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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00404508
Recruitment Status : Completed
First Posted : November 28, 2006
Last Update Posted : November 28, 2006
Psicofarma S.A. de C.V.
National Council of Science and Technology, Mexico
Information provided by:
National Institute of Cancerología

Brief 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.

Condition or disease Intervention/treatment Phase
Refractory Solid Tumors Drug: Hydralazine and magnesium valproate Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Epigenetic Therapy With Hydralazine and Magnesium Valproate to Overcome Chemotherapy Resistance in Refractory Solid Tumors
Study Start Date : September 2005
Study Completion Date : October 2006

Primary Outcome Measures :
  1. Clinical benefit (complete response, partial response and stable disease)
  2. Safety

Secondary Outcome Measures :
  1. Global DNA methylation
  2. HDAC inhibition
  3. Gene promoter demethylation from serum DNA

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00404508

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National Institute of Cancerologia
Mexico City, Tlalpan, Mexico, 14080
Sponsors and Collaborators
National Institute of Cancerología
Psicofarma S.A. de C.V.
National Council of Science and Technology, Mexico
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Study Director: Alfonso Duenas-Gonzalez, MD PhD National Institute of Cancerologia

Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information Identifier: NCT00404508     History of Changes
Other Study ID Numbers: 005/32/DII
First Posted: November 28, 2006    Key Record Dates
Last Update Posted: November 28, 2006
Last Verified: November 2006

Keywords provided by National Institute of Cancerología:
Magnesium Valproate
Chemotherapy resistance
Epigenetic therapy

Additional relevant MeSH terms:
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Valproic Acid
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Antihypertensive Agents
Vasodilator Agents