Clinical trial NCT00533299: Hydralazine Valproate for Ovarian Cancer
Official title: Randomized, Double-Blind, Phase III Trial of Chemotherapy Plus the Transcriptional Therapy Hydralazine and Magnesium Valproate Versus Chemotherapy Plus Placebo in Cisplatin-Resistant Recurrent Ovarian Cancer.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Ovarian Cancer
Keywords: Epigenetics, hydralazine, valproate, ovarian cancer
Lead sponsor: National Institute of Cancerología
Sponsor class: OTHER_GOV
First posted: 2007-09-21
Enrollment: 211
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The current standard for recurrent, persistent or metastatic cisplatin-resistant ovarian cancer is palliative chemotherapy with either topotecan, liposomal doxorubicin or gemcitabine, however, the results need to be improved. Epigenetic aberrations play an important role in cancer progression by silencing growth regulatory genes and there is now evidence that inhibitors of DNA methylation and HDAC inhibition synergize the cytotoxicity of chemotherapy.

Objective. To determine the superiority of epigenetic therapy with hydralazine and valproate plus topotecan over placebo plus topotecan upon progression-free survival.

Hypothesis. Hydralazine and magnesium valproate associated to topotecan will increase progression-free survival from 6 to 9 months as compared with the same regimen of chemotherapy plus placebo.

Detailed description: Randomized, double-blind phase III trial. A total of 211 patients (alpha 0.5, power 0.8)with cisplatin-resistant recurrent or persistent cancer will be randomized to topotecan + placebo or topotecan + hydralazine + valproate for 6 courses every 4 weeks. Patients will receive an oral dose of hydralazine of 182mg (rapid) or 83mg (slow) according to the acetylator phenotype in a single daily dose and magnesium valproate at an oral dose of 40mg/Kg t.i.d. Both drugs in a slow-release formulation. Experimental drugs or placebo will start from seven days before day 1 of chemotherapy until the end of the sixth course.

Eligibility criteria: Inclusion Criteria:

* Measurable or evaluable disease(evaluable according to CA125 criteria of GCIG) Cisplatin resistant ovarian cancer
* Persistent or progression to first line platinum-based chemotherapy
* Relapse within 6 months after completing first line platinum-based chemotherapy
* Platinum-sensitive disease who are failed to second line therapy based on platinum.
* Adequate organic function as defined by: hemoglobin \>10 g/L, leukocytes \>4000/mm3, platelets \>100 000mm3; normal creatinine value and creatinine clearance \>60 mL/min; total bilirubin \< 1.5 upper normal limit value

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;
* Newly diagnosed hypertension patients with or without pharmacological treatment are allowed as long as their treatment do not include hydralazine.
* Previous use of the experimental drugs (hydralazine and magnesium valproate) as well as if patients were pregnant or breast-feeding.

Other exclusion criteria are uncontrolled systemic disease or infection.

Primary outcomes:
measure: Progression-Free Survival
timeFrame: 2-years
Secondary outcomes:
measure: Safety, response, overall survival.
timeFrame: 2-years
Other outcomes:
Locations:
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cancerologia
state: Tlalpan
Study officials:
affiliation: Instituto Nacional de Cancerologia, Columbia
name: Dolores Gallardo, MD
role: PRINCIPAL_INVESTIGATOR
References: