Clinical Trials Register

Summary
EudraCT Number:	2020-005607-39
Sponsor's Protocol Code Number:	D134BC00001
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-09-14
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

Poland - Office for Medicinal Products

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)

Międzynarodowe, wieloośrodkowe, kontrolowane placebo badanie III fazy, prowadzone w dwóch ramionach z zastosowaniem metodyki podwójnie ślepej próby i randomizacji, oceniające skuteczność i bezpieczeństwo selumetynibu u dorosłych pacjentów z objawowymi, nieoperacyjnymi nerwiakowłókniakami splotowatymi (PN) w przebiegu nerwiakowłókniakowatości typu 1 (NF1)

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

Skuteczność i bezpieczeństwo selumetynibu u dorosłych pacjentów z objawowymi, nieoperacyjnymi nerwiakowłókniakami splotowatymi (PN) w przebiegu nerwiakowłókniakowatości typu 1 (NF1)

A.3.2

Name or abbreviated title of the trial where available

KOMET

A.4.1

Sponsor's protocol code number

D134BC00001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04924608

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	1877240-9479
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 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)

Nerwiakowłókniakowatość typu 1 (NF1) z objawowymi, nieoperacyjnymi nerwiakowłókniakami splotowatymi (PN)

E.1.1.1

Medical condition in easily understood language

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

Dorośli z nerwiakowłókniakowatością typu 1 (NF1) z objawowymi, nieoperacyjnymi nerwiakowłókniakami splotowatymi (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 compare the effect of selumetinib relative to placebo by assessment of confirmed partial and complete response rate (ORR) using volumetric MRI analysis as determined by ICR (per REiNS criteria) in participants with NF1 who have symptomatic, inoperable PN

Porównanie wpływu selumetynibu względem placebo przez ocenę potwierdzonego odsetka odpowiedzi obiektywnych (ORR) za pomocą wolumetrycznego badania MRI w oparciu o niezależną ocenę centralną (ICR) (zgodnie z kryteriami REiNS) u uczestników z NF1, którzy mają objawowe, nieoperacyjne PN

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 by assessment of confirmed partial and complete response rate (ORR) using volumetric MRI analysis as determined by ICR (per REiNS criteria) in participants with NF1 who have symptomatic, inoperable PN.
- To assess the safety and tolerability of selumetinib alone and as compared to placebo
- To assess the PK of selumetinib

• Porównanie wpływu selumetynibu względem placebo na podstawie oceny zmiany nasilenia przewlekłego bólu związanego z docelowymi PN
• Wykazanie skuteczności selumetynibu poprzez ocenę potwierdzonego odsetka odpowiedzi obiektywnych (ORR) za pomocą wolumetrycznego badania MRI w oparciu o niezależną ocenę centralną (ICR) (zgodnie z kryteriami REiNS) u uczestników z NF1, którzy mają objawowe, nieoperacyjne PN
• Ocena bezpieczeństwa stosowania i tolerancji samego selumetynibu oraz w porównaniu z placebo
• Ocena farmakokinetyki (PK) selumetynibu

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

Prosimy odnieść się do sekcji 8.1.8.10 Protokołu Badania

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

• Uczestnik musi mieć ≥18 lat podczas oceny przesiewowej z rozpoznanym objawowe, nieoperacyjne PN w przebiegu NF1
• U uczestników powinien występować przynajmniej jeden PN mierzalny za pomocą wolumetrycznego badania MRI
• Udokumentowany wynik dotyczący przewlekłego bólu związany z docelowymi PN jako minimum – przynajmniej w okresie przesiewowym;
• Uczestnicy powinni w stabilny sposób przyjmować leki z powodu bólu związanego z PN w czasie włączenia do badania
• Odpowiednia czynność narządów i szpiku kostnego

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

• Osoby z potwierdzonym lub podejrzewanym glejakiem złośliwym lub MPNST (dopuszcza się udział w badaniu osób z glejakiem nerwu wzrokowego, którzy nie wymagają chemioterapii lub radioterapii)
• Nowotwór złośliwy wyleczony radykalnie w wywiadzie i brak objawów czynnej choroby w okresie ≥5 lat przed pierwszą dawką badanego leczenia, z niskim potencjalnym ryzykiem nawrotów
• Uczestnicy z istotnymi klinicznie chorobami krążenia, z uwzględnieniem rozpoznanej dziedzicznej choroby wieńcowej, ostrego zespołu wieńcowego w okresie 6 miesięcy przed rozpoczęciem leczenia, niewyrównanej dławicy piersiowej, objawowej niewydolności serca, kardiomiopatii, ciężkiej zastawkowej choroby serca, nieprawidłowej wartości LVEF i niewyrównanego nadciśnienia
• Uczestnicy z wynikami badań okulistycznych/chorobami oczu z uwzględnieniem ciśnienia wewnątrzgałkowego >21 mmHg, dDystrofii nabłonka barwnikowego siatkówki/centralnej retinopatii surowiczej (RPED/CSR) lub niedrożności żył siatkówki (RVO)
• Wcześniejsza ekspozycja na inhibitory 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.

Odsetek odpowiedzi obiektywnych (ORR) oceniany za pomocą wolumetrycznego badania MRI w oparciu o niezależną ocenę centralną (ICR) zgodnie z kryteriami 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 or the last evaluable assessment up to and including end of Cycle 16 assessment in the absence of progression.

Ocena ORR będzie przeprowadza regularnie zgodnie ze zdefiniowanymi uprzednio punktami czasowymi do wystąpienia progresji choroby lub ostatniej możliwej do przeprowadzenia oceny do końca 16 cyklu włącznie, w przypadku braku progresji

E.5.2

Secondary end point(s)

- Change from baseline in chronic target PN pain intensity
- Objective Response Rate (ORR)
- 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.

• Różnica pod względem średniej zmiany nasilenia przewlekłego bólu związanego z docelowymi PN w stosunku do stanu wyjściowego
• Odsetek odpowiedzi obiektywnej (ORR)
• Czas trwania odpowiedzi (DoR)
• Czas przeżycia bez progresji choroby (PFS)
• Czas do progresji choroby (TTP)
• Czas do uzyskania odpowiedzi (TTR)
• Różnica pod względem najkorzystniejszej procentowej zmiany rozmiarów docelowych PN w stosunku do stanu wyjściowego
• Łagodzenie przewlekłego bólu, stosowanie leków przeciwbólowych, wpływu bólu na funkcjonowanie pacjenta, funkcjonowanie fizyczne, jakość życia w oparciu o dane raportowane przez pacjenta oraz stan zdrowia
• Bezpieczeństwo i tolerancja
• Ocena stężenia i parametrów farmakokinetycznych selumetynibu i N desmetyloselumetynibu

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.

Ocena będzie przeprowadza regularnie do wystąpienia progresji lub zakończenia badania

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

United States

France

Poland

Netherlands

Spain

Germany

Italy

Russian Federation

United Kingdom

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 (Last Visit Last Subject)

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.

Po zakończeniu badania zostanie wprowadzony mechanizm zapewniający uczestnikom kontynuowanie przyjmowania selumetynibu tak długo, jak długo w opinii badacza odnoszą korzyść kliniczną z leczenia i nie spełniają kryteriów przerwania leczenia.

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

2022-01-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-12

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
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