Phase I/II Study of Decitabine and Valproic Acid in Relapsed/Refractory Leukemia or Myelodysplastic Syndromes

November 14, 2018 updated by: M.D. Anderson Cancer Center

Phase I/II Study of 5-aza-2'-Deoxycytidine and Valproic Acid in Patients With Relapsed/Refractory Leukemia or Myelodysplastic Syndromes

Valproic acid is a medication that is currently used in the prevention of seizures, bipolar disorder, and migraine headaches. Researchers hope that it may improve the effects of decitabine. Decitabine is a chemotherapy drug with known activity in leukemia and myelodysplastic syndromes.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Recent studies have shown synergy between demethylating agents and histone deacetylase inhibitors. It has been shown that both DNA methylation and histone deacetylation work together in affecting gene expression.

Therefore, drugs that inhibit DNA methylation and those that inhibit histone deacetylase can reactivate silenced genes in combination better than they can individually. Decitabine (5 aza-2'deoxycytidine), a drug that produces marked DNA hypomethylator, has demonstrated antileukemic activity at low doses. There are several drugs that have been shown to have histone acetylase activity. One of these is valproic acid that has been used safely for many years as an anti-seizure medication.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • M.D. Anderson Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. FOR PHASE I COMPONENT OF THE STUDY: Patients with refractory or relapsed: acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS) are eligible. Patients with chronic lymphocytic leukemia (CLL) are eligible if fludarabine based therapy has failed. Patients with chronic myeloid leukemia (CML) are eligible if they have documented hematologic resistance to imatinib mesylate or have not achieved or lost any cytogenetic response to imatinib mesylate after 12 months of therapy.
  2. Untreated patients older than 60 years of age with AML or MDS who refuse or are not eligible for frontline chemotherapy, are eligible.
  3. Performance status of =/< 2 by the ECOG scale.
  4. Signed informed consent indicating that patients are aware of the investigational nature of this study in keeping with the policies of UTMDACC.
  5. Age > 2 years.
  6. Patients must have been off chemotherapy for 2 weeks prior to entering this study and recovered from the toxic effects of that therapy, unless there is evidence of rapidly progressive disease. Use of hydroxyurea for patients with rapidly proliferative disease is allowed for the first two weeks on therapy. Imatinib mesylate (Gleevec) and anagrelide must also be stopped 2 weeks prior to entering this study.
  7. Adequate liver function (bilirubin of < 2mg%, SGPT < 3 x ULN) and renal function (creatinine < 2mg%).
  8. Women of childbearing potential must practice contraception. Men and women must continue birth control for the duration of the trial.
  9. INCLUSION OF PHASE II PORTION OF THE STUDY: As in the phase I portion but only patients with AML or high-risk MDS (blasts > or = 10%), including untreated patients older than 60 years of age with AML or MDS who refuse or are not eligible for frontline chemotherapy, will be eligible in this portion of the study.

Exclusion Criteria:

  1. Nursing and pregnant females are excluded.
  2. Patients with active and uncontrolled infections are excluded.
  3. Patients with a known ornithine transcarbamylase disorder, history of unexplained coma or a family history of ornithine transcarbamylase disorder are excluded from this study.
  4. Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, pancreatitis, psychiatric illness that would limit compliance with study requirements.
  5. Patients with history of hepatitis B, C, alcoholic liver disease or evidence of hepatopathy will be excluded.
  6. Patients already receiving valproic acid or receiving other anticonvulsivants will be excluded.
  7. Untreated patients younger than 60 years will not be candidates for this study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Decitabine + Valproic acid
Decitabine 15 mg/m^2 by vein over 1 hour times 10 days
Drug: Decitabine
15 mg/m^2 by vein over 1 hour times 10 days
Other Names:
  • Dacogen®
Drug: Valproic acid
20 mg/kg given orally daily for 10 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) of Valproic Acid + Decitabine
Time Frame: Up to 8 weeks of therapy
MTD is the dose level at which less than two participants develop a dose limiting toxicity (DLT). Response evaluated after completing first cycle, 4-8 weeks of therapy.
Up to 8 weeks of therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

M.D. Anderson Cancer Center

Collaborators

Eisai Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 23, 2004

Primary Completion (Actual)

November 8, 2006

Study Completion (Actual)

November 8, 2006

Study Registration Dates

First Submitted

December 29, 2003

First Submitted That Met QC Criteria

December 30, 2003

First Posted (Estimate)

December 31, 2003

Study Record Updates

Last Update Posted (Actual)

November 15, 2018

Last Update Submitted That Met QC Criteria

November 14, 2018

Last Verified

November 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2003-0314

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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