Pharmacokinetics, Safety and Efficacy of the Selumetinib Granule Formulation in Children Aged ≥1 to <7 Years With NF1-related Symptomatic, Inoperable PN

NCT05309668 | Active Not Recruiting Phase 1 Results FDA Drug

• 2 other identifiers: D1346C000042020-005608-20
• Study Type: interventional
• Target: 36
• Locations: 7 countries
• Sites: 16

Brief Summary

This study is designed to define a dosing regimen and assess the pharmacokinetics(PK) and safety of the granule formulation; the study will also include descriptive analyses of exploratory efficacy endpoints. The study will inform the benefit risk profile of the granule formulation in children aged ≥ 1 to \< 7 years with NF1 related symptomatic, inoperable PN.

Conditions

Neurofibromatosis Type 1

Outcome Measures

Primary Outcomes (2)

• Selumetinib AUC0-12 Derived After Single Dose Administration

  To determine the pharmacokinetics of selumetinib after administration of the selumetinib granule formulation

  Pre-dose and 1, 2, 3, 4, 6, 8 and 10-12 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1) (each cycle is 28 days)

• Adverse Events Graded by CTCAE Ver 5.0

  To assess the safety and tolerability of the selumetinib granule formulation.

  from screening until 30 days after last dose

Secondary Outcomes (18)

• Palatability Using the Parent-reported Observer Palatability Questionnaire

  Twice daily (morning and evening), from the first day of study treatment (Cycle 1 Day 1) for one week, from Cycle 7 Day 1 for one week (each cycle is 28 days)

• Selumetinib and N-desmethyl Selumetinib AUC0-12 Derived After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

• Selumetinib and N-desmethyl Selumetinib Cmax Derived After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4, 6, 8, 10-12 and 18-24 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

• Selumetinib and N-desmethyl Selumetinib AUC0-6 Derived After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4 and 6 hours after selumetinib single dose on the first day of study treatment (Cycle 1 Day 1). Pre-dose, 1, 2, 3, 4 and 6 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

• Objective Response Rate

  At screening, at week 17 (Cycle5 Day1), week 33 (Cycle9 Day1), week 49 (Cycle13 Day1), week 73 (Cycle19 Day1) and week 97 (Cycle25 Day1), end of treatment (each cycle is 28 days)

Other Outcomes (8)

• Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-6 After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

• Selumetinib and N-desmethyl Selumetinib BSA Normalised AUC0-12 After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

• Selumetinib and N-desmethyl Selumetinib BSA Normalised AUClast After Single and Multiple Dose Administration

  Pre-dose and 1, 2, 3, 4, 6, 8, 10-12, and 18-24 hours post-dose after selumetinib single dose on the first day of treatment (Cycle 1 Day 1). Pre-dose and 1, 2, 3, 4, 6, 8, and 10-12 hours post-dose on Cycle 2 Day 1 (each cycle is 28 days)

Study Arms (1)

Selumetinib single arm

EXPERIMENTAL

This study consists of a screening period (up to 28 days), a treatment period (25 cycles) and a long term safety follow-up for participants until they are 5 years old or commence an alternative systemic NF1-PN treatment, whichever is the earlier. Participants may continue treatment with selumetinib throughout the long term safety follow-up as long as they are considered to be receiving clinical benefit in the opinion of their Investigator. A safety follow up assessment will be performed 30 days after the last dose of study intervention for all study participants.

Drug: Selumetinib granule formulation; Drug: Selumetinib capsule formulation

Interventions

Selumetinib granule formulation DRUG

Selumetinib granule formulation will be administered using BSA-based dosing. The granule formulation dose schema to be used in the study will be established in the dose finding phase. At enrolment participants must have a BSA within the range 0.40 to 1.09 m2; once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.

Selumetinib single arm

Selumetinib capsule formulation DRUG

Selumetinib capsule formulation will be administered using BSA-based dosing. Once participants attain a BSA between 1.10 and 1.29 m2 they will be encouraged to transition to the capsule formulation, if feasible, although all participants must remain on the granule formulation until after they have completed their third cycle of treatment.

