Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II	Treatment	Completed	18 and over	NCI	AECM-0205125 NCI-5598, 5598, NCT00049114

Objectives

Primary

1. 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)
2. 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

1. Determine the clinical complete response rate in patients treated with this regimen.
2. Determine the toxicity profile of this regimen in these patients.
3. 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.
4. 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.

Entry Criteria

Disease Characteristics:

• 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

Prior/Concurrent Therapy:

Biologic therapy

• Not specified

Chemotherapy

• 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/m²
    • At least 1 year between completion of adjuvant therapy and relapse
• Phase II:
  • No prior chemotherapy for locally advanced breast cancer

Endocrine therapy

• 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)

Radiotherapy

• 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

Surgery

• Not specified

Other

• 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

Patient Characteristics:

Age

• 18 and over

Sex

• Female

Menopausal status

• Not specified

Performance status

• ECOG 0-1

  OR

• Karnofsky 70-100%

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm³
• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³

Hepatic

• Bilirubin normal
• AST/ALT no greater than 2.5 times upper limit of normal

Renal

• Creatinine normal

  OR

• Creatinine clearance at least 60 mL/min

Cardiovascular

• LVEF normal
• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia

Other

• 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

Expected Enrollment

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.

Outcomes

Recommended phase II dose of tipifarnib as measured by dose-limiting toxicity during first course
Pathological complete response in the breast after 4 courses

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.

Sparano JA, Moulder S, Kazi A, et al.: Targeted inhibition of farnesyltransferase in locally advanced breast cancer: a phase I and II trial of tipifarnib plus dose-dense doxorubicin and cyclophosphamide. J Clin Oncol 24 (19): 3013-8, 2006.[PUBMED Abstract]

Sparano JA, Vahdat L, Moulder S, et al.: Phase I-II trial of tipifarnib plus cyclophosphamide and doxorubicin in patients with metastatic and locally advanced breast cancer: clinical and molecular effects. [Abstract] Breast Cancer Res Treat 88 (1): A-1067, 2004.

Trial Contact Information

Trial Lead Organizations

Albert Einstein Cancer Center at Albert Einstein College of Medicine

Joseph Sparano, MD, Protocol chair		Ph: 718-904-2555 Email: jsparano@montefiore.org

Registry Information
Official Title		A Phase II Study Of Tipifarnib (Zarnestra) Plus Doxorubicin And Cyclophosphamide In Patients With Locally Advanced Breast Cancer
Trial Start Date		2003-02-05
Registered in ClinicalTrials.gov		NCT00049114
Date Submitted to PDQ		2002-09-05
Information Last Verified		2007-01-18
NCI Grant/Contract Number		CM17103, CA013330

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