• To determine the maximum tolerated doses (MTD) of ZARNESTRA (R115777), a farnesyl transferase inhibitor (FTI), and Gleevec, when given in combination to patients with chronic phase CML. [ Time Frame: July 2006 ] [ Designated as safety issue: No ]
  

• To assess the toxicity of the ZARNESTRA and Gleevec combination in these patients. [ Time Frame: July 2009 ] [ Designated as safety issue: No ]
  

R115777 is a new drug that blocks the function of an enzyme that is important in making some proteins work. One of the most important targets for this enzyme is a protein that can make cells become cancer. Imatinib mesylate is a drug that blocks the function of the protein that comes from the Philadelphia chromosome. The Philadelphia chromosome is an abnormality in chromosomes 9 and 22 that changes blood cells into leukemia cells.

Before treatment starts, participants will have a physical exam, blood tests (About 3 tubes, 2 teaspoons each), and a bone marrow biopsy. The bone marrow will be removed with a large needle.

Participants in this study will take imatinib mesylate by mouth every day for as long as they stay on study, which means as long as it works. Participants will also take R115777 twice a day for 2 weeks. This will be repeated every 3 weeks. The amount of each of these medications that participants take will depend on when they enter the study. The doses will be slowly increased from participant to participant until the highest dose that does not cause serious side effects is found.

Participants will be asked to visit their doctor for a physical exam and measurement of vital signs. The frequency of doctor visits will vary depending on physical condition. Blood tests (about 2 teaspoons each) will be done every week during the first 3 weeks of treatment. Blood tests will then be done every 8-12 weeks for the length of the study, as needed. The blood samples will be used for routine lab tests. A bone marrow sample will also be taken to check and measure cells related to the disease every 3 months in the first year and then every 6-12 months. Participants can stay on study for as long as the treatment is considered to be beneficial. Participants will be taken off study if their disease gets worse or intolerable side effects occur.

This is an investigational study. The FDA has authorized the use of imatinib mesylate for patients with CML. It is the combination of imatinib mesylate and R115777 that is experimental. R115777 has been authorized for investigational use only. Only R115777 will be provided free of charge. A maximum of 30 patients will take part in this study. All will be enrolled at M. D. Anderson.

Optional Procedures: Participants who agree will have an additional small amount of bone marrow (about 1 teaspoon) every time they have a bone marrow aspiration. This does not require any additional bone marrow aspiration procedures. A small amount of blood (about 1 teaspoon) will also be collected periodically when scheduled blood samples are collected for routine tests.

Participants who agree will also have two bone marrow aspirates (about 1 teaspoon, total) collected at the start of the study and at the end of Cycle 2. The RNA sample that is taken from the aspirates will not be stored. Participants who change their mind after giving bone marrow for this study may ask for the samples to be destroyed.

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

Inclusion:

• Patients 16 years or older with Philadelphia chromosome (Ph)- or BCR/ABL-positive CML (as determined by cytogenetics, FISH, or PCR) are eligible if they are not candidates for known regimens or protocol treatments of higher efficacy or priority. Patients must be in the chronic phase of CML.
• Patients must have failed therapy with imatinib mesylate. Failure will be defined as: 1) patients who have failed to achieve or have lost a complete hematologic remission at 3 months from the start of therapy with imatinib mesylate, or 2) patients who have failed to achieve or have lost at least a minimal cytogenetic response after 6 months of therapy with imatinib mesylate, or 3) patients who have failed to achieve or have lost a major cytogenetic response after 12 months of therapy with imatinib mesylate
• Chronic phase will be defined by the following features: 1) blasts in peripheral blood or bone marrow <10%, 2) basophils in PB or BM <20%, 3) platelets >100 x 10(9)/L, 4) absence of clonal evolution
• Patients must sign an informed consent
• Performance status </= 2 by Zubrod scale
• Patients must have adequate hepatic functions (bilirubin </= 2.0 mg/dl) and renal functions (creatinine </=2 mg/dl)
• WBC </= 30 x 10(9)/L. Patients may receive Hydroxyurea (or other similar agent) to bring the WBC below this level. Hydroxyurea (or its equivalent) must be discontinued 24 hours before the start of therapy.
• Patients of childbearing potential should practice effective methods of contraception.

Exclusion:

• Patients under 16 years of age.
• Pregnant and nursing females will be excluded.