Tipifarnib, Doxorubicin, and Cyclophosphamide in Treating Women With Locally Advanced Breast Cancer

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00049114

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Breast Cancer Stage II Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer	Drug: doxorubicin hydrochloride Drug: cyclophosphamide Drug: tipifarnib Biological: filgrastim Procedure: therapeutic conventional surgery Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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:

Determine the clinical complete response rate in patients treated with this regimen.
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.
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).

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

62 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I-II Study of R115777 (ZARNESTRA) Plus Doxorubicin and Cyclophosphamide in Patients With Locally Advanced Breast Cancer and Metastatic Breast Cancer

Study Start Date :

Feb 1, 2003

Actual Primary Completion Date :

Jan 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (doxorubicin, cyclophosphamide, tipifarnib, G-CSF) 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 G-CSF subcutaneously on days 2-13. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable 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.	Drug: doxorubicin hydrochloride Other Names: ADM ADR Adria Adriamycin PFS Adriamycin RDF Drug: cyclophosphamide Given IV Other Names: CPM CTX Cytoxan Endoxan Endoxana Drug: tipifarnib Given orally Other Names: R115777 Zarnestra Biological: filgrastim Given subcutaneously Other Names: G-CSF Neupogen Procedure: therapeutic conventional surgery Undergo complete resection Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (doxorubicin, cyclophosphamide, tipifarnib, G-CSF)

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 G-CSF subcutaneously on days 2-13. Treatment repeats every 2 weeks for 4 courses in the absence of disease progression or unacceptable 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.

Drug: doxorubicin hydrochloride

Other Names:

ADM

ADR

Adria

Adriamycin PFS

Adriamycin RDF

Drug: cyclophosphamide

Given IV

Other Names:

CPM

CTX

Cytoxan

Endoxan

Endoxana

Drug: tipifarnib

Given orally

Other Names:

R115777

Zarnestra

Biological: filgrastim

Given subcutaneously

Other Names:

G-CSF

Neupogen

Procedure: therapeutic conventional surgery

Undergo complete resection

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

Pathological complete response in the breast [8 weeks]
95% confidence intervals of these estimates will be obtained.

Secondary Outcome Measures

Proportion of patients who have a clinical complete response [8 weeks]
95% confidence intervals of these estimates will be obtained.
Grade 3 or 4 toxicities assessed using NCI CTCAE version 3.0 [Up to 5 years]
Toxicity will be summarized by type, frequency and severity. This will be compared with an historical database.
Median disease-free survival [Up to 5 years]
Will be summarized, and 95% confidence intervals of these estimates will be obtained.
Percentage of patients free of disease [1 year]
Will be summarized, and 95% confidence intervals of these estimates will be obtained.
Percentage of patients free of disease [2 years]
Will be summarized, and 95% confidence intervals of these estimates will be obtained.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed adenocarcinoma of the breast
Phase I (closed to accrual as of 1/19/04):
Nonregional stage IV disease
Phase II:
Locally advanced disease, according to AJCC staging criteria:
Stage IIB
Stage IIIA
Stage IIIB
Stage IIIC
At least 1 bidimensionally or unidimensionally measurable indicator lesion
Hormone receptor status:
Not specified
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:
Used in adjuvant setting
Cumulative dose was no greater than 240 mg/m^2
At least 1 year between completion of adjuvant therapy and relapse
Phase II:
No prior chemotherapy for locally advanced breast cancer
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):
More than 4 weeks since prior radiotherapy
Phase II:
No prior radiotherapy for locally advanced breast cancer
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