Phase II Study of Idarubicin, Cytarabine, and Vorinostat With High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) - Full Text View

Sponsor:	M.D. Anderson Cancer Center
Collaborator:	Merck
Information provided by:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT00656617

Purpose

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.

Condition	Intervention	Phase
Acute Myeloid Leukemia (AML) Myelodysplastic Syndrome (MDS)	Drug: Idarubicin Drug: Cytarabine Drug: Vorinostat	Phase II

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title:	Phase II Study of Idarubicin, Cytarabine, and Vorinostat in Patients With High-Risk MDS and AML

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic Leukemia, Childhood

Drug Information available for: Cytarabine hydrochloride Idarubicin hydrochloride Idarubicin Suberoylanilide hydroxamic acid Cytarabine

U.S. FDA Resources

Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:

Progression free survival [ Time Frame: 7 Months ] [ Designated as safety issue: No ]

Estimated Enrollment:	105
Study Start Date:	April 2008
Estimated Study Completion Date:	April 2010
Estimated Primary Completion Date:	April 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Idarubicin + Ara-C + Vorinostat: Experimental	Drug: Idarubicin 12 mg/m^2 IV over 1 hour daily x 3 (days 4 to 6) Drug: Cytarabine 1.5 g/m^2 IV as a continuous infusion over 24 hours daily (days 4 to 7) Drug: Vorinostat Initial dose level 500 mg orally three times a day for 3 days (days 1 to 3).

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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 routine bone marrow aspirates and biopsies before initiating treatment and approximately on Day 21 and Day 28 after initiating therapy.

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.

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

Eligibility

Ages Eligible for Study:	15 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Diagnosis of 1) AML (WHO classification definition of >/= 20% blasts), or 2) 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 chemonaïve, 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 </= 2
Serum biochemical values with the following limits unless considered due to leukemia: creatinine </=2 mg/dl; total bilirubin </=2 mg/dL, unless increase is due to hemolysis or congenital disorder; transaminases (SG PT or SGOT) </=2.5x ULN;
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 B or C infection. Active disease is defined as elevated liver enzymes and/or clinical symptoms of hepatitis in addition to positive blood test for hepatitis surface antigen. In the absence of elevated liver enzymes and/or clinical symptoms, the blood test for hepatitis core antigens is not required.
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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00656617

Contacts

Contact: Guillermo Garcia-Manero, M.D.

713/745-3428

ggarciam@mdanderson.org

Locations

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

Sponsors and Collaborators

M.D. Anderson Cancer Center

Merck

Investigators

Study Chair:

Guillermo Garcia-Manero, M.D.

M.D. Anderson Cancer Center

More Information

Additional Information:

M.D. Anderson's Website This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	U.T.M.D. Anderson Cancer Center ( Guillermo Garcia-Manero, M.D./Associate Professor )
Study ID Numbers:	2007-0835
Study First Received:	April 7, 2008
Last Updated:	August 6, 2009
ClinicalTrials.gov Identifier:	NCT00656617 History of Changes
Health Authority:	United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:

Acute Myeloid Leukemia
(AML)
Myelodysplastic syndrome
(MDS)
Leukemia

Idarubicin
Cytarabine
Vorinostat
Ara-C

Additional relevant MeSH terms:

Anticarcinogenic Agents
Anti-Inflammatory Agents
Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Immunologic Factors
Precancerous Conditions
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Leukemia, Myeloid, Acute
Leukemia
Preleukemia
Pathologic Processes

Sensory System Agents
Syndrome
Therapeutic Uses
Anti-Inflammatory Agents, Non-Steroidal
Analgesics
Cytarabine
Disease
Neoplasms by Histologic Type
Hematologic Diseases
Myelodysplastic Syndromes
Vorinostat
Enzyme Inhibitors
Leukemia, Myeloid
Protective Agents
Antiviral Agents

ClinicalTrials.gov processed this record on November 27, 2009