Tipifarnib in Treating Older Patients With Acute Myeloid Leukemia

PRIMARY OBJECTIVES:

I. To determine the complete remission (CR) rate in acute myeloid leukemia (AML) patients
prospectively selected for tipifarnib (ZARNESTRA) treatment on the basis of a 2-gene
signature (RASGRP1:APTX ratio) in bone marrow aspirates.

SECONDARY OBJECTIVES:

I. To determine the median overall and 1-year survival of patients treated with this regimen
II. To determine the median relapse-free survival of patients treated with this regimen.

III. To determine the safety of this regimen in these patients IV. To determine the
immunophenotypic expression of RASGRP1 on baseline bone marrow blasts and assess correlation
with PCR-based detection.

OUTLINE: This is a multicenter study.

Patients receive tipifarnib orally twice daily on days 1-21. Treatment repeats every 28 days
for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Bone marrow aspirate and/or biopsy are collected at baseline and on day 28 of course 1 and 2
for RasGRP1 protein expression analysis by qRT-PCR.

After completion of study therapy, patients are followed up every 30 days.

Inclusion Criteria:

- Previously untreated acute myeloid leukemia (AML) (de novo or secondary)

- No diagnosis of acute promyelocytic leukemia (APL)

- Deemed unsuitable for or refuses standard induction chemotherapy

- RASGRP1:APTX ratio >= 5, through bone marrow screening

- No patients with known leukemic involvement of the central nervous system

- ECOG performance status =< 2

- No WBC >= 30,000/uL (hydroxyurea permitted up to 24 hours prior to initiation of
therapy)

- Serum creatinine less than 1.5 times the upper limit of the normal range (ULN)
(National Cancer Institute [NCI] Common Toxicity Criteria [CTC] Grade 1)

- Total bilirubin less than 1.5 times ULN (unless the increase is unequivocally due to
hemolysis or Gilbert syndrome)

- ALT and AST less than 2.5 times ULN (NCI CTC Grade 1)

- Men must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry and for the duration of study participation

- No symptomatic neuropathy of grade 2 or worse

- No uncompensated disseminated intravascular coagulation (DIC) or uncontrolled
bleeding

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to tipifarnib (R115777), such as the imidazole drugs, including
clotrimazole, ketoconazole, miconazole, econazole, fenticonazole, isoconazole,
sulconazole, ticonazole, or terconazole

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Known HIV-positive patients NOT on antiretroviral therapy AND with a CD4 cell count <
400/mm³ are eligible

- No other concurrent cytotoxic or biologic antileukemic therapy

- No patients who are receiving any other investigational agents

- Use of enzyme-inducing anticonvulsants (e.g., phenytoin, fosphenytoin, phenobarbital,
primidone, carbamazepine, oxcarbazepine) while taking tipifarnib (R115777) is
contraindicated

- If clinically indicated, subjects may use non-enzyme-inducing anticonvulsants
during treatment with R115777