Clinical trial NCT03931928: Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients
Official title: Genotype and Phenotype Guided Supplementation of TAMoxifen Standard Therapy With ENDOXifen in Breast Cancer Patients (TAMENDOX)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
DCIS
Keywords: tamoxifen
endoxifen
endocrine receptor positive breast cancer
adjuvant therapy
Lead sponsor: Robert Bosch Gesellschaft für Medizinische Forschung mbH
Sponsor class: OTHER
First posted: 2019-04-30
Enrollment: 356
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: (Z-)endoxifen plasma concentration > 32 nM
timeFrame: 42 days (-2 days/+7 days)
Secondary outcomes:
measure: Increase in steady state (Z)-endoxifen concentration
timeFrame: 42 days (-2 days/+7 days)
measure: Change in steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen and other tamoxifen metabolites following (Z-)endoxifen supplementation
timeFrame: 42 days (-2 days/+7 days)
Other outcomes:
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability])
timeFrame: AE/SAE occurring while the subject is on IMP, or within 30 days of the patient's last dose of IMP
Locations:
city: Salzgitter
country: Germany
facility: Gemeinschaftspraxis für Gynäkologie und Geburtshilfe Salzgitter
state: Albert-Schweitzer-Straße 18
city: Suhl
country: Germany
facility: Zentralklinikum Suhl, Klinik für Frauenheilkunde/Geburtsmedizin, Zentrum für klinische Studien
state: Albert-Schweitzer-Straße 2
city: Winnenden
country: Germany
facility: Rems-Murr-Klinikum-Winnenden, Frauenklinik
state: Am Jakobsweg 1
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
state: Auerbachstr. 112
city: Hildesheim
country: Germany
facility: Onkologische Gemeinschaftspraxis Hildesheim, Gynäkologie
state: Bahnhofsplatz 5
city: Stendal
country: Germany
facility: Johanniter-Krankenhaus Stendal, Klinik für Frauenheilkunde und Geburtshilfe
state: Bahnhofstr. 24-26
city: Magdeburg
country: Germany
facility: Klinikum Magdeburg, Klinik für Hämatologie/Onkologie
state: Birkenallee 34
city: Memmingen
country: Germany
facility: Klinikum Memmingen, Brustzentrum
state: Bismarckstraße 23
city: Bamberg
country: Germany
facility: Klinikum am Bruderwald Bamberg, Hämatologie/Internistische Onkologie
state: Buger Straße 80
city: Bamberg
country: Germany
facility: MVZ am Klinikum am Bruderwald Bamberg
state: Buger Straße 80
city: Tübingen
country: Germany
facility: Universitätsfrauenklinik Tübingen
state: Calwer Straße 7
city: Gifhorn
country: Germany
facility: Helios Klinikum Gifhorn, Interdisziplinäres Brustzentrum
state: Campus 6
city: Karlsruhe
country: Germany
facility: ViDiA Christliche Kliniken Karlsruhe, Frauenklinik
state: Diakonissenstr.28
city: Quedlinburg
country: Germany
facility: Klinikum Quedlinburg, Frauenklinik
state: Ditfurter Weg 24
city: Frankfurt am Main
country: Germany
facility: Klinikum Höchst Frankfurt am Main, Klinik für Gynäkologie und Geburtshilfe
state: Gotenstr. 6-8
city: Bremen
country: Germany
facility: Evangelisches Diakonie-Krankenhaus Bremen, Frauenklinik
state: Gröpelinger Heerstraße 406-408
city: Augsburg
country: Germany
facility: Onkologische Gemeinschaftspraxis Brudler-Heinrich-Bangerter Augsburg
state: Halderstraße 29
city: Ostfildern
country: Germany
facility: medius Klinik Ostfildern-Ruit, Brustzentrum
state: Hedelfingerstraße 166
city: Wuppertal
country: Germany
facility: Helios Universitätsklinikum Wuppertal GmbH, Brustzentrum
state: Heusnerstraße 40
city: Esslingen
country: Germany
facility: Klinikum Esslingen, Klinik für Frauenheilkunde, Brustzentrum
state: Hirschlandstraße 97
city: Sigmaringen
country: Germany
facility: SRH Kliniken Sigmaringen, Gynäkologie und Geburtshilfe
state: Hohenzollerstr. 40
city: Wernigerode
country: Germany
facility: Harz-Klinikum Wernigerode, Abteilung Gynäkologie und Geburtshilfe
state: Ilsenburger Straße 15
city: Passau
country: Germany
facility: Klinikum Passau, Gynäkologische Onkologie
state: Innstraße 76
city: Dortmund
country: Germany
facility: St. Johannes Hospital Dortmund, Klinische Forschung
state: Johannesstraße 9-17
city: Bottrop
country: Germany
facility: Marienhospital Bottrop, Klinik für Gynäkologie und Geburtshilfe
state: Josef-Albers-Straße 70
city: Mainz
country: Germany
facility: Universitätsfrauenklinik Mainz, Klinik und Poliklinik für Geburtshilfe und Frauenheilkunde
state: Langenbeckstr. 1
city: Dresden
country: Germany
facility: Onkozentrum Dresden, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie
state: Leipziger Straße 120
city: Wiesbaden
country: Germany
facility: HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Klinik für Gynäkologie und gyn. Onkologie
state: Ludwig-Erhard-Straße 100
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus Düsseldorf GmbH & Co. KG, Brustzentrum
state: Luise-Rainer-Straße 6-10
city: Witten
country: Germany
facility: Marienhospital Witten, Brustzentrum
state: Marienplatz 2
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karlsruhe, Frauenklinik
state: Moltkestr. 90
city: Köln
country: Germany
facility: Kliniken der Stadt Köln, Brustzentrum Köln-Holweide
state: Neufelder Straße 32
city: Speyer
country: Germany
facility: Diakonissen-Krankenhaus Speyer, Klinik für Gynäkologie und Geburtshilfe
state: Paul-Egell-Straße 33
city: Ludwigsburg
country: Germany
facility: Klinikum Ludwigsburg, Frauenklinik
state: Posilipostraße 4
city: Berlin Köpenick
country: Germany
facility: DRK Kliniken Berlin-Köpenick, Frauenklinik
state: Salvador-Allende-Straße 2-8
city: Eggenfelden
country: Germany
facility: MVZ Eggenfelden, Gynäkologische Onkologie
state: Schellenbruckerstr. 15
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg Reutlingen, Frauenklinik
state: Steinenbergstr. 31
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera GmbH, Klinik für Frauenheilkunde/Geburtsmedizin
state: Straße Des Friedens 122
city: Kassel
country: Germany
facility: Elisabeth Krankenhaus Kassel gGmbH, Brustzentrum
state: Weinbergstr. 7
city: Gifhorn
country: Germany
facility: MVZ am Schlosssee Gifhorn
state: Zur Allerwelle 4
Study officials:
affiliation: Margarete Fischer-Bosch-Institute of Clinical Pharmacology
name: Matthias Schwab, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: