Neoadjuvant Tipifarnib, Docetaxel, and Capecitabine in Treating Patients With Locally Advanced or Metastatic Solid Tumors or Stage IIIA or Stage IIIB Breast Cancer

Study Overview
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Brief Summary
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Phase I/II trial to study the effectiveness of neoadjuvant tipifarnib combined with docetaxel and capecitabine in treating patients who have locally advanced or metastatic solid tumors or stage IIIA or stage IIIB breast cancer. Tipifarnib may stop the growth of tumor cells by blocking the enzymes necessary for cancer cell growth. Drugs used in chemotherapy, such as docetaxel and capecitabine, use different ways to stop tumor cells from dividing so they stop growing or die. Combining tipifarnib with docetaxel and capecitabine may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose and recommended dose of capecitabine in combination with docetaxel and tipifarnib in patients with locally advanced or metastatic solid tumors. (Phase Ib) II. Determine the complete pathological and clinical response rate in patients with stage IIIA or IIIB breast cancer treated with this regimen. (Phase II) SECONDARY OBJECTIVES: I. Determine the toxicity of this regimen in these patients. II. Determine disease-free and overall survival of patients treated with this regimen. OUTLINE: This is a multicenter, dose-escalation study of capecitabine. Patients in phase II are stratified according to type of breast cancer (inflammatory vs noninflammatory). Phase Ib: Patients receive oral tipifarnib twice daily and oral capecitabine twice daily on days 1-14 and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of capecitabine 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: Patients receive oral tipifarnib twice daily for 6 days. Beginning at least 48 hours after completion of the initial dose of tipifarnib, patients receive treatment as in phase Ib for up to 6 courses at the MTD of capecitabine. Patients in phase Ib are followed at 3 months. Patients in phase II are followed every 4 months for up to 5 years. PROJECTED ACCRUAL: A total of 24-53 patients (9-18 for phase Ib and 15-35 for phase II) will be accrued for this study within 14-35 months.

Official Title
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Phase Ib/II Neoadjuvant Trial of the Farnesyltransferase Inhibitor, R115777 With Docetaxel and Capecitabine for Patients With Stage IIIA or IIIB Breast Cancer

Conditions
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Adult Solid Neoplasm, Inflammatory Breast Carcinoma, Male Breast Carcinoma, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Docetaxel
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Tipifarnib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed solid tumor Locally advanced or metastatic No known standard therapy that is potentially curative or definitely capable of extending life expectancy No history of metastatic brain disease within the past 6 months Treated metastatic brain disease is allowed provided disease has been stable for more than 6 months and does not require concurrent steroids or anti-seizure medication Histologically confirmed breast cancer Stage IIIA or stage IIIB, including ipsilateral palpable supraclavicular lymph node(s) without other distant metastasis Invasive disease confirmed by 1 of the following*: Incisional biopsy Punch biopsy (applicable for clinical T4b tumors) Core needle (cutting needle) biopsies No distant metastatic disease Hormone receptor status: Not specified Male or female Performance status - ECOG 0-1 Absolute neutrophil count at least 2,000/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 10.0 g/dL Bilirubin no greater than upper limit of normal (ULN) Alkaline phosphatase no greater than 2.5 times ULN AST no greater than 2.5 times ULN Creatinine no greater than 1.25 times ULN Creatinine clearance at least 50 mL/min No cardiac arrhythmia Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No active infection requiring antibiotics No diabetes No symptomatic neurologic condition No other uncontrolled serious medical condition No other malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix No history of hypersensitivity to intravenous paclitaxel or other medication containing Cremophor EL or polysorbate 80 as a carrier (phase Ib) Phase Ib only: More than 4 weeks since prior immunotherapy More than 4 weeks since prior biologic therapy No concurrent immunotherapy Phase Ib and II: No concurrent prophylactic filgrastim (G-CSF) Phase Ib only: More than 1 year since prior adjuvant docetaxel before metastatic relapse More than 4 weeks since prior chemotherapy and recovered No prior capecitabine AND docetaxel (in combination or as single agents) Prior capecitabine OR docetaxel allowed No other concurrent chemotherapy Phase II only: No prior cytotoxic chemotherapy for breast cancer Phase Ib only: More than 3 weeks since prior radiotherapy No prior radiotherapy to more than 25% of bone marrow No concurrent radiotherapy Phase II only: No prior radiotherapy for breast cancer Phase Ib only: More than 4 weeks since prior major surgery Phase II only: No prior surgery (other than core or incisional biopsy for diagnostic purposes) for breast cancer Phase Ib only: No other ancillary investigational therapy Phase Ib and II: No concurrent sorivudine or brivudine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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, capecitabine, docetaxel)<br>Phase Ib: Patients receive oral tipifarnib twice daily and oral capecitabine twice daily on days 1-14 and docetaxel IV over 30-60 minutes on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Phase II: Patients receive oral tipifarnib twice daily for 6 days. Beginning at least 48 hours after completion of the initial dose of tipifarnib, patients receive treatment as in phase Ib for up to 6 courses at the MTD of capecitabine. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Tipifarnib<br>* Given orally (PO)<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity (DLT) as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (Phase I) |  | 21 days | 
| Pathologic complete response rate (Phase II) | Estimated by the number of patients with a complete pathologic response divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true pathologic complete response probability will be calculated according to the approach of Duffy and Santner. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical tumor response (complete response [CR] or partial response [PR]) (Phase I) | Clinical responses will be summarized by simple descriptive summary statistics. | Up to 5 years | 
| Overall survival | The distribution of survival time will be estimated using the method of Kaplan-Meier. | From registration to death due to any cause, assessed up to 5 years | 
| Toxicity as assessed by the National Cancer Institute (NCI) CTCAE version 3.0 |  | Up to 5 years |