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Azacytidine and Valproic Acid in Patients With Advanced Cancers

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: NCT00496444
Recruitment Status : Completed
First Posted : July 4, 2007
Last Update Posted : August 1, 2012
Celgene Corporation
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Tracking Information
First Submitted Date  ICMJE July 2, 2007
First Posted Date  ICMJE July 4, 2007
Last Update Posted Date August 1, 2012
Study Start Date  ICMJE May 2005
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 26, 2009)
To find the highest safe dose of the drug azacitidine that can be given in combination with valproic acid in the treatment of solid tumors. [ Time Frame: 4 Years ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Azacytidine and Valproic Acid in Patients With Advanced Cancers
Official Title  ICMJE Phase I Study of Low-Dose Hypomethylating Agent Azacitidine Combined With the Histone Deacetylase Inhibitor Valproic Acid in Patients With Advanced Cancers
Brief Summary

Primary Objective:

1. To evaluate side effects and maximum tolerated dose of azacitidine and valproic acid in patients with advanced cancer.

Secondary Objectives:

  1. To perform a preliminary assessment of the histone acetylation and DNA methylation effects of this combination on peripheral blood mononuclear cells (PBMC).
  2. To assess the clinical anti-tumor activity (objective response including complete and partial responses) of this combination in patients with advanced cancer, in a descriptive fashion.
Detailed Description

Azacitidine is a new chemotherapy drug that is designed to destroy cancer cells at high doses. At low doses, it is designed to destroy some cancer cells as well as cause changes that may make cancer cells less harmful. Valproic acid is a drug that is used in every day practice in the treatment of seizures, migraine headache, and mood disturbance in bipolar disorders.

Before you can start receiving the study drug, you will have what are called "screening tests." These tests will help the doctor decide if you are eligible to take part in the study. You will have a complete physical exam, including routine blood tests (about 4 teaspoons). You may have to get either a CT scan or a MRI to measure your disease if you have not had one within 1 month. Women who are able to have children must have a negative blood-pregnancy test.

If you are found to be eligible to take part in this study, you will receive the study drug in "cycles." Cycles will generally be 4 weeks long but may be longer, depending on any side effects you experience from the azacitidine. During each cycle, you will receive azacitidine under the skin once each day for the first 10 days (Day 1 to Day 10). You will then have an 18-day break during which you will not receive azacitidine injections for the rest of the cycle. Additionally, you will take valproic acid pills by mouth, every day, starting the first day of the first cycle (Day 1 to Day 28). You will take valproic acid every day while on study without interruption.

The dose of azacitidine that you receive will depend on when you enroll in this study. You will be part of a study group "cohort" (6 patients will be enrolled in each cohort). All members of a cohort receive the same dose of azacitidine when they begin receiving the study drug. Each new cohort will receive a higher dose than the cohort before. The dose of azacitidine that you receive may be adjusted depending on how well you tolerate it. The starting dose of valproic acid is fixed for all the patients, but this dose may be adjusted by your physician based on the results of your blood work.

You will have a physical exam and blood tests (about 1 tablespoon each) every two weeks of the first two study drug cycles. For further cycles, you will have a physical exam and blood test only once a month. Your disease will be measured by CT scan or MRI after every 2 treatment cycles.

You may continue to receive the study drug on this study until your disease gets worse or intolerable side effects occur. After your participation in this study is over, you will receive follow-up care, as is standard of care for your disease.

This is an investigational study. The FDA has approved azacitidine for a blood disease known as myelodysplastic syndrome. Its use in this study is experimental. The valproic acid is a drug approved by the FDA for treatment of seizure, bipolar disorders, and migraine headaches. Up to 68 patients will take part in the study. All will be enrolled at M. D. Anderson.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Cancers
Intervention  ICMJE
  • Drug: Azacitidine
    Starting Dose 20 mg/m^2 administered subcutaneously (under the skin), daily, for ten days (Days 1 -10) of every 4 Week Cycle.
    Other Names:
    • 5-Azacitidine
    • 5-aza
    • Vidaza
    • 5-AZC
    • AZA-CR
    • Ladakamycin
    • NSC-102816
  • Drug: Valproic Acid
    Starting Dose 10 mg/Kg once daily by mouth, every day of 4 Week Cycle.
    Other Name: Depakene
Study Arms  ICMJE Experimental: Azacitidine + Valproic Acid
  • Drug: Azacitidine
  • Drug: Valproic Acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 26, 2009)
Original Estimated Enrollment  ICMJE
 (submitted: July 3, 2007)
Actual Study Completion Date  ICMJE October 2009
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with pathologically confirmed malignancy that is metastatic or unresectable and refractory to standard therapy or for whom there is no standard therapy that induces complete remission (CR) of at least 10% or an increased survival of at least 3 months.
  2. There is no maximum allowable number of prior chemotherapy regimens, provided all other eligibility criteria are met.
  3. No chemotherapy, radiotherapy, investigational agents or surgery within four weeks.
  4. ECOG performance status 2 or less.
  5. Normal organ and marrow function - ANC > 1500/microL - Platelets > 100,000/microL - Total bilirubin < 2.0 mg/dL - Creatinine < 2.0 mg/dL
  6. The effect of azacytidine on the development of human fetus is unknown. Because of the chemotherapy agents are known to be teratogenic, women and men of childbearing potential must agree to use adequate contraception prior to study entry and for the duration of the study.
  7. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  1. Uncontrolled concurrent illness such as neutropenic fever,shock, symptomatic congestive heart failure (NYHA class III or IV).
  2. Hypersensitivity to divalproex sodium, valproic acid, or valproate sodium
  3. Known or suspected hypersensitivity to azacitidine or mannitol.
  4. Nursing and pregnant women.
  5. Patients with urea cycle disorders (UCD): - History of unexplained coma, encephalopathy, or mental retardation - Encephalopathy associated with a protein load - Pregnancy-related or postpartum encephalopathy - History of elevated plasma ammonia or glutamine - Those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance. - Those with a family history of UCD or unexplained infant deaths (particularly males).
  6. Patients with a known ornithine transcarbamylase disorder, history of unexplained coma or a family history of ornithine transcarbamylase disorder are excluded from this study.
  7. Patients younger than 2-year old since valproic acid safety is not proven in this age group.
  8. Leukemias and MDS are excluded
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00496444
Other Study ID Numbers  ICMJE 2004-0735
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party M.D. Anderson Cancer Center
Study Sponsor  ICMJE M.D. Anderson Cancer Center
Collaborators  ICMJE Celgene Corporation
Investigators  ICMJE
Principal Investigator: Razelle Kurzrock, MD M.D. Anderson Cancer Center
PRS Account M.D. Anderson Cancer Center
Verification Date July 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP