Clinical Trials Register

Summary
EudraCT Number:	2017-002930-22
Sponsor's Protocol Code Number:	IOM-050371
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:	2017-11-22
Trial results	View 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

2017-002930-22

A.3

Full title of the trial

A randomized, open-label, multicenter, two-arm, phase III study to evaluate efficacy and quality of life in patients with metastatic hormone receptor-positive HER2-negative breast cancer receiving ribociclib in combination with endocrine therapy or chemotherapy with or without bevacizumab in first line

Randomisierte, offene, zwei-armige Phase III Studie zur Untersuchung der Wirksamkeit und der Lebensqualität von Patientinnen mit metastasiertem HER2-negativem, Hormonrezeptor-positivem Brustkrebs unter Erstlinienbehandlung mit endokriner Therapie in Kombination mit Ribociclib oder Chemotherapie mit / ohne Bevacizumab.

A.3.1

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

A clinical study to evaluate efficacy and quality of life in postmenopausal patients with metastatic hormone receptor-positive HER2-negative breast cancer receiving ribociclib in combination with endocrine therapy or chemotherapy with or without bevacizumab in first line

Klinische Studie zur Untersuchung der Wirksamkeit und der Lebensqualität von postmenopausalen Patientinnen mit metastasiertem HER2-negativem, Hormonrezeptor-positivem Brustkrebs unter Erstlinienbehandlung mit endokriner Therapie in Kombination mit Ribociclib oder Chemotherapie mit / ohne Bevacizumab.

A.3.2

Name or abbreviated title of the trial where available

RIBBIT

A.4.1

Sponsor's protocol code number

IOM-050371

A.5.4

Other Identifiers

Name:	Study code Novartis	Number:	CLEE011ADE04T
Name:	AIO code	Number:	AIO-MAM-0117/ass

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	iOMEDICO AG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma GmbH
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	iOMEDICO AG
B.5.2	Functional name of contact point	Dr. Beate Niemeier
B.5.3	Address:
B.5.3.1	Street Address	Ellen-Gottlieb-Straße 19
B.5.3.2	Town/ city	Freiburg
B.5.3.3	Post code	79106
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49761152420
B.5.5	Fax number	+497611524280
B.5.6	E-mail	info@iomedico.com

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	Yes
D.2.1.1.1	Trade name	Kisqali
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	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	RIBOCICLIB
D.3.9.1	CAS number	1211441-98-3
D.3.9.4	EV Substance Code	SUB180246
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	200
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	Comparator
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PACLITAXEL
D.3.9.1	CAS number	33069-62-4
D.3.9.4	EV Substance Code	SUB09583MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	6
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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: 3
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	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	EXEMESTANE
D.3.9.1	CAS number	107868-30-4
D.3.9.4	EV Substance Code	SUB07492MIG
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	25
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: 4
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	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	ANASTROZOLE
D.3.9.1	CAS number	120511-73-1
D.3.9.4	EV Substance Code	SUB05502MIG
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
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: 5
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	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	LETROZOLE
D.3.9.1	CAS number	112809-51-5
D.3.9.4	EV Substance Code	SUB08444MIG
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	2.5
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: 6
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BEVACIZUMAB
D.3.9.1	CAS number	216974-75-3
D.3.9.4	EV Substance Code	SUB16402MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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: 7
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	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	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	300
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Capecitabine
D.3.9.1	CAS number	154361-50-9
D.3.9.3	Other descriptive name	CAPECITABINE
D.3.9.4	EV Substance Code	SUB12474MIG
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	500
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: 8
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fulvestrant
D.3.9.1	CAS number	129453-61-8
D.3.9.3	Other descriptive name	FULVESTRANT
D.3.9.4	EV Substance Code	SUB13933MIG
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	250
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: 9
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Implant
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GOSERELIN
D.3.9.1	CAS number	65807-02-5
D.3.9.4	EV Substance Code	SUB07962MIG
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	3.6
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: 10
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Prolonged-release suspension for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intramuscular use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEUPRORELIN ACETATE
D.3.9.1	CAS number	74381-53-6
D.3.9.4	EV Substance Code	SUB02900MIG
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	3.75
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: 11
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Prolonged-release suspension for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEUPRORELIN ACETATE
D.3.9.1	CAS number	74381-53-6
D.3.9.4	EV Substance Code	SUB02900MIG
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	11.25
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

The study will include adult women with HR-positive, HER2-negative advanced breast cancer with visceral metastases, who received no prior therapy for advanced disease.

