Clinical Trials Register

Summary
EudraCT Number:	2015-000617-43
Sponsor's Protocol Code Number:	CLEE011F2301
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-10-09
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

Portugal - INFARMED

A.2

EudraCT number

2015-000617-43

A.3

Full title of the trial

MONALEESA-3: A randomized double-blind, placebocontrolled study of ribociclib in combination with fulvestrant for the treatment of men and postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment

A.3.1

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

Study of Efficacy and Safety of LEE011 with endocrine treatment in men and Postmenopausal Women with Advanced Breast Cancer

A.3.2

Name or abbreviated title of the trial where available

Monaleesa-3

A.4.1

Sponsor's protocol code number

CLEE011F2301

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	Novartis Pharma AG
B.1.3.4	Country	Switzerland
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 Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farma - Produtos Farmacêuticos, S.A.
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Avenida Professor Doutor Cavaco Silva, nº10E
B.5.3.2	Town/ city	Porto Salvo
B.5.3.3	Post code	2740-255
B.5.3.4	Country	Portugal
B.5.4	Telephone number	+35121 000 86 00
B.5.5	Fax number	+35121 000 88 25
B.5.6	E-mail	ensaios.clinicos@novartis.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	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.3.2	Product code	LEE011
D.3.4	Pharmaceutical form	Capsule, hard
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	1374639-75-4
D.3.9.2	Current sponsor code	LEE011
D.3.9.3	Other descriptive name	LEE011
D.3.9.4	EV Substance Code	SUB31644
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	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	Faslodex
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca UK 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.3.1	Product name	fulvestrant
D.3.4	Pharmaceutical form	Solution for 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/ml milligram(s)/millilitre
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.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	Capsule, hard
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

men and postmenopausal women with HR+, HER2-negative advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer

E.1.1.1

Medical condition in easily understood language

advanced metastatic breast cancer

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	LLT
E.1.2	Classification code	10072737
E.1.2	Term	Advanced breast cancer
E.1.2	System Organ Class	100000004864

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 determine whether treatment with ribociclib + fulvestrant prolongs progression free survival (PFS) compared to treatment with placebo + fulvestrant in men and postmenopausal women with HR+, HER2-negative breast cancer.

E.2.2

Secondary objectives of the trial

1. To determine whether treatment with ribociclib + fulvestrant prolongs overall survival (OS) compared to treatment with placebo + fulvestrant.
2. To evaluate the two treatment arms with respect to overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR) and duration of response (DOR).
3. To evaluate the two treatment arms with respect to time to deterioration of ECOG performance status.
4. To evaluate the safety and tolerability of ribociclib in combination with fulvestrant.
5. To evaluate patient reported outcomes for health-related quality of life in the two treatment arms.
6. To characterize the pharmacokinetics (PK) of ribociclib (and relevant metabolites) when given in combination with fulvestrant.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patient is an adult male/female ≥ 18 years
2. Female is postmenopausal.
3. Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory (based on most recent analyzed biopsy) and has HER2-negative breast cancer (based on most recent analyzed biopsy).
4. Patient must have either measurable disease by RECIST 1.1 or at least one predominantly lytic bone lesion.
5. Patient has advanced (loco regionally recurrent not amenable to curative therapy (e.g. surgery and/or radiotherapy) or metastatic) breast cancer.
Patients may be:
• newly diagnosed advanced/metastatic breast cancer, treatment naïve
• relapsed with documented evidence of relapse more than 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
• relapsed with documented evidence of relapse on or within 12 months from completion of (neo)adjuvant endocrine therapy with no treatment for advanced/metastatic disease
• relapsed with documented evidence of relapse more than 12 months from completion of (neo)adjuvant endocrine therapy and then subsequently progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor) for advanced/metastatic disease
• advanced/metastatic breast cancer at diagnosis that progressed with documented evidence of progression after one line of endocrine therapy (with either an antiestrogen or an aromatase inhibitor)
6. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
7. Patient has adequate bone marrow and organ function

