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

NCT ID: NCT03931928

Last Updated: 2021-09-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 356 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-10
• Study Completion Date: 2021-05-03

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.

Conditions

Breast Cancer; DCIS

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Control group (Group 1)

All patients receive Placebo

Group Type: NO_INTERVENTION

No interventions assigned to this group

Group 2

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

Group Type: EXPERIMENTAL

(Z)-Endoxifen supplementation according to genotype

Intervention Type: DRUG

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)

Group 3

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

Group Type: EXPERIMENTAL

(Z)-Endoxifen supplementation according to plasma levels

Intervention Type: DRUG

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)

Interventions

(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)

Intervention Type: 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)

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Robert Bosch Gesellschaft für Medizinische Forschung mbH (RBMF)

OTHER

Sponsor Role: lead

Responsible Party

Matthias Schwab

Prof. Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matthias Schwab, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Margarete Fischer-Bosch-Institute of Clinical Pharmacology

Locations

Gemeinschaftspraxis für Gynäkologie und Geburtshilfe Salzgitter

Salzgitter, Albert-Schweitzer-Straße 18, Germany

Zentralklinikum Suhl, Klinik für Frauenheilkunde/Geburtsmedizin, Zentrum für klinische Studien

Suhl, Albert-Schweitzer-Straße 2, Germany

Rems-Murr-Klinikum-Winnenden, Frauenklinik

Winnenden, Am Jakobsweg 1, Germany

Robert-Bosch-Krankenhaus

Stuttgart, Auerbachstr. 112, Germany

Onkologische Gemeinschaftspraxis Hildesheim, Gynäkologie

Hildesheim, Bahnhofsplatz 5, Germany

Johanniter-Krankenhaus Stendal, Klinik für Frauenheilkunde und Geburtshilfe

Stendal, Bahnhofstr. 24-26, Germany

Klinikum Magdeburg, Klinik für Hämatologie/Onkologie

Magdeburg, Birkenallee 34, Germany

Klinikum Memmingen, Brustzentrum

Memmingen, Bismarckstraße 23, Germany

Klinikum am Bruderwald Bamberg, Hämatologie/Internistische Onkologie

Bamberg, Buger Straße 80, Germany

MVZ am Klinikum am Bruderwald Bamberg

Bamberg, Buger Straße 80, Germany

Universitätsfrauenklinik Tübingen

Tübingen, Calwer Straße 7, Germany

Helios Klinikum Gifhorn, Interdisziplinäres Brustzentrum

Gifhorn, Campus 6, Germany

ViDiA Christliche Kliniken Karlsruhe, Frauenklinik

Karlsruhe, Diakonissenstr.28, Germany

Klinikum Quedlinburg, Frauenklinik

Quedlinburg, Ditfurter Weg 24, Germany

Klinikum Höchst Frankfurt am Main, Klinik für Gynäkologie und Geburtshilfe

Frankfurt am Main, Gotenstr. 6-8, Germany

Evangelisches Diakonie-Krankenhaus Bremen, Frauenklinik

Bremen, Gröpelinger Heerstraße 406-408, Germany

Onkologische Gemeinschaftspraxis Brudler-Heinrich-Bangerter Augsburg

Augsburg, Halderstraße 29, Germany

medius Klinik Ostfildern-Ruit, Brustzentrum

Ostfildern, Hedelfingerstraße 166, Germany

Helios Universitätsklinikum Wuppertal GmbH, Brustzentrum

Wuppertal, Heusnerstraße 40, Germany

Klinikum Esslingen, Klinik für Frauenheilkunde, Brustzentrum

Esslingen am Neckar, Hirschlandstraße 97, Germany

SRH Kliniken Sigmaringen, Gynäkologie und Geburtshilfe

Sigmaringen, Hohenzollerstr. 40, Germany

Harz-Klinikum Wernigerode, Abteilung Gynäkologie und Geburtshilfe

Wernigerode, Ilsenburger Straße 15, Germany

Klinikum Passau, Gynäkologische Onkologie

Passau, Innstraße 76, Germany

St. Johannes Hospital Dortmund, Klinische Forschung

Dortmund, Johannesstraße 9-17, Germany

Marienhospital Bottrop, Klinik für Gynäkologie und Geburtshilfe

Bottrop, Josef-Albers-Straße 70, Germany

Universitätsfrauenklinik Mainz, Klinik und Poliklinik für Geburtshilfe und Frauenheilkunde

Mainz, Langenbeckstr. 1, Germany

Onkozentrum Dresden, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie

Dresden, Leipziger Straße 120, Germany

HELIOS Dr. Horst Schmidt Kliniken Wiesbaden, Klinik für Gynäkologie und gyn. Onkologie

Wiesbaden, Ludwig-Erhard-Straße 100, Germany

Luisenkrankenhaus Düsseldorf GmbH & Co. KG, Brustzentrum

Düsseldorf, Luise-Rainer-Straße 6-10, Germany

Marienhospital Witten, Brustzentrum

Witten, Marienplatz 2, Germany

Städtisches Klinikum Karlsruhe, Frauenklinik

Karlsruhe, Moltkestr. 90, Germany

Kliniken der Stadt Köln, Brustzentrum Köln-Holweide

Cologne, Neufelder Straße 32, Germany

Diakonissen-Krankenhaus Speyer, Klinik für Gynäkologie und Geburtshilfe

Speyer, Paul-Egell-Straße 33, Germany

Klinikum Ludwigsburg, Frauenklinik

Ludwigsburg, Posilipostraße 4, Germany

DRK Kliniken Berlin-Köpenick, Frauenklinik

Köpenick, Salvador-Allende-Straße 2-8, Germany

MVZ Eggenfelden, Gynäkologische Onkologie

Eggenfelden, Schellenbruckerstr. 15, Germany

Klinikum am Steinenberg Reutlingen, Frauenklinik

Reutlingen, Steinenbergstr. 31, Germany

SRH Wald-Klinikum Gera GmbH, Klinik für Frauenheilkunde/Geburtsmedizin

Gera, Straße Des Friedens 122, Germany

Elisabeth Krankenhaus Kassel gGmbH, Brustzentrum

Kassel, Weinbergstr. 7, Germany

MVZ am Schlosssee Gifhorn

Gifhorn, Zur Allerwelle 4, Germany

Countries

Germany

Other Identifiers

2016-000418-31

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

IKP275 / GBG91

Identifier Type: -

Identifier Source: org_study_id