NCT03326388

Intermittent Dosing Of Selumetinib In Childhood NF1 Associated Tumours

A Paediatric Phase I/II Study Of Intermittent Dosing Of The Mek-1 Inhibitor Selumetinib In Children With Neurofibromatosis Type-1 And Inoperable Plexiform Neurofibroma And/Or Progressive Optic Pathway Glioma

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 14 (actual)
• Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust · Academic / Other
• Sex: All
• Age: 3 Years – 18 Years
• Healthy volunteers: Not accepted

Summary

Phase I and II study of the MEK inhibitor Selumetinib given twice daily on 5 out of 7 days in children with NF1 and inoperable plexiform neurofibromas or progressive/relapsed optic pathway gliomas. This study will test the early and late toxicities of selumetinib when it is given in this intermittent schedule (in 5 out of 7 days) and will also test the effectiveness of the drug in reducing the size of plexiform neurofibromas and optic pathway gliomas in children with NF1. It will also test the effectiveness of the drug in improving the participants function in day to day life.

Detailed description

Neurofibromatosis type 1 (NF1) is a common autosomal dominant, progressive disorder with an incidence of 1 in 3,500 of the population. NF1 is characterized by diverse, progressive cutaneous, neurological, skeletal and neoplastic manifestations with no standard drug treatment options available. Patients with NF1 have an increased risk of developing tumours of the central and peripheral nervous system including plexiform neurofibromas (PN) (27%) and optic gliomas (15-20%). Genetic aberrations targeting the Ras-mitogen-activated protein kinase (MAPK) signalling pathway are a hallmark molecular feature of Low Grade Gliomas (including optic pathway gliomas) and NF1 as well as some low-grade glial-neuronal tumours. The gene responsible for NF1 has been cloned and encodes a protein called neurofibromin. Loss of Neurofibromin is associated with elevated levels of Ras, and Activated Ras results in the initiation of a cascade of signalling events such as activation of Raf and MAPK that leads to increased cell proliferation. Thus MAPK inhibitors offer an attractive novel therapeutic option for both NF1 related PN and optic pathway gliomas This study will comprise 2 phases. Phase 1 will be a dose escalation phase, designed to establish the correct dose of selumetinib. Phase 1 will be open to NF-1 participants, aged 3 to ≤18 years with inoperable plexiform neurofibromas (PN). This phase of the study will investigate a new intermittent schedule of oral administration of selumetinib, (given twice daily on 5 out of every 7 days) to determine the maximum tolerated dose (MTD) and a recommended phase 2 dose. The starting dose level will be 25mg/m2/dose given twice daily. This was the MTD determined by the Paediatric Brain Tumour Consortium study of Selumetinib in children with NF1 related LGG and the National Cancer Institute study of children with NF1 inoperable PN. In both of these trials selumetinib was given twice daily, every day. The purpose of this phase 1 study will allow the investigators to define the acute and chronic toxicities and pharmacokinetics (PK) of Selumetinib in this population and contribute to determining the effect of Selumetinib on the growth rate of PN. The Phase 2 part of the study will be a dose expansion study and will be open to 2 groups of participants. Those with progressive NF-1 related optic pathway gliomas (OPG), and those with NF1 related inoperable PN. This part of the study will only commence when the recommended phase 2 dose is established from part 1. The purpose of this part of the study is to determine the effectiveness of the 5 out of 7 day intermittent dosing schedule of Selumetinib, using response rates (and duration of response), appropriate MRI criteria and functional assessments (REINs criteria). The investigators plan to further evaluate the acute and chronic toxicities of selumetinib in this population and to assess the clinical status and quality of life in this population.

Conditions

• Neurofibromatosis Type 1
• Plexiform Neurofibroma
• Optic Nerve Glioma

Interventions

Type	Name	Description
DRUG	Selumetinib	Selumetinib Intermittent Dosing

Timeline

• Start date: 2019-09-26
• Primary completion: 2024-02-14
• Completion: 2024-02-14
• First posted: 2017-10-31
• Last updated: 2024-04-04

Locations

2 sites across 1 country: United Kingdom