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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03931928
Recruitment Status : Completed
First Posted : April 30, 2019
Last Update Posted : September 17, 2021
Sponsor:
Information provided by (Responsible Party):
Matthias Schwab, Robert Bosch Gesellschaft für Medizinische Forschung mbH

Study Description
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Brief Summary:

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 356 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
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
Actual Primary Completion Date : May 3, 2021
Actual Study Completion Date : May 3, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arms and Interventions
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Arm Intervention/treatment
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)


Outcome Measures
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Primary Outcome Measures :
  1. (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


Secondary Outcome Measures :
  1. 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

  2. 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


Other Outcome Measures:
  1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]) [ Time Frame: AE/SAE occurring while the subject is on IMP, or within 30 days of the patient's last dose of IMP ]
    All AE/SAE occuring in the intervention period will descriptively reported


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Patients with ductal carcinoma in situ (DCIS) or early stage breast cancer.
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent obtained prior to study entry. The patient must be accessible for scheduled visits and treatment.
  2. Pre- and postmenopausal women with ductal carcinoma in situ (DCIS) or early stage breast cancer. This includes stage I, IIA, IIB, and IIIA breast cancers.
  3. ER+/PR+, ER+/PR- or ER-/PR+ receptor status. Criteria for endocrine sensitivity is ≥1% ER-positive or PR-positive tumor cells on immune-histochemical staining
  4. Patients on standard tamoxifen monotherapy (20 mg/d) for at least three months or patients who had switched from AI to tamoxifen who are on tamoxifen treatment for at least three months
  5. Age ≥ 18 years
  6. Body mass index of 18.5 to 35.0 kg/m2
  7. The Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  8. Absolute neutrophil count greater than or equal to 1 500/µL
  9. Platelets greater than or equal to 100 000/µL
  10. Total bilirubin within less than or equal to 1.5 times institutional upper limit of normal
  11. AST/ALT less than or equal to 2.5 times institutional upper limit of normal

  12. The subjects need to be either

    1. of non-childbearing potential (documented postmenopausal status, defined as no menses for 12 months without an alternative medical cause, or post hysterectomy, bilateral salpingectomy or bilateral oophorectomy) or
    2. of childbearing potential (WOCBP) with negative serum pregnancy test (due to the known reproduction toxicity of tamoxifen found in preclinical studies, WOCBP need to use a highly effective non-hormonal contraception. These are copper IUDs, bilateral tubal ligation, a vasectomized partner (vasectomy at least three months prior to screening) or sexual abstinence. Male or female condoms with/ without spermicide or caps, diaphragms or sponges with spermicide are associated with a failure rate > 1% per year and are thus not sufficient during the intervention period.
  13. Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE version 5.0 Grade ≤ 2 (except alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion)
  14. Surgery and radiation therapy of the breast has to be completed upon study entry

Exclusion Criteria:

  1. Subjects who are unable to understand written and verbal instructions
  2. Locally advanced (Stadium IIIB or IIIC) or metastatic (Stage IV) breast cancer at the time of surgery
  3. Ongoing chemotherapy and/or treatment with trastuzumab within the last three months; participation in another trial with any investigational/not-marketed drug within 3 months prior to baseline visit
  4. Other active second malignancy
  5. Invalid result of genotyping
  6. Pregnancy
  7. Breast feeding/lactation
  8. Oral contraceptives containing estrogens and/or progesterones
  9. Pathologic vaginal bleeding in pre-menopausal women or vaginal bleeding in post-menopausal patients
  10. Current severe acute somatic or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in judgement of the investigator, would make the patient inappropriate for entry into this study.
  11. Severe chronic cardiac or pulmonary disease (heart failure NYHA class 3 and 4), COPD GOLD C or D
  12. Chronic or acute renal disease with a glomerular filtration rate < 60 ml/min/1.73 m2, and any patient on peritoneal dialysis or hemodialysis
  13. Medical history of thromboembolism (deep vein thrombosis or pulmonary embolism)
  14. QTc interval >0.47 sec at screening ECG

  15. Concurrent treatment with strong to moderate inhibitors of CYP2D6 which may alter tamoxifen metabolism (Consortium on Breast Cancer Pharmacogenomics 2008):

    paroxetine, fluoxetine, bupropion, quinidine and duloxetine, diphenhydramine, thioridazine, amiodarone, cimetidine, sertraline

  16. Known allergies against an ingredient of the investigational product or tamoxifen
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03931928


Locations
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Sponsors and Collaborators
Robert Bosch Gesellschaft für Medizinische Forschung mbH
Investigators
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Principal Investigator: Matthias Schwab, Prof. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology
More Information
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Layout table for additonal information
Responsible Party: Matthias Schwab, Prof. Dr. med., Robert Bosch Gesellschaft für Medizinische Forschung mbH
ClinicalTrials.gov Identifier: NCT03931928    
Other Study ID Numbers: IKP275 / GBG91
2016-000418-31 ( EudraCT Number )
First Posted: April 30, 2019    Key Record Dates
Last Update Posted: September 17, 2021
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Matthias Schwab, Robert Bosch Gesellschaft für Medizinische Forschung mbH:
tamoxifen
endoxifen
endocrine receptor positive breast cancer
adjuvant therapy
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Tamoxifen
Estrogen Antagonists
Hormone Antagonists
 Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Bone Density Conservation Agents