Trial Information

A Phase I Study of R115777 (Zarnestra) in Combination With Induction Chemotherapy in Patients With Newly Diagnosed, High Risk Acute Myeloid Leukemia

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of tipifarnib when given in combination with
induction therapy comprising cytarabine, daunorubicin, and etoposide followed by
consolidation therapy comprising high-dose cytarabine in patients with newly diagnosed
high-risk acute myeloid leukemia.

Secondary

- Determine the qualitative and quantitative toxic effects of this regimen, in terms of
organ specificity, time course, predictability, and reversibility, in these patients.

- Determine the rate of complete remission in patients treated with this regimen.

- Determine the remission duration, overall survival, and relapse-free and event-free
survival of patients treated with this regimen.

- Determine the pharmacokinetics of this regimen in these patients.

- Correlate pharmacodynamic measurements and levels of tumor necrosis factor-alpha with
clinical response in patients treated with this regimen.

OUTLINE: This is a dose-escalation study of tipifarnib.

- Induction therapy: Patients receive cytarabine IV continuously on days 1-7;
daunorubicin IV and etoposide IV over 2 hours on days 5-7; and oral tipifarnib twice
daily on days 5-12.

Patients undergo bone marrow biopsy on day 17 OR days 17 and 24 (if day 17 bone marrow
biopsy shows suspicious disease). Patients achieving a complete remission (CR) proceed to
consolidation therapy. Patients with residual disease, defined as > 5% leukemic blasts in a
bone marrow of ≥ 20% cellularity, receive a second course of induction therapy comprising
cytarabine IV continuously on days 1-5; daunorubicin IV and etoposide IV over 2 hours on
days 4 and 5; and oral tipifarnib twice daily on days 4-9. Patients achieving a CR after a
second course of induction therapy proceed to consolidation therapy. Patients not achieving
a CR after a second course of induction therapy are removed from the study.

Cohorts of 3-6 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 3 or 2
of 6 patients experience dose-limiting toxicity. An additional 12 patients are treated at
the MTD.

- Consolidation therapy: Patients receive high-dose cytarabine IV twice daily on days 1,
3, and 5. Treatment repeats approximately every 6-8 weeks for 4 courses.

After completion of study treatment, patients are followed every 3-6 months for up to 5
years.

PROJECTED ACCRUAL: A maximum of 30 patients will be accrued for this study within 10-15
months.