This phase I/II trial is studying the side effects and best dose of tipifarnib when given
with idarubicin and cytarabine and to see how well it works in treating patients with newly
diagnosed myelodysplastic syndromes or acute myeloid leukemia. Drugs used in chemotherapy,
such as idarubicin and cytarabine, work in different ways to stop cancer cells from dividing
so they stop growing or die. Tipifarnib (Zarnestra) may stop the growth of cancer cells by
blocking the enzymes necessary for their growth. Giving idarubicin and cytarabine with
tipifarnib may kill more cancer cells
I. To determine the tolerability of the combination of R115777 (Zarnestra™) and Idarubicin
plus cytarabine by defining the DLT and MTD. (Phase I) II. To determine the efficacy of the
combination of Idarubicin, cytarabine and ZARNESTRA in patients with high-risk MDS and AML.
OUTLINE: This is a dose-escalation study of tipifarnib. Patients are stratified according to
age (< 50 versus ≥ 50) and, in patients ≥ 50 years of age, cytogenetics (diploid versus
PHASE I: Patients receive cytarabine IV continuously on days 1-3 (or 1-4), idarubicin
intravenous (IV) over 1 hour on days 1-3, and oral tipifarnib twice daily on days 1-21.
Treatment repeats every 21 days for up to 2 courses in the absence of disease progression or
Cohorts of 6 patients receive escalating doses of tipifarnib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity.
PHASE II: Patients receive cytarabine, idarubicin, and tipifarnib as in phase I at the MTD.
Patients in both phases who respond to induction therapy proceed to consolidation
CONSOLIDATION MAINTENANCE THERAPY: Patients receive consolidation therapy comprising
cytarabine IV continuously on days 1-3, idarubicin IV over 1 hour on days 1-2, and
tipifarnib twice daily on days 1-14. Treatment repeats every 4-6 weeks for 5 courses in the
absence of unacceptable toxicity.
Patients then begin maintenance therapy comprising oral tipifarnib twice daily on day 1-21.
Treatment repeats every 4-6 weeks for 6 courses in the absence of unacceptable toxicity.
- Diagnosis of 1) AML (WHO classification definition of > 20% blasts), or 2) high risk
MDS (defined as the presence of > 10% blasts)
- Patients must be chemo-naïve, i.e. not have received any prior chemotherapy (except
hydrea) for AML or MDS; they could have received transfusions, hematopoietic growth
factors or vitamins; temporary measures such as pheresis or hydrea (0.5 to 5g daily
for up to 3 days) are allowed
- ECOG PS of 0-1 at screening
- Creatinine =< 2 mg/dl
- Total bilirubin =< 2 mg/dL, unless increase is due to hemolysis
- Transaminases (SGPT) =< 2.5 x ULN
- Ability to take oral medication
- Ability to understand and provide signed informed consent
- Subjects with APL
- Presence of active systemic infection
- Any coexisting medical condition that in the judgment of the treating physician is
likely to interfere with study procedures or results
- Nursing women, women of childbearing potential with positive urine pregnancy test, or
women of childbearing potential who are not willing to maintain adequate
contraception (such as birth control pills, IUD, diaphragm, abstinence, or condoms by
their partner) over the entire course of the study
- Known allergy to imidazole drugs (such as clotrimazole, ketoconazole, miconazole,
econazole, fenticonazole, isoconazole, sulconazole, tioconazole, terconazole)