E.4

Principal exclusion criteria

1. Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment.
2. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy), fulvestrant or any CDK4/6 inhibitor.
3. Patient with inflammatory breast cancer at screening .
4. Patients with Child pugh scroe B or C
5. Patients has received prior neoadjuvant/adjuvant treatment with antracyclines at cumulative doses of 450mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin
6. Patient with CNS involvement unless they are at least 4 weeks from prior therapy completion to starting the study treatment
and have stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases
7. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality including any of the following:
• History of angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG), myocardial infarction within 6 months prior to study entry
• Documented cardiomyopathy
• Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO)
• Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome or any of the following:
a) Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
b) Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g. within 5half-lives or 7 days prior to starting study drug)
c) Inability to determine the QTcF interval
• Clinically significant cardiac arrhythmias including but not limited to (e.g., ventricular tachycardia), complete left bundle branch block, highgrade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
• Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg
• Bradycardia (heart rate < 50 bmp at rest), by ECG (mean of triplicate) and pulse.
• Tachycardia (heart rate > 90 bpm at rest), by ECG (mean of triplicate) and pulse
• On screening, inability to determine the QTcF interval on the ECG (ie:unreadable or not interpretable) or QTcF >450 msec (using Fridericia's correction). All as determined by screening ECG (mean of triplicateECGs).
8. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to star the treatment:
• Known strong inducers or inhibitors of CYP3A4/5,
• That have a known risk to prolong the QT interval or induce Torsades de Pointes.
• Those have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.
• Herbal preparations/medications, dietary supplements (except vitamins).
Other exclusion criteria as per full protocol may apply

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause. PFS will be assessed according to RECIST 1.1..

E.5.1.1

Timepoint(s) of evaluation of this end point

final analysis around 26 months from the date of first patient randomized

E.5.2

Secondary end point(s)

1. Overall survival: Time from date of randomization to the date of death from any cause.
2. ORR: Proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1.
3. CBR: Percentage of patients with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1
4. TTR: Time from randomization to the first documented and confirmed response (complete response or partial response) as defined in RECIST 1.1
5. DOR: Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1
6. ECOG: Time to definitive deterioration of ECOG performance status from baseline: Time to deterioration of ECOG performance Status.
7. Safety and tolerability of LEE001: Determined by type, frequency and severity of Adverse Events per CTCAE version 4.03 and type, frequency and severity of laboratory toxicities per CTCAE version 4.03
8. Time to 10% deterioration in the global health status/QOL scale score of the EORTC QLQ-C30: Patient reported outcomes for health related quality of life
9. A change from baseline in the global health status/QOL scale score of the EORTC QLQ-C30: Patient reported outcomes for health related quality of life
10. Concentration by time point for ribociclib (and relevant metabolites)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. 58 months from date of first patient randomized.
2. ORR: up to approximately 26 months
3. CBR: up to approximately 26 months
4. TTR: up to approximately 26 months
5. DOR: up to approximately 26 months
6. ECOG performance status deterioration: up to approximately 26 months
7. safety and tolerability: up to approximately 26 months
8. 10% deterioration in QOL: up to approximately 26 months
9. change from baseline in QOL: up to approximately 26 months
10. concentration by time point: up to approximately 26 month

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

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of Life (QoL)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

146

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Canada

China

Colombia

Hong Kong

Israel

Jordan

Korea, Republic of

Lebanon

Malaysia

Mexico

Russian Federation

Saudi Arabia

Singapore

South Africa

Taiwan

Thailand

Turkey

United States

Austria

Belgium

Bulgaria

Czechia

Denmark

France

Germany

Hungary

Italy

Netherlands

Norway

Poland

Portugal

Spain

Sweden

Switzerland

United Kingdom

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 end of the study for a given patient is defined as when the patient permanently
discontinues study treatment with ribociclib + fulvestrant or placebo + fulvestrant and all the end of trial procedures are completed.

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

396

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

264

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.4.2

For a multinational trial

F.4.2.1

In the EEA

289

F.4.2.2

In the whole clinical trial

660

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)

Patients continuing to derive benefit from study treatment at the end of the study in the opinion of the investigator will be able to continue receiving trial therapy on a separate protocol. Alternatively Novartis will provide study treatment to the investigator as per local regulations.

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

2016-01-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-13

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

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