Clinical Trials Register

Summary
EudraCT Number:	2020-005608-20
Sponsor's Protocol Code Number:	D1346C00004
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-10-19
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

2020-005608-20

A.3

Full title of the trial

A Phase I/II, Single-Arm, Open label Study to Evaluate the Pharmacokinetics, Safety/Tolerability and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥ 1 to < 7 Years with Neurofibromatosis Type 1 (NF1) Related Symptomatic, Inoperable Plexiform Neurofibromas (PN) (SPRINKLE)

Estudio de fase I/II, abierto y de un solo brazo para evaluar la farmacocinética, seguridad/tolerabilidad y eficacia de la formulación granulada de selumetinib en niños de ≥ 1 a < 7 años con neurofibromas plexiformes (NP) sintomáticos e inoperables relacionados con neurofibromatosis tipo 1 (NF1) (SPRINKLE)

A.3.1

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

Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children aged ≥ 1 to < 7 Years with Neurofibromatosis Type 1 (NF1) Related Symptomatic, Inoperable Plexiform Neurofibromas (PN) (SPRINKLE)

Farmacocinética, Seguridad y Eficacia de la formulación granulada de Selumetinib en niños ≥ 1 to < 7 años con neurofibromas plexiformes (NP) sintomáticos e inoperables relacionados con neurofibromatosis tipo 1 (NF1) (SPRINKLE)

A.3.2

Name or abbreviated title of the trial where available

SPRINKLE

A.4.1

Sponsor's protocol code number

D1346C00004

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/341/2021

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	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	0034900200444
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 granules in sprinkle capsules for opening 5 mg
D.3.2	Product code	AZD6244
D.3.4	Pharmaceutical form	Granules
D.3.4.1	Specific paediatric formulation	Yes
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	5
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 granules in sprinkle capsules for opening 7.5 mg
D.3.2	Product code	AZD6244
D.3.4	Pharmaceutical form	Granules
D.3.4.1	Specific paediatric formulation	Yes
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	7.5
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: 3
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	Koselugo 10mg
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB, Sweden
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	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 capsules 10mg
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: 4
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	Koselugo 25mg
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB, Sweden
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	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 capsules 25mg
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	24
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

Neurofibromatosis Type 1 (NF1) Related Plexiform Neurofibromas (PN)

Neurofibromas plexiformes (NP) sintomáticos e inoperables relacionados con Neurofibromatosis tipo 1 (NF1)

E.1.1.1

Medical condition in easily understood language

Neurofibromatosis Type 1 (NF1) Related Plexiform Neurofibromas (PN)

Neurofibromas plexiformes (NP) sintomáticos e inoperables relacionados con Neurofibromatosis tipo 1 (NF1)

E.1.1.2

Therapeutic area

Not possible to specify

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

1. To determine the PK of selumetinib after administration of the selumetinib granule formulation.
2. To assess the safety and tolerability of the selumetinib granule formulation.

1. Determinar la FC de selumetinib tras la administración de la formulación granulada de selumetinib.
2. Evaluar la seguridad y la tolerabilidad de la formulación granulada de selumetinib.

E.2.2

Secondary objectives of the trial

1. To assess the palatability of the selumetinib granule formulation.
2. To further assess the PK of selumetinib and N desmethyl selumetinib metabolite after administration of the selumetinib granule formulation.
3. To evaluate the efficacy of the selumetinib granule formulation by assessment of ORR as determined by ICR per REiNS criteria.

1. Evaluar la palatabilidad de la formulación granulada de selumetinib.
2. Evaluar más la FC de selumetinib y del metabolito N-desmetil selumetinib después de la administración de la formulación granulada de selumetinib.
3. Evaluar la eficacia de la formulación granulada de selumetinib mediante la evaluación de TRG determinado por una revisión central independiente según criterios REiNS.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male and female participants aged ≥ 1 to < 7 years of age at the time their legally authorised representative (parent or guardian) signs the informed consent.
2. All study participants must be diagnosed with with symptomatic inoperable PN as defined in protocol.
3. Participants must have at least one measurable PN, defined as a PN of at least 3 cm measured in one dimension, which can be seen on at least 3 imaging slices and have a reasonably well-defined contour. Participants who have undergone surgery for resection of a PN are eligible provided the PN was incompletely resected and is measurable. The target PN will be defined as the clinically most relevant PN, which is symptomatic, inoperable and measurable by volumetric MRI analysis.
4. Performance status: Participants must have a Lansky performance of ≥ 70 except in participants who are wheelchair bound or have limited mobility secondary to a need for mechanical breathing support (such as an airway PN requiring tracheostomy or continuous positive airway pressure) who must have a Lansky performance of ≥ 40.
5. Participants must have a BSA ≥ 0.4 and ≤ 1.09 m2 at study entry (date of ICF signature).
6. Mandatory provision of consent for the study signed and dated by a participant's legally authorised representative (parent or guardian) along with the paediatric assent form, if applicable

