Clinical Trials Register

Summary
EudraCT Number:	2020-005607-39
Sponsor's Protocol Code Number:	D134BC00001
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-18
Trial results

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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

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).

Studio internazionale di fase III, multicentrico, con disegno parallelo, randomizzato, in doppio cieco, controllato con placebo, a 2 bracci volto a valutare l’efficacia e la sicurezza di selumetinib in partecipanti adulti affetti da NF1 che presentano neurofibromi plessiformi sintomatici inoperabili (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

Efficacia e sicurezza di Sselumetinib in partecipanti adulti affetti da NF1 che presentano neurofibromi plessiformi sintomatici inoperabili

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
B.5.2	Functional name of contact point	Clinical Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	NA
B.5.3.2	Town/ city	NA
B.5.3.3	Post code	NA
B.5.3.4	Country	United States
B.5.4	Telephone number	18772409479
B.5.5	Fax number	000000000000000
B.5.6	E-mail	information.center@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 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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)

Neurofibromatosi di tipo 1 (NF1) con Neurofibroma Plessiforme (PN) sintomatico, inoperabile

E.1.1.1

Medical condition in easily understood language

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

Adulti con neurofibromatosi di tipo 1 (NF1) che hanno neurofibromi plessiformi (PN) sintomatici e inoperabili

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

Dimostrare l’efficacia di Selumetinib in partecipanti affetti da NF1 che presentano PN sintomatico ed inoperabile, mediante la valutazione di ORR

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

• Comparare l’effetto di Selumetinib rispetto al placebo, mediante la valutazione dell’intensità del dolore cronico causato dal PN target.
• Dimostrare l’efficacia di Selumetinib da solo e rispetto al placebo, mediante la valutazione di ulteriori variabili di risposta tumorale, dell’attività palliativa sul dolore cronico causato dal PN target, dell’utilizzo di antidolorifici, l’interferenza col dolore, della funzionalità fisica, dell’HRQoL e dello stato di salute.
• Valutare sicurezza e tollerabilità di Selumetinib da solo e rispetto al placebo
• Valutare la PK di 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

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Please reference Section 8.1.8.10 of the Clinical Study Protocol

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Si prega di fare riferimento alla sezione 8.1.8.10 del Protocollo di Studio

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

• Adulti di età = 18 anni al momento dell’arruolamento, con diagnosi di NF1 che presentano PN sintomatico ed inoperabile.
• Almeno un PN target, misurabile mediante analisi di RM volumetrica.
• Score del dolore cronico causato dal PN target documentato per un periodo minimo durante lo screening.
• Utilizzo stabile di antidolorifici per il trattamento del dolore cronico causato dal PN al momento dell’arruolamento.
• Funzionalità d’organo e del midollo adeguate.

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 o MPNST, sospetti o confermati (i gliomi ottici che non richiedono chemioterapia o radioterapia sono esenti da questa esclusione).
• Storia pregressa di neoplasie maligne, ad eccezione di quelle trattate a scopo curativo, senza malattia attiva nota per un periodo = 5 anni antecedente alla prima dose di intervento di studio e con basso rischio potenziale di recidiva.
• Malattia cardiovascolare clinicamente significativa, incluse: malattia coronarica ereditaria, sindrome coronarica acuta nei 6 mesi precedenti all’arruolamento, angina incontrollata, insufficienza cardiaca sintomatica, cardiomiopatia, grave cardiopatia valvolare, LVEF anormale e ipertensione incontrollata.
• Reperti/Condizioni oftalmologiche, compresi: pressione intraoculare > 21 mmHg, RPED/CSR o RVO.
• Precedente trattamento con inibitori di 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

Tasso di risposta obiettiva (ORR), usando analisi di RM volumetrica, come stabilito da ICR secondo criteri 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

La valutazione dell’ORR sarà effettuata regolarmente in time points predefiniti fino alla progressione della malattia

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 Ndesmethyl selumetinib

• Variazione dell’intensità del dolore cronico causato dal PN target, rispetto al basale
• Durata della risposta (DoR)
• Sopravvivenza libera dalla progressione (PFS)
• Tempo alla progressione (TTP)
• Tempo alla risposta (TTR)
• Migliore percentuale di variazione del volume del PN target, rispetto al basale
• Attività palliativa sul dolore, utilizzo di antidolorifici, interferenza col dolore, funzionalità fisica, qualità della vita collegati alla salute patient-reported outcomes (PROs) e stato di salute
• Sicurezza ed efficacia
• Concentrazione plasmatica e parametri farmacocinetici (PK) di Selumetinib e N-desmethyl 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

Le valutazioni saranno effettuate regolarmente fino alla progressione della malattia o fino alla conclusione dello studio

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

Information not present in EudraCT

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

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

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:

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

Dopo la fine dello studio, sarà in atto un meccanismo per garantire che i partecipanti saranno in grado di continuare a prendere selumetinib fino a quando ne trarranno un beneficio clinico, come giudicato dallo sperimentatore e in assenza di criteri di interruzione.

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

2021-09-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-08

P. End of Trial
P.	End of Trial Status	Ongoing

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