A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer
I. Determine the maximum tolerated dose of tipifarnib when administered with doxorubicin and
cyclophosphamide in women with metastatic breast cancer (non-regional stage IV disease).
(Phase I closed to accrual as of 1/19/04) II. Determine the pathologic complete remission
rate in patients with locally advanced breast cancer (stages IIB, IIIA, IIIB, or IIIC)
treated with the recommended phase II dose of this regimen.
I. Determine the clinical complete response rate in patients treated with this regimen.
II. Determine the toxicity profile of this regimen in these patients. III. Correlate
pretreatment levels of ErbB1, 2, 3, 4 and phosphorylated levels of Akt, STAT3, and Erk ½
with clinical response in these patients and with percent inhibition of proliferation
(Ki-67) and percent induction of apoptosis in post-treatment tumor specimens.
IV. Correlate percent decrease of farnesyltransferase (FTase) activity levels, HDJ-2
farnesylation, phospho-Akt, phospho-STAT3, and phospho-Erk ½ with clinical response rates in
these patients and with percent inhibition of proliferation (Ki-67) and percent inhibition
OUTLINE: This is a multicenter, dose-escalation study of tipifarnib. Patients are stratified
according to presence of inflammatory carcinoma (yes vs no).
PHASE I (nonregional stage IV disease) (closed to accrual as of 1/19/04): Patients receive
doxorubicin IV over 10-15 minutes and cyclophosphamide IV over 30 minutes on day 1, oral
tipifarnib twice daily on days 2-7, and filgrastim (G-CSF) subcutaneously on days 2-13.
Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or
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.
PHASE II (stage IIB, IIIA, IIIB, or IIIC): Patients receive tipifarnib at the MTD and
doxorubicin, cyclophosphamide, and G-CSF as in phase I (phase I closed to accrual as of
1/19/04). After the fourth course, patients may undergo complete resection.
Patients are followed every 3-4 months for 3 years, every 6 months for 2 years, and then
PROJECTED ACCRUAL: Approximately 3-12 patients will be accrued for phase I (closed to
accrual as of 1/19/04) of this study. A total of 21-50 patients will be accrued for phase II
of this study.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Pathological complete response in the breast
95% confidence intervals of these estimates will be obtained.
Albert Einstein College of Medicine of Yeshiva University
United States: Food and Drug Administration
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