Research Updates

Overview: 

In 2019, ANZCHOG approached the Children's Tumour Foundation (CTF) to support its efforts to run a phase II MEK Inhibitor clinical trial across multiple paediatric and adolescent/young adult cancer centres in Australia and New Zealand.

This is the first Australian-led clinical trial of the MEK Inhibitor drug, Trametinib and the first NF research study to receive funding from the Australian Federal Government. The seven-year study will investigate the effectiveness of Trametinib for the treatment of plexiform neurofibromas and optic pathway gliomas. In addition to monitoring the expected reduction in tumour size, it will also monitor the improvement in pain, function, and quality of life, as well as brain function and social development.

For the past 18 months, the Children's Tumour Foundation has been advocating and raising funds to support the trial, which is expected to start enrolling patients as early as January 2021.

Once the trial is complete, the results will contribute to a body of evidence that supports making this drug affordable and available to anyone living with these specific tumour types as a front-line treatment, and not a last resort.

Current Status: Recruitment In Progress from January 2021

Eligibility Criteria:  Enrolments are expected to begin as early as January 2021 with for up to 60 patients from hospitals around the country and will occur directly through existing patient lists. To be eligible for the trial, a patient will need:

• to be aged between 3 months and 25 years when they start the trial
• to have NF1 
• to have an optic pathway glioma where the tumour has continued to grow or the vision tests have deteriorated after treatment such as chemotherapy; or
• to have a plexiform neurofibroma which is causing significant problems and where surgery is not an option. This could include symptoms like nerve pain, cosmetic issues, nerve or spinal compression and other problems. 

The team are also looking for volunteers with NF1 who do not have a plexiform NF or progressive OPG and therefore do not need treatment with Trametinib. These children will be asked to complete the same cognitive (learning) assessments as children receiving the medication to provide a comparison.

Hospitals involved in the study:

Source of Recruitment: NF Clinics / The CTF / Via Referral from any hospital

Treatment: Trametinib

Expected Timings :  starting January 2021

• Recruitment Duration: 2 Years
• Treatment Duration: 2 Years
• Follow-up Duration: 3 Years
• Total trial Duration: 7 Years

More Information about the Trial:

MRFF has also contributed more than $760,000 to this study.

Click the below link to be redirected to the official Australian and New Zealand Clinical Trial Registry (ANZCTR) website.

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Findings Available: No

Overview: 

To compare the efficacy, acceptability and safety of magnetic resonance imaging with mammography for screening in women with NF1 aged 30-50 years.

Current Status: Recruitment Commenced

Source of Recruitment: NF Clinic

Findings Available: No

Overview: 

The project seeks to address whether addressing the cosmetic disfigurement in patients with neurofibromatosis type 1 leads to an improvement in quality of life, itch, and an improvement in an objectively measured visual aesthetic score of the disease. This project also seeks to characterise symptoms of itch in NF1, evaluate outcomes of intervention and explore potential psychosocial impacts before and after treatment.

Current Status: Recruitment Commenced

Source of Recruitment: NF Clinic

Findings Available: No

Overview: 

This research project aims to understand the different features of Neurofibromatosis type 1 (NF1) and to direct future research into this condition by inclusion of clinical data in a registry.

The team hope that by studying more people investigators will be able to better understand why this condition is so variable as well as allow for better diagnosis, predict the type or severity of problems people may have and allow for further research to find ways to prevent or treat them in the future.

The study will gather information from medical histories, family histories, scan results (ultrasound, CT and MRI) as required for clinical care, clinical examinations at the NF clinic and/or genetics clinic visits, clinical examination at ophthalmology clinic, neuropsychological test results and genetic test results as required for clinical care.

This study is planned to be ongoing for many years with the intention of collecting information from hunders of people of different ages with different features associated with NF1.

Current Status: Recruiting

Source of Recruitment: NF Clinic, Melbourne

Findings Available: No

Overview: 

Recent evidence suggests that 1 in every 4 children with NF1 has autism spectrum disorder. This project seeks to better understand links between NF1 and autism. 

This study combines the power of accurate and deep clinical and behavioural phenotyping with novel neuroimaging markers and state-of-the-art laboratory protocols, including genomic testing and neuronal modelling using patient-derived induced pleuripotent stem cells (iPSCs). This will allow the team to map causal pathways from gene to neural circuits to symptoms. 