1. Participantes niños y niñas de ≥1 a <7 años de edad en el momento en que su representante legal autorizado (progenitor o tutor) firma el consentimiento informado.
2. Todos los participantes deben tener un diagnóstico de NF1 con NP sintomáticos e inoperables según se define en protocolo.
3. Los participantes deben tener al menos un NP medible, definido como un NP de al menos 3 cm medido en una dimensión, que pueda verse en al menos 3 cortes de imágenes y tenga un contorno razonablemente bien definido. Los participantes que se hayan sometido a cirugía para la resección de un NP son aptos siempre que el NP se haya resecado de forma incompleta y sea medible. El NP diana se definirá como el NP clínicamente más relevante, sintomático e inoperable, que se puede medir mediante el análisis volumétrico de la RM.
4. Estado funcional: Los participantes deben tener un rendimiento de Lansky ≥70 excepto en participantes en silla de ruedas o con movilidad reducida por la necesidad de soporte respiratorio mecánico (como un NP en vías respiratorias que requiera traqueotomía o presión positiva continua en las vías respiratorias) que deben tener un rendimiento de Lansky ≥ 40.
5. Los participantes deben tener una superficie corporal ≥ 0,4 y ≤ 1,09 m2 al incorporarse al estudio (fecha de la firma del FCI).
6. Entrega obligatoria del consentimiento para el estudio firmado y fechado por el representante legalmente autorizado del participante (progenitor o tutor) junto con el formulario de consentimiento pediátrico, cuando proceda.

E.4

Principal exclusion criteria

1. Participants with confirmed or suspected malignant glioma or MPNST. Participants with low grade glioma (including optic glioma) not requiring systemic therapy are permitted.
2. History of malignancy except for malignancy treatment with curative intent with no known active disease ≥ 2 years before the first dose of study intervention and of low potential risk of recurrence.
3. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of selumetinib.
4. A life-threatening illness, medical condition, organ system dysfunction or laboratory finding which, in the Investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of selumetinib, or put the study outcomes at undue risk.
5. Participants with clinically significant cardiovascular disease as defined in the protocol.
6. Liver function tests: Bilirubin > 1.5 × the ULN for age with the exception of those with Gilbert syndrome (≥ 3 × ULN) or AST/ALT > 2 × ULN.
7. Renal Function: Creatinine clearance or radioisotope glomerular filtration rate < 60 mL/min/1.73 m2 or Serum creatinine > 0.8 mg/dL (for participants aged ≥ 1 to < 4 years) or > 1.0 mg/dL (for participants aged ≥ 4 years).
8. Have inadequate haematological function defined as: An absolute neutrophil count < 1500/μL or Haemoglobin < 9g/dL or Platelets < 100,000/μL or Have had a transfusion (of red cells or other blood derived products) within the 28 days prior to study entry (date of ICF signature).
9. Participants with ophthalmological findings/condition as listed in the protocol.
10. Have any unresolved chronic toxicity with CTCAE Grade ≥ 2 which are associated with previous therapy for NF1-PN (except hair changes such as alopecia or hair lightening)
11. Participants who have previously been treated with a MEKi (including selumetinib) and have had disease progression, or due to toxicity have either discontinued treatment and/or required a dose reduction.
12. Have received or are receiving an IMP or other systemic NF1-PN target treatment (including MEKi) within 4 weeks prior to the first dose of study intervention, or within a period during which the IMP or systemic PN target treatment has not been cleared from the body (eg, a period of 5 'half-lives'), whichever is longer.
13. Receiving herbal supplements or medications known to be strong or moderate inhibitors or inducers of the CYP2C19 and CYP3A4 enzymes unless such products can be safely discontinued at least 14 days or 5 half-lives (whichever is longer) before the first dose of study medication.
14. Inability to undergo MRI and/or contraindication for MRI examinations. Prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI.

