Selumentinib for the Prevention of Plexiform Neurofibroma Growth and Morbidity in Young Children with Neurofibromatosis Type 1 (NF1)
Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder that affects 1 in 3,500 people in the United States. Up to half of people with NF1 will develop tumors called plexiform neurofibromas (PN). PN can appear anywhere in the body and, while not cancers, can cause problems including pain, weakness, and disfigurement. PN grow most rapidly in young children and usually cannot be removed completely by surgery. Recently, selumetinib (Koselugo [TM]) became the first FDA-approved medicine to treat PN, which cause clinical problems in children with NF1. Though selumetinib improved some PN-related problems such as pain, we know that other symptoms, such as nerve damage or blindness, cannot be reversed. At present, treatment is not usually started unless PN are growing and cause symptoms. Starting treatment earlier, before the PN causes symptoms, may prevent some of these devastating complications. However, we do not know how many children with NF1 have asymptomatic tumors in high-risk locations, meaning PN in locations that could cause problems if they continue to grow, such as near the airway or the eye. We also do not yet know whether treatment of an asymptomatic PN will prevent these tumors from growing and causing future symptoms. The goal of our proposed study is to answer three key questions, which will help guide the care of children with NF1 in the future. First, to learn how many children age 1-8 years with NF1 have an asymptomatic PN and where those PN are located. Second, to determine whether treating asymptomatic PN in a high-risk location with selumetinib can prevent future tumor growth and symptoms. Third, we will learn whether growing tumors that shrink or stabilize with selumetinib at the standard FDA-approved dose (twice daily every day) can maintain that response when switched to an intermittent (lower) dose. This question is important because children who take selumetinib for PN often need to stay on the medication for a long time (years) and may have side effects, like skin rash or diarrhea, which might be improved by a lower dose. However, we do not yet know whether the lower dose will be enough to maintain the tumor response achieved with standard dosing. To answer these questions, this study is divided into three parts. In Part 1, children aged 1-8 years with NF1 and no known PN will undergo a whole-body magnetic resonance imaging (WBMRI) to evaluate for the presence of a PN. If the MRI shows a PN in a high-risk location, the child will be able to enroll on Part 2 of the study. In Part 2, children will be randomly assigned either to treatment with selumetinib or to close observation with no treatment. If patients have PN growth or develop new PN-related symptoms while on observation, they will be offered treatment on Part 3. In Part 3, they will receive selumetinib at the standard (every day) dose, and if the tumor responds, they will be switched to a different dosing schedule (selumetinib taken 5 days of the week) to see whether the response can be maintained at the lower dose. This study will provide important information that will help guide the clinical management of children with NF1. If early treatment of PN is successful in preventing the development of clinical problems such as disfigurement or blindness, this would be a major success. It would then make sense to do a routine WBMRI in all children diagnosed with NF1 so that these types of tumors can be found and treated early. On the other hand, if treatment is not found to be helpful, then performing screening MRI scans and starting treatment before the PN grow or cause symptoms may not make sense. Either way, data from this study will help guide future clinical management and treatment of children with PN.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110796
Entities
People
- Laura Metrock
Organizations
- United States Army
- University of Alabama at Birmingham