Clinical Trials Register

Summary
EudraCT Number:	2016-000418-31
Sponsor's Protocol Code Number:	IKP275
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-12-18
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2016-000418-31

A.3

Full title of the trial

GENOTYPE AND PHENOTYPE GUIDED SUPPLEMENTATION OF TAMOXIFEN STANDARD THERAPY WITH ENDOXIFEN IN BREAST CANCER PATIENTS.

GENOTYP- UND PHÄNOTYPBASIERTE SUPPLEMENTIERUNG EINER STANDARD-TAMOXIFENTHERAPIE MIT DEM AKTIVEN METABOLITEN ENDOXIFEN BEI BRUSTKREBS-PATIENTINNEN.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical study to investigate the effect of endoxifen therapy in breast cancer patients with reduced endoxifen blood concentration.

Klinische Studie zur Untersuchung der Wirkung einer Endoxifen-Therapie bei Brustkrebs-Patientinnen mit verringerter Endoxifen-Blutkonzentration.

A.3.2

Name or abbreviated title of the trial where available

TAMENDOX

A.4.1

Sponsor's protocol code number

IKP275

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03931928

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1237-9906

A.5.4

Other Identifiers

Name:

GBG Forschungs GmbH

Number:

GBG 91

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Robert Bosch Gesellschaft für medizinische Forschung mbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Bundesministerium für Bildung und Forschung
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Robert Bosch Gesellschaft für medizinische Forschung mbH
B.5.2	Functional name of contact point	Sponsor
B.5.3	Address:
B.5.3.1	Street Address	Auerbachstraße 112
B.5.3.2	Town/ city	Stuttgart
B.5.3.3	Post code	70376
B.5.3.4	Country	Germany
B.5.4	Telephone number	497118101 3700
B.5.5	Fax number	49711859295
B.5.6	E-mail	matthias.schwab@ikp-stuttgart.de

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	(Z)-Endoxifen (1.5mg)
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Endoxifen
D.3.9.1	CAS number	1032008-74-4
D.3.9.3	Other descriptive name	ENDOXIFEN
D.3.9.4	EV Substance Code	SUB193570
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1.5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	(Z)-Endoxifen (3mg)
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Endoxifen
D.3.9.1	CAS number	1032008-74-4
D.3.9.3	Other descriptive name	ENDOXIFEN
D.3.9.4	EV Substance Code	SUB193570
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with ductal carcinoma in situ (DCIS) or early stage breast cancer.

Patientinnen mit ductalem Carcinoma in situ (DCIS) oder Mamma-Karzinom (Stadium I, IIA, IIB und IIIA).

E.1.1.1

Medical condition in easily understood language

Patients with primary breast cancer.

Patientinnen im Frühstadium der Brustkrebserkrankung.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006199
E.1.2	Term	Breast cancer stage I
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006200
E.1.2	Term	Breast cancer stage II
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006201
E.1.2	Term	Breast cancer stage III
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To increase (Z)-endoxifen steady state concentrations in patients with compromised CYP2D6 to levels observed in patients with full CYP2D6 activity. The target concentration is >32 nM.

E.2.2

Secondary objectives of the trial

- To increase (Z)-endoxifen steady state concentrations in patients with CYP2D6 genotype predicted very low activity (PM genotype) to levels observed in patients with full CYP2D6 activity by supplementation with 3 mg/day (Z)-endoxifen (> 32 nM).
- To increase (Z)-endoxifen steady state concentrations in patients with CYP2D6 genotype predicted reduced activity (IM genotype) to levels observed in patients with full CYP2D6 activity by supplementation with 1.5 mg/day (Z)-endoxifen (> 32 nM).
- To increase (Z)-endoxifen steady state concentrations in patients with basal (Z)-endoxifen plasma levels ≤ 15 nM to levels observed in patients with full CYP2D6 activity by supplementation with 3 mg/day (Z)-endoxifen (> 32 nM).
- To increase (Z)-endoxifen steady state concentrations in patients with basal (Z)-endoxifen plasma levels > 15 nM and ≤ 25 nM to levels observed in patients with full CYP2D6 activity by supplementation with 1.5 mg/day (Z)-endoxifen (> 32 nM).
...

E.2.3

Trial contains a sub-study

E.3

Principal 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
a. 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
b. 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

E.4

Principal 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 > 470 ms 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, bupropione, quinidine and duloxetine, diphenhydramine, thioridazine, amiodarone, cimetidine, sertraline
16. Known allergies against an ingredient of the investigational product or Tamoxifen

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is reached if in one or both intervention groups, the proportion of patients with steady state (Z)-endoxifen plasma concentration > 32nM is greater or equal to the proportion of patients in the control group that reaches steady state (Z)-endoxifen plasma concentration of > 32nM.

E.5.1.1

Timepoint(s) of evaluation of this end point

E.5.2

Secondary end point(s)

- Increase in steady state (Z)-endoxifen concentration from baseline to end of intervention (Visit 3) in patients with or without supplementation of (Z)-endoxifen.
- Steady state plasma concentrations of tamoxifen, desmethyltamoxifen, 4-hydroxytamoxifen, and other tamoxifen metabolites following (Z)-endoxifen supplementation for 6 weeks.

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial ends when the last patient has completed the end of study examination (LVLS).

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

643

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

643

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

643

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None.

Keine.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-04-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-05-03

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