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

• Status: Completed
• Trial end date: 2006-10-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: National Institute of Cancerología
• Collaborators: National Council of Science and Technology, Mexico; Psicofarma S.A. de C.V.
• Treatments: Hydralazine; Valproic Acid

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.