Selumetinib single arm

Eligibility Criteria

• Age: 1 Year - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• All study participants must be diagnosed with NF1 with symptomatic inoperable PN as defined in protocol.
• 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.
• 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.
• Participants must have a BSA ≥ 0.4 and ≤ 1.09 m2 at study entry (date of ICF signature).
• 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.

You may not qualify if:

• Participants with confirmed or suspected malignant glioma or MPNST. Participants with low grade glioma (including optic glioma) not requiring systemic therapy are permitted.
• 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.
• 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.
• 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.
• Participants with clinically significant cardiovascular disease as defined in the protocol.
• 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.
• 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).
• Participants with ophthalmological findings/condition as listed in the protocol.
• 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)
• 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.
• 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).
• 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.
• Has received radiotherapy in the 6 weeks prior to start of study intervention or any prior radiotherapy directed at the target or non-target PN.
• Receiving herbal supplements or medications known to be strong or moderate inhibitors of the CYP3A4 and CYP2C19 enzymes or inducers of the CYP3A4 enzyme 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.
• 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.

Sponsors & Collaborators

• AstraZeneca: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (16)

Research Site

Akron, Ohio, 44308, United States

Location

Research Site

Philadelphia, Pennsylvania, 19104, United States

Location

Research Site

Houston, Texas, 77030, United States

Location

Research Site

Richmond, Virginia, 23219, United States

Location

Research Site

Hamburg, 20246, Germany

Location

Research Site

München, 80337, Germany

Location

Research Site

Tübingen, 72076, Germany

Location

Research Site

Milan, 20133, Italy

Location

Research Site

Rome, 00165, Italy

Location

Research Site

Nagoya, 466-8560, Japan

Location

Research Site

Setagaya City, 157-8535, Japan

Location

Research Site

Rotterdam, 3015 GD, Netherlands

Location

Research Site

Moscow, 119620, Russia

Location

Research Site

Moscow, 125412, Russia

Location

Research Site

Barcelona, 08950, Spain

Location

Research Site

Madrid, Spain

Location

Related Publications (1)

• Hernaiz Driever P, Kordes UR, Brecht IB, Saletti V, Fisher MJ, Doughton G, Arefayene M, Rigazio A, Lluch N, Llorente N, Diede SJ, Salvador H. Pharmacokinetics and Safety of Selumetinib Granule Formulation in Children With Symptomatic, Inoperable Neurofibromatosis Type 1-Related Plexiform Neurofibromas (SPRINKLE; phase I/II). J Clin Oncol. 2026 Apr;44(10):849-860. doi: 10.1200/JCO-25-01447. Epub 2026 Jan 27.

  PMID: 41592259 DERIVED

MeSH Terms

Conditions

Neurofibromatosis 1

Interventions

AZD 6244; Dosage Forms

Condition Hierarchy (Ancestors)

Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Pharmaceutical Preparations; Technology, Pharmaceutical; Investigative Techniques

Limitations and Caveats

The outcome measure "Primary Outcome: Selumetininb AUC0-12₂ Derived After Single Dose Administration" is one of two co-primary endpoints. The second co-primary endpoint - "Adverse Events Graded by CTCAE Version 5.0" - is still ongoing. As a result, the study has not yet reached the Primary Completion Date at the time these results were submitted. Full results, including data for the second co-primary endpoint, will be submitted upon completion of the study.

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

information.center@astrazeneca.com

1-877-240-9479

Study Officials

• Study physician Study physician, MD

  AstraZeneca

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 26, 2021
• First Posted: April 4, 2022
• Study Start: January 21, 2022
• Primary Completion (Estimated): November 30, 2027
• Study Completion (Estimated): April 28, 2028
• Last Updated: December 18, 2025
• Results First Posted: May 14, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

Locations

ES (2); JP (2); RU (2); US (4); DE (3); IT (2); NL (1)