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

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; DCIS
• Intervention / Treatment: Drug: (Z)-Endoxifen supplementation according to genotype; Drug: (Z)-Endoxifen supplementation according to plasma levels

• Study Type: Interventional
• Enrollment (Actual): 356
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Albert-Schweitzer-Straße 18
    • Salzgitter, Albert-Schweitzer-Straße 18, Germany, 38226
      • Gemeinschaftspraxis für Gynäkologie und Geburtshilfe Salzgitter
  • Albert-Schweitzer-Straße 2
    • Suhl, Albert-Schweitzer-Straße 2, Germany, 98527
      • Zentralklinikum Suhl, Klinik für Frauenheilkunde/Geburtsmedizin, Zentrum für klinische Studien
  • Am Jakobsweg 1
    • Winnenden, Am Jakobsweg 1, Germany, 71364
      • Rems-Murr-Klinikum-Winnenden, Frauenklinik
  • Auerbachstr. 112
    • Stuttgart, Auerbachstr. 112, Germany, 70376
      • Robert-Bosch-Krankenhaus
  • Bahnhofsplatz 5
    • Hildesheim, Bahnhofsplatz 5, Germany, 31134
      • Onkologische Gemeinschaftspraxis Hildesheim, Gynäkologie
  • Bahnhofstr. 24-26
    • Stendal, Bahnhofstr. 24-26, Germany, 39576
      • Johanniter-Krankenhaus Stendal, Klinik für Frauenheilkunde und Geburtshilfe
  • Birkenallee 34
    • Magdeburg, Birkenallee 34, Germany, 39130
      • Klinikum Magdeburg, Klinik für Hämatologie/Onkologie
  • Bismarckstraße 23
    • Memmingen, Bismarckstraße 23, Germany, 87700
      • Klinikum Memmingen, Brustzentrum
  • Buger Straße 80
    • Bamberg, Buger Straße 80, Germany, 96049
      • Klinikum am Bruderwald Bamberg, Hämatologie/Internistische Onkologie
    • Bamberg, Buger Straße 80, Germany, 96049
      • MVZ am Klinikum am Bruderwald Bamberg
  • Calwer Straße 7
    • Tübingen, Calwer Straße 7, Germany, 72076
      • Universitätsfrauenklinik Tübingen
  • Campus 6
    • Gifhorn, Campus 6, Germany, 38518
      • Helios Klinikum Gifhorn, Interdisziplinäres Brustzentrum
  • Diakonissenstr.28
    • Karlsruhe, Diakonissenstr.28, Germany, 76199
      • ViDia Christliche Kliniken Karlsruhe, Frauenklinik
  • Ditfurter Weg 24
    • Quedlinburg, Ditfurter Weg 24, Germany, 06484
      • Klinikum Quedlinburg, Frauenklinik
  • Gotenstr. 6-8
    • Frankfurt am Main, Gotenstr. 6-8, Germany, 65929
      • Klinikum Höchst Frankfurt am Main, Klinik für Gynäkologie und Geburtshilfe
  • Gröpelinger Heerstraße 406-408
    • Bremen, Gröpelinger Heerstraße 406-408, Germany, 28239
      • Evangelisches Diakonie-Krankenhaus Bremen, Frauenklinik
  • Halderstraße 29
    • Augsburg, Halderstraße 29, Germany, 86150
      • Onkologische Gemeinschaftspraxis Brudler-Heinrich-Bangerter Augsburg
  • Hedelfingerstraße 166
    • Ostfildern, Hedelfingerstraße 166, Germany, 73760
      • medius Klinik Ostfildern-Ruit, Brustzentrum
  • Heusnerstraße 40
    • Wuppertal, Heusnerstraße 40, Germany, 42283
      • Helios Universitätsklinikum Wuppertal GmbH, Brustzentrum
  • Hirschlandstraße 97
    • Esslingen, Hirschlandstraße 97, Germany, 73730
      • Klinikum Esslingen, Klinik für Frauenheilkunde, Brustzentrum
  • Hohenzollerstr. 40
    • Sigmaringen, Hohenzollerstr. 40, Germany, 72488
      • SRH Kliniken Sigmaringen, Gynäkologie und Geburtshilfe
  • Ilsenburger Straße 15
    • Wernigerode, Ilsenburger Straße 15, Germany, 38855
      • Harz-Klinikum Wernigerode, Abteilung Gynäkologie und Geburtshilfe
  • Innstraße 76
    • Passau, Innstraße 76, Germany, 94032
      • Klinikum Passau, Gynäkologische Onkologie
  • Johannesstraße 9-17
    • Dortmund, Johannesstraße 9-17, Germany, 44137
      • St. Johannes Hospital Dortmund, Klinische Forschung
  • Josef-Albers-Straße 70
    • Bottrop, Josef-Albers-Straße 70, Germany, 46236
      • Marienhospital Bottrop, Klinik für Gynäkologie und Geburtshilfe
  • Langenbeckstr. 1
