Hydralazine Valproate for Cervical Cancer

Randomized, Double-Blind, Phase III Trial of Chemotherapy Plus the Transcriptional Therapy Hydralazine and Magnesium Valproate Versus Chemotherapy Plus Placebo in Recurrent and Metastatic Cervical Cancer.

The current standard for recurrent, persistent or metastatic cervical cancer is palliative chemotherapy with cisplatin topotecan, 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 standard cisplatin topotecan against placebo plus cisplatin topotecan upon progression-free survival.

Hypothesis. Hydralazine and magnesium valproate associated to cisplatin topotecan will increase progression-free survival from 4.6 to 7.6 months as compared with the same regimen of chemotherapy plus placebo.

Study Overview

• Status: Unknown
• Conditions: Metastatic Cervical Cancer
• Intervention / Treatment: Drug: Placebo; Drug: Hydralazine and magnesium valproate

Detailed Description

Randomized, double-blind phase III trial. A total of 143 patients (alpha 0.5, power 0.8)with metastatic, persistent or recurrent cervical cancer without previous systemic treatment will be randomized to cisplatin topotecan + placebo or cisplatin topotecan hydralazine valproate for 6 courses every 3 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.

• Study Type: Interventional
• Enrollment (Anticipated): 143
• Phase: Phase 3

Contacts and Locations

Study Locations

• Mexico
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 14080
      • Recruiting
      • Instituto Nacional de Cancerologia
      • Principal Investigator: Lucely Cetina, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• informed consent, histological diagnosis of persistent, recurrent or metastatic cervical carcinoma; measurable disease by physical examination, CT Scan, MRI or PET-CT. Biopsy is required for confirmation only if the lesion is unique, has less than 2cm in the longest diameter or has no clearly defined borders.
• Patients should have no previous systemic treatment (could have received chemotherapy as radiosensitization to the pelvis and or para-aortic field.
• Aged >18 years, performance status 0-2 according to ECOG classification, and adequate liver, hematological and renal 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 2	Drug: Hydralazine and magnesium valproate; Cisplatin + Topotecan plus hydralazine valproate; Other Names: TRANSKRIP R/L
Placebo Comparator: 1	Drug: Placebo; Cisplatin + Topotecan plus placebo; Other Names: TRANSKRIP R/L

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	2-years

Secondary Outcome Measures

Outcome Measure	Time Frame
Response rate, safety, overall survival.	2-years

Collaborators and Investigators

• Sponsor: National Institute of Cancerología
• Collaborators: Psicofarma S.A. de C.V.
• Investigators: Study Chair: Myrna Candelaria, MD, Instituto Nacional de Cancerologia, Columbia

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (Anticipated): September 1, 2010
• Study Completion (Anticipated): December 1, 2010

Study Registration Dates

• First Submitted: September 18, 2007
• First Submitted That Met QC Criteria: September 18, 2007
• First Posted (Estimate): September 20, 2007

Study Record Updates

• Last Update Posted (Estimate): March 30, 2009
• Last Update Submitted That Met QC Criteria: March 27, 2009
• Last Verified: March 1, 2009

More Information

Terms related to this study

• Keywords: Randomized; Phase III; Cervical cancer; Valproate; Hydralazine; Epigenetic therapy
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Uterine Cervical Neoplasms; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid; Hydralazine
• Other Study ID Numbers: 006/027/ICI