Clofarabine, Idarubicin, and Cytarabine (CIA) Versus Fludarabine, Idarubicin, and Cytarabine (FLAI) in Acute Myelogenous Leukemia (AML) and High-Risk Myelodysplastic Syndrome

The Study Drugs:

Clofarabine is designed to interfere with the growth and development of cancer cells.

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

Cytarabine and Fludarabine are designed to insert themselves into the DNA of cancer cells
and stop the DNA from repairing itself.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on when you join this study. Up to 4 groups of 6 participants will be enrolled
in the Phase I portion of the study. Up to 280 participants will be enrolled in Phase II.

Phase I:

If you are enrolled in the Phase I portion, the dose of clofarabine you receive will depend
on when you joined this study. The first group of participants will receive the lowest dose
level of clofarabine. Each new group will receive a higher dose of clofarabine than the
group before it, if no intolerable side effects were seen. This will continue until the
highest tolerable dose of clofarabine is found.

All participants will receive the same dose level of idarubicin and cytarabine.

Phase II:

If you are enrolled in the Phase II portion, you will be randomly assigned (as in the flip
of a coin) to 1 of 2 groups:

- If you are in Group 1, you will receive clofarabine, idarubicin, and cytarabine. You
will receive clofarabine at the highest dose that was tolerated in the Phase I portion.

- If you are in Group 2, you will receive fludarabine, idarubicin, and cytarabine.

Study Drug Administration:

Study drug(s) will be given in what are called "cycles." Each cycle is 28 days.

Phase I:

On Days 1-5:

- You will receive clofarabine by vein over about 1 hour.

- You will receive cytarabine by vein over about 2 hours.

- On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

Phase II (Induction):

The first cycle of study drugs is called Induction. If the doctor thinks it is needed, you
will have up to 2 Induction cycles.

If you are in Group 1:

On Days 1-5 of each cycle:

- You will receive clofarabine by vein over about 1 hour.

- You will receive cytarabine by vein over about 2 hours.

- On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

If you are in Group 2:

On Days 1-5 of each cycle:

- You will receive fludarabine by vein over about 30 minutes.

- You will receive cytarabine by vein over about 2 hours.

- On Days 1-3 only, you will receive idarubicin by vein over about 30 minutes.

If the doctor thinks it is needed, you may receive less than 5 days of treatment in the
induction cycle.

If the doctor thinks it is needed, your dose level will be reduced after Induction.

Phase II (Consolidation):

If the disease responds to the study drugs, you may receive up to 6 more cycles of study
drugs. This is called Consolidation.

If you are in Group 1:

On Days 1-3 of each cycle :

- You will receive clofarabine by vein over about 1 hour.

- You will receive cytarabine by vein over about 2 hours.

- After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive
idarubicin by vein over about 30 minutes.

If you are in Group 2:

On Days 1-3 of each cycle:

- You will receive fludarabine by vein over about 30 minutes

- You will receive cytarabine by vein over about 2 hours.

- After 1 to 2 hours of receiving cytarabine on Days 1-2 only, you will receive
idarubicin by vein over about 30 minutes

If the cancer does not completely respond after Cycle 1, you may repeat induction (Cycle 1).
If the cancer completely responds, you will begin the consolidation cycles.

If the doctor thinks it is needed, you may receive less than 3 days of treatment in the
consolidation cycles.

Study Visits:

You will have a physical exam, including measurement of your vital signs before the start of
each cycle. Blood (about 2 teaspoons) will be drawn for routine tests every 3-7 days.

On Day 28 of every 2-3 cycles (+/- 7 days), if the doctor thinks it is needed, you will have
a bone marrow aspirate to check the status of the disease. To collect a bone marrow
aspirate, an area of the hip is numbed with anesthetic, and a small amount of bone marrow is
withdrawn through a large needle.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest or up to 8 total cycles. You will no longer be able to take the study drugs if the
disease gets worse or intolerable side effects occur.

Your participation on the study will be over once you have completed the long-term
follow-up.

Long-Term Follow-up:

Every 3 months for 1 year after you are off study, you will be called and asked how you are
feeling, about any side effects you may be having, and about any other drugs you may be
taking. These calls should last about 5 minutes each.

This is an investigational study. Cytarabine and Idarubicin are FDA approved and
commercially available for the treatment of AML. Fludarabine is FDA approved and
commercially available for the treatment of chronic lymphocytic leukemia (CLL). Clofarabine
is FDA approved and commercially available for the treatment of acute lymphoblastic leukemia
(ALL). The combination of these study drugs is investigational.

Up to 292 patients will take part in Phase I and Phase II of this study. All will be
enrolled at MD Anderson.

Inclusion Criteria:

1. Sign an IRB-approved informed consent document.

2. Age 18 to 60. Patients above the age of 60 only with principal investigator (PI)
approval

3. Diagnosis of newly diagnosed AML [other than acute promyelocytic leukemia (APL)] or
high-risk (intermediate-2 or high by IPSS or > 10% blasts, including CMML) MDS. Prior
therapy with hydrea and the use of a single or a two day dose of cytarabine (up to 3
g/m2) for emergency use up to 24 hours prior to start of study therapy is allowed.
Prior therapy for MDS or other AHD is not allowed.

4. ECOG performance status of
5. Organ function as defined below (unless due to leukemia): Serum creatinine mg/dL Total bilirubin related to disease.

6. Women of childbearing potential must have a negative serum or urine pregnancy test
within 7 days and must agree to practice acceptable contraceptive methods. Men must
agree not to father a child and agree to use a condom if his partner is of child
bearing potential.

7. Cardiac ejection fraction >/= 40% (by either cardiac echo or MUGA scan).
Documentation of recent (
Exclusion Criteria:

1. Breast feeding females

2. Patients with uncontrolled active infections (viral, bacterial, and fungal are not
eligible).

3. Patients with active secondary malignancy will not be eligible.