Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders

PRIMARY OBJECTIVES:

- To describe the toxicities of R115777 (tipifarnib) in adult patients with
myeloproliferative disorders.

- To assess hematologic responses, including changes in white blood cell count and
erythroid responses.

SECONDARY OBJECTIVES:

- To assess bone marrow cytogenetic responses to R115777.

- To analyze for the presence of neuroblastoma (N)/Kirsten rat sarcoma viral oncogene
homolog (K-Ras) mutations in patient bone marrow samples.

- To analyze the effect of R115777 on Ras /DnaJ (Hsp40) homolog, subfamily A, member
1(HDJ-2) farnesylation in patient bone marrow/peripheral blood mononuclear cells.

- To analyze the effect of R115777 on mitogen-activated protein (MAP) kinase activation in
patient bone marrow mononuclear cells.

- To perform colony forming unit granulocyte-macrophage (CFU-GM) cytotoxicity assays using
patients' hematopoietic cells with R115777.

OUTLINE:

Patients receive tipifarnib orally (PO) twice daily (BID) on days 1-21. Treatment repeats
every 28 days for up to 4 courses in the absence of disease progression or unacceptable
toxicity. Patients achieving a good hematologic response may continue treatment at the
discretion of the treating physician.

INCLUSION CRITERIA:

- Patients with a diagnosis (> 3 months prior to enrollment) of:

- Chronic myeloid leukemia (CML) (Philadelphia chromosome positive or polymerase
chain reaction [PCR] positive for breakpoint cluster region [BCR]-Abelson murine
leukemia viral oncogene homolog 1 [ABL]) in chronic phase with:

- Persistent or progressive disease on maximum tolerated interferon therapy,
or STI571 (if eligible and able to receive this drug), as evidenced by
increasing white blood cell (WBC) count, peripheral blood myeloid immaturity
and/or progressive anemia, and/or persistence or relapse of abnormal
cytogenetic and/or molecular findings

- Interferon or STI571 intolerant

- CML (Philadelphia chromosome positive or PCR positive for BCR-ABL) in accelerated
phase (< 20% blasts in the peripheral blood and bone marrow) with persistent or
progressive disease on STI571 (if eligible and able to receive this drug)

- CML patients are eligible if they have not received interferon or STI571 because
they are allergic to these drugs or refuse their use

- Chronic myelomonocytic leukemia (CMML)

- Proliferative-type (WBC > 12,000/mL)

- Less than 5% blasts in the peripheral blood and < 20% blasts in the bone marrow

- Undifferentiated myeloproliferative disorder (UMPD)

- Atypical (i.e. Philadelphia chromosome-negative) CML

- Four weeks must have elapsed since the use of any previous pharmacotherapy including
interferon, hematopoietic growth factors, and cytotoxic chemotherapy (6 weeks for
prior mitomycin or nitrosoureas); hydroxyurea may be used to manage elevated cell
counts in patients up to the time they begin investigational therapy

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0, 1, or 2

- Patients are capable of swallowing capsules

- Total bilirubin is > 1.5 X the upper limit of normal (ULN) where the analysis is
performed; for example, for Stanford University Hospital, the ULN for total bilirubin
is 1.3

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) are > 2 X the ULN; for
example, for Stanford University Hospital, the ULN for ALT is 35, and the ULN for AST
is 41

- Serum creatinine of < 2.0

- Life expectancy > 4 months

- Written inform consent must be obtained

EXCLUSION CRITERIA:

- Blast crisis phase of CML and atypical CML/ undifferentiated myeloproliferative
disorders

- Patients with > 20% blasts in the peripheral blood or bone marrow are excluded

- Prior allogeneic bone marrow transplantation

- Patients with severe disease other than CML, CMML, or UMPD which is expected to
prevent compliance with the protocol

- Patients with septicemia or other severe infections

- Pregnant or breast-feeding females

- Women of reproductive age should use contraception while on study

- Patients may not receive androgens during the study

- Requirement for ongoing therapy with corticosteroids (> 10 mg/d prednisone or
equivalent steroid dosage) other than as pre-medication for transfusions

- Patients with iron deficiency; if a marrow aspirate is not available, transferrin
saturation must be > 20% and serum ferritin > 50 ng/mL; this exclusion criterion will
be removed if the iron deficiency state is corrected before enrollment

- Patients with other contributing causes of anemia such as autoimmune or hereditary
hemolytic disorders, gastrointestinal (GI) blood loss, B12 or folate deficiency, or
hypothyroidism; patients who require platelet transfusions, or have
thrombocytopenia-related bleeding

- Inability to return for follow-up visits/studies to assess toxicity and response to
therapy