Study of Usefulness of Genotyping to Predict Docetaxel Exposure and Adverse Events

Study Overview
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Brief Summary
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Twenty patients with verified high risk breast cancer will be included in the study. Patients will receive three cycles of docetaxel followed by three cycles of CEF for their adjuvant treatment. The phenotype of CYP3A and the genotype of CYP3A5 and MDR1 will be assessed. Also the effect of docetaxel in the activity of CYP3A will be measured by peroral midazolam. Primary Object: The primary object of this study is to define, if it is possible to predict the clearance and/ or toxicity of docetaxel by assessing activity of CYP3A4 by midazolam test (CYP3A4 phenotype) CYP3A5 genotype MDR1 genotype Secondary object: The secondary object of this study is to define whether the treatment with docetaxel alters the activity of CYP3A4 enzyme in previously untreated breast cancer patients.

Official Title
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Activity of CYP3A and Genotypes of CYP3A5 and MDR1 as Predictors of the Clearance and Adverse Effects of Docetaxel, and the Effect of Docetaxel to CYP3A Activity in Previously Untreated Breast Cancer Patients

Conditions
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CYP3A Phenotyping, CYP3A5 and MDR1 Genotyping, Docetaxel Toxicity, Associations Between Genetic Data and Docetaxel Toxicity

Intervention / Treatment
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* Drug: docetaxel + CEF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects may be included in the study only if they meet all of the following criteria: The patient has received information on the purpose of the study and the meaning of the treatment, and has given verbal and written consent to participate in the study. The patient is accessible for treatment and follow-up. Histologically verified diagnosis of breast cancer High risk for recurrence ( node positive or node negative if T2 with histological grade 2 or 3, or Pgr negative) No metastases Females, age =<60 No concomitant regular medication which is either substrate, inducer or inhibitor of CYP3A4 Exclusion Criteria: Subjects will be excluded from the study for any of the following reasons: Poor performance status,>=2 according to WHO Inadequate bone marrow reserve defined as: hemoglobin < 100 g/L leukocytes < 3.0 x 10E9/L or neutrophiles < 1.5 x 10E9/L plateless < 120 x 10E9/L Inadequate liver function defined as: ALAT is > 1.5 x units of normal level elevated bilirubin (unless verified Gilbert´s syndrome) alkaline phosphatase is > 2.5 x units of normal level History of concomitant serious physical or psychiatric disease, which makes a regular cytotoxic treatment impossible cardiac insufficience; severe arrhythmia; severe hypertension; cardiac infarction within one year or other active cardiac disease pregnant or lactating patients abuse of alcohol or any narcotic substances

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Breast cancer<br>Twenty patients with verified high risk breast cancer will be included in the study. | Drug: docetaxel + CEF<br>* Docetaxel 80 mg/m² of body surface area (BSA) will be given as an i.v. infusion during 60 minutes on day 0 in a 20-day schedule. The cycle is repeated three times. Three weeks after the last docetaxel regimen, all patients will receive the CEF-combination treatment. In CEF-combination cyclophosphamide will be given 600 mg/m²of BSA as an i.v. infusion during 15 - 30 minutes on day 0 in a 20-day schedule. This is followed by fluorouracil given 600 mg/m² of BSA as an i.v. infusion during 15 - 30 minutes . Epirubicin will be given 60 mg/m² of BSA as an i.v. infusion during 15 - 30 minutes. This combination therapy will be repeated three times.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| docetaxel toxicity | There were no specific outcome measures in this study. The chemotherapy was given in a predetermined schedule and additionally blood samples were drawn for genotyping. The adverse events were recorded and compared with the data from genotyping. |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| survival | No specific outcome measures. Survival data was collected and compared with the data from genotyping. |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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docetaxel toxicity, CYP3A activity, CYP3A5, MDR1, peroral midazolam