Phase II Study of Idarubicin, Cytarabine, and Vorinostat in Patients With High-Risk MDS and AML

Condition(s) targeted: Acute Myeloid Leukemia (AML); Myelodysplastic Syndrome (MDS)

Intervention: Idarubicin (Drug); Cytarabine (Drug); Vorinostat (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: M.D. Anderson Cancer Center

Official(s) and/or principal investigator(s):
Guillermo Garcia-Manero, M.D., Study Chair, Affiliation: M.D. Anderson Cancer Center

Overall contact:
Guillermo Garcia-Manero, M.D., Phone: 713/745-3428, Email: ggarciam@mdanderson.org

The goal of this clinical research study is to find the highest safe dose of vorinostat that can be given in combination with idarubicin and ara-C for the treatment of AML and high-risk MDS.

Once the highest safe dose is found, researchers will then try to learn if this combination treatment can help to control AML and high-risk MDS in newly diagnosed patients. The safety of this treatment combination will also be studied.

Official title: Phase II Study of Idarubicin, Cytarabine, and Vorinostat in Patients With High-Risk MDS and AML

Study design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study

Primary outcome: To determine the efficacy (rate of progression free survival at 7 months) of vorinostat in combination with idarubicin and ara-C induction chemotherapy in patients with high-risk MDS and AML.

Secondary outcome:

To determine the safety of the combination as well as to characterized it toxicity.

To determine in vivo the molecular effects of these therapy in patients with leukemia.

Detailed description: The Study Drugs Vorinostat is designed to change the gene expression profile of leukemia cells, which may cause the cells to die.

Idarubicin is designed to cause breaks in DNA (the genetic material of cells). This may cause cancer cells to die.

Ara-C is designed to insert itself into DNA of cancer cells and stop the DNA from repairing itself.

This dose combination has not been tested in humans before, at this dose level and schedule.

Screening Tests Before you can start treatment on this study, 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 physical exam, including measurement of your vital signs (blood pressure, heart rate, breathing rate, and temperature), height, and weight.

Your complete medical history will be recorded. You will be asked how well you are able to perform the normal activities of daily living (a performance status evaluation).

Blood (about 1 tablespoon) will be drawn for routine tests. You will have a bone marrow aspiration and/or biopsy performed. To perform a bone marrow aspiration and bone marrow biopsy, an area of the hip bone is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle.

You will have a test of your heart function, either an echocardiogram or a multigated acquisition (MUGA) scan.

Women who are able to have children must have a negative blood (about 1 teaspoon) or urine pregnancy test.

Study Drug Administration Induction Therapy If you are found to be eligible to take part in this study, you will begin induction therapy. During induction therapy, the dose level of vorinostat may vary based on when you join the study and on the side effects seen in other participants. The first group of 3 participants will receive the highest dose level of vorinostat. If intolerable side effects are experienced, the next group of 3 participants will receive a lower dose of vorinostat. This will continue until the highest dose of vorinostat with no intolerable side effects is found. The dose levels of the other drugs will not change.

In the Induction phase, you will receive 1 or 2 induction cycles of therapy on the following schedule:

On Days 1-3, you will take vorinostat by mouth 3 times a day. On Days 4-6, you will receive idarubicin through a needle in your vein over 1 hour.

On Days 4-7, you will receive ara-C by vein as a non-stop infusion. On Days 4-7, you will receive solumedrol or dexamethasone to help reduce the risk of side effects associated with ara-C. The drug will be given by vein over a few seconds.

Consolidation Therapy

If the disease responds during Induction, you may be able to receive up to 5 additional 4-6 week study cycles. During these Consolidation Cycles, you will take the study drugs on the following cycle:

On Days 1-3, you will take vorinostat by mouth 3 times a day. On Days 4 and 5, you will receive idarubicin through a needle in your vein over 5 minutes.

On Days 4-6, you will receive ara-C by vein as a non-stop infusion. On Days 4 and 5, you will also receive either solumedrol or dexamethasone by vein over a few seconds.

Maintenance Therapy If you go into remission, you will begin maintenance therapy. While on maintenance therapy, you will take vorinostat by mouth 3 times a day on Days 1-14 of each 28-day study cycle. You may have up to 12 Maintenance Cycles.

Study Visits At least every week during Cycle 1, and then at least once a month during each additional cycle, blood (about 1-2 teaspoons) will be drawn for routine tests. You will also have a bone marrow aspirate and biopsy.

Length of Study You may continue to receive the study drugs for up to 18 cycles. You will be taken off study early if the disease gets worse or intolerable side effects occur.

