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

NCT ID: NCT00049114

Last Updated: 2013-06-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-02-28

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.

Detailed Description

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.

Conditions

Inflammatory Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

doxorubicin hydrochloride

Intervention Type: DRUG

cyclophosphamide

Intervention Type: DRUG

Given IV

tipifarnib

Intervention Type: DRUG

Given orally

filgrastim

Intervention Type: BIOLOGICAL

Given subcutaneously

therapeutic conventional surgery

Intervention Type: PROCEDURE

Undergo complete resection

laboratory biomarker analysis

Intervention Type: OTHER

Correlative studies

Interventions

doxorubicin hydrochloride

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

tipifarnib

Given orally

Intervention Type: DRUG

filgrastim

Given subcutaneously

Intervention Type: BIOLOGICAL

therapeutic conventional surgery

Undergo complete resection

Intervention Type: PROCEDURE

laboratory biomarker analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

ADM; ADR; Adria; Adriamycin PFS; Adriamycin RDF; CPM; CTX; Cytoxan; Endoxan; Endoxana; R115777; Zarnestra; G-CSF; Neupogen

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph Sparano

Role: PRINCIPAL_INVESTIGATOR

Albert Einstein College of Medicine

Locations

Albert Einstein College of Medicine

The Bronx, New York, United States

Countries

United States

Other Identifiers

02-05-125

Identifier Type: -

Identifier Source: secondary_id

AECM-0205125

Identifier Type: -

Identifier Source: secondary_id

NCI-5598

Identifier Type: -

Identifier Source: secondary_id

CDR0000257811

Identifier Type: -

Identifier Source: secondary_id

N01CM62204

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2012-02500

Identifier Type: -

Identifier Source: org_study_id