Hydralazine and Valproate Added to Chemotherapy for Breast Cancer

Study Overview
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Brief Summary
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Aberrant DNA methylation and histone deacetylation participate in cancer development and progression, as epigenetic alterations are common to breast cancer, in this phase II study, the demethylating hydralazine plus the HDAC inhibitor magnesium valproate will be added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.

Detailed Description
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Eligible patients after signing the informed consent and will undergo study evaluation and then typed for acetylator phenotype before being treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day -7 until chemotherapy ends. Chemotherapy will consists in a regimen of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days, followed by surgery to assess the pathological response. Adjuvant radiation and additional treatment will be done in off-protocol basis according to standard institutional policies. Blood samples and core-needle biopsies will be taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate. Global cytosine content (global DNA methylation) and histone deacetylase activity will be assessed in peripheral blood DNA. The transcriptional profile in the primary breast tumor before and after treatment will also be analyzed as well as the plasma levels of hydralazine and valproic acid.

Official Title
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A Phase II Clinical Study of Hydralazine and Valproic Acid in Combination With Neoadjuvant Cytotoxic Chemotherapy in Stage IIB and IIIA Breast Carcinoma

Conditions
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Locally Advanced Breast Cancer

Intervention / Treatment
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* Drug: Hydralazine and magnesium valproate administration
* Procedure: Core-needle biopsy of the breast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 and older; histologically proven invasive T2-3, N0-2, and M0 (stages IIB-IIIA) breast carcinoma; Eastern Cooperative Oncology Group performance status ≤2. Hematological function: Absolute leukocyte count ≥4,000/mm3, platelets ≥100,000/mm3, hemoglobin ≥9.0 g/dL. Hepatic function: total bilirubin, aspartate amino transferase and alanine amino transferase <1.5 the upper normal limit. Renal function: creatinine ≤1.2 mg/dL or a calculated creatinine clearance of ≥60 mL/min. Written informed consent. Exclusion Criteria: A history of allergy to sulphas, hydralazine, or magnesium valproate. Past or present condition of rheumatic disease, central nervous system disease, heart failure from aortic stenosis and postural hypotension as diagnosed by a physician. Previous use of the experimental drugs. Pregnancy and breast-feeding. Uncontrolled systemic disease or infection.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Hydralazine and magnesium valproate administration|nan|
|Procedure: Core-needle biopsy of the breast|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global DNA methylation |  |  | 
| Histone Deacetylase Activity |  |  | 
| Global gene expression |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological response |  |  | 
| Hydralazine plasma levels |  |  | 
| Valproic acid plasma levels |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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locally advanced breast cancer, hydralazine, magnesium valproate, epigenetic therapy, gene expression