RATIONALE: Drugs used in chemotherapy, such as cytarabine, daunorubicin, and etoposide, work
in different ways to stop the growth of cancer cells, either by killing the cells or by
stopping them from dividing. Tipifarnib may stop the growth of cancer cells by blocking some
of the enzymes needed for cell growth. Giving combination chemotherapy together with
tipifarnib may kill more cancer cells.
PURPOSE: This phase I trial is studying the side effects and best dose of tipifarnib when
given together with combination chemotherapy in treating patients with newly diagnosed acute
- 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.
- 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
- 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
PROJECTED ACCRUAL: A maximum of 30 patients will be accrued for this study within 10-15
- Histologically or cytologically confirmed acute myeloid leukemia (AML) according to
the WHO classification system
- High-risk disease
- Newly diagnosed disease
- Patients with secondary AML due to prior chemotherapy for a different malignancy
- No known inv(16), t(8;21), or t(15;17) cytogenetic abnormality
- No acute promyelocytic leukemia
- No CNS leukemia
- 18 to 59
- ECOG 0-2
- More than 6 months
- Not specified
- AST and ALT ≤ 2.5 times upper limit of normal
- Bilirubin normal
- Creatinine normal OR
- Creatinine clearance ≥ 60 mL/min
- Ejection fraction > 50% by echocardiogram or MUGA
- No symptomatic congestive heart failure
- No unstable angina pectoris
- No cardiac arrhythmia
- No known HIV positivity
- No history of allergic reactions attributed to compounds of similar chemical or
biological composition to tipifarnib
- No allergy to imidazoles (e.g., clotrimazole, ketoconazole, miconazole, or econazole)
- No ongoing or active infection
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No other uncontrolled illness
- No psychiatric illness or social situation that would preclude study compliance
PRIOR CONCURRENT THERAPY:
- No concurrent epoetin alfa
- See Disease Characteristics
- No prior chemotherapy for AML or myelodysplastic syndromes except hydroxyurea
- Not specified
- No concurrent palliative radiotherapy
- Not specified
- More than 30 days since prior investigational agents
- No other concurrent investigational or commercial agents or therapies for the