    • Mainz, Langenbeckstr. 1, Germany, 55131
      • Universitätsfrauenklinik Mainz, Klinik und Poliklinik für Geburtshilfe und Frauenheilkunde
  • Leipziger Straße 120
    • Dresden, Leipziger Straße 120, Germany, 01127
      • Onkozentrum Dresden, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie
  • Ludwig-Erhard-Straße 100
    • Wiesbaden, Ludwig-Erhard-Straße 100, Germany, 65199
      • HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Klinik für Gynäkologie und gyn. Onkologie
  • Luise-Rainer-Straße 6-10
    • Düsseldorf, Luise-Rainer-Straße 6-10, Germany, 40235
      • Luisenkrankenhaus Düsseldorf GmbH & Co. KG, Brustzentrum
  • Marienplatz 2
    • Witten, Marienplatz 2, Germany, 58452
      • Marienhospital Witten, Brustzentrum
  • Moltkestr. 90
    • Karlsruhe, Moltkestr. 90, Germany, 76133
      • Städtisches Klinikum Karlsruhe, Frauenklinik
  • Neufelder Straße 32
    • Köln, Neufelder Straße 32, Germany, 51067
      • Kliniken der Stadt Köln, Brustzentrum Köln-Holweide
  • Paul-Egell-Straße 33
    • Speyer, Paul-Egell-Straße 33, Germany, 67346
      • Diakonissen-Krankenhaus Speyer, Klinik für Gynäkologie und Geburtshilfe
  • Posilipostraße 4
    • Ludwigsburg, Posilipostraße 4, Germany, 71640
      • Klinikum Ludwigsburg, Frauenklinik
  • Salvador-Allende-Straße 2-8
    • Berlin Köpenick, Salvador-Allende-Straße 2-8, Germany, 12559
      • DRK Kliniken Berlin-Köpenick, Frauenklinik
  • Schellenbruckerstr. 15
    • Eggenfelden, Schellenbruckerstr. 15, Germany, 84307
      • MVZ Eggenfelden, Gynäkologische Onkologie
  • Steinenbergstr. 31
    • Reutlingen, Steinenbergstr. 31, Germany, 72764
      • Klinikum am Steinenberg Reutlingen, Frauenklinik
  • Straße Des Friedens 122
    • Gera, Straße Des Friedens 122, Germany, 07548
      • SRH Wald-Klinikum Gera GmbH, Klinik für Frauenheilkunde/Geburtsmedizin
  • Weinbergstr. 7
    • Kassel, Weinbergstr. 7, Germany, 34117
      • Elisabeth Krankenhaus Kassel gGmbH, Brustzentrum
  • Zur Allerwelle 4
    • Gifhorn, Zur Allerwelle 4, Germany, 38518
      • MVZ am Schlosssee Gifhorn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
(Z-)endoxifen plasma concentration > 32 nM	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	42 days (-2 days/+7 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in steady state (Z)-endoxifen concentration	Increase in steady state (Z)-endoxifen concentration from baseline to end of intervention (Visit 3) in patients with or without supplementation of (Z)-endoxifen	42 days (-2 days/+7 days)
Change in steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen and other tamoxifen metabolites following (Z-)endoxifen supplementation	Assessment of steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen, and other tamoxifen metabolites following (Z)-endoxifen supplementation for 6 weeks	42 days (-2 days/+7 days)

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: Robert Bosch Gesellschaft für Medizinische Forschung mbH
• Investigators: Principal Investigator: Matthias Schwab, Prof. Dr., Margarete Fischer-Bosch-Institute of Clinical Pharmacology

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2019
• Primary Completion (Actual): May 3, 2021
• Study Completion (Actual): May 3, 2021

Study Registration Dates

• First Submitted: April 26, 2019
• First Submitted That Met QC Criteria: April 26, 2019
• First Posted (Actual): April 30, 2019

Study Record Updates

• Last Update Posted (Actual): September 17, 2021
• Last Update Submitted That Met QC Criteria: September 16, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: adjuvant therapy; tamoxifen; endoxifen; endocrine receptor positive breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Tamoxifen
• Other Study ID Numbers: IKP275 / GBG91; 2016-000418-31 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No