A Phase II Study of Epigenetic Therapy to Overcome Chemotherapy Resistance in Refractory Solid Tumors

Condition(s) targeted: Refractory Solid Tumors

Intervention: Hydralazine and magnesium valproate (Drug)

Phase: Phase 2

Status: Completed

Sponsored by: National Institute of Cancerología

Official(s) and/or principal investigator(s):
Alfonso Duenas-Gonzalez, MD PhD, Study Director, Affiliation: National Institute of Cancerologia

Chemotherapy resistance, either innate or acquired requires for its development, expression changes on a large number of genes therefore, it has been hypothesized that epigenetic-mediated changes could be the responsible driving force for chemotherapy resistance. Aberrant DNA methylation and histone deacetylation are the main epigenetic alterations hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) may overcome resistance in refractory solid tumors.

Patients will be treated with hydralazine and magnesium valproate starting from day - 7 until

chemotherapy ends which consists on the same pre-study protocol regimen on which patients progressed. Response and toxicity were evaluated. Global DNA methylation and HDAC activity were evaluated in the peripheral blood cells, as well as the plasma levels of valproic acid and hydralazine.

Official title: A Phase II Study of Epigenetic Therapy With Hydralazine and Magnesium Valproate to Overcome Chemotherapy Resistance in Refractory Solid Tumors

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Clinical benefit (complete response, partial response and stable disease)

Safety

Secondary outcome:

Global DNA methylation

HDAC inhibition

Gene promoter demethylation from serum DNA

Detailed description: Eligible patients after signing informed consent will undergo study evaluation and

acetylation status typing before being treated. Patients will begin treatment (day - 7) with

a daily dose of a slow-release formulation of hydralazine tablets containing either 182 mg for rapid-acetylators or 83 mg for slow-acetylators and slow-release tablets containing 700mg of magnesium valproate at a dose of 40mg/Kb t. i.d. Both hydralazine and magnesium

valproate will be administered from day - 7 until the last day of the last chemotherapy

cycle. Chemotherapy will initiate at day 1 (after seven days of being taken hydralazine and magnesium valproate) with the same pre-study protocol regimen at which patients showed tumor progression. Toxicity will be evaluated after each course of chemotherapy. Response will be evaluated at the third course of chemotherapy. Promoter of selected genes will be evaluated by methylation-specific PCR in serum DNA before and after 7 days of treatment with hydralazine and valproate.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Aged18 years and older.

- Histologically proven malignant solid tumors who were receiving their second, third

or fourth line of palliative chemotherapy and who showed at the second or third course progressive disease as their maximum response according to the RECIST criteria or to the IGCG CA125 criteria in case of ovarian cancer patients.

- Measurable disease defined by 1 of the following criteria: Any unidimensional

measurable lesion ≥ 10 mm by standard MRI or CT scan for solid tumors; or at least 1 non-measurable lesion that is evaluable by nuclear medicine, tumor markers, or other reliable measures.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤2; Absolute leukocyte

count (≥4000/mm3), platelets ≥100,000/mm3, hemoglobin ≥9. 0 g/dL; total bilirubin, aspartate amino transferase (AST) and alanine amino transferase (ALT) <1. 5 the upper normal limit (UNL), creatinine ≤1. 2 mg/dL or a calculated creatinine clearance of ≥60 mL/min.

- Life expectancy of more than three months,

- Written informed consent.

Exclusion Criteria:

- History of allergy to hydralazine or 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 (hydralazine and magnesium valproate)

- Pregnancy or breast-feeding.

- Uncontrolled systemic disease or infection.

National Institute of Cancerologia, Mexico City, Tlalpan 14080, Mexico

Starting date: September 2005
Last updated: November 27, 2006