Azacitidine (AZA) in Minimal Residual Disease (MRD) Chronic Myeloid Leukemia (CML)

Phase I-II Study of Low-Dose Azacitidine (Vidaza) in Patients With Chronic Myeloid Leukemia Who Have Minimal Residual Disease While Receiving Therapy With Tyrosine Kinase Inhibitors (VZ-CML-PI-0236)

This is a 2 part study. The goal of the first part of this clinical research study is to find the highest tolerable dose of azacitidine that can be given with a TKI that you are already taking (such as Gleevec, Sprycel, or Tasigna). The safety of this drug will also be studied. The goal of the second part is to see if this combination may improve your response to the TKI you are already taking.

Azacitidine is designed to change genes that are thought to cause leukemia. By changing these genes, the drug may help to stop them from causing the disease to grow.

Study Drug Administration:

If you are found to be eligible to take part in this study, you will continue receiving the same TKI at the dose you had been receiving for the last 6 months.

You will receive azacitidine either as an injection under your skin or through a vein every day for 3 to 7 days of each 28-day cycle. The dose and how often you take the drug will depend on when you enter the study. The study staff will tell you how often you will receive the drug.

In the first part of the study, you will be assigned to a dose level of azacitidine based on when you join this study. Up to 2 dose levels of azacitidine will be tested. At least 3 participants will be enrolled at each dose level. The first group of participants will receive the lowest dose level. The next group will receive a higher dose than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of azacitidine is found. This is called the Dose Escalation Group.

Once the highest tolerated dose has been found, an extra 36 participants will receive azacitidine at this dose level. This is called the Expansion Group.

If you have severe side effects from the study drug, the study doctor may decide to reduce and/or stop drug dosing until your side effects improve. If the doctor thinks it is in you best interest, your dose may be increased.

Study Visits:

At every visit, you will be asked about any side effects you have had and to list any drugs you may be taking.

• Every 1-2 weeks for 8 weeks, then at the start of every cycle, blood (about 1 teaspoon) will be drawn for routine tests.
• Every 2-4 weeks for 8 weeks, then before each cycle, blood (about 1 teaspoon) will also be drawn to test your kidney and liver function.
• Before each cycle for 3 cycles, then every 3-6 cycles until 1 year, then every 6-12 cycles, blood (about 1 tablespoon) drawn for molecular testing.
• Every 3-6 months in Year 1, then as often the doctor thinks it is needed, you will have a bone marrow aspirate to check the status of the disease.
• If you are in the Expansion Group, every 3 months (+/- 1 month) for the first 6 months, then every 6-12 months, you will have a complete physical exam.
• If you are in the Dose Escalation Group, every 2 weeks for the first month, Months 1, 2, 3, and 6 (+/- 1 month), and then every 6-12 months, you will have a complete physical exam.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-treatment and follow-up visits.

This is an investigational study. TKIs are approved for the treatment of CML. Azacitidine is FDA approved and commercially available for the treatment of patients with MDS. The combination of these drugs to treat CML is investigational.

Up to 48 patients will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Patients 16 years or older with Philadelphia chromosome (Ph)- or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR).
2. Patients must have received FDA-approved TKI therapy for at least 18 months and not have increased their dose of FDA-approved TKI in the last 6 months. Patients participating on frontline protocols 2005-0048 (nilotinib) and 2005-0422 (dasatinib) are eligible for enrollment on this study.
3. Phase II patients must be in complete cytogenetic remission. For the phase I portion of the study, patients may be included without a complete cytogenetic remission provided they are in chronic phase.
4. Phase II patients must have detectable BCR-ABL transcript levels meeting at least one of the following criteria: Patient has never achieved a major molecular response, and transcript levels have shown in at least two consecutive measures separated by at least 1 month to have increased by any value, or Achieved a major molecular response that has been lost with an increase in transcript levels by at least 1-log, confirmed in two consecutive analyses separated by at least 1 month, or The patient has received therapy for at least 2 years and does not have a sustained major molecular response, or The patient has received therapy for at least 5 years and does not have a sustained complete molecular response. Patients included in the phase I portion of the study are eligible regardless of their level of BCR-ABL transcripts.
5. Patients must not have had a known continuous interruption of imatinib therapy of greater than 14 days or for a total of 6 weeks in the 6 months prior to enrollment.
6. Patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of the hospital.
7. ECOG performance status </= 2.
8. Adequate organ function defined as: bilirubin < 2x upper limit of normal (ULN) (unless associated with Gilbert's syndrome), and ALT or AST </= 2.5x ULN.
9. ANC >/=1 x10(9)/L and platelets >/= 50 x10(9)/L.
10. Serum creatinine < 1.8 mg/dL or creatinine clearance greater or equal than 40 cc/min as defined by the Cockcroft-Gault Equation*. Males(mL/min):(140-age)* ABW(kg) / 72* (serum creatinine(mg/dl)); Females (mL/min):0.85*(140-age)* ABW(kg) / 72*(serum creatinine (mg/dl))
11. Women of childbearing potential should be advised to avoid becoming pregnant and practice effective methods of contraception. Men should be advised not to father a child while receiving treatment with azacitidine. Azacitidine is classified as Pregnancy Category D. Females of childbearing potential: Recommendation is for 2 effective contraceptive methods during the study. Adequate forms of contraception are double-barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, and tubal ligation. Male patients with female partners who are of childbearing potential: Recommendation is for male and partner to use at least 2 effective contraceptive methods, as described above, during the study.
12. Women of childbearing potential should have a pregnancy test within 7 days before initiation of study drug.

Exclusion Criteria:

1. Patients receiving any other investigational agents.
2. Patients who are pregnant or breast-feeding.
3. Patients with clinically significant heart disease (NYHA Class III or IV).
4. Known or suspected hypersensitivity to azacitidine or mannitol.
5. Patients with advanced malignant hepatic tumors.