|- candidate number||4297|
|- NTR Number||NTR1509|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||27-okt-2008|
|- Secondary IDs||P07.234 |
|- Public Title||CYPTAM study.|
|- Scientific Title||The CYPTAM study: effect of CYP2D6 genotype on pharmacokinetics and clinical outcome in tamoxifen treated breast cancer patients.|
|- hypothesis||The prodrug tamoxifen is metabolized to its most potent metabolite endoxifen by the enzyme CYP2D6. Up to 25% of Caucasians harbour genetic variants leading to a less active CYP2D6. This may lead to lower endoxifen levels and thus lower tamoxifen efficacy. In the CYPTAM documentation study CYP2D6 genotype and endoxifen concentrations are prospectively related to tamoxifen response in the adjuvant setting. In the CYPTAM pharmacokinetic study, CYP2D6 poor and intermediate metabolizers will temporarily (2 months) receive an escalated tamoxifen dose to investigate the possibility to achieve endoxifen levels similar to those found in CYP2D6 extensive metabolizers.|
|- Healt Condition(s) or Problem(s) studied||Mamma carcinoma, Breast cancer, Early intervention, Tamoxifen|
|- Inclusion criteria||1. Pre- and postmenopausal women who will receive tamoxifen or have already been using tamoxifen during a maximum period of one year, as part of a standard adjuvant therapy for newly diagnosed breast cancer.
2. Willing and able to give written informed consent (separate for documentation and pharmacokinetics study).
3. Age >= 18 years.
|- Exclusion criteria||1. Other malignancy within the previous 5 years (except adequately treated in situ carcinoma of cervix or basal cell carcinoma).|
2. Hormone receptor negative primary tumors.
Exclusion criteria for PHARMACOKINETICS study only:
1. A medical history of venous thromboembolic events (deep venous thrombosis or pulmonary embolism).
2. Patients who are pregnant or breastfeeding.
3. Patients with a prolonged QT interval on ECG registration.
4. Hemoglobin< 6.0 mmol/L, WBC < 3.0 x 109/L, platelets < 100 x 109/L, bilirubin exceeding normal limits, ASAT and ALAT > 2.5 times the upper limit of normal.
|- mec approval received||yes|
|- multicenter trial||yes|
|- planned startdate ||1-feb-2008|
|- planned closingdate||1-feb-2013|
|- Target number of participants||650|
|- Interventions||None: |
Tamoxifen is only temporarily (2 months) escalated in a selected group of 12 poor and 12 intermediate metabolizers for pharmacokinetic purposes without expected effect on clinical outcome in the CYPTAM pharmacokinetic study.
Amendment: Only for the CYPTAM phenotyping study: patients receive once 0,5 mg/kg 13C- dextrometorphan. Target number of participants is 200.
|- Primary outcome||1. To associate CYP2D6 genotype and tamoxifen metabolite plasma concentration to relapse free survival (RFS), disease free survival (DFS) and overall survival (OS) (documentation study).|
2. To investigate the effect of a temporary one-step dose escalation of tamoxifen on endoxifen plasma concentration in poor and intermediate metabolizers (pharmacokinetics study).
Amendment: To correlate the CYP2D6 genotype and the serum endoxifen concentrations to the CYP2D6 phenotype determined by a dextromethorphan breath test (DM-BT).
|- Secondary outcome||1. To evaluate tamoxifen toxicity in patients participating in dose escalation |
|- Timepoints||Accrual period is 2 years followed by 2 years of follow-up (mean FU time is 3 years)|
|- Trial web site||N/A|
|- status||open: patient inclusion|
|- CONTACT FOR PUBLIC QUERIES||MD. V.O. Dezentje|
|- CONTACT for SCIENTIFIC QUERIES||Dr. H. Gelderblom|
|- Sponsor/Initiator ||Leiden University Medical Center (LUMC)|
(Source(s) of Monetary or Material Support)
|Leiden University Medical Center (LUMC)|
|- Brief summary||Tamoxifen is commonly used for the adjuvant treatment of breast cancer. |
However, not all women with hormone receptor positive breast cancer benefit from adjuvant tamoxifen. This variable response on tamoxifen may partially be explained by individual differences in biotransformation of tamoxifen to active metabolites.
Tamoxifen is considered a pro-drug and is metabolized to its most active metabolite endoxifen by the hepatic enzyme CYP2D6. Enzymatic activity is highly associated with CYP2D6 genotype. Several - mostly retrospective - studies have associated the poor metabolizer (PM) genotype *4/*4 and the intermediate metabolizer (IM) genotype *1/*4 with worse clinical outcome compared to the extensive metabolizer (EM) genotype *1/*1. However, as some other studies show conflicting results, more and preferably prospective studies are needed. Currently, only the variant *4 allele (being one of the > 80 CYP2D6 alleles known to date) has been investigated in Caucasian populations. Therefore, estimation of the impact of other CYP2D6 genotypes on tamoxifen efficacy is warranted.
Endoxifen plasma concentrations may also be a predictor of tamoxifen response. Previous studies showed significantly lower endoxifen plasma concentrations in poor metabolizers compared to extensive metabolizers, but did not (yet) associate this with outcome. Increasing the administered tamoxifen dose in poor and intermediate metabolizers, may consequently increase endoxifen plasma concentrations and thus tamoxifen response.
Prospective studies may help introduce CYP2D6 genotyping as a tool to tailor hormonal treatment of breast cancer in the future. We started a prospective study that will associate many different CYP2D6 genotypes by Amplichip as well as endoxifen plasma concentration with tamoxifen efficacy.
Amendment: CYP2D6 phenotype will be determined by a 13C-dextromethorphan breath test and correlated to the CYP2D6 genotype and endoxifen levels.
Furthermore, we will investigate the effect of dose escalation in PMs and IMs on endoxifen levels. The CYPTAM study is therefore subdivided into three different studies:
1. CYPTAM Documentation Study
Two blood samples from each participant will be collected after >= 2 months of tamoxifen therapy. CYP2D6 genotype and endoxifen plasma concentration will be determined and associated with clinical outcome;
2. CYPTAM Pharmacokinetics Study;
3. CYPTAM Phenotyping Study (amendment): One blood sample from each participant of the CYPTAM documentation study will be collected after >= 2 months of tamoxifen therapy and endoxifen plasma concentration will be determined and associated with CYP2D6 phenotype, determined by a 13C-dextromethorphan breath test. Fifty minutes after ingestion of 0,5 mg/kg 13C-dextromethorphan, patients will exhale in a 1.3 L breath bag. A 13CO2/12CO2 ratio will be determined by infrared spectrophotometry. Delta-over-baseline after 50 minutes (DOB50) values were calculated from baseline and postdose 13CO2/12CO2 ratios, reflecting CYP2D6 activity.
After genotyping is performed as part of the documentation study, only poor and intermediate metabolizers will be approached to participate in a genotype-directed dose escalation study. Patients will be asked to visit the LUMC twice for endoxifen plasma concentration analysis during two months use of an increased tamoxifen dosage. After these 2 months patients will be set back to their standard tamoxifen dose of 20 mg.
All studies require separate informed consent: patients participating in the documentation study are not automatically included in the pharmacokinetics study and phenotyping study.
|- Main changes (audit trail)|
|- RECORD||27-okt-2008 - 8-sep-2011|