Diese Studie schließt erwachsene weibliche Patientinnen mit HR-positivem, HER2-negativem Brustkrebs mit viszeralen Metastasen ein, die keine vorangegangene Therapie in der fortgeschrittenen Situation erhalten haben.

E.1.1.1

Medical condition in easily understood language

The study population includes patients with metastatic hormone receptor-positive HER2-negative breast cancer, who received no prior therapy for advanced disease.

Die Studie umfasst Patientinnen mit metastasiertem HER2-negativem, Hormonrezeptor-pos. Brustkrebs, die keine vorangegangene Therapie in der fortgeschrittenen Situation erhalten haben.

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10057654
E.1.2	Term	Breast cancer female
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.1.2 Medical condition or disease under investigation

E.1.2	Version	23.0
E.1.2	Level	LLT
E.1.2	Classification code	10070577
E.1.2	Term	Oestrogen receptor positive breast cancer
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	20.1
E.1.2	Level	PT
E.1.2	Classification code	10055113
E.1.2	Term	Breast cancer metastatic
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 compare the efficacy in terms of progression free survival (PFS) of ribociclib plus endocrine therapy with capecitabine with bevacizumab or paclitaxel with or without bevacizumab as first-line treatment of adult women with HR-positive, HER2-negative advanced breast cancer presenting with visceral metastasis.

Vergleich der Wirksamkeit gemessen am progressionsfreien Überleben (PFS) der Kombination von Ribociclib mit einem Aromataseinhibitor (AI) / Fulvestrant gegen Capecitabin mit Bevacizumab oder Paclitaxel mit / ohne Bevacizumab als Erstlinientherapie des HR positiven, HER2 negativen Mammakarzinom mit viszeraler Metastasierung bei erwachsenen Patientinnen

E.2.2

Secondary objectives of the trial

Secondary objectives:
- To assess and compare the two treatment arms with respect to the following efficacy outcomes: response rates, clinical benefit rate (CBR), time to response (TTR) and overall survival (OS).
- To determine safety and tolerability in the two treatment arms in terms of (S)AEs, ECOG performance status, routine safety laboratory and electrocardiogram.
- To evaluate and compare patient reported health-related QoL in terms of EORTC QLQ-C30 scores and single questions on burden by side effects and time spent on treatment in the two treatment arms.

Sekundäre Studienziele:
- Vergleich der beiden Studienarme hinsichtlich der folgenden Wirksamkeitsparameter: Ansprechraten (ORR), klinische Benefitrate (CBR), Zeit bis zum Ansprechen (TTR) und Gesamtüberleben (OS).
- Bestimmung der Sicherheit und Verträglichkeit der beiden Behandlungsarme hinsichtlich der (S)UEs, ECOG Performance Status, Routinelaboruntersuchungen und Elektrokardiogramm.
- Einschätzung und Vergleich der beiden Behandlungsarme in Bezug auf die gesundheitsbezogene Lebensqualität (QoL) mittels Auswertung des EORTC QLQ-C30 Fragebogen sowie weiterer Einzelfragen zur Belastung durch Nebenwirkungen der Therapie und Zeitaufwand für die Therapie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Locally confirmed diagnosis of metastatic adenocarcinoma of the breast without prior systemic antineoplastic therapy in the palliative setting.
• Hormone receptor (HR)-positive disease, defined as estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive.
• Human epidermal growth factor receptor 2 (HER2)-negative disease (defined as IHC status HER2 negative/+ or IHC HER2++ with CISH/FISH negative).
• Any menopausal status. If pre-/perimenopausal, agreement to receive LHRH (goserelin or leuprorelin) agonist / ovarian ablation in case of randomization to arm A.
• Women with child bearing potential must agree to use an effective method of contraception while taking study medication and for the time-period indicated in the respective SmPC thereafter.
• Presence of visceral metastases (additional non-visceral metastases are allowed).
• Presence of target and / or non-target lesions according to RECIST v1.1
• Patients eligible for palliative treatment with AI / fulvestrant + ribociclib and capecitabine + bevacizumab or paclitaxel + / - bevacizumab according to the respective SmPCs.
• Signed written informed consent prior to beginning of protocol-specific procedures.

