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

NCT00404508 | Completed Phase 2

• 1 other identifier: 005/32/DII
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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.

Conditions

Refractory Solid Tumors

Keywords

Hydralazine; Magnesium Valproate; Chemotherapy resistance; Epigenetic therapy

Outcome Measures

Primary Outcomes (2)

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

• Safety

Secondary Outcomes (3)

• Global DNA methylation

• HDAC inhibition

• Gene promoter demethylation from serum DNA

Interventions

Hydralazine and magnesium valproate DRUG

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Cancerología: lead
• Psicofarma, S.A. De C.V.: collaborator
• National Council of Science and Technology, Mexico: collaborator

Study Sites (1)

National Institute of Cancerologia

Mexico City, Tlalpan, 14080, Mexico

Location

Related Publications (1)

• Candelaria M, Gallardo-Rincon D, Arce C, Cetina L, Aguilar-Ponce JL, Arrieta O, Gonzalez-Fierro A, Chavez-Blanco A, de la Cruz-Hernandez E, Camargo MF, Trejo-Becerril C, Perez-Cardenas E, Perez-Plasencia C, Taja-Chayeb L, Wegman-Ostrosky T, Revilla-Vazquez A, Duenas-Gonzalez A. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors. Ann Oncol. 2007 Sep;18(9):1529-38. doi: 10.1093/annonc/mdm204.

  PMID: 17761710 DERIVED

MeSH Terms

Interventions

Hydralazine; Valproic Acid

Intervention Hierarchy (Ancestors)

Phthalazines; Pyridazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Alfonso Duenas-Gonzalez, MD PhD

  National Institute of Cancerologia

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV

Study Record Dates

• First Submitted: November 25, 2006
• First Posted: November 28, 2006
• Study Start: September 1, 2005
• Study Completion: October 1, 2006
• Last Updated: November 28, 2006

Record last verified: 2006-11

Locations

ME (1)