Tipifarnib and Fulvestrant in Hormone Receptor-Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II Trial of Tipifarnib (R115777, Zarnestra™) in Combination With Fulvestrant (Faslodex®) in Postmenopausal Hormone Receptor-Positive Breast Cancer

Conditions
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Estrogen Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: fulvestrant
* Drug: tipifarnib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (tipifarnib, fulvestrant)<br>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*. | Drug: fulvestrant<br>* Given intramuscularly<br>* Other names: ICI 182,780;Drug: tipifarnib<br>* Given IV<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) (CR Rate, PR Rate, and SD) | Number of participants met the definition of Clinical Benefit Rate.Tumor response was assessed every three cycles by CT using RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria in Solid Tumors (RECIST 1.0) for target lesions: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; Progressive Disease (PD): At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (TTP) | TTP was estimated using the Kaplan-Meier method. | From randomization until progression of the disease, assessed up to 4 years | 
| Duration of Response | DOR was defined for responders as the time from the onset of first response to disease progression and for non-responders as zero | Up to 4 years | 
| Toxicity as Assessed by NCI CTCAE Version 3.0 | Number of Participants with serious (grade 3) or life-threatening (grade 4) adverse events | Up to 4 years | 
| Median Overall Survival | The 95% confidence intervals will be used. | From randomization until death or censored at the date of last follow-up, assessed up to 4 years |