A Phase I Trial of Oral Etoposide in Combination With the Farnesyltransferase Inhibitor R115777 (ZARNESTRA, Tipifarnib, NSC #702818, IND #58,359) in Elderly Adults With Newly Diagnosed Acute Myelogenous Leukemia (AML)
I. To determine the feasibility, tolerability, and toxicities of administering a fixed dose
of R115777 in combination with escalating doses of VP-16 in elderly adults ( = 70 years)
with newly diagnosed, previously untreated acute myelogenous leukemia (AML).
II. To determine the maximal tolerated dose (MTD) of R115777 + VP-16 combination, including
the duration of R115777 administration, for future Phase II trials.
III. To obtain preliminary descriptive data regarding the effects of R115777 + VP-16 on cell
cycle progression and apoptosis in AML marrow cells.
IV. To study mechanisms of leukemia cell resistance to R115777 in combination with
OUTLINE: This is a multicenter, dose-escalation study.
Patients receive oral tipifarnib twice daily on days 1-14 OR 1-21 and oral etoposide once
daily on days 1-3 and 8-10. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity. Patients who achieve a complete response (CR) may
receive up to 5 additional courses of therapy beyond documentation of CR.
Cohorts of 3-6 patients receive escalating doses of tipifarnib and etoposide 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. Up to 14 additional
patients receive treatment at the MTD.
After completion of study treatment, patients are followed at 1 month and then every 3
PROJECTED ACCRUAL: A total of 3-100 patients will be accrued for this study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of patients who experience dose limiting toxicities (DLT), based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0
Up to 28 days
Johns Hopkins University
United States: Food and Drug Administration
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