scholarly journals Clinical trial design in neurofibromatosis type 1 as a model for other tumor predisposition syndromes

2020 ◽  
Vol 2 (Supplement_1) ◽  
pp. i134-i140
Author(s):  
Andrea M Gross ◽  
Brigitte C Widemann
Keyword(s):  
Clinical Trials ◽  
Neurofibromatosis Type 1 ◽  
Clinical Trial Design ◽  
Neurofibromatosis Type ◽  
Lessons Learned ◽  
Benign Tumors ◽  
Pediatric Cancer Patients ◽  
Patient Reported ◽  
Trial Endpoints

Abstract Up to 10% of all pediatric cancer patients may have an underlying germline mutation which predisposed them to develop a malignancy. With more patients being tested for and diagnosed with genetic tumor predisposition syndromes, there has been improved characterization of their many nonmalignant manifestations. However, designing and implementing clinical trials to treat the nonmalignant tumor and non-tumor manifestations of these syndromes poses many unique challenges. Unlike trials for malignancies where tumor response and survival can be used as straightforward trial endpoints, the nonmalignant manifestations are often chronic, evolve more slowly over time, and may not be immediately life-threatening. Therefore, they will likely require a different approach to both testing and treatment with a focus on more functional and patient-reported outcome trial endpoints. The recent success of treatment trials for the benign tumors plexiform neurofibromas in the tumor predisposition syndrome neurofibromatosis type 1 (NF1) can be used as a model for the development of clinical trials in other tumor predisposition syndromes. In this article, we review the unique challenges associated with targeting the nonmalignant aspects of these conditions as well as some of the lessons learned from the NF1 experience which may be applied to other syndromes in the future.

scholarly journals REiNS: Recommendations for Social Skills Endpoints for Clinical Trials in Neurofibromatosis Type 1

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012422
Author(s):  
Jennifer A. Janusz ◽  
Bonita P. Klein-Tasman ◽  
Jonathan M. Payne ◽  
Pamela L. Wolters ◽  
Heather L. Thompson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Social Skills ◽  
Social Functioning ◽  
Neurofibromatosis Type 1 ◽  
Rating Scale ◽  
Neurofibromatosis Type ◽  
Autism Spectrum ◽  
The Social ◽  
Two Measures

Objective:We reviewed parent-report social skills measures to identify and recommend consensus outcomes for use in clinical trials of social deficit in children and adolescents (ages 6-18 years) with Neurofibromatosis Type 1 (NF1).Method:Searches were conducted via PubMed and ClinicalTrials.gov to identity social skills outcome measures with English language versions used in clinical trials in the past 5 years with populations with known social skills deficits, including Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). Measures were rated by the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Neurocognitive Committee on patient characteristics, use in published studies, domains assessed, availability of standard scores, psychometric properties, and feasibility to determine their appropriateness for use in NF1 clinical trials.Results:Two measures were ultimately recommended by the committee – the Social Responsiveness Scale-2 (SRS-2) and the Social Skills Improvement System- Rating Scale (SSIS-RS).Conclusions:Each of the two measures assesses different aspects of social functioning. The SSIS-RS is appropriate for studies focused on broader social functioning, while the SRS-2 is best for studies targeting problematic social behaviors associated with ASD. Researchers will need to consider the goals of their study when choosing a measure, and specific recommendations for their use are provided.

scholarly journals TMOD-23. PRECLINICAL DRUG EVALUATION IN A GENETICALLY ENGINEERED MINIPIG MODEL OF NEUROFIBROMATOSIS TYPE 1

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi267-vi267
Author(s):  
Sara Osum ◽  
Anat Stemmer-Rachamimov ◽  
Brigitte Widemann ◽  
Eva Dombi ◽  
Jeremie Vitte ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Animal Model ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
New Drugs ◽  
Optic Pathway Glioma ◽  
Large Animal ◽  
Safety And Efficacy ◽  
Mek Inhibitors

