Official Title: “Hydralazine as a Demethylating Agent in Rectal Cancer”

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

1. Result in re-expression of epigenetically silenced TSGs in rectal cancer specimens.

2. Decrease the global methylation in primary cancer cells compared to pre-treatment

Study Type: Interventional

Study Design: Health Services Research, Open Label, Single Group Assignment, Efficacy Study

Study Primary Completion Date: May 2008

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

Intervention(s) in this Clinical Trial

• 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

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • 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

Primary 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
    Safety Issue?: No

Secondary 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
    Safety Issue?: No

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:

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

Exclusion Criteria:

• 1. Pre-existing hypotension (as defined in this protocol BP 100/50)
• 2. Pre-existing liver disease (liver function tests over 2x upper limits of normal ULM).
• 3. Pre-existing kidney (serum creatinine over 2 mg/dl).
• 4. Medical necessity to remain on beta-blockers that cannot be met by other agents.
• 5. 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Arkansas

Overall Clinical Trial Officials and Contacts

Ahmed M Safar, MD Principal Investigator University of Arkansas  

Information obtained from ClinicalTrials.gov on August 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00575640

Study ID Number: 2004-03

ClinicalTrials.gov Identifier: NCT00575640

Health Authority: United States: Institutional Review Board