Tipifarnib and Fulvestrant in Hormone Receptor-Positive Metastatic Breast Cancer

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.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed adenocarcinoma of the
breast

- Patients must be postmenopausal

- 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 leptomeningeal 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