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Hydralazine as a Demethylating Agent in Rectal Cancer

Primary Purpose

Rectal Cancer

Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Hydralazine
Sponsored by
University of Arkansas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional health services research trial for Rectal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Active Comparator

    Arm Label

    1

    Arm Description

    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

    Outcomes

    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.

    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.

    Full Information

    First Posted
    December 14, 2007
    Last Updated
    March 3, 2015
    Sponsor
    University of Arkansas
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00575640
    Brief Title
    Hydralazine as a Demethylating Agent in Rectal Cancer
    Official Title
    Hydralazine as a Demethylating Agent in Rectal Cancer
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2015
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    No enrollment
    Study Start Date
    November 2004 (undefined)
    Primary Completion Date
    May 2008 (Actual)
    Study Completion Date
    undefined (undefined)

    3. Sponsor/Collaborators

    Name of the Sponsor
    University of Arkansas

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    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
    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

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Rectal Cancer

    7. Study Design

    Primary Purpose
    Health Services Research
    Study Phase
    Phase 1, Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    1
    Arm Type
    Active Comparator
    Arm Description
    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 Type
    Drug
    Intervention Name(s)
    Hydralazine
    Intervention Description
    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 Outcome Measure Information:
    Title
    The study design calls for an initial phase of dose-escalation in cohorts of 3 patients. There are no intra-patient changes in dose.
    Secondary Outcome Measure Information:
    Title
    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.

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility 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.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Ahmed M Safar, MD
    Organizational Affiliation
    University of Arkansas
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Hydralazine as a Demethylating Agent in Rectal Cancer

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