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

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.

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 MD Anderson.

Inclusion Criteria:

1. Diagnosis of 1) AML (WHO classification definition of >/= 20% blasts), or 2)
intermediate-2 or high-risk MDS (defined by the IPSS classification2).

2. Patients aged 15 to 65 years;

3. 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.

4. 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;

5. 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 ;

6. ECOG performance status
7. Serum biochemical values with the following limits unless considered due to leukemia:
creatinine hemolysis or congenital disorder; transaminases (SG PT or SGOT)
8. Ability to swallow oral medication;

9. Ability to understand and provide signed informed consent;

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

11. Diagnosis of 1) AML (WHO classification definition of > 20% blasts), or 2)
intermediate-2 or high-risk MDS (defined by the IPSS classification2 )with Flt-3
mutation. Flt-3 extension phase.

12. Patients aged 15 to 65 years are eligible. Flt-3 extension phase.

13. 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. All patients should be Flt-3 positive. Flt-3 extension
phase.

14. Patients with newly diagnosed Flt3 positive AML are allowed. Flt-3 extension phase.

15. 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. Flt-3
extension phase.

16. ECOG performance status
17. Serum biochemical values with the following limits unless considered due to leukemia.
creatinine hemolysis or congenital disorder - transaminases (SG PT or SGOT) extension phase.

18. Ability to swallow oral medication. Flt-3 extension phase.

19. Ability to understand and provide signed informed consent. Flt-3 extension phase.

20. Cardiac ejection fraction must be >/=50% (by either MUGA scan or echocardiography).
Flt-3 extension phase.

Exclusion Criteria:

1. Diagnosis of acute promyelocytic leukemia;

2. 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;

3. 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);

4. Symptomatic CNS involvement;

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

6. Patient has known human immunodeficiency virus (HIV) infection or known HIV-related
malignancy;

7. 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.

8. Patient is pregnant or breast-feeding;

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

10. Patient has a history of thrombotic disorders;

11. 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.

12. Diagnosis of acute promyelocytic leukemia. Flt-3 extension phase.

13. 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. Flt-3 extension
phase.

14. 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). Flt-3 extension
phase.

15. Symptomatic CNS involvement. Flt-3 extension phase.

16. Patient is unable to take and/or tolerate oral medications on a continuous basis.
Flt-3 extension phase.

17. Patient has known human immunodeficiency virus (HIV) infection or known HIV-related
malignancy. Flt-3 extension phase.

18. 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. Flt-3
extension phase.

19. Patient is pregnant or breast-feeding. Flt-3 extension phase.

20. Patient has a known allergy or hypersensitivity to any component of vorinostat. Flt-3
extension phase.

21. Patient has a history of thrombotic disorders. Flt-3 extension phase.

22. 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. Flt-3 extension phase.