1. Participantes con sospecha o confirmación de glioma maligno o TMVNP. Se permiten los participantes con glioma de bajo glioma (incluido glioma óptico) que no requieran terapias sistémicas.
2. Antecedentes de neoplasia maligna excepto en caso de tratamiento de la neoplasia maligna con intención curativa sin enfermedad activa conocida durante ≥2 años antes de la primera dosis de la intervención del estudio y de riesgo bajo de recurrencia.
3. Náuseas y vómitos resistentes, enfermedad gastrointestinal crónica, incapacidad para tragar el producto formulado o resección intestinal significativa anterior que impediría la absorción, la distribución, el metabolismo o la excreción adecuados de selumetinib.
4. Enfermedad potencialmente mortal, patología, insuficiencia orgánica o hallazgo de laboratorio que, en opinión del investigador, podría poner en peligro la seguridad del participante, interferir en la absorción o el metabolismo de selumetinib o poner los resultados del estudio en riesgo indebido.
5. Participantes con enfermedad cardiovascular clínicamente significativa según protocolo.
6. Pruebas de función hepática: Bilirrubina >1,5 × LSN para la edad, con la excepción de aquellos con síndrome de Gilbert (≥3 × LSN) o AST/ALT >2 × LSN.
7. Función renal: Aclaramiento de creatinina o tasa de filtración glomerular mediante radioisótopos <60 ml/min/1,73 m2. Creatinina sérica >0,8 mg/dl (para participantes de ≥1 a <4 años) o >1,0 mg/dl (para participantes de ≥4 años).
8. Tener una función hematológica inadecuada definida como: Recuento absoluto de neutrófilos <1500/µL, Hemoglobina <9 g/dl o Plaquetas <100 000/μl o Haberse sometido a una transfusión (de eritrocitos u otros hemoderivados) en los 28 días anteriores a la incorporación al estudio (fecha de la firma del FCI).
9. Participantes con hallazgos oftalmológicos/afecciones oftalmológicas listados en protocolo.
10. Tener otra toxicidad crónica no resuelta de grado ≥2 según los CTCAE que se asocie al tratamiento anterior para NP-NF1 (excepto alteraciones capilares como alopecia o aclaramiento del cabello).
11. Participantes tratados previamente con un inhibidor de MEK (incluido selumetinib) y que han presentado progresión de la enfermedad, o que debido a toxicidad interrumpieron el tratamiento y/o necesitaron una reducción de la dosis.
12. Haber recibido o estar recibiendo un PEI u otro tratamiento sistémico dirigido a NF1-NP (incluido inhibidor de MEK) en las 4 semanas anteriores a la primera dosis de la intervención del estudio, o en un periodo durante el que el PEI o el tratamiento sistémico dirigido al NP no se haya eliminado del organismo (p. ej., un periodo de 5 “semividas”), lo que dure más.
13. Recibir complementos herbarios o medicamentos que se sabe que son inhibidores fuertes o moderados de CYP2C19 y CYP3A4 o inductores de la enzima CYP3A4, a menos que el uso de estos productos pueda interrumpirse de forma segura al menos 14 días o 5 semividas (lo que sea más largo) antes de la primera dosis del medicamento del estudio.
14. Incapacidad para someterse a RM y/o contraindicación para las exploraciones por RM. Prótesis o aparatos ortopédicos o dentales que podrían interferir en el análisis volumétrico del NP diana en la RM.

E.5 End points

E.5.1

Primary end point(s)

1. Selumetinib AUC0-12 derived after single dose administration
2. Safety and tolerability will be evaluated in terms of AEs, clinical safety laboratory assessments (clinical chemistry, haematology, urinalysis), physical examination, weight, vital signs, ECG, ECHO, ophthalmologic assessment, knee (or wrist) MRI/X-ray, and performance status.
3. Assessments related to AEs will include: occurrence/frequency; relationship to study intervention; CTCAE grade; seriousness; death; AEs leading to discontinuation of study intervention; AEs of special interest.

