Clinical Trials Register

Summary
EudraCT Number:	2015-003400-24
Sponsor's Protocol Code Number:	I3Y-MC-JPBZ
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-12-10
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

Spain - AEMPS

A.2

EudraCT number

2015-003400-24

A.3

Full title of the trial

monarcHER: A Phase 2, Randomized, Multicenter, 3-Arm, Open-Label Study to Compare the Efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant to Standard-of-Care Chemotherapy of Physician?s Choice plus Trastuzumab in Women with HR+, HER2+ Locally Advanced or Metastatic Breast Cancer

monarcHER: Estudio fase 2, aleatorizado, multicéntrico, abierto, de 3 grupos, para comparar la eficacia del tratamiento de combinación con abemaciclib y trastuzumab (con o sin fulvestrant) frente al estándar de tratamiento con la combinación de trastuzumab y la quimioterapia de referencia que determine el investigador, en mujeres con cáncer de mama HR+, HER2+ localmente avanzado o metastásico

A.3.1

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

A Study of Abemaciclib plus Trastuzumab with or without Fulvestrant in Participants with HR+, HER2+ Metastatic Breast Cancer.

Estudio de Abemaciclib mas Trastuzumab con o sin Fulvestrat en pacientes con cancer de mama metastasico HR+, HER2+

A.3.2

Name or abbreviated title of the trial where available

monarcHER

A.4.1

Sponsor's protocol code number

I3Y-MC-JPBZ

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	Lilly S.A.
B.1.3.4	Country	Spain
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	Eli Lilly and Company
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Lilly
B.5.2	Functional name of contact point	Clinical Trial Registry Office
B.5.3	Address:
B.5.3.1	Street Address	Avda de la Industria 30
B.5.3.2	Town/ city	Alcobendas Madrid
B.5.3.3	Post code	28108
B.5.3.4	Country	Spain
B.5.4	Telephone number	3491663 53 27
B.5.5	Fax number	34916633481
B.5.6	E-mail	ensayosclinicos@lilly.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.3.1	Product name	abemaciclib
D.3.2	Product code	LY2835219
D.3.4	Pharmaceutical form	Capsule
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	abemaciclib
D.3.9.3	Other descriptive name	ABEMACICLIB
D.3.9.4	EV Substance Code	SUB171907
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	50
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.2.5	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.3.2	Product code	L02BA03
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.3.9.3	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.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

Hormone receptor positive, HER2-positive advanced breast cancer

cáncer de mama HR+, HER2+ localmente avanzado o metastásico

E.1.1.1

Medical condition in easily understood language

Metastatic breast cancer

Cancer de Mama Metastasico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to compare the efficacy of abemaciclib plus trastuzumab plus fulvestrant and abemaciclib plus trastuzumab to standard-of-care single-agent chemotherapy of physician?s choice plus trastuzumab with respect to progression free survival (PFS).

El objetivo principal de este estudio es comparar la eficacia de la politerapia con abemaciclib, trastuzumab y fulvestrant y de la politerapia con abemaciclib y trastuzumab con la de trastuzumab y el fármaco quimioterápico de referencia que determine el investigador, en lo que respecta a la supervivencia sin progresión (SSP)

E.2.2

Secondary objectives of the trial

To review overall survival, objective response rate, duration of response, disease control rate, clinical benefit rate, safety and tolerability of abemaciclib, treatment impact on pain, disease symptoms and overall quality of life, pharmacokinetics of abemaciclib and relationship between abeamciclib, trastuzumab and fulvestrant exposure and clinical outcomes

Tasa de supervivencia global; Tasa de respuestas objetivas; Duración de la respuesta; Tasa de control de la enfermedad; Tasa de beneficio clínico; Seguridad y tolerabilidad de abemaciclib en politerapia con trastuzumab y fulvestrant; Efecto en el dolor, los síntomas de la enfermedad y la calidad de vida global, para lo que se utilizará el Cuestionario breve modificado para la evaluación del dolor (m-BPI-sf) y el Cuestionario de calidad de vida ? Core 30 de la EORTC QLQ-C30 y las puntuaciones del estado de salud obtenidas a partir del cuestionario EQ-5D 5L; Farmacocinética de abemaciclib y sus metabolitos, fulvestrant y trastuzumab en la población destinataria; Relación entre la exposición a abemaciclib, trastuzumab y fulvestrant y la respuestaEl objetivo exploratorio de este estudio es:
? Explorar posibles biomarcadores relacionados con el mecanismo de acción de abemaciclib, el ciclo celular o la patogenia del cáncer de mama y su relación con el resultado clínico.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Have diagnosis of HR+, HER2+ metastatic breast cancer on the primary tumor or metastatic lesion
2. Have unresectable locally advanced recurrent breast cancer or metastatic breast cancer
3. Have adequate tumor tissue available and collected prior to randomization
4. Have previously received at least two HER2 directed therapies for advanced disease
5. Must have received trastuzumab emtansine (TDM1) in any disease setting
6. Must have received a taxane in any disease setting
7. Have discontinued all previous therapies for cancer (except trastuzumab) for at least 21 days for myelosuppressive agents or 14 days for non-myelosupprevice agents
8. Have postmenopausal status
9. Have performance status of 0 to 1 on the ECOG scale
10. Must have LVEF of 50% or higher at baseline

