PHASE I-II STUDY OF IDARUBICIN, CYTARABINE AND R115777 (TIPIFARNIB, ZARNESTRA; 702818; IND 58359), A FARNESYLTRANSFERASE INHIBITOR, IN PATIENTS WITH HIGH-RISK MYELODYSPLASTIC SYNDROMES AND ACUTE MYELOID LEUKEMIAS
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of Participants With Complete Response
Complete Response (CR) is required bone marrow blasts ≤5% and recovery of normal hematopoiesis with an absolute neutrophil count (ANC) of 1*10^9/L or more and platelet count of 100*10^9/L or more; and a complete response without platelets (CRp) is the same criteria as CR but with platelet counts from 20*10^9/L to less than 100*10^9/L.
21 Day Cycle
M.D. Anderson Cancer Center
United States: Food and Drug Administration
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