Docetaxel Combined With Ketoconazole in Treatment of Breast Cancer

• 1. Evaluate the clinical response rate of 70mg docetaxel with ketoconazole in metastatic breast cancer. [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]
• 2. Evaluate the pathological response rate in the primary tumor following four cycles of docetaxel and ketoconazole. [ Time Frame: 5 months ] [ Designated as safety issue: No ]

• 1. Evaluate the clinical response rate of 70mg docetaxel with ketoconazole in metastatic breast cancer.
• 2. Evaluate the pathological response rate in the primary tumor following four cycles of docetaxel and ketoconazole.

• 1. To study tumor genomics and proteomics and serum proteomics in breast cancer in response to docetaxel/ketoconazole. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• 2. To compare tumor genomics and proteomics and serum proteomics in breast cancer in response to docetaxel/ketoconazole to that induced by docetaxel alone in a prior study (HO B17/02). [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• 3. To correlate docetaxel pharmacokinetics with (1)Genetic polymorphisms of drug metabolizing enzymes(2)Drug toxicity & tumor response(3)Peripheral mononuclear cell gene expression profiles [ Time Frame: 3 years ] [ Designated as safety issue: No ]
• (4) To study ondansetron pharmacokinetics and correlate that with genetic polymorphisms [ Time Frame: 3 years ] [ Designated as safety issue: No ]

• 1. To study tumor genomics and proteomics and serum proteomics in breast cancer in response to docetaxel/ketoconazole.
• 2. To compare tumor genomics and proteomics and serum proteomics in breast cancer in response to docetaxel/ketoconazole to that induced by docetaxel alone in a prior study (HO B17/02).
• 3. To correlate docetaxel pharmacokinetics with
• a. Genetic polymorphisms of drug metabolizing enzyes including MDR-1, Cyp3A and GSTs.
• b. Drug toxicity and tumor response.
• c. Peripheral mononuclear cell gene expression profiles
• 4. To study ondansetron pharmacokinetics and correlate that with genetic polymorphisms

Patients with locally advanced or metastatic breast cancer and with measurable primary breast tumor will be treated with 70mg docetaxel combined with ketoconazole. Serial tumor biopsies and plasma samples will be taken for gene expression and proteomics studies to identify biomarkers that may predict for treatment response.

We hypothesize that 70mg docetaxel co-administered with ketoconazole would result in similar clinical efficacy as conventional doses of docetaxel (75mg/m2 body surface area) in terms of clinical and pathological response rates in metastatic breast cancer. We further hypothesize that tumor genomic and proteomic changes and serum proteomic changes would correlate with tumor response. We are also looking to correlate drug pharmacokinetics with treatment toxicity, genotype of drug metabolizing enzymes and transporters, and peripheral mononuclear cell gene expression profiles. The primary objectives are to evaluate the clinical response rate of 70mg docetaxel with ketoconazole in metastatic breast cancer, and to evaluate the pathological response rate in the primary tumor following four cycles of docetaxel and ketoconazole.

Inclusion Criteria:

• Female, age >= 18 years.
• Histologic or cytologic diagnosis of breast carcinoma.
• T3-4 breast cancer with measurable primary breast tumor, defined as palpable tumor with both diameters 2.0cm or greater as measured by caliper.
• Patients must not have received prior chemotherapy or hormonal therapy for the treatment of breast cancer.
• Karnofsky performance status of 70 or higher.
• Estimated life expectancy of at least 12 weeks.

• Adequate organ function including the following:

  - Bone marrow: Absolute neutrophil (segmented and bands) count (ANC) >= 1.5 x 109/L Platelets >= 100 x 109/L

  - Hepatic: Bilirubin <= 1.5 x upper limit of normal (ULN), ALT or AST <= 2.5x ULN, (or <5 X with liver metastases)

  - Renal: creatinine <= 1.5x ULN

• Left ventricular ejection fraction >=50%
• Signed informed consent from patient or legal representative.
• Patients with reproductive potential must use an approved contraceptive method if appropriate (eg, intrauterine device, birth control pills, or barrier device) during and for three months after the study. Females with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.

Exclusion Criteria:

• Prior treatment for locally advanced or metastatic breast cancer.
• Treatment within the last 30 days with any investigational drug.
• Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
• Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Pregnancy.
• Breast feeding.
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
• Poorly controlled diabetes mellitus.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• Symptomatic brain metastasis.
• History of significant neurological or mental disorder, including seizures or dementia.
• Peripheral neuropathy of CTC grade 2 or above (NCI CTC version 3).
• History of hypersensitivity to drugs formulated in Tween 80, the vehicle used for commercial docetaxel formulations.