This data will drive the evidence for personalised and targeted clinical trials in NF1 that are directed towards causal mechanisms rather than symptoms.

Current Status: Recruiting

Source of Recruitment: NF Clinic, Database already held by the Institute

Findings Available: No

Overview: 

This year we solved the structure of NF1, providing the first complete atomic map of the gigantic NF1 protein8. This breakthrough provides unprecedented mechanistic detail into NF1 activity and regulation. In particular, the structure allows us to: 

1. map all disease-associated missense and nonsense mutations across the protein to understand how each mutation dysregulates NF1 structure and function, and 
2. shows us that NF1 also functions as a multifaceted signalling platform to regulate a plethora of cellular functions beyond RAS-based growth pathways. 

These recent discoveries perfectly position the team to investigate key knowledge gaps that limit our understanding of NF1 disease variability.

Current Status: Funding requested

Source of Recruitment: N/A

Findings Available: Yes

Overview: 

The study will explore the genetic changes that lead to this type of cancer in NF1 patients to create a new diagnostic intervention. Liquid biopsies are an exciting new area of genomics which help us detect cancer through a simple blood test. 

Current Status: Active

Source of Recruitment: NF Clinics

Findings Available: No

Overview: 

Neurofibromatosis Type 1 (NF1) is one of the most common single-gene inherited disorders globally, with an incidence of 1:2500 individuals. While several phenotypes are associated with the disorder, the most common manifestation is cutaneous neurofibroma. The majority of adults develop these distressing cutaneous neurofibromas (cNF), which increase in severity with age. 

Adult patients report cosmetic disfigurement due to cNF as the greatest burden of living with NF1. There is no way to predict tumour severity which can range from <100 to thousands. Youth and families experience reduced quality of life due to concerns about this uncertain future. 

In the proposed research, Dr Dudding-Byth will assemble a consortium of internationally recognised experts in NF1 with access and capacity to recruit phenotype patients to drive the largest genome-wide association study of the modifier gene networks driving the cutaneous phenotype variance in NF1. Individualised pharmacological annotation of these networks will be used to identify precision treatment options to characterise potential treatment pathways.

Current Status: Development

Source of Recruitment: NF Clinic, Institution Database and the Children's Tumour Foundation

Findings Available: No

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Overview: 

It has been recently identified that 45% of children with NF1 have impairing auditory deficits leading to a reduced ability to understand speech in noisy environments (e.g. a classroom). The severity was significant enough to cause impairing disruptions to children’s everyday communication and academic progress. There is some evidence from the general population that similar auditory deficits can be treated with non-invasive remote microphone listening (RML) devices, which improve amplify the teacher’s voice for the student. 

The trial will test the clinical benefits of using these devices in children with NF1. Similar to the effects of prescribing glasses for children with myopia/hypermetropia, these devices may confer immediate benefits for functional hearing ability. 

The trial will be referred to as TAP-iN (Treating Auditory Problems in Neurofibromatosis), and will seek to enrol children with NF1 aged 5-12 years. An initial auditory assessment will be completed with the child, and will include listening to speech in background noise. Children who may benefit from the device will then be randomised to (1) 2 weeks of RML device use in the classroom followed by 2 weeks of no device use (or vice versa). After completing this, participants will be invited to use the device for a longer period of time (approximately 9 months) to so we can see whether the RML device leads to improvements in classroom learning compared to children with NF1 that do not wear the RML device. 

It is hoped that the study will provide convincing evidence for a novel, non-invasive intervention targeting a common and impairing problem in NF1.

Current Status: seeking ethics approval

Source of Recruitment: NF clinics at The Royal Children’s Hospital/Murdoch Children’s Research Institute and The Children’s Hospital at Westmead.  Information about participation in the trial will be released once the trial is open and ready to recruit.

Findings Available: No

Overview: 

NF is extremely variable and can result in cognitive impairment, progressive disfigurement and physical disability. The needs of patients with NF frequently involve multiple specialists, requiring a multidisciplinary care approach. This project aims to strengthen existing services and support service sustainability in the longer term through the development of an integrated, state-wide service delivery model of care for NF patients in NSW.

