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

Refractory Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00404508
• Other study ID #: 005/32/DII
• Status: Completed
• Phase: Phase 2
• First received: November 25, 2006
• Last updated: November 27, 2006
• Start date: September 2005
• Est. completion date: October 2006

Study information

• Verified date: November 2006
• Source: National Institute of Cancerología
• Contact: n/a
• Is FDA regulated: No
• Health authority: Mexico: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: October 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Refractory Solid Tumors

Intervention

Drug:
• Hydralazine and magnesium valproate

Locations

Country	Name	City	State
Mexico	National Institute of Cancerologia	Mexico City	Tlalpan

Sponsors (3)

Lead Sponsor	Collaborator
National Institute of Cancerología	National Council of Science and Technology, Mexico, Psicofarma S.A. de C.V.

Country where clinical trial is conducted

Mexico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical benefit (complete response, partial response and stable disease)
Primary	Safety
Secondary	Global DNA methylation
Secondary	HDAC inhibition
Secondary	Gene promoter demethylation from serum DNA