Clinical trial NCT01110291: Study of Usefulness of Genotyping to Predict Docetaxel Exposure and Adverse Events
Official title: 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
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: CYP3A Phenotyping
CYP3A5 and MDR1 Genotyping
Docetaxel Toxicity
Associations Between Genetic Data and Docetaxel Toxicity
Keywords: docetaxel toxicity
CYP3A activity
CYP3A5
MDR1
peroral midazolam
Lead sponsor: University of Turku
Sponsor class: OTHER
Collaborators: name: Sanofi
name: Turku University Hospital
name: Vaasa Central Hospital, Vaasa, Finland
name: medbase Oy Ltd
First posted: 2010-04-26
Enrollment: 20
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Twenty patients with verified high risk breast cancer.

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

Subjects may be included in the study only if they meet all of the following criteria:

1. 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.
2. Histologically verified diagnosis of breast cancer
3. High risk for recurrence ( node positive or node negative if T2 with histological grade 2 or 3, or Pgr negative)
4. No metastases
5. Females, age =\<60
6. 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:

1. Poor performance status,\>=2 according to WHO
2. 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
3. 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
4. History of concomitant serious physical or psychiatric disease, which makes a regular cytotoxic treatment impossible
5. cardiac insufficience; severe arrhythmia; severe hypertension; cardiac infarction within one year or other active cardiac disease
6. pregnant or lactating patients
7. abuse of alcohol or any narcotic substances

Primary outcomes:
measure: docetaxel toxicity
Secondary outcomes:
measure: survival
Other outcomes:
Locations:
city: Turku
country: Finland
facility: Turku University Hospital
Study officials:
affiliation: Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland
name: Johanna Hilli, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Oncology, Vaasa Central Hospital, Vaasa, Finland
name: Liisa Sailas, MD
role: STUDY_CHAIR
affiliation: Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland
name: Sirkku Jyrkkiö, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland
name: Seppo Pyrhönen, MD, PhD
role: STUDY_CHAIR
affiliation: medbase Oy Ltd, Turku, Finland
name: Kari Laine, MD, PhD
role: STUDY_CHAIR
References:
citation: Hilli J, Sailas L, Jyrkkio S, Pyrhonen S, Laine K. NCT01110291: induction of CYP3A activity and lowered exposure to docetaxel in patients with primary breast cancer. Cancer Chemother Pharmacol. 2011 Jun;67(6):1353-62. doi: 10.1007/s00280-010-1426-6. Epub 2010 Aug 27.