The primary objective of this study is to determine the proportion of patients that reach an endoxifen level of 16 nmol/L or higher using MIPD. Secondary objectives: 1. To determine the total success rate of the POP-PK model as well as in different…
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Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the proportion of patients that reach an endoxifen
level of 16 nmol/L or higher after three months of tamoxifen treatment. The
main study parameter is the endoxifen level at 3 months after baseline.
Secondary outcome
1. The total success rate of the POP-PK model as well as in different groups,
stratified by dosage as predicted by the POP-PK model.
2. The predictive value of the POP-PK model for patients who do not reach the
16 nmol/L endoxifen threshold with the highest prescribed tamoxifen dose of 40
mg;
3. The correlation between the endoxifen values from an early blood sample (at
baseline and 4-6 weeks after baseline) and the steady-state concentration of
endoxifen;
4. The difference in incidence of side-effects and quality of life between
baseline and 3 months after tamoxifen treatment as determined by FACT-ES
questionnaires.
5. The intra-patient difference in cognitive test performance and self-reported
cognition between baseline and after two years of tamoxifen treatment.
6. The association between tamoxifen, dose, plasma concentrations of tamoxifen
and endoxifen and intra-patient differences in cognitive test performance and
self-reported cognition.
Background summary
Adjuvant treatment with tamoxifen is the standard of care for women with
estrogen receptor positive (ER+) breast cancer. Tamoxifen is converted to
endoxifen, its active metabolite, via CYP2D6 enzymes. The literature states
that an endoxifen concentration of at least 16 nmol/L is needed to produce a
therapeutic effect. Therapeutic Drug Monitoring (TDM) has been proven to be a
successful technique to reach the 16 nmol/L endoxifen threshold after 6 months.
However, in general TDM can only be used when a drug is in steady-state, which
for endoxifen is reached after 3 months for normal metabolizers. For poor- and
intermediate metabolizers, the time until steady-state is presumably even
longer. This could possibly result in undertreatment within the first 3 to 6
months of tamoxifen treatment. In this study, model-informed precision dosing
(MIPD) will be used to counter this problem. The Pharmacokinetic-model, which
is used for MIPD, includes CYP2D6 genotype, co-medication, age, body height,
BMI and CYP2D6/CYP3A inhibitor use to predict a patient tailored dose. Using
MIPD, our aim is to decrease the proportion of patients that are undertreated
within the first three months of tamoxifen treatment.
Study objective
The primary objective of this study is to determine the proportion of patients
that reach an endoxifen level of 16 nmol/L or higher using MIPD.
Secondary objectives:
1. To determine the total success rate of the POP-PK model as well as in
different groups, stratified by dosage as predicted by the POP-PK model.
2. To establish the predictive value of the POP-PK model for patients which
will not reach the 16 nmol/L endoxifen threshold with the highest prescribed
tamoxifen dose of 40 mg.
3. To test if an early blood sample (at baseline and 4-6 weeks after baseline)
is indicative for the steady-state concentration;
4. To compare the incidence of side-effects and quality of life of breast
cancer patients between baseline and the final assessment after 3 months
5. To investigate change in objective cognitive functioning, measured by a
validated online cognitive test (Amsterdam Cognition Scan), and subjective
cognitive functioning, measured by a validated questionnaire, between the start
of tamoxifen treatment and two years after start of tamoxifen treatment
6. To investigate the association between tamoxifen dose, tamoxifen plasma
concentrations and endoxifen plasma concentrations and change in objective and
subjective cognitive functioning.
Study design
This is a non-randomized, single-center, single-arm, MIPD intervention study.
The control arm will be provided by the TOTAM study (METC: 2017543/NTR:
NL6918).
Intervention
At baseline, CYP2D6 genotype, BMI and body height will be measured.
Additionally, information about concomitant CYP2D6 and CYP3A inhibitor use and
age will be collected. Based on these predictors, a patient-tailored tamoxifen
dose will be predicted at baseline using a POP-PK model. This tamoxifen dose
can either be 20, 30 or 40 mg. Patients will be seen in the out-patient clinic
for pharmacokinetic blood sampling at baseline, after 4-6 weeks and after 3
months. The tamoxifen and endoxifen levels after three months will be used to
assess the primary and secondary outcomes. At baseline, patients will be asked
to complete a cognition test.
Study burden and risks
This study may provide a more personalized adjuvant tamoxifen therapy for
breast cancer patients. Therefore, patients could benefit individually by
reaching adequate levels sooner. Over the course of the study, three blood
samples will be taken from each individual patients. The risks of these blood
samples are considered low. Additionally, the dose of 30 or 40 mg tamoxifen at
baseline may cause more side-effects than the standard dose of 20 mg tamoxifen.
However, prospective studies have shown no correlation between tamoxifen dose
and incidence of side effects. Therefore, these risks are also considered low
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Dr. Molewaterplein 40
Rotterdam 3015GD
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. Age >= 18 years;
2. WHO Performance Status <= 1
3. Patients with primary breast cancer, with a prescription for adjuvant
tamoxifen treatment.
4. Willing to abstain from strong and moderate CYP3A4 or CYP2D6 inhibitors or
inducers, according to: CYTOCHROME P450 DRUG INTERACTION TABLE - Drug
Interactions (iu.edu);
5. Able and willing to sign the Informed Consent Form;
6. Able and willing to undergo blood sampling for PK analysis.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded
from participation in this study:
1. Patients with known alcoholism, drug addiction and/or psychiatric or
physiological condition which in the opinion of the investigator would impair
treatment compliance;
2. > 2 weeks of tamoxifen treatment before inclusion
3. Patients who*s endoxifen levels have been used for therapeutic drug
monitoring in the past.
4. Evidence of a neurological disorder which might affect cognitive functioning
(only for cognition scan part)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2022-002426-28-NL |
| CCMO | NL81896.078.22 |