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
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.
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.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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