[1] diagnóstico de cáncer de mama HR+, HER2+ avanzado; [2] tener cáncer de mama localmente avanzado, recurrente e irresecable o cáncer de mama metastásico ; [3] disponer de una muestra de tejido aceptable (biopsia realizada recientemente o tejido conservado), obtenida antes de la aleatorización; [4] presentar enfermedad mensurable, no mensurable, o ambas, de acuerdo con los criterios RECIST, versión 1.1; [5] haber recibido anteriormente al menos 2 tratamientos dirigidos al HER2 para la enfermedad avanzada; deben haber recibido T-DM1 para la enfermedad en cualquier contexto; [6] deben haber recibido un taxano para la enfermedad en cualquier contexto; [7] pueden haber recibido cualquier hormonoterapia (salvo fulvestrant); [8] haber entrado en la posmenopausia (menopausia natural o por cirugía, o inducida por inhibición de la función ovárica; [9] tener una categoría funcional (CF) de 0 o 1 en la escala del Eastern Cooperative Oncology Group (ECOG); [10] en el período basal deben tener una fracción de eyección ventricular izquierda (FEVI) ? 50 %;

E.4

Principal exclusion criteria

1. Have visceral crisis
2. Known CNS metastases that are untreated, symptomatic or require steroids to control symptoms
3. Received prior treatment with any CDK4 or CDK6 inhibitor
4. Have had major surgery within 14 days prior to randomization
5. Received treatment with a drug that has not received regulatory approval for any indication within 14 to 21 days of randomization for non-myelosuppressive or non-myelosupprevice agent, respectively
6. Have serious preexisting medical conditions that would preclude participation in this study
7. Have a history within the last 6 months of symptomatic congestive heart failure, myocardial infarction or unstable angina
8. Have a personal history within the last 12 months of any of the following conditions: syncope of cardiovascular etiology, ventricular tachycardia, ventricular fibrillation or sudden cardiac arrest

[19] tener crisis viscerales; [20] presentar metástasis en el sistema nervioso central (SNC) que no se hayan tratado, sean sintomáticas o requieran corticosteroides para controlar los síntomas; [21] haberse sometido a una intervención de cirugía mayor en el transcurso de los 14 días previos a la aleatorización, para posibilitar la cicatrización de la herida y de la zona donde se haya realizado la cirugía; [22] haber recibido tratamiento previo con cualquier inhibidor de la CDK 4 y la CDK 6; [23] haber recibido tratamiento con un fármaco que no haya sido aprobado por las autoridades sanitarias para ninguna indicación, en el transcurso de los 14 días (en el caso de los fármacos sin acción mielodepresora) o de los 21 días (en el caso de los fármacos mielodepresores) anteriores a la aleatorización; [24] tener una enfermedad preexistente grave que, de acuerdo con el criterio del investigador, impediría la participación en el estudio; [25] tener antecedentes, en el transcurso de los 6 últimos meses, de insuficiencia cardiaca congestiva sintomática, infarto de miocardio o angina inestable; [26] tener antecedentes personales, en el transcurso de los 12 últimos meses, de cualquiera de los procesos patológicos siguientes: sincope de origen cardiovascular, taquicardia ventricular, fibrilación ventricular o paro cardiaco súbito

E.5 End points

E.5.1

Primary end point(s)

Progression-free survival (PFS)

Supervivencia libre de progresion

E.5.1.1

Timepoint(s) of evaluation of this end point

One planned primary analysis for PFS performed after 165 events have been observed. Within 28 days of randomization, baseline tumor assessment will be performed for each patient. Repeat scans will be done every 6 weeks for 36 weeks from first dose of therapy, then every 9 weeks and within 14 days of clinical progression.

El análisis principal se realizará una vez que se hayan producido 165 eventos de SSP. Las evaluaciones basales del tumor se realizarán en el transcurso de los 28 días anteriores a la aleatorización de cada paciente. La prueba de imagen específica que se hubiera realizado en el período basal para evaluar las lesiones óseas debe repetirse, utilizando el mismo método, cada 6 semanas (± 3 días laborales) durante las 36 semanas posteriores a la primera dosis del tratamiento del estudio, y posteriormente cada 9 semanas (± 3 días laborales), así como en el transcurso de los 14 días posteriores al momento en el que se produzca la progresión clínica.

E.5.2

Secondary end point(s)

OS rate, ORR, DoR, disease control., clinical benefit rate, safety and tolerability, impact on pain, disease symptom

Supervivencia global; Tasa de respuestas objetivas; Duración de la respuesta; Tasa de control de la enfermedad; Tasa de beneficio clínico; Seguridad y Tolerabilidad

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to a total of 2 interim analysis and a final analysis for OS may be performed if PFS is significant for both abemaciclib arms. Health outcome scales are administered day 1 of each cycle.

Podrán realizarse hasta 2 análisis provisionales y un análisis final de la SG, en los que se compararán los datos combinados de los 2 grupos de tratamiento con abemaciclib

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Quality of life, pain management and disease symptom control

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

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

Yes

E.8.2.3.1

Comparator description

Trastuzumab plus physician's choice of standard of care single agent chemotherapy.

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

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

Belgium

Brazil

Canada

France

Germany

Greece

Italy

Korea, Republic of

Mexico

Spain

United Kingdom

United States

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

Ultima visita ultimo paciente

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:

160

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

225

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)

Upon discontinuation the following will occur: physical exam; vitals; ECOG performance status; survival information; adverse events collection; concomitant medications; central hematology/chemistry and biomarker plasma sample collection; ECGl tumor tissue collection and health outcomes scales.
Postdiscontinuation follow-up will be approximately every 9 weeks until the patient's death or overall study completion.

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

2016-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-15

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

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