Clinical Trials Register

Summary
EudraCT Number:	2020-005607-39
Sponsor's Protocol Code Number:	D134BC00001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2021-06-23
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

Spain - AEMPS

A.2

EudraCT number

2020-005607-39

A.3

Full title of the trial

A Phase III, Multicentre, International Study with a Parallel, Randomised, Double blind, Placebo-controlled, 2 Arm Design to Assess the Efficacy and Safety of Selumetinib in Adult Participants with NF1 who have Symptomatic, Inoperable Plexiforn Neurofibromas (KOMET)

Ensayo fase III, multicéntrico e internacional con un diseño paralelo, aleatorizado, doble ciego, controlado con placebo, de 2 grupos para evaluar la eficacia y la seguridad de selumetinib en pacientes adultos con NF1 que tienen neurofibromas plexiformes sintomáticos e inoperables (KOMET)

A.3.1

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

Efficacy and Safety of Selumetinib in Adults with NF1 who have Symptomatic, Inoperable Plexiform Neurofibromas

Eficacia y seguridad de selumetinib en adultos con NF1 que tienen neurofibromas plexiformes
sintomáticos e inoperables (KOMET).

A.3.2

Name or abbreviated title of the trial where available

KOMET

A.4.1

Sponsor's protocol code number

D134BC00001

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Farmacéutica Spain, S.A.
B.5.2	Functional name of contact point	Unidad de Investigación Clínica
B.5.3	Address:
B.5.3.1	Street Address	C/ Serrano Galvache, 56; Parque Norte, Edificio Álamo
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28033
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34900200444
B.5.6	E-mail	informacionEECC-Spain@astrazeneca.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2050
D.3 Description of the IMP
D.3.1	Product name	Selumetinib 10mg capsule
D.3.2	Product code	AZD6244
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	Selumetinib
D.3.9.1	CAS number	943332-08-9
D.3.9.2	Current sponsor code	AZD6244
D.3.9.3	Other descriptive name	selumetinib hyd-sulfate
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	10
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2050
D.3 Description of the IMP
D.3.1	Product name	Selumetinib 25mg capsule
D.3.2	Product code	AZD6244
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	Selumetinib
D.3.9.1	CAS number	943332-08-9
D.3.9.2	Current sponsor code	AZD6244
D.3.9.3	Other descriptive name	selumetinib hyd-sulfate
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.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

Neurofibromatosis Type 1 (NF1) with Symptomatic, Inoperable Plexiform Neurofibromas (PN)

E.1.1.1

Medical condition in easily understood language

Adults with Neurofibromatosis Type 1 (NF1) who have Symptomatic, Inoperable Plexiform Neurofibromas (PN)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10029270
E.1.2	Term	Neurofibromatosis, type 1 (von Recklinghausen's disease)
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate the effectiveness of Selumetinib by assessment of ORR in participants with NF1 who have symptomatic, inoperable PN.

Demostrar la efectividad de Selumetinib mediante la evaluación de la TRO en pacientes con NF1 que tengan NP sintomático e inoperable.

E.2.2

Secondary objectives of the trial

- To compare the effect of selumetinib relative to placebo by assessment of chronic target PN pain intensity
- To demonstrate the effectiveness of selumetinib alone and as compared to placebo by assessment of additional tumour response variables, chronic target PN pain palliation, pain medication use, pain interference, physical functioning, HRQoL and health status
- To assess the safety and tolerability of selumetinib alone and as compared to placebo
- To assess the PK of selumetinib

- Comparar el efecto de selumetinib en relación con el placebo mediante la evaluación de la intensidad del dolor crónico del NP objetivo
- Demostrar la efectividad de selumetinib en monoterapia y en comparación con placebo mediante la evaluación de variables adicionales de respuesta tumoral, paliación del dolor crónico del NP diana, interferencia del dolor, función física, calidad de vida relacionada con la salud y estado de salud
- Evaluar la seguridad y tolerabilidad de selumetinib en monoterapia y en comparación con placebo
- Evaluar la FC de selumetinib

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Please reference Section 8.1.8.10 of the Clinical Study Protocol

Por favor, referirse a la Sección 8.1.8.10 del Protocolo del Estudio Clínico

E.3

Principal inclusion criteria

- Adults ≥ 18 years at enrollment with diagnosis of NF1 with symptomatic, inoperable PN
- At least one target PN measurable by volumetric MRI analysis
- Chronic target PN pain score documented for minimum period during screening period
- Stable chronic PN pain medication use at enrollment
- Adequate organ and marrow function

- Adultos ≥ 18 años en el momento de inclusión con diagnóstico de NF1 y NP sintomático e inoperable.
- Al menos un NP diana medible por análisis de RM volumétrico.
- Puntuación del dolor crónico del NP objetivo documentado por un tiempo mínimo durante el periodo de selección.
- Uso estable de analgésicos para el dolor crónico del NP en el momento de inclusión.
- Función adecuada de órganos y médula ósea.

