Hydralazine as a Demethylating Agent in Rectal Cancer - Full Text View

Sponsored by:	University of Arkansas
Information provided by:	University of Arkansas
ClinicalTrials.gov Identifier:	NCT00575640

Purpose

Clinically feasible dose of Hydralazine for ~ 3 months, by virtue of its demethylating effect, will:

Result in re-expression of epigenetically silenced TSGs in rectal cancer specimens.
Decrease the global methylation in primary cancer cells compared to pre-treatment

Condition	Intervention	Phase
Rectal Cancer	Drug: Hydralazine	Phase I Phase II

MedlinePlus related topics: Cancer

Drug Information available for: Hydralazine Hydralazine hydrochloride

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Health Services Research, Open Label, Single Group Assignment, Efficacy Study
Official Title:	Hydralazine as a Demethylating Agent in Rectal Cancer

Further study details as provided by University of Arkansas:

Primary Outcome Measures:

The study design calls for an initial phase of dose-escalation in cohorts of 3 patients. There are no intra-patient changes in dose. [ Time Frame: unknown ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Subsequent to this Phase I scheme, the study will continue with the selected dose-level (on toxicity and tolerability grounds) to accrue patients in a phase II scheme. [ Time Frame: unknown ] [ Designated as safety issue: No ]

Estimated Enrollment:	47
Study Start Date:	November 2004
Primary Completion Date:	May 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator The objective of this study is to determine the MTD for Hydralazine added to standard neoadjuvant chemotherapy for operable recta cancer. Four dose levels of hydralazine are planned: Dose Level 1: 150 mg/d 50 mg PO TID Dose Level 2: 200 mg/d 50 mg PO QID Dose Level 3: 225 mg/d 75 mg PO TID	Drug: Hydralazine Dose Level 1: 150 mg/d 50 mg PO TID Dose Level 2: 200 mg/d 50 mg PO QID Dose Level 3: 225 mg/d 75 mg PO TID

Detailed Description:

This study will be conducted as a phase I/II clinical trial. In addition to determining the maximum tolerated dose (MTD) of hydralazine, the phase I trial will be performed to identify unexpected toxicities that may occur when hydralazine is used in conjunction with neoadjuvant chemotherapy in normotensive patients with rectal cancer. Once the phase I trial is successfully completed, the phase II trial to evaluate the efficacy of hydralazine in producing a demethylation effect will begin.

This phase I/II trial will require between 31 to 47 patients to complete.

Phase I Study The objective of this study is to determine the MTD for Hydralazine added to standard neoadjuvant chemotherapy for operable recta cancer. Four dose levels of hydralazine are planned:

Dose Level 1: 150 mg/d 50 mg PO TID Dose Level 2: 200 mg/d 50 mg PO QID Dose Level 3: 225 mg/d 75 mg PO TID

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

The principal objective of this study is to perform a molecular evaluation for the reversal of methylation in clinical material collected at two different time points. The first sample representing untreated (the biopsy sample), and later a hydralazine-treated specimen (the resection specimen).

Accordingly, we are not using routine inclusion criterion for enrollment (such as histology or clinical stage), but realize that the majority of operable rectal cancers will be stages II-III, and that treatment—again not specified or restricted—will very likely follow the standard therapy for this disease (infusional 5-Fluorouracil and radiation therapy). The accrual target at the phase II segment of this trial is small and that does not allow for any traditional clinical endpoints assessment (such as response rate, time to treatment failure or survival). Accordingly, we do not plan on following these endpoint as part of this study.

Patients referred to the surgery or gastroenterology services for diagnostic evaluation for rectal cancer will be candidates to participate in this study. Patients with history of elevated blood pressure and who are already on anti-hypertensive drugs would be ideal candidates for this project. In such situation, hydralazine will replace other anti-hypertensives for the duration of study only. There is no age limit for this study. Inclusion criteria are as follows:

Operable rectal cancer (the overwhelming majority are Adenocarcinoma)
Signed informed consent
Baseline blood pressure OFF anti-hypertensives over 100/50 mmHg

Exclusion Criteria:

Pre-existing hypotension (as defined in this protocol BP 100/50)
Pre-existing liver disease (liver function tests over 2x upper limits of normal ULM).
Pre-existing kidney (serum creatinine over 2 mg/dl).
Medical necessity to remain on beta-blockers that cannot be met by other agents.
Coronary even in the preceding 2 months prior to enrollment. Coronary evens include any of the following:
- Acute Myocardial Infarction
- Cardiac catheterization regardless of outcome of procedure or need of intervention
- History of Valvular heart disease
- History of hypertrophic cardiomyopathy with left ventricular outflow tract obstruction.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00575640

Sponsors and Collaborators

University of Arkansas

Investigators

Principal Investigator:

Ahmed M Safar, MD

University of Arkansas

More Information

No publications provided

Responsible Party:	University of Arkansas for Medical Sciences ( Ahmed M. Safar, MD )
Study ID Numbers:	2004-03
Study First Received:	December 14, 2007
Last Updated:	December 3, 2008
ClinicalTrials.gov Identifier:	NCT00575640 History of Changes
Health Authority:	United States: Institutional Review Board

Study placed in the following topic categories:

Vasodilator Agents
Digestive System Neoplasms
Rectal Neoplasms
Gastrointestinal Diseases
Hydralazine
Rectal Neoplasm
Cardiovascular Agents
Intestinal Diseases

Antihypertensive Agents
Rectal Diseases
Intestinal Neoplasms
Digestive System Diseases
Rectal Cancer
Gastrointestinal Neoplasms
Colorectal Neoplasms

Additional relevant MeSH terms:

Vasodilator Agents
Digestive System Neoplasms
Rectal Neoplasms
Gastrointestinal Diseases
Hydralazine
Cardiovascular Agents
Intestinal Diseases
Antihypertensive Agents
Rectal Diseases

Pharmacologic Actions
Intestinal Neoplasms
Neoplasms
Neoplasms by Site
Digestive System Diseases
Therapeutic Uses
Gastrointestinal Neoplasms
Colorectal Neoplasms

ClinicalTrials.gov processed this record on May 07, 2009