RATIONALE: Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using fulvestrant may fight breast cancer by blocking the uptake of estrogen. Combining tipifarnib with fulvestrant may kill tumor cells that did not respond to first-line therapy.

PURPOSE: This phase II trial is studying how well giving tipifarnib together with fulvestrant works as second-line therapy in treating postmenopausal women with hormone receptor-positive inoperable locally advanced or metastatic breast cancer that has progressed after previous first-line endocrine therapy.

Condition	Treatment or Intervention	Phase
recurrent breast cancer stage IIIB breast cancer stage IIIC breast cancer stage IV breast cancer	Drug: fulvestrant  Drug: tipifarnib  Procedure: antiestrogen therapy  Procedure: drug resistance inhibition  Procedure: endocrine therapy  Procedure: enzyme inhibitor therapy  Procedure: hormone therapy	Phase II

Further Study Details: 

OBJECTIVES: Primary

• Determine the efficacy of tipifarnib and fulvestrant as second-line therapy, in terms of clinical benefit rate (a combination of complete and partial response rates and stable disease for more than 24 weeks), in postmenopausal women with hormone receptor-positive inoperable locally advanced or metastatic breast cancer with progressive disease after prior first-line endocrine therapy.

Secondary

• Determine the median time to progression and duration of response in patients treated with this regimen.
• Determine the median overall survival of patients treated with this regimen.
• Determine the toxicity profile of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive fulvestrant intramuscularly on day 1 and oral tipifarnib twice daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity*.

NOTE: *Fulvestrant continues even if tipifarnib is held for toxicity.

Patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 45 patients will be accrued for this study within 1 year.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the breast of 1 of the following stages:
• Metastatic disease (stage IV)
• Inoperable locally advanced disease
• At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
• Progressive disease, defined by 1 of the following:
• Progressive disease after 1 prior endocrine therapy for metastatic breast cancer, including a selective estrogen receptor modulator (SERM) (e.g., tamoxifen or toremifene) OR an aromatase inhibitor (AI) (e.g., anastrazole, letrozole or exemestane)
• Relapsed while receiving adjuvant therapy with a SERM or an AI
• Relapsed within 6 months of completing adjuvant therapy with a SERM or an AI
• No rapidly progressive, life-threatening metastases, including any of the following:
• Extensive hepatic involvement (> 50% involvement of the liver)
• Symptomatic lymphangitic metastases
• Brain or leptomeningeal involvement
• Hormone receptor status:
• Estrogen receptor- and/or progesterone receptor-positive disease

PATIENT CHARACTERISTICS: Age

• 18 and over

Sex

• Female

Menopausal status

• Postmenopausal, defined as 1 of the following:
• At least 12 months without spontaneous menstrual bleeding
• Prior bilateral salpingo-oophorectomy with or without hysterectomy
• At least 55 years of age with a prior hysterectomy with or without oophorectomy
• Under 55 years of age with a prior hysterectomy without oophorectomy OR unknown status AND documented follicle-stimulating hormone levels consistent with postmenopausal range within the past 4 weeks
• Receiving a GnRH analog to supress ovarian function (e.g., goserelin 3.6 mg every 4 weeks)

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• More than 3 months

Hematopoietic

• WBC ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• See Disease Characteristics
• Bilirubin ≤ 2 mg/dL
• AST and ALT ≤ 2.5 times upper limit of normal (ULN)

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No arrhythmia

Other

• No prior allergic reaction attributed to compounds of similar chemical or biological composition to tipifarnib or other study agents (e.g., imidazoles or quinolones)
• No peripheral neuropathy ≥ grade 2
• No ongoing or active infection
• No other invasive malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No psychiatric illness or social situation that would preclude study compliance
• No other concurrent uncontrolled illness

PRIOR CONCURRENT THERAPY: Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for metastatic disease
• Prior adjuvant or neoadjuvant chemotherapy is allowed

Endocrine therapy

• See Disease Characteristics
• At least 28 days since prior fulvestrant
• Only 1 prior dose allowed
• Concurrent gonadotropin-releasing hormone (GnRH) analog allowed provided progressive disease occurred while on a GnRH analog and a SERM or an AI
• No concurrent SERM or AI

Radiotherapy

• More than 4 weeks since prior radiotherapy

Surgery

• Not specified

Other

• Recovered from prior therapy
• No prior farnesyltransferase inhibitors
• No other concurrent anticancer treatment
• Concurrent bisphosphonates for bone metastases allowed
• No other concurrent investigational agents
• No concurrent combination antiretroviral therapy for HIV-positive patients

Florida
      H. Lee Moffitt Cancer Center and Research Institute at University of South Florida, Tampa,  Florida,  33647-9497,  United States; Recruiting
New York
      Albert Einstein Cancer Center at Albert Einstein College of Medicine, Bronx,  New York,  10467-2490,  United States; Recruiting
      Mount Sinai Medical Center, New York,  New York,  10029,  United States; Recruiting
      New York Weill Cornell Cancer Center at Cornell University, New York,  New York,  10021,  United States; Recruiting
      North Shore University Hospital, Manhasset,  New York,  11030,  United States; Recruiting
      NYU Cancer Institute at New York University Medical Center, New York,  New York,  10016,  United States; Recruiting

Study chairs or principal investigators

Linda T. Vahdat, MD,  Study Chair,  Cornell University Medical College   

Study ID Numbers:  CDR0000360837; NYWCCC-NCI-6205; NCI-6205; NCT00082810
Record last reviewed:  May 2004
Last Updated:  March 10, 2005
Record first received:  May 14, 2004
ClinicalTrials.gov Identifier:  NCT00082810
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08