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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Inflammatory Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Intervention / Treatment
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* Drug: doxorubicin hydrochloride
* Drug: cyclophosphamide
* Drug: tipifarnib
* Biological: filgrastim
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (doxorubicin, cyclophosphamide, tipifarnib, G-CSF)<br>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<br> <br> * Other names: Adriamycin RDF;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: tipifarnib<br>* Given orally<br>* Other names: Zarnestra;Biological: filgrastim<br>* Given subcutaneously<br>* Other names: Neupogen;Procedure: therapeutic conventional surgery<br>* Undergo complete resection<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete response in the breast | 95% confidence intervals of these estimates will be obtained. | 8 weeks | 

Secondary Outcome Measures

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