1. Derivado de AUCO-12 de selumetinib después de la administración de una dosis única.
2. Se evaluará la seguridad y tolerabilidad en términos de AA, evaluación de seguridad clínica de resultados de laboratorio (bioquímica clínica, hematología y urinálisis), examen físico, peso, signos vitales, ECG, ecocardiograma, evaluación oftalmológica, RM/radiografía de rodilla/muñeca y estado funcional.
3. La evaluación relacionada con AAs incluirá: ocurrencia/frecuencia; relación con el medicamento del ensayo; grado CTCAE; severidad; muerte; AAs que conllevan la interrupción del tratamiento; AAs de especial interés.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. PK: Cycle 1 Day 1
2. Safety: from screening until 30 days after last dose

1. FC: Ciclo 1 Dia 1
2. Seguridad: desde selección hasta 30 días después de la última dosis

E.5.2

Secondary end point(s)

1. Palatability using the parent-reported observer palatability assessment
2. Plasma concentrations and PK parameters of selumetinib including, but not limited to: Selumetinib AUC0-12 derived after multiple dose administration; Cmax, AUC0-6, AUClast, tmax, tlast derived after single and multiple dose administration; AUC0-24, CL/F, Vz/F and t1/2 after single dose administration; Rac Cmax, Rac AUC, CL/F and VSS/F derived after multiple dose administration.
3. Plasma concentrations and PK parameters of N desmethyl selumetinib including, but not limited to: Cmax, AUC0-6, AUC0-12, AUClast, tmax, tlast derived after single and multiple dose administration; Rac Cmax and Rac AUC derived after multiple dose administration; Parent to metabolite ratio for AUC and Cmax after single and multiple dose administration.
4. Objective Response Rate (ORR)

1. Palatabilidad usando evaluación de palatabilidad por observador reportada por los padres.
2. Concentración plasmática y parámetros FC de selumetinib incluyendo, pero no limitándose, a Selumetinib AUC0-12 derivado tras la administración de dosis múltiple, Cmax, AUC0-6, AUClast, tmax, tlast derivado tras la administración de una dosis única y múltiple; AUC0-24, CL/F, Vz/F y t1/2 después de una administración única de dosis; Rac Cmax, Rac AUC, CL/F y VSS/F derivado tras la administración de dosis múltiple.
3. Concentración plasmática y parámetros FC de N desmetil selumetinib incluyendo, pero no limitándose, a Cmax, AUC0-6, AUCo-12, AUClast, tmax, tlast derivado después de una administración única y múltiple de dosis; Rac Cmax y Rac AUC derivado después de una administración de dosis múltiple; Relación padre / metabolito para AUC y Cmax después de la administración de dosis únicas y múltiples.
4. Tasa de Respuesta Objetiva (TRO).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Palatability: Cycle 1 Day 1 to Day 8 (1 week), Cycle 7 Day 1 to Day 8 (1 week)
2. PK: Cycle 1 Day 1, Cycle 2 Day 1, Cycle 5 Day 1, Cycle 13 Day 1, Cycle 25 Day 1 (1 cycle = 28 days)
3: ORR: Screening, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 19 Day 1, Cycle 25 Day 1, End of Treatment

1. Palatabilidad: Ciclo 1 Dia 1 a Dia 8 (1 semana), Ciclo 7 Dia 1 a Día 8 (1 semana).
2. FC: Ciclo 1 Día 1, Ciclo 2 Día 1, Ciclo 5 Día 1, Ciclo 13 Día 1, Ciclo 25 Día 1 (1 ciclo=28 días).
3. TRG: Selección, Ciclo 5 Día 1, Ciclo 9 Día 1, Ciclo 13 Día 1, Ciclo 19 Día 1, Ciclo 25 Día 1, Final de Tratamiento.

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

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

to define a dosing regimen and assess the PK and safety of the granule formulation

Definir una régimen de dosificación y evaluar la FC y seguridad de la formulación granulada.

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

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

Russian Federation

United States

Germany

Italy

Netherlands

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

LVLS

UVUP

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

F.4.2.2

In the whole clinical trial

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)

If selumetinib is approved locally and reimbursed for use in paediatric patients with NF1 who have symptomatic, inoperable PN, participants should be switched to the commercial supply at the end of the study. However, if the participant is unable to access the commercial supply and they are still receiving clinical benefit, AstraZeneca and the Investigator will discuss how the participant could continue to receive selumetinib if he/she is benefiting from treatment.

Si selumetinib es aprobado localmente y reembolsado para su uso en pacientes pediátricos con NF1 con PN sintomáticos e inoperables, los participantes deberán pasarse a la medicación comercial al final del estudio. Sin embargo, si los participantes no pueden acceder a la medicación comercial y continúan recibiendo beneficio clínico del tratamiento, AstraZeneca y el investigador hablarán sobre cómo el paciente puede continuar recibiendo selumetinib si é/ella se están beneficiando del tratamiento.

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

2022-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-02-14

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

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