E.4

Principal exclusion criteria

- Confirmed or suspected malignant glioma or MPNST (optic glioma not requiring chemotherapy or radiation therapy are exempt from this exclusion)
- History of malignancy except for malignancy treated with curative intent with no known active disease ≥ 5 years before the first dose of study intervention and of low potential risk for recurrence
- Clinically significant cardiovascular disease, including inherited coronary disease, acute coronary syndrome within 6 months prior to enrollment, uncontrolled angina, symptomatic heart failure, cardiomyopathy, severe valvular heart disease, abnormal LVEF and uncontrolled hypertension
- Ophthalmological findings/conditions including intraocular pressure > 21 mmHg, RPED/CSR or RVO
- Prior exposure to MEK inhibitors

- Glioma maligno confirmado o sospechoso o tumor maligno de la vaina de nervio periférico (los gliomas ópticos que no requieran quimioterapia o radiación están exentos de esta exclusión)
- Antecedentes de malignidad exceptuando malignidad tratada con intención curativa sin enfermedad activa conocida en ≥ 5 años previos a la primera dosis de la intervención del ensayo y con bajo riesgo potencial de recurrencia.
- Enfermedad cardiovascular clínicamente significativa, incluyendo enfermedad coronaria hereditaria, síndrome coronario agudo en los 6 meses previos a la inclusión, angina no controlada, insuficiencia cardiaca sintomática, miocardiopatía, valvulopatía grave, fracción de eyección del ventrículo izquierdo fuera de lo normal e hipertensión no controlada.
- Hallazgos/afecciones oftalmológicos, incluyendo presión intraocular > 21 mmHg, desgarros del epitelio pigmentario de la retina/coriorretinopatía serosa central u oclusión de la vena retiniana.
- Previa exposición a inhibidores de MEK.

E.5 End points

E.5.1

Primary end point(s)

Objective Response Rate (ORR) using volumetric MRI analysis as determined by ICR per REiNS criteria.

Tasa de respuesta objetiva (TRO) usando un análisis de RM volumétrica determinado mediante RCI, según los criterios REiNS.

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessments for ORR will be collected regularly at predefined time points until disease progression.

Las evaluaciones de TRO se recogerán regularmente a tiempos predefinidos hasta la progresión de la enfermedad.

E.5.2

Secondary end point(s)

- Change from baseline in chronic target PN pain intensity
- Duration of Response (DoR)
- Progression Free Survival (PFS)
- Time to progression (TTP)
- Time to Response (TTR)
- Best percentage change from baseline in target PN volume
- Pain palliation, pain medication use, pain interference, physical functioning, health related quality of life PROs and health status.
- Safety and tolerability
- Plasma concentrations and PK parameters of selumetinib and N-desmethyl selumetinib.

- Cambio en la intensidad del dolor crónico del NP objetivo con respecto al valor inicial
- Duración de la respuesta
- Supervivencia sin progresión (SSP)
- Tiempo hasta la progresión (TTP)
- Tiempo hasta la respuesta (TTR)
- Mejor cambio porcentual desde el inicio en el volumen del NP objetivo
- Paliación del dolor, uso de analgésicos, interferencia del dolor, función física, resultados notificados por el paciente de calidad de vida relacionada con la salud y estado de salud.
- Seguridad y tolerabilidad
- Concentraciones plasmáticas y parámetros FC de selumetinib y N-desmetil selumetinib.

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments will be made regularly until disease progression or until the end of the study.

Las evaluaciones se harán regularmente hasta progresión de la enfermedad o hasta el final del ensayo.

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

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

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

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

Australia

Brazil

Canada

China

Japan

Russian Federation

United States

France

Germany

Italy

Netherlands

Poland

Spain

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

LSLV

LSLV (Última visita del último 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

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:

139

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

Yes

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

146

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)

Following the end of the study, a mechanism will be in place to ensure that participants will be able to continue taking selumetinib as long as they derive clinical benefit, as judged by the investigator and in the absence of discontinuation criteria.

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

2021-10-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-21

P. End of Trial
P.	End of Trial Status	Restarted

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