Abstract We have employed gene-editing technology to create a Neurofibromatosis Type 1 (NF1) minipig that replicates the broad spectrum of disease that develops in NF1 patients and meets the National Institute of Health’s diagnostic criteria for NF1. The NF1 boars are fertile and the NF1 mutant allele is transmitted at a Mendelian rate with no reduction in fitness of offspring that inherit this allele. To date, we have observed 100% penetrance of café au lait macules, a phenotype that occurs in nearly every NF1 patient, but has never been demonstrated in any other animal model. The NF1 minipig develops cutaneous neurofibromas and optic pathway glioma, that histologically resemble human tumors. Additionally, we have observed other NF1-associated phenotypes including Lisch nodules, tibial dysplasia, white matter decompaction, hypopigmentation, and freckling of the skin. The FDA has emphasized the need for development and testing of new therapies in large animal disease models prior to human studies. Therefore, we have conducted pharmacological studies in our NF1 swine to look at the pharmacokinetic and pharmacodynamic properties MEK inhibitors, currently in clinical trials for NF1. We have demonstrated that oral administration of the MEK inhibitors results in clinically relevant plasma levels of the drug and inhibition of Ras signaling, and that certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. We envision this large animal model of NF1 will become a standard in the evaluation of the safety and efficacy of new drugs prior to Phase I clinical trials. Further, an NF1 minipig may enable researchers to better understand the biological and genetic mechanisms underlying this complex disease, detect NF1-related tumors earlier, identify biomarkers, discover novel drug targets, and test new drugs and combination therapies for safety and efficacy.

scholarly journals Clinical Trials Targeting Neurofibromatoses-associated Tumors: A Systematic Review

2022 ◽  
Author(s):  
Gabriel Roman Souza ◽  
Ahmed Abdalla ◽  
Daruka Mahadevan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Partial Response ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Clinical Findings ◽  
Surface Receptors ◽  
Associated Tumors

Abstract Background There is a paucity of literature that comprehensively analyzes previous and current clinical trials targeting neurofibromatoses-related tumors. This article aims to provide readers of drug development efforts targeting these tumors by analyzing translational and clinical findings. Methods This systematic review was written according to the PRISMA guidelines. Inclusion criteria were clinical trials involving patients with neurofibromatosis type 1, type 2, or schwannomatosis that were treated with therapies targeting neurofibromatoses-associated tumors and that were registered on clinicaltrials.gov. In addition, a search was performed in PubMed, Web of Science, Google Scholar, and Embase European for articles fully describing these clinical trials. Results A total of 265 clinical trials were registered and screened for eligibility. Ninety-two were included in this systematic review involving approximately 4,636 participants. The number of therapies analyzed was more than 50. Drugs under investigation mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. Selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68-71% partial response for inoperable or progressive plexiform neurofibromas in children 2 years of age and older and bevacizumab for a neurofibromatosis type 2-related tumor with approximately 36-41% partial response for vestibular schwannomas in patients 12 years of age and older. Conclusions This systematic review presents the results of previous clinical investigations and those under development for neurofibromatoses-associated tumors. Clinicians may use this information to strategize patients to appropriate clinical trials.

scholarly journals Optic Nerve Incidentaloma

2017 ◽  
Vol 1 (1) ◽  
pp. oapoc.0000004
Author(s):  
Andrea Grosso ◽  
Eric J. Sigler ◽  
John Randolph
Keyword(s):  
Optic Nerve ◽  
Tuberous Sclerosis ◽  
Tuberous Sclerosis Complex ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Benign Tumors ◽  
Healthy Individuals ◽  
Imaging Characteristics ◽  
Astrocytic Hamartoma

Retinal astrocytic hamartomas are rare, benign tumors of glial origin. These lesions are often associated with systemic syndromes, including tuberous sclerosis complex and neurofibromatosis type 1, but also may be encountered in otherwise healthy individuals as an acquired lesion. We present the following case to illustrate clinical and imaging characteristics typically seen in astrocytic hamartoma found as “optic nerve incidentaloma” in an otherwise healthy teenager.

scholarly journals Lessons Learned from Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic

2020 ◽  
Author(s):  
Matthew F Pullen ◽  
Katelyn A Pastick ◽  
Darlisha A Williams ◽  
Alanna A Nascene ◽  
Ananta S Bangdiwala ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Randomized Clinical Trials ◽  
Clinical Trial Design ◽  
Patient Reported Outcome Measures ◽  
Patient Reported Outcome ◽  
Lessons Learned ◽  
Online Data ◽  
Global Pandemic ◽  
Patient Reported

Abstract As the SARS-CoV-2 pandemic evolved, it was apparent that well designed and rapidly conducted randomized clinical trials were urgently needed. However, traditional clinical trial design presented several challenges. Notably, disease prevalence initially varied by time and region, and the pockets of outbreaks evolved geographically over time. Coupled with an occupational hazard from in-person study visits, timely recruitment would prove difficult in a traditional in-person clinical trial. Thus, our team opted to launch nationwide internet-based clinical trials using patient-reported outcome measures. In total, 2795 participants were recruited using traditional and social media, with screening and enrollment performed via an online data capture system. Follow-up surveys and survey reminders were similarly managed through this online system with manual participant outreach in the event of missing data. Here, we present a narrative of our experience running internet-based clinical trials and provide recommendations for the design of future clinical trials during a world pandemic.

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