Current Status: Ongoing

Source of Recruitment: n/a

Findings Available: No

Overview: 

Paediatric sleep problems are a common occurrence and are associated with significant daytime impairments. Paediatric sleep problems can present as the primary sleep disorder, as a secondary consequence of an underlying medical issue or as a psychiatric disorder. They can also compromise social, academic and neurobehavioural functioning. Evidence suggests an increase risk for sleep problems in children with NF1. 

This research study will characterise the sleep profile of children with NF1 utilising comprehensive sleep history and objective assessment. This work will provide novel insight into the frequency of sleep disturbances and sleep disorders and identify the biopsychosocial factors contributing to poor sleep in NF1. 

This study will also examine the impact of poor sleep on day-to-day functioning of children with NF1. Results from this study will be important for the design of future intervention studies and guide future patient management for sleep disturbance in children with NF1.

Current Status: Recruitment Commenced

Source of Recruitment: NF Clinics

Findings Available: No

Overview: 

Dopamine dysregulation has been identified as a key modulator of behavioural impairment in Neurofibromatosis Type 1 (NF1) and a potential therapeutic target. Preclinical research involving NF1 mouse models suggests methylphenidate, a stimulant medication that increases dopaminergic neurotransmission, rescues spatial-learning and attentional dysfunction. 

This randomised, double-blind placebo-controlled trial will assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1

Treatment: Methylphenidate/placebo

Current Status: Recruitment Commenced

Source of Recruitment: NF Clinics / CTF (previous)

Findings Available: No

Overview: 

Unprecedented advances and enhanced application of genomic technologies in health care are driving an explosion in genetic knowledge that is set to transform the face of modern medicine. Unfortunately, while this knowledge is rapidly leading to increased diagnostic power, translation through to therapeutic benefit and improved health outcomes is progressing at a much slower pace. 

The goal of this project is to address this increasing gap for patients affected by Neurofibromatosis Type 1 (NF1) through the development of novel, safe and efficient therapeutic options based on vector-driven genome editing. 

To achieve this goal, we have assembled an accomplished team with the relevant technological and clinical expertise, access to world-class facilities and resources, including NF1 patient samples, as well as unique expertise in the clinical development of gene therapy technologies.

Current Status: Active

Source of Recruitment: Not applicable

Findings Available: No

Overview: 

An AB:BA crossover study examining neuropsychology, speech pathology and developmental assessments between face-to-face and tele-health delivery modes in 6 to 15 year old children and adolescents with Neurofibromatosis Type 1 (NF1), autism spectrum disorder (ASD) and typically developing controls (TDCs).

The study will be administered between 3-24 months apart in order to determine whether these methods are reproducible across settings and within groups of 6-15 year old children and adolescents. In addition, the study will examine the acceptability and feasibility of tele-health for conducting cognitive, speech, language and developmental assessments according to parent/guardian, child/adolescent and clinical satisfaction levels. 

Current Status: Recruiting

Source of Recruitment: NF Clinic, Database already held by institution and social media

Findings Available: No

Overview: 

Using mice with a genetic mutation in the NF1 gene, Prof Hannan and his team hope to study how autism, behavioural and cognitive deficits occur by using the latest genetic technologies. This explorative study will then be used to test new therapies in mice for these issues in the hope that effective treatments for NF1 in people may be discovered.

Current Status: Commenced

Source of Recruitment: n/a

Findings Available: No

Overview: 

Reduced muscle tone, muscle weakness and fatigue can impact considerably on quality of life for children with Neurofibromatosis type 1 (NF1). Human muscle biopsies and mouse models of NF1 deficiency in muscle show intramyocellular lipid accumulation, and preclinical data has indicated that L-carnitine supplementation can ameliorate this phenotype. 

The goal of this study is to examine whether daily L-carnitine supplementation is safe and feasible, and will improve muscle strength and reduce fatigue in children with NF1.

Treatment: L-carnitine

Current Status: Published

Source of Recruitment: NF Clinics / CTF (previous)

Findings Available: Yes

Findings Summary: 

The outcomes of the study for testing Carnitine for muscle weakness broadly showed (i) no adverse events (ii) some functional improvements and patient reports of benefit, in the n=6 participants aged 8-12.

Published article:  L-carnitine supplementation for muscle weakness and fatigue in children with neurofibromatosis type 1: A Phase 2a clinical trial