• Frauen mit vor Ort bestätigter Diagnose eines metastasierten Adenokarzinom der Brust ohne vorangegangene systemische antineoplatische Therapie in der palliativen Situation.
• Hormonrezeptor (HR)-positive Erkrankung, definiert als Östrogenrezeptor (ER)-positiv und / oder Progesteronrezeptor (PgR)-positiv.
• Human epidermal growth factor receptor 2 (HER2)-negative Erkrankung, definiert als IHC-Status HER2 negativ/+ oder IHC HER2++ bei CISH/FISH negativem Befund.
• Jeder Menopausenstatus. Bei Prä-/perimenopausalen Frauen Zustimmung zu einer Therapie mit einem LHRH-Agonisten (Goserelin oder Leuprorelin) oder einer Ovarektomie sofern sie in Arm A randomisiert werdenen.
• Frauen im gebärfähigen Alter müssen zustimmen während der Studientherapie und im Anschluss für den in der Fachinformation angegebenen Zeitraum nach der letzten Dosis eine wirksame Verhütungsmethode anzuwenden.
• Vorhandensein von viszeralen Metastasen (zusätzlich können weitere nicht-viszerale Metastasen vorhanden sein).
• Vorliegen von Zielläsionen und / oder nicht-Zielläsionen gemäß RECIST v1.1.
• Patienten müssen gemäß der entsprechenden Fachinformationen für eine palliative Therapie mit Ribociclib + AI /Fulvestrant und Capecitabin + Bevacizumab oder Paclitaxel +/- Bevacizumab qualifizieren.
• Unterschriebene, schriftliche Einwilligung nach erfolgter Aufklärung vor Beginn von protokollspezifischen Maßnahmen.

E.4

Principal exclusion criteria

• Any prior systemic palliative therapy
• Prior treatment with any CDK4/6 inhibitor.
• Prior adjuvant or neoadjuvant taxane therapy if last application within 12 months prior to entering the study.
• Patient is concurrently using other anti-cancer therapy.
• Patient has had major surgery within 28 days prior to randomization or has not recovered from major side effects or wound is not fully recovered.
• Patient has received extended-field radiotherapy ≤ 4 weeks or limited-field radiotherapy ≤ 2 weeks prior to randomization.
• Known hypersensitivity to ribociclib, AI, fulvestrant, paclitaxel, capecitabine, bevacizumab or any of their excipients, or against peanut, soya, CHO cell products or macrogolglycerol ricinoleate-35.
• Participation in prior investigational studies within 30 days prior to randomization or within 5-half lives of the investigational product, whichever is longer.

• Jegliche vorangegangene Palliativtherapie.
• Vorangegangene Therapie mit irgendeinem CDK4/6 Inhibitor.
•Vorangegangene adjuvante oder neoadjuvante Therapie mit einem Taxan, wenn die letzte Verabreichung innerhalb von 12 Monaten vor Studieneinschluss war.
• Die Patientin erhält gleichzeitig eine andere anti-tumorale Therapie
• Die Patientin hatte in den letzten 28 Tagen vor Randomisierung eine große Operation oder hat sich noch nicht von den bedeutenden Nebenwirkungen einer solchen erholt oder die Wunde ist noch nicht verheilt.
• Die Patientin hat vor Randomisierung eine Bestrahlung erhalten (innerhalb von 4 Wochen eine extended-field Bestrahlung oder innerhalb von 2 Wochen eine limited-field Bestrahlung).
• Bekannte Überempfindlichkeit gegen Ribociclib, AI, Fulvestrant, Capecitabin, Paclitaxel, Bevacizumab oder irgendeinen ihrer Inhaltsstoffe oder gegen Erdnuss, Soja, CHO-Zellprodukte oder Macrogolglycerolricinoleat.
• Vorangegangene Teilnahme an einer klinischen Prüfung innerhalb von 30 Tagen oder 5 Halbwertszeiten des Prüfpräparats vor Randomisierung, je nach dem was länger ist.

