for breast cancer. HDAC inhibitors work by unsilencing tumor suppressor genes and other genes in the cancer cells that are repressed; when the genes are turned back on by the drug, it leads to death of the cancer cells. HDAC inhibitors such as vorinostat have been shown to enhance the effects of chemotherapy and trastuzumab in experimental systems. The purpose of this trial is to determine the optimal dose of vorinostat to use in combination with standard chemotherapy alone (or in combination with plus trastuzumab for HER2-positive disease), and to determine whether vorinostat enhances the effectiveness of standard chemotherapy (+/- trastuzumab) in patients with locally advanced breast cancer.

Detailed Description
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This is a phase I-II trial in which patients with stage IIB-IIIC breast cancer will receive: Neoadjuvant weekly paclitaxel (80 mg/m2 IV weekly x 12 weeks) plus vorinostat (200 or 300 mg PO BID on days 1-3 each paclitaxel dose) and trastuzumab (4 mg/kg loading dose, 2 mg/kg IV weekly x 12 total doses if HER2 positive, followed by: Doxorubicin (60 mg/m2) plus cyclophosphamide (600 mg/m2) every 2 weeks x 4 cycles (plus G-CSF), followed by: Surgery (lumpectomy or mastectomy)

Official Title
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Phase I-II Trial of Vorinostat Plus Weekly Paclitaxel (+/- Trastuzumab) Followed by Doxorubicin-cyclophosphamide in Patients With Locally Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Vorinostat
* Drug: Paclitaxel
* Drug: Trastuzumab
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Procedure: Surgery


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the breast associated with the following stages: IIB, IIIA, IIIB or IIIC. Tumor must be Her2/neu positive No prior chemotherapy, radiation or definitive therapeutic surgery Exclusion Criteria: May not be receiving any other investigational agents Uncontrolled intercurrent illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vorinostat Plus Paclitaxel<br>Vorinostat (PO days 1-3) plus weekly paclitaxel x 12 weeks (and trastuzumab if HER2-positive), followed by doxorubicin-cyclophosphamide every 2 weeks x 4 cycles, followed by surgery | Drug: Vorinostat<br>* Vorinostat 200 or 300 mg PO BID on days 1-3 of each weekly paclitaxel dose<br>* Other names: Zolinza;Drug: Paclitaxel<br>* Paclitaxel 80 mg/m2 weekly for 12 weeks<br>* Other names: Taxol;Drug: Trastuzumab<br>* Trastuzumab (if HER2-positive) 4 mg/kg, then 2 mg/kg weekly for 12 weeks including loading dose<br>* Other names: Perception;Drug: Doxorubicin<br>* Doxorubicin 60 mg/m2 every 2 weeks for 8 weeks<br>* Other names: Adriamycin;Drug: Cyclophosphamide<br>* Cyclophosphamide 600 mg/m2 every 2 weeks for 8 weeks<br>* Other names: Cytoxan;Procedure: Surgery<br>* Surgical excision of tumor from breast<br>* Other names: Mastectomy or lumpectomy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose of Vorinostat in Combination With Weekly Paclitaxel/Trastuzumab | Dose limiting toxicity in cycle 1 | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological Complete Response (CR) Rate in Patients With Her2/Neu Positive Locally Advanced Breast Cancer. | Pathological Complete Response (CR) defined as absence of invasive cancer at surgery | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vorinostat, Neoadjuvant Chemotherapy