Study of Lonafarnib and Gleevec in Chronic Myelogenous Leukemia

Existing pre-clinical and clinical data suggest that SCH66336, a farnesyl transferase
inhibitor,exhibits significant activity against CML cells, and in fact may have synergistic
activity in combination with imatinib mesylate. Thus, the objectives to the study are (1) to
determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of lonafarnib
(SCH66336), a farnesyl transferase inhibitor, in combination with imatinib mesylate (Gleevec)
in patients with chronic phase, accelerated phase, and blast crisis CML; (2) to assess the
pharmacokinetics of the combination of lonafarnib and Gleevec in these patients; and (3) to
assess in a preliminary way the biologic activity of the combination of lonafarnib and
Gleevec in these patients.

1. Patients with Philadelphia chromosome (ph) positive CML in any of the following
categories:

1. Chronic phase patients must have failed therapy with Gleevec. Failure will be
defined as: (i) Patients who have not achieved or have lost their hematologic
response at 3 months from the start of therapy with Gleevec, or (ii) Patients who
have not achieved or have lost their cytogenetic response after 6 months of
therapy with Gleevec, or (iii) Patients who have not achieved or have lost their
major cytogenetic response after 12 months of therapy with Gleevec.

2. Patients in accelerated phase, defined as the presence of any of the following
features: (i) blasts in peripheral blood (PB) or bone marrow (BM) >/= 15% (but <
30%), (ii) blasts + promyelocytes in PB or BM >/= 30%, (iii) basophils in PB or
BM >/= 20%, (iv) platelets < 100 x 10e9/L unrelated to therapy, (v) clonal
evolution.

3. Patients in blast phase, defined by the presence of >/= 30% blasts in peripheral
blood and/or bone marrow, or the presence of extramedullary disease.

2) Patients in accelerated or blastic phase are eligible whether they have
received and/or failed Gleevec or not.

3) Age >/= 16 years.

4) Patients must sign an informed consent indicating that they are aware of the
investigational nature of this study in keeping eith the policies of the
hospital. The only acceptable consent form is attached at the end of the
protocol.

5) Performance status
6) Patients must have adequate hepatic functions (bilirubin renal functions (creatinine
7) Exclusion criteria:

1. Patients with QTc > 500 msec.

2. Patients with severe heart disease (cardiac class III and IV) will be excluded.