E.5 End points

E.5.1

Primary end point(s)

PFS assessed by local investigator using RECIST v1.1 criteria. PFS is defined as time from randomization to progression of disease or death of any cause, whichever comes first. It will be assessed by imaging until progressive disease or start of next-line therapy.

PFS beurteilt durch den lokalen Untersucher mittels RECIST v1.1 Kriterien. PFS ist definiert als Zeit von der Randomisierung bis zur Krankheitsprogression oder Tod jeglicher Ursache, je nach dem, was zuerst auftritt.

E.5.1.1

Timepoint(s) of evaluation of this end point

Study data will be analyzed in one final analysis, based on the current number of randomized patients.
The final analysis will be performed after end of study and will provide data on all endpoints.

Die Studiendaten werden in einer finalen Analyse, basierend auf der aktuellen Anzahl rekrutierter Patientinnen ausgewertet.
Die finale Analyse wird nach dem Ende der Studie durchgeführt und liefert Daten zu allen Endpunkten.

E.5.2

Secondary end point(s)

Secondary endpoints:
Efficacy:
• ORR (complete or partial response) assessed by the local investigator according to RECIST v1.1.
• CBR (complete or partial response or stable disease lasting 24 weeks or more) assessed by the local investigator according to RECIST v1.1.
• TTR (time from randomization to first occurrence of any response (complete or partial)) assessed by the local investigator according to RECIST v1.1
• OS, defined as time from randomization to death of any cause

Safety and tolerability:
• (S)AEs, frequency and severity graded according to CTCAE v4.03 until 30 days after EOT
• ECOG performance status
• Routine safety laboratory until EOT
• Electrocardiogram (QTc time) until EOT

Patient-reported outcomes in QoL:
• Quality of Life over time and change from baseline in the global health scale and all functional and symptom scores of the EORTC QLQ C30
• Burden by side effects of treatment at all questionnaire time points (single item)
• Burden by time spent on treatment at all questionnaire time points (four single item)

Sekundäre Endpunkte:
Wirksamkeit:
• ORR (komplettes oder partielles Ansprechen) erfasst durch den lokalen Untersucher mittels RECIST v1.1.
• CBR (komplettes oder partielles Ansprechen oder stabile Erkrankung für mindestens 24 Wochen) erfasst durch den lokalen Untersucher mittels RECIST v1.1.
• TTR (Zeit von der Randomisierung bis zum ersten Ansprechen (komplett oder partiell)) erfasst durch den lokalen Untersucher mittels RECIST v1.1.
• Gesamtüberleben definiert als Zeit von der Randomisierung bis zum Tod jeglicher Ursache.

Sicherheit und Verträglichkeit:
• (Schwerwiegende) Unerwünschte Ereignisse ((S)UE): Häufigkeit und Schweregrad gemäß CTCAE v4.03 bis 30 Tage nach Ende der Therapie
• ECOG Performance Status
• Routinelaboruntersuchungen bis zum Therapieende
• Elektrokardiogramm (EKG) bis zum Therapieende

Vom Patienten berichtete Lebensqualität:
• Lebensqualität über die Zeit und Veränderung im Vergleich zur Baseline der Skala „globaler Gesundheitsstatus“ und aller funktionellen und Symptom –Skalen des EORTC QLQ C30
• Belastung durch Nebenwirkungen der Therapie zu allen Fragebogenzeitpunkten (Einzelfrage)
• Zeitliche Belastung durch die Therapie zu allen Fragebogenzeitpunkten (vier Einzelfragen)

E.5.2.1

Timepoint(s) of evaluation of this end point

Study data will be analyzed in one final analysis, based on the current number of randomized patients.
The final analysis will be performed after end of study and will provide data on all endpoints.

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

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

E.8.1.3

Single blind

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)

Yes

E.8.2.2

Placebo

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

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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)

If patients discontinue study treatment (e.g. due to progression, toxicity or regular end of treatment) the investigator will offer appropriate treatment options according to current knowledge and treatment standards.

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

2018-02-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-02-14

P. End of Trial
P.	End of Trial Status	Completed

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