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Hydralazine as a Demethylating Agent in Rectal Cancer

Phase 1/Phase 2
18 Years
Not Enrolling
Rectal Cancer

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Trial Information

Hydralazine as a Demethylating Agent in Rectal Cancer

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

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

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

- History of Valvular heart disease

- History of hypertrophic cardiomyopathy with left ventricular outflow tract

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Health Services Research

Outcome Measure:

The study design calls for an initial phase of dose-escalation in cohorts of 3 patients. There are no intra-patient changes in dose.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Ahmed M Safar, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Arkansas


United States: Institutional Review Board

Study ID:




Start Date:

November 2004

Completion Date:

Related Keywords:

  • Rectal Cancer
  • Rectal Neoplasms