This is an investigational study. Idarubicin is FDA approved for use in combination with other approved drugs for the treatment of AML. Vorinostat is FDA approved and commercially available for the treatment of some forms of cutaneous lymphoma. Ara-C is FDA approved for use in the treatment of leukemia. The use of these drugs together is investigational.

Vorinostat will be provided at no cost to you while you are on study.

Up to 105 patients will take part in this study. All will be enrolled at M. D. Anderson.

Optional Procedures: If you agree, leftover blood from the routine tests will be collected for tests to learn how well the study combination blocks proteins on leukemia cells.

If you agree, leftover bone marrow samples collected during the routine tests will be tested to learn how well the study combination blocks proteins on leukemia cells.

Most of the samples for this testing will be stored in a laboratory at M. D. Anderson, but some samples could be sent to researchers at the University of Maryland or at Merck Co., Inc. for this testing.

Before your blood and bone marrow tissue can be used for research, the people doing the research must get specific approval from the Institutional Review Board (IRB) of M. D. Anderson. The IRB is a committee made up of doctors, researchers, and members of the community. The IRB is responsible for protecting the participants involved in research studies and making sure all research is done in a safe and ethical manner. All research done at M. D. Anderson, including research involving your blood and bone marrow tissue from this bank, must first be approved by the IRB.

Your samples will be given a code number. No identifying information will be directly linked to your samples. Only the researcher in charge will have access to the code numbers and be able to link the samples to you. This is to allow medical data related to the samples to be updated as needed. Other researchers using your samples will not be able to link this data to you.

There are no additional costs to you for taking part in the optional procedures.

You do not have to agree to take part in the optional procedures in order to receive treatment on this study.

Minimum age: 15 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Diagnosis of 1) AML (WHO classification definition of >/= 20% blasts), or

intermediate-2 or high-risk MDS (defined by the IPSS classification2).

- Patients aged 15 to 65 years;

- For the initial run-in phase of the study, patients with relapsed or refractory

disease or patients with secondary untreated disease are eligible, however, these patients must not have had prior exposure to a histone deacetylase inhibitor, prior antecedent hematological disorder or secondary disease with complex cytogenetics.

- For the actual phase II portion of the study: patients must be chemo-naïve, i. e., not

have received any chemotherapy (except hydrea) for AML or MDS. They may have received hypomethylating agents for prior MDS and transfusions, hematopoietic growth factors or vitamins. Temporary prior measures such as apheresis or hydrea are allowed;

- In those patients that have received prior therapy, at least 2 weeks need to have

elapsed before participating in this study. Treatment may start earlier if deemed in the best interest of the patient after discussion with the PI of the study ;

- ECOG performance status

- Serum biochemical values with the following limits unless considered due to leukemia:

creatinine - Ability to swallow oral medication;

- Ability to understand and provide signed informed consent;

- Cardiac ejection fraction must be >/=50% (by either MUGA scan or echocardiography).

Exclusion Criteria:

- Diagnosis of acute promyelocytic leukemia;

- Active, uncontrolled, systemic infection considered opportunistic, life threatening or

clinical significant at the time of treatment, or any severe concurrent disease, which in the opinion of the investigator and after discussion with the principal investigator, would make the patient inappropriate for study entry;

- Male and female patients who are fertile agree to use an effective barrier method of

birth control (i. e., latex condom, diaphragm, cervical cap, etc.) to avoid pregnancy. Female patients need a negative serum or urine pregnancy test within 7 days of study enrollment (applies only if patient of childbearing potential. Non childbearing is defined as 1 year or more postmenopausal or surgically sterilized);

- Symptomatic CNS involvement;

- Patient is unable to take and/or tolerate oral medications on a continuous basis;

- Patient has known human immunodeficiency virus (HIV) infection or known HIV-related

malignancy;

- Patient has active hepatitis A, B or C infection;

- Patient is pregnant or breast-feeding;

- Patient has a known allergy or hypersensitivity to any component of vorinostat;

- Patient has a history of thrombotic disorders;

- History of any psychiatric condition that might impair the patient's ability to

understand or to comply with the requirements of the study or to provide informed consent.

Guillermo Garcia-Manero, M.D., Phone: 713/745-3428, Email: ggarciam@mdanderson.org

The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, United States; Recruiting
Guillermo Garcia-Manero, M.D., Phone: 713-745-3428, Email: ggarciam@mdanderson.org

M.D. Anderson's Website

Starting date: April 2008
Ending date: April 2010
Last updated: April 15, 2008