Tipifarnib, Doxorubicin, and Cyclophosphamide in Treating Women With Locally Advanced Breast Cancer - Full Text View

Sponsor:	Albert Einstein College of Medicine of Yeshiva University
Collaborator:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00049114

Purpose

RATIONALE: 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.

PURPOSE: Phase II trial to study the effectiveness of combining tipifarnib with doxorubicin and cyclophosphamide in treating women who have locally advanced breast cancer.

Condition	Intervention	Phase
Breast Cancer	Biological: filgrastim Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: tipifarnib Procedure: conventional surgery	Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official Title:	A Phase II Study Of Tipifarnib (Zarnestra) Plus Doxorubicin And Cyclophosphamide In Patients With Locally Advanced Breast Cancer

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Cyclophosphamide Doxorubicin Doxorubicin hydrochloride Myocet Filgrastim R 115777 Tipifarnib

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Recommended phase II dose of tipifarnib as measured by dose-limiting toxicity during first course [ Designated as safety issue: Yes ]
Pathological complete response in the breast after 4 courses [ Designated as safety issue: No ]

Estimated Enrollment:	62
Study Start Date:	February 2003

Detailed Description:

OBJECTIVES:

Primary

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)
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

Determine the clinical complete response rate in patients treated with this regimen.
Determine the toxicity profile of this regimen in these patients.
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).

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

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/mm^3
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3

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

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/m^2
  - 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00049114

Locations

United States, New York
Albert Einstein Cancer Center at Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Beth Israel Medical Center - Petrie Division
New York, New York, United States, 10003-3803
Eastchester Center for Cancer Care
Bronx, New York, United States, 10469
New York Weill Cornell Cancer Center at Cornell University
New York, New York, United States, 10021

Sponsors and Collaborators

Albert Einstein College of Medicine of Yeshiva University

National Cancer Institute (NCI)

Investigators

Study Chair:

Joseph A. Sparano, MD

Albert Einstein College of Medicine of Yeshiva University

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Sparano JA, Moulder S, Kazi A, Vahdat L, Li T, Pellegrino C, Munster P, Malafa M, Lee D, Hoschander S, Hopkins U, Hershman D, Wright JJ, Sebti SM. 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. 2006 Jul 1;24(19):3013-8. Epub 2006 Jun 12.

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.

Study ID Numbers:	CDR0000257811, AECM-0205125, NCI-5598
Study First Received:	November 12, 2002
Last Updated:	February 6, 2009
ClinicalTrials.gov Identifier:	NCT00049114 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by National Cancer Institute (NCI):

inflammatory breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Skin Diseases
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Breast Neoplasms
Cyclophosphamide
Antibiotics, Antineoplastic
Immunosuppressive Agents
Doxorubicin

Pharmacologic Actions
Neoplasms
Neoplasms by Site
Therapeutic Uses
Myeloablative Agonists
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Alkylating Agents
Breast Diseases
Tipifarnib

ClinicalTrials.gov processed this record on November 30, 2009