Selumetinib Paediatric NF1 Japan Study

A Phase 1 Open Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Selumetinib, a Selective Mitogen Activated Protein Kinase Kinase (MEK) 1 Inhibitor, in Japanese Paediatric Subjects With Neurofibromatosis Type 1 (NF1) and Inoperable and Symptomatic Plexiform Neurofibromas (PN)

This is a phase I open label study designed to evaluate the safety, tolerability, PK and efficacy of selumetinib in Japanese paediatric patients with neurofibromatosis type 1 and inoperable and symptomatic plexiform neurofibroma.

Study Overview

• Status: Completed
• Conditions: Neurofibromatosis Type 1
• Intervention / Treatment: Drug: Selumetinib

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Minato-ku, Japan, 105-8471
    • Research Site
  • Nagoya-shi, Japan, 466-8560
    • Research Site
  • Setagaya-ku, Japan, 157-8535
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Three years of age or older, and less than or equal to 18 years of age at the time of obtaining informed consent. BSA greater than or equal to 0.55 m2, and able to swallow the whole study drug (capsules) without entire contents unpacked from the capsules.
• NF1 and inoperable and symptomatic PN who have PN-related morbidities (symptom and/or complications), as judged by the investigator.
• Inoperable PN is defined as PN that cannot be surgically completely removed without risk for substantial morbidity due to encasement of, or close proximity to, vital structures, invasiveness, or high vascularity of the PN.
• A PN is defined as a neurofibroma that has grown along the length of a nerve and may involve multiple fascicles and branches. A spinal PN involves two or more levels with connection between the levels or extending laterally along the nerve.

• In addition to PN, subjects must have at least 1 other diagnostic criterion for NF1 as follows:

  1. Six or more café-au-lait macules >5 mm in greatest diameter in pre-pubertal individuals and >15 mm in greatest diameter in post-pubertal individuals.
  2. Freckling in the axillary or inguinal regions.
  3. Optic glioma.
  4. Two or more Lisch nodules (iris hamartomas).
  5. A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis.
  6. A first-degree relative with NF1.
• At least one measurable typical or nodular PN in principle, defined as a lesion of at least 3 cm measured in one dimension.
• Adequate organ/haematological function

Key Exclusion Criteria:

• Evidence of malignant peripheral nerve sheath tumour.
• Prior malignancy (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, low grade optic pathway gliomas associated with NF1 which does not require systemic treatment or other cancer from which the subject had been disease free for ≥2 years or which would not have limited survival to <2 years) or other cancer requiring treatment with chemotherapy or radiation therapy.
• Clinically significant cardiovascular disease
• Known history of human immunodeficiency virus, serologic status reflecting active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or any uncontrolled active systemic infection
• Subjects with clinically significant ophthalmological findings/conditions
• Inability to undergo MRI and/or contraindication for MRI (i.e. prosthesis or orthopaedic or dental braces that would interfere with volumetric analysis of target PN on MRI).
• Have refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would adversely affect the absorption/bioavailability of the orally administered study medication.
• Receiving supplementation with vitamin E greater than 100% of the daily recommended dose.
• Receiving herbal supplements or medications known to be strong inhibitors or inducers of the cytochrome P450 (CYP) 3A4 enzymes unless such products can be safely discontinued at least 14 days before the first dose of study medication.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Selumetinib	Drug: Selumetinib; Selumetinib 25 mg/m2 BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability in terms of adverse events	Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms, safety laboratory parameters, echocardiogram and ophthalmologic assessment.	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum plasma concentration (Cmax)	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Area under the plasma concentration-time curve (AUC)	Pharmacokinetics (PK) parameters will be derived using standard non-compartmental methods.	From obtaining the first informed consent until 30 days after the last dose (Selumetinib). Expected duration is approximately two years.
Overall response rate	Defined as the proportion of subjects who achieve a response by independent central review per Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) criteria.	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Duration of response	Defined as the time from the date of the first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression, as determined by independent central review per REiNS criteria.	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Clinical Global Impression of Change (CGIC)	Comprehensive evaluation will be performed by investigator on the changes of PN related morbidities (symptoms and/or complications), and relevant findings including imaging studies and physical exams from baseline.	Assessed at every 2 cycles for the first year and every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.
Total scale score of Paediatric Quality of Life Inventory (PedsQL; self- and parent-reported)	Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). A Total Scale Score will also be derived as the sum of all the items divided by the number of items answered on all the scales.	Assessed at every 4 cycles until drug permanently discontinued. Expected duration is approximately 2 years. Each cycle is 28 days.

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2020
• Primary Completion (Actual): June 16, 2021
• Study Completion (Actual): March 24, 2023

Study Registration Dates

• First Submitted: July 29, 2020
• First Submitted That Met QC Criteria: July 29, 2020
• First Posted (Actual): July 31, 2020

Study Record Updates

• Last Update Posted (Actual): April 26, 2023
• Last Update Submitted That Met QC Criteria: April 25, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Nerve Sheath Neoplasms; Neurocutaneous Syndromes; Peripheral Nervous System Neoplasms; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma
• Other Study ID Numbers: D1346C00013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal.

All request will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing 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.
• IPD Sharing 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No