A Phase II Study Of The Farnesyltransferase Inhibitor ZANESTRA (R115777, NSC #702818, IND #58,359) In Complete Remission Following Induction And/Or Consolidation Chemotherapy In Adults With Poor-Risk Acute Myelogenous Leukemia (AML) And High-Risk Myelodysplasia (MDS)

PRIMARY OBJECTIVES:

I. To determine the duration of disease-free survival (DFS) and overall survival (OS) when ZARNESTRA is administered after intensive induction and consolidation chemotherapy to adults with poor risk acute myelogenous leukemia (AML) or high-risk myelodysplasia (MDS) in first complete remission (CR).

SECONDARY OBJECTIVES:

I. To determine the tolerability and toxicities of ZARNESTRA when administered in a chronic dosing schedule over a 48 week period to adults in first CR following intensive cytotoxic chemotherapies.

OUTLINE: This is a multicenter study.

Patients receive oral tipifarnib twice daily on days 1-14. Treatment repeats every 21 days for up to 16 courses in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 14-44 patients will be accrued for this study within 11-15 months.

Inclusion criteria

• Pathological Confirmation of the Diagnosis of AML, MDS
• PMNs >= 1,000/ul
• Platelets >= 30,000/ul
• Hematocrit >= 27% and/or Hemoglobin >= 9 gm/dl unsupported
• ECOG Performance Status 0-2
• Patients must be able to give informed consent
• Female patients of childbearing age must have negative pregnancy test
• AST, ALT and Alkaline Phosphatase =<2.5 x normal
• Bilirubin =< 1.5 x normal
• Serum Creatinine =< 2.0 mg/dl or Creatinine Clearance >= 40 ml/min
• Left Ventricular Ejection Fraction >= 25%
• Patients with poor-risk AML or high-risk MDS who have completed both induction and consolidation chemotherapy; poor risk AML is defined by one or more of the following characteristics:

• Antecedent Hematologic Disorder
• AML Arising from MDS
• Therapy-related AML
• Age >= 60 (in absence of favorable cytogenetics)
• Adverse Cytogenetics (i.e., -5/5q, -7/7q, +8, 20q-, 11q23 abnormalities, complex karyotype; other abnormalities may be considered at discression of study chair)
• Hyperleukocytosis at diagnosis (Blasts >= 30,000/mm^3 at diagnosis in absence of favorable cytogenetics)

High Risk MDS is defined by one or more of the following characteristics:

• RAEB and RAEB-t, with IPSS Score >= 1.5 (adverse cytogenetics, > 10% marrow blasts, cytopenias in at least 2 lineages): See Appendix E (Greenberg, et al. Blood 89:2079-2088,1997)36
• CMML with > 5% marrow blasts
• Therapy-related MDS

Exclusion criteria

• Any previous treatment with ZARNESTRA
• Ongoing participation in any Phase II or III clinical trial where DFS and OS are primary endpoints (unless patient is withdrawn from that trial)
• Acute promyelocytic (FAB M3) subtype
• Presence of (8;21) translocation or inversion 16 genotype as sole abnormality
• Eligible for curative allogeneic stem cell transplantation
• Known allergy to imidazole drugs (e.g., ketoconazole, miconazole)
• Presence of Residual AML (> 5% marrow blasts) or MDS, as Determined by Morphology, Flow Cytometry, and/or Cytogenetics
• Active, Uncontrolled Infection
• Disseminated Intravascular Coagulation
• Active CNS Leukemia
• Concomitant Chemotherapy, Radiation Therapy or Immunotherapy
• Women who are pregnant or lactating will not be eligible for this trial, as the investigational agent may be harmful to the developing fetus or nursing infant