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Tamoxifen

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Estrogen Receptor Modulators

Patients will receive (Z)-endoxifen dosed according to CYP2D6 "genotype"

Patients will receive (Z)-endoxifen dosed according to (Z)-endoxifen steady state plasma concentrations (phenotype) at screening

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)

(Z)-Endoxifen supplementation according to genotype

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 supplementation according to plasma levels

Matthias Schwab, Prof. Dr.

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.

Patients with ductal carcinoma in situ (DCIS) or early stage breast cancer.

Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients

Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients (TAMENDOX)

All AE/SAE occuring in the intervention period will descriptively reported

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 from baseline to end of intervention (Visit 3) in patients with or without supplementation of (Z)-endoxifen

Assessment of steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen, and other tamoxifen metabolites following (Z)-endoxifen supplementation for 6 weeks

Robert Bosch Gesellschaft für Medizinische Forschung mbH

Prof. Dr. med.

Dose escalation of tamoxifen in patients with low endoxifen levels

Howard Gurney, MBBS,FRACP

Tamoxifen is an important drug for the treatment of breast cancer. Used adjuvantly after operation in early breast cancer, tamoxifen reduces annual recurrence rate by half and cancer death by one third. Used preventatively it also reduces the risk of breast cancer by 50% in women at high risk for developing the disease Tamoxifen needs to be activated in the body to an active form called endoxifen, mainly by the enzyme called CYP2D6. Patients have variable capability to activate tamoxifen due to variable function of this enzyme. Studies showed clear correlation of specific genetic variant of CYP2D6 with endoxifen blood levels. It is estimated that up to 25% Caucasian population have reduced or even absent CYP2D6 function. More recently, there were studies that showed the correlation with genetic variant of CYP2D6 and breast cancer relapse in early breast cancer patients treated with tamoxifen. Food and Drug Authority (FDA) in America and recommended checking CYP2D6 genotype in patients receiving tamoxifen treatment, but they did not specify how to interpret the genotype results and what kind actions to take in patient with adverse genotype. The aim of the investigators study is to see if increasing tamoxifen in patients with genetic polymorphism of CYP2D6 will increase endoxifen level to the same range of most patients who have wild type (normal functional)CYP2D6.

Study of Tamoxifen Dose Escalation in Breast Cancer Patients With CYP2D6 Polymorphisms

A Multi-Centre Study of Tamoxifen Dose Escalation Study in Breast Cancer Patients With CYP2D6 Polymorphisms

St George Hospital, Australia

Western Sydney Local Health District

A/Prof Howard Gurney

Carcinoma

Afimoxifene

Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen will be measured.

i) a self-testing capillary kit, the rhelise™ kit for measuring the concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen and ii) a patient interactive digital tool (app) mBraze to collect data about symptoms and guide breast cancer patients on adjuvant tamoxifen.

Tamoxifen 20 mg

Elham Hedayati, MD PhD

Tamoxifen is a potent and effective drug reducing the risk of dying from breast cancer in the adjuvant setting. Although more modern drugs have partly replaced tamoxifen, it is helpful in the neoadjuvant and metastatic settings as a single drug. Despite that, in the adjuvant setting, it is a valuable drug.

This study aims to validate and study the feasibility of serial assessments, including therapeutic drug monitoring of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen by capillary blood sampling, combined with patient-reported symptom scores. This will provide preliminary data to allow us to develop a future multicentre randomised clinical trial of personalised dose monitoring and adjustment of adjuvant tamoxifen therapy to enhance the quality of life and breast cancer outcomes.

This repeated-measures, prospective, open-label, single-centre study is designed for women with stage 0-3 breast cancer receiving adjuvant tamoxifen 20 mg/day.

Inclusion criteria:

1. Female patients aged ≥ 18 years with hormone-positive stage 0-3 breast cancer.
2. Performance status Eastern Cooperative Oncology Group (ECOG) 0-2.
3. Ongoing daily adjuvant tamoxifen minimum of 2 months ± gonadotropin-releasing hormone (GnRH) analogues ± radiation therapy (RT) for stage 3 breast cancer.
4. Locally recurrent disease, previously treated with adjuvant tamoxifen.
5. Able to use software applications developed specifically for small, wireless computing devices, such as smartphones and tablets.
6. Have small, wireless computing devices, such as smartphones and tablets.

Exclusion Criteria:

1. Fulfilling any of the contraindications for tamoxifen.
2. Metastatic (stage IV) breast cancer.
3. Included in other clinical studies receiving not approved investigational medicinal drug.
4. Ongoing pregnancy or lactation.
5. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

No. Of Subjects: 40 female subjects.

Measured components: Tamoxifen, 4-hydroxytamoxifen and Z-endoxifen

Study design: Blood samples for measurement of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen will be drawn capillary in total at 4-time points, at inclusion (baseline), and after 1, 2, and 3 weeks for each participant; and venously in total at 2-time points, at inclusion (baseline), and after 3 weeks for each participant.

At each time, participants will be asked to leave 2 vials of capillary blood (50ul x2) using the rhelise™ kit and 2 samples of conventional venous blood for blood and plasma (5 ml x 2).

