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Phase I Study of Low-Dose Hypomethylating Agent Azacitidine Combined With the Histone Deacetylase Inhibitor Valproic Acid in Patients With Advanced Cancers

Phase 1
2 Years
Not Enrolling
Advanced Cancers

Thank you

Trial Information

Phase I Study of Low-Dose Hypomethylating Agent Azacitidine Combined With the Histone Deacetylase Inhibitor Valproic Acid in Patients With Advanced Cancers

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

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.

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

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

8. Leukemias and MDS are excluded

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

4 Years

Safety Issue:


Principal Investigator

Razelle Kurzrock, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Institutional Review Board

Study ID:




Start Date:

May 2005

Completion Date:

October 2009

Related Keywords:

  • Advanced Cancers
  • Advanced Cancers
  • Azacytidine
  • 5-Azacitidine
  • 5-aza
  • Vidaza
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • NSC-102816
  • Valproic Acid
  • Depakene
  • Neoplasms



U.T.M.D. Anderson Cancer Center Houston, Texas  77030