A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer
A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer
Drugs used in chemotherapy, such as doxorubicin and cyclophosphamide, work in different ways to stop tumor cells from dividing so they stop growing or die. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining tipifarnib with doxorubicin and cyclophosphamide may kill more tumor cells. Phase II trial to study the effectiveness of combining tipifarnib with doxorubicin and cyclophosphamide in treating women who have locally advanced breast cancer.
PRIMARY OBJECTIVES:
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.
SECONDARY OBJECTIVES:
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 of apoptosis.
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 unacceptable toxicity.
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 annually thereafter.
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.
Inclusion Criteria:
Histologically or cytologically confirmed adenocarcinoma of the breast
Phase I (closed to accrual as of 1/19/04):
Phase II:
Locally advanced disease, according to AJCC staging criteria:
At least 1 bidimensionally or unidimensionally measurable indicator lesion
Hormone receptor status:
Female
Performance status - ECOG 0-1
Performance status - Karnofsky 70-100%
Not specified
WBC at least 3,000/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Bilirubin normal
AST/ALT no greater than 2.5 times upper limit of normal
Creatinine normal
Creatinine clearance at least 60 mL/min
LVEF normal
No symptomatic congestive heart failure
No unstable angina pectoris
No cardiac arrhythmia
No other invasive malignancies within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
No prior allergic reactions attributed to compounds of similar chemical or biological composition to tipifarnib or other agents used in the study (e.g., imidazoles or quinolones)
No ongoing or active infection
No other concurrent uncontrolled illness that would preclude study participation
No psychiatric illness or social situation that would preclude study compliance
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
Not specified
Phase I (closed to accrual as of 1/19/04):
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
No more than 1 prior adjuvant/neoadjuvant regimen and 1 prior regimen for metastatic disease
Prior doxorubicin allowed provided the following are true:
Phase II:
At least 1 week since prior tamoxifen or other selective estrogen receptor modulators for prevention or other indications (e.g., osteoporosis, ductal carcinoma in situ, or invasive breast cancer)
Phase I (closed to accrual as of 1/19/04):
Phase II:
Not specified
No antacids within 2 hours of study drug administration
No concurrent combination antiretroviral therapy for HIV-positive patients
No other concurrent anticancer therapy
No other concurrent investigational agents