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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00075010
Recruitment Status : Completed
First Posted : December 31, 2003
Last Update Posted : November 15, 2018
Eisai Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Leukemia Myelodysplastic Syndromes Drug: Decitabine Drug: Valproic acid Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of 5-aza-2'-Deoxycytidine and Valproic Acid in Patients With Relapsed/Refractory Leukemia or Myelodysplastic Syndromes
Actual Study Start Date : January 23, 2004
Actual Primary Completion Date : November 8, 2006
Actual Study Completion Date : November 8, 2006

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 Name: Dacogen®

Drug: Valproic acid
20 mg/kg given orally daily for 10 days

Primary Outcome Measures :
  1. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00075010

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United States, Texas
M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Eisai Inc.
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Principal Investigator: Guillermo Garcia-Manero, M.D. M.D. Anderson Cancer Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: M.D. Anderson Cancer Center Identifier: NCT00075010     History of Changes
Other Study ID Numbers: 2003-0314
First Posted: December 31, 2003    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018

Keywords provided by M.D. Anderson Cancer Center:
Relapsed/Refractory Leukemia
Myelodysplastic Syndromes

Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Valproic Acid
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs