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
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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.
Razelle Kurzrock, MD
M.D. Anderson Cancer Center
United States: Institutional Review Board
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