Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients (TAMENDOX)
|ClinicalTrials.gov Identifier: NCT03931928|
Recruitment Status : Suspended (COVID-19 pandemic)
First Posted : April 30, 2019
Last Update Posted : July 7, 2020
In hormone-receptor positive breast cancer or DCIS (ductal carcinoma in situ) tamoxifen remains an important treatment option for patients before menopause and those patients after menopause who cannot be treated with aromatase-inhibitors. Nonetheless, a considerable amount of patients suffer a relapse of their cancer while on treatment with tamoxifen. Tamoxifen is a drug that is metabolized to a variety of compounds by the human liver, and the most important antihormonally active metabolite is called (Z)-Endoxifen. It is known that patients who have a reduced or absent activity of the drug-metabolizing enzyme CYP2D6 have lower levels of (Z)-Endoxifen. Furthermore, it has been observed that patients on tamoxifen therapy who have absent CYP2D6 activity are at a 2-fold increased risk for disease recurrence, and patients with lower CYP2D6 compared to patients with normal CYP2D6 activity still have a 1.4-fold increased risk for disease recurrence.
This trial will include patients who are already on tamoxifen therapy for at least 3 months and is designed to show that in patients with absent or low CYP2D6 activity, (Z)-Endoxifen supplementation - that is giving (Z)-Endoxifen in addition to tamoxifen for the study period of 42 days - can increase blood levels of (Z)-Endoxifen to therapeutic concentrations. It is planned to included 504 patients in this blinded, randomized trial, which will have a placebo group (receiving no (Z)-Endoxifen) and two intervention groups that will receive 0, 1.5 or 3 mg (Z)-Endoxifen depending on their CYP2D6 genetics or their (Z)-Endoxifen levels at the start of the study.
The trial is not designed to evaluate outcome measures (that is recurrence or survival rates) of (Z)-Endoxifen supplementation in tamoxifen treated patients, but will document the safety of the combined administration of tamoxifen and (Z)-Endoxifen.
|Condition or disease||Intervention/treatment||Phase|
|Breast Cancer DCIS||Drug: (Z)-Endoxifen supplementation according to genotype Drug: (Z)-Endoxifen supplementation according to plasma levels||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||750 participants|
|Intervention Model:||Parallel Assignment|
|Official Title:||Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients (TAMENDOX)|
|Actual Study Start Date :||September 10, 2019|
|Estimated Primary Completion Date :||March 2021|
|Estimated Study Completion Date :||December 2021|
No Intervention: Control group (Group 1)
All patients receive Placebo
Experimental: Group 2
Patients will receive (Z)-endoxifen dosed according to CYP2D6 "genotype"
Drug: (Z)-Endoxifen supplementation according to genotype
Group 2: CYP2D6 genotype predicted intermediate metabolizer receive 1.5 mg, poor metabolizer receive 3 mg (Z)-Endoxifen and extensive or ultrarapid metabolizer receive 0 mg endoxifen (Placebo)
Experimental: Group 3
Patients will receive (Z)-endoxifen dosed according to (Z)-endoxifen steady state plasma concentrations (phenotype) at screening
Drug: (Z)-Endoxifen supplementation according to plasma levels
Group 3: Patients will receive (Z)-endoxifen according to (Z)-endoxifen steady state plasma concentrations (phenotype) at screening (i.e. ≤ 15 nM receive 3 mg, > 15 and ≤ 25 nM receive 1.5 mg (Z)-Endoxifen and > 25 nM receive 0 mg (Placebo)
- (Z-)endoxifen plasma concentration > 32 nM [ Time Frame: 42 days (-2 days/+7 days) ]The primary endpoint is reached if in one or both intervention groups, the proportion of patients with steady state (Z)-endoxifen plasma concentration > 32 nM is greater or equal to the proportion of patients in the control group that reaches steady state (Z)-endoxifen plasma concentration of > 32 nM
- Increase in steady state (Z)-endoxifen concentration [ Time Frame: 42 days (-2 days/+7 days) ]Increase in steady state (Z)-endoxifen concentration from baseline to end of intervention (Visit 3) in patients with or without supplementation of (Z)-endoxifen
- Change in steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen and other tamoxifen metabolites following (Z-)endoxifen supplementation [ Time Frame: 42 days (-2 days/+7 days) ]Assessment of steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen, and other tamoxifen metabolites following (Z)-endoxifen supplementation for 6 weeks
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]) [ Time Frame: AE/SAE occurring while the subject is on IMP, or within 28 days of the patient's last dose of IMP ]All AE/SAE occuring in the intervention period will descriptively reported
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03931928
|Principal Investigator:||Matthias Schwab, Prof. Dr.||Margarete Fischer-Bosch-Institute of Clinical Pharmacology|