Therapeutic Dose Monitoring (TDM) of Tamoxifen

Therapeutic Dose Monitoring (TDM) of Tamoxifen and Its Active Metabolites in Combination With Patient-reported Symptom Scores Among Patients With Breast Cancer Receiving Adjuvant Tamoxifen Treatment

Blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen at baseline, two weeks, 1, 2, and 3 weeks by capillary and venous blood sampling (whole blood/plasma).

Correlations of blood concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen between venous blood samples and capillary blood samples (Sensitivity and specificity).

Capillary blood test concentrations of tamoxifen, 4-hydroxytamoxifen and Z-endoxifen were taken by the patient and the research nurse.

Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress score ((fatigue, insomnia, pain, body image, and systemic therapy side-effect and cognitive-, emotional-, role-, sexual and social functioning).

Correlations between tamoxifen, 4-hydroxytamoxifen and Z-endoxifen concentrations and symptom distress in the same patient.

- The interview on user acceptability and attitudes toward mBraze.

- Self-reported usability and user experience of the mBraze app measured with system usability scale (SUS).

- The interview on user acceptability and attitudes toward self-testing.

Karolinska University Hospital

MD, PhD

Increase tamoxifen dose into 40 mg/day for patients with low endoxifen level and poor/intermediate metabolizer CYP2D6 phenotype.

Patients with low endoxifen level and poor/intermediate metabolizer CYP2D6 phenotype will receive tamoxifen dose escalation into 40 mg/day.

Tamoxifen dose adjustment

Baitha P. Maggadani

The objectives of this study is to perform CYP2D6 genotyping and metabolite concentrations analysis on ER+ breast cancer patients who are taking tamoxifen and give dose recommendations based on the CYP2D6 genotypes and endoxifen levels.

Tamoxifen Dose Adjustment on Indonesian Female ER+ Breast Cancer Patients Based on CYP2D6 Genotype and Endoxifen Levels

Tamoxifen Dose Adjustment on ER+ Breast Cancer Patients Based on Genomic and Metabolite Concentrations Analysis

Nalagenetics Pte Ltd

Immune System Diseases

Hypersensitivity

Anticoagulants

Other Dietary Supplements

Citric Acid

Sodium Citrate

Citrate

tamoxifen citrate

laboratory biomarker analysis

pharmacological study

Alexandre Bodmer, MD

Khalil Zaman, MD

RATIONALE: Estrogen can promote growth of endocrine sensitive breast cancer cells. Endocrine therapy with tamoxifen citrate may fight breast cancer by blocking the use of estrogen by the tumor cells. Pharmacokinetics and -genomics can have an impact on the efficacy of the treatment.

PURPOSE: This phase III trial is studying blood samples to see if the level of active metabolites of tamoxifen can be improved in patients with breast cancer.

OBJECTIVES:

Primary

* To determine how the increase of tamoxifen citrate dose influences the level of its major metabolites in patients with hormone-sensitive breast cancer.

Secondary

* To characterize the population pharmacokinetic profile
* To investigate the role of the other CYPs
* To assess the relation between clinical symptoms and CYP2D6 genotypes and/or active metabolites levels
* To explore the correlation between genotypes/metabolites levels and clinical outcomes in terms of tumor relapse.
* To assess the feasibility, efficacy, and safety of concentration-guided adjustment of tamoxifen citrate dosage.
* To conduct other exploratory analysis based on the eventual new data coming up in the future.

OUTLINE: Patients receive oral tamoxifen citrate (at a dose of 40 mg/day) daily for 4 months in the absence of disease progression or unacceptable toxicity.

Blood samples are collected for PK, genotyping, phenotyping, and further analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients	NCT03931928	Breast Cancer DCIS	(Z)-Endoxifen s... (Z)-Endoxifen s...	18 Years -	Robert Bosch Gesellschaft für Medizinische Forschung mbH
Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients	NCT03931928	Breast Cancer DCIS	(Z)-Endoxifen s... (Z)-Endoxifen s...	18 Years -	Robert Bosch Gesellschaft für Medizinische Forschung mbH
Study of Tamoxifen Dose Escalation in Breast Cancer Patients With CYP2D6 Polymorphisms	NCT01075802	Breast Cancer CYP2D6 Polymorp...	Tamoxifen	18 Years -	Western Sydney Local Health District
Therapeutic Dose Monitoring (TDM) of Tamoxifen	NCT05133674	Breast Cancer Breast Carcinom... Breast Tumors Cancer of Breas... Malignant Neopl...	Tamoxifen 20 mg	18 Years -	Karolinska University Hospital
Tamoxifen Dose Adjustment on Indonesian Female ER+ Breast Cancer Patients Based on CYP2D6 Genotype and Endoxifen Levels	NCT04312347	ER+ Breast Canc...	Tamoxifen dose ...	18 Years -	Nalagenetics Pte Ltd
Tamoxifen Dose Adjustment on Indonesian Female ER+ Breast Cancer Patients Based on CYP2D6 Genotype and Endoxifen Levels	NCT04312347	ER+ Breast Canc...	Tamoxifen dose ...	18 Years -	Nalagenetics Pte Ltd
Tamoxifen Citrate in Patients With Breast Cancer	NCT00963209	Breast Cancer	tamoxifen citra... laboratory biom... pharmacological...	18 Years -	Centre Hospitalier Universitaire Vaudois

Spots Global Cancer Trial Database for endoxifen

Every month we try and update this database with for endoxifen cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for endoxifen

Every month we try and update this database with for endoxifen cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for endoxifen cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.