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

Breast Cancer Clinical Trial

— TAMENDOX  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03931928
• Other study ID #: IKP275 / GBG91
• Secondary ID: 2016-000418-31
• Status: Completed
• Phase: Phase 2
• Start date: September 10, 2019
• Est. completion date: May 3, 2021

Study information

• Verified date: September 2021
• Source: Robert Bosch Gesellschaft für Medizinische Forschung mbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 356
• Est. completion date: May 3, 2021
• Est. primary completion date: May 3, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• DCIS

Intervention

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)
• (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)

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Robert Bosch Gesellschaft für Medizinische Forschung mbH

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Primary	(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	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)
Secondary	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)