Tipifarnib and Fulvestrant as Second-Line Therapy in Treating Postmenopausal Women With Hormone Receptor-Positive Inoperable Locally Advanced or Metastatic Breast Cancer With Progressive Disease After Previous First-Line Endocrine Therapy

• Time to progression (TTP) [ Time Frame: From randomization until progression of the disease, assessed up to 4 years ] [ Designated as safety issue: No ]
• Duration of response [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
• Toxicity as assessed by NCI CTCAE version 3.0 [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
  The frequency of serious (grade 3) or life-threatening (grade 4) adverse events in this study will be compared to published data of fulvestrant and tipifarnib alone.
• Median overall survival [ Time Frame: From randomization until death or censored at the date of last follow-up, assessed up to 4 years ] [ Designated as safety issue: No ]
  The 95% confidence intervals will be used.

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. 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 use of estrogen. Combining tipifarnib with fulvestrant may kill tumor cells that did not respond to first-line therapy.

PRIMARY OBJECTIVES:

I. To determine the efficacy of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant based on clinical benefit rate (CBR, a combination of complete response rate, partial response rate, and stable disease for more than 24 weeks) in postmenopausal women with hormone receptor-positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

SECONDARY OBJECTIVES:

I. To determine the median time to progression (TTP) and duration of response of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant in postmenopausal women with hormone receptor-positive metastatic breast cancer.

II. To determine the median overall survival of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant in postmenopausal women with hormone receptor- positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

III. To determine the toxicity profile of tipifarnib (R115777, Zarnestra™) in combination with fulvestrant versus fulvestrant alone (from historical control) in postmenopausal women with hormone receptor positive metastatic breast cancer who have progressive disease after first-line endocrine therapy.

OUTLINE:

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.

• Estrogen Receptor-positive Breast Cancer
• Progesterone Receptor-positive Breast Cancer
• Recurrent Breast Cancer
• Stage IIIB Breast Cancer
• Stage IIIC Breast Cancer
• Stage IV Breast Cancer

• Drug: fulvestrant
  Given intramuscularly
  Other Names:

  • Faslodex
  • ICI 182,780
• Drug: tipifarnib
  Given IV
  Other Names:

  • R115777
  • Zarnestra

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed adenocarcinoma of the breast
• Patients must be postmenopausal, defined as: (1) a history of at least 12 months without spontaneous menstrual bleeding, (2) prior bilateral salpingo-oophorectomy, with or without hysterectomy, (3) age >= 55 years with a prior hysterectomy with or without oophorectomy, (4) age < 55 years with a prior hysterectomy without oophorectomy or unknown status, with a documented FSH level in postmenopausal range within 4 week s of registration, (5) receiving a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (eg, goserelin 3.6 mg q 4 weeks)
• Patients must have stage IV disease or inoperable locally advanced disease
• Patients must have ER- and/or PR-positive disease as determined by their local pathology laboratory
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan; all sites of disease should be noted and followed
• Prior hormonal therapy as adjuvant therapy and/or for metastatic disease is permitted; patients previously treated with two or more prior doses of fulvestrant are not eligible; patients who have received one prior dose of fulvestrant within 28 days are eligible so long as they meet other eligibility criteria
• Patients must have ECOG performance status 0-2 (Karnofsky >= 60%)
• Patients must have life expectancy of greater than 3 months
• Leukocytes >= 3,000/uL
• Absolute neutrophil count >= 1,500/uL
• Platelets >= 100,000/uL
• Total bilirubin =< 2 mg/dL
• AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal
• Creatinine less than or equal to 1.5 times the institutional upper limits of normal
• Patients must be disease-free of prior invasive malignancies for >= 5 years with the exception of: curatively-treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix
• Patients must have the ability to understand and the willingness to sign a written informed consent document
• Patients who have had previous therapy with farnesyltransferase inhibitor

Exclusion Criteria:

• Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; patients who have had prior chemotherapy for metastatic disease are not eligible; prior adjuvant or neoadjuvant chemotherapy is allowed
• Patients may not be receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to tipifarnib (R115777, Zarnestra™) or other agents used in the study (e.g., imidazoles, quinolones)
• Presence of rapidly progressive, life-threatening metastases; this includes patients with extensive hepatic involvement (> 50% of the liver involved), symptomatic lymphangitic metastases, or brain or eptomeningeal involvement
• Concomitant anticancer treatment with the following exceptions: (1) bisphosphonates for bone metastases, (2) a GnRH analog is permitted if the patient had progressive disease on a GnRH analog plus a SERM or an AI; the GnRH analog may continue but the SERM or AI must be discontinued
• Grade 2 or more peripheral neuropathy
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with tipifarnib or other agents administered during the study.; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated