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WHO International Clinical Trials Registry Platform

The World Health Organization (WHO) has a Web site to help researchers, doctors and patients obtain information on clinical trials.

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Early trial results shrink pediatric neural tumors

In a clinical trial of selumetinib, a new oral drug, children with the genetic disorder neurofibromatosis type 1 (NF1) and plexiform neurofibromas, tolerated selumetinib with most experiencing shrinkage of their tumors. NF1 affects 1 in 3,000 people.

Plexiform neurofibromas develop in up to 50 percent of people with NF1. The majority of these tumors, which can cause significant pain, disability, and disfigurement, are diagnosed in early childhood and grow rapidly prior to adolescence. Complete surgical removal of the tumors is rarely possible, and tumors not completely removed tend to grow back.

The primary aim of the clinical trial was to evaluate selumetinib toxicity and safety in patients with neurofibromatosis type 1, NF1, and other inoperable plexiform neurofibromas. Encouragingly, most of the selumetinib-related toxic effects were mild. At present, though, no therapies are considered effective for NF1 related large plexiform neurofibromas. However, the current trial showed a 20 percent reduction, some more, in tumor volume in over 70 percent of 24 child patients.

Reduction responses were observed in tumors previously growing at a rate of more than 20 percent per year — as well as in non-progressing lesions.

Tumor shrinkage was also maintained long term, for approximately two years, and as of early 2016, no disease progression had been observed in any of the 24 trial participants.

Anecdotal evidence of decrease in tumor-related pain, improvement in motor function, and decreased disfigurement, was also reported.

"Some may say that a 20 percent volume reduction is too small to be meaningful, but to me, just stopping the growth of these devastating tumors is an important achievement," said Dr. Widemann. "The difference we see in these patients is truly unprecedented."

The disease-causing gene for NF1 was first identified in 1990 by two independent teams, one of them led by NIH Director Francis S. Collins PhD MD, at that time Chief of Medical Genetics at the University of Michigan. The other team was led by Ray White PhD, Executive Director of the Huntsman Cancer Institute  (HCI) at the University of Utah.

Previous research had revealed deregulation of the RAS signaling pathway was the most likely cause of tumor development. Numerous drugs targeting the RAS-related signaling pathway have had disappointing results in other phase I and phase II clinical trials.

Selumetinib, from AstraZeneca, inhibits the MEK protein a part of the RAS complex network of signaling pathways. It had demonstrated activity in some advanced cancers, but isn't yet approved by the U.S. Food and Drug Administration for use in the USA.

Trial enrollment began in September 2011 and 24 children (11 girls, 13 boys) participated. It was taken orally as a capsule twice daily continuously, over an average of 30 month cycles. The majority of patients are still continuing with therapy — some have for as long as five years — without observed adverse effect on their development or overall health.

Experiments in mice with similar neurofibromas confirmed inhibition of the MEK protein function in tumors. Inhibition of MEK protein dropped as quickly as two hours after taking the drug began. Additionally, animals receiving treatment with regular interruptions, still had tumor responses, indicating even limited MEK inhibition could iniate tumors to shrink.

"In the future, we may wish to look at intermittent dosing in patients to minimize toxicity and retain maximal outcomes."

Brigitte C. Widemann MD, Acting Chief, National Cancer Institute, Pediatric Oncology Branch, National Institutes of Health, USA.

In some patients, particularly after dose reduction, a loss of response to selumetinib and slow regrowth of tumors was observed. Researchers believe additional studies are warranted to characterize tumors that stop responding to selumetinib. An NCI selumetinib phase II trial for adults with NF1 is currently underway. Serial tissue samples are being taken which should provide information about possible mechanisms of resistance to selumetinib.

A larger phase II pediatric trial is also now enrolling patients, and should help establish the efficacy of selumetinib treatment in children.

In this new trial, evaluations are being performed to assess the effect of selumetinib on plexiform neurofibroma related disfigurement, pain, quality of life, and function.

The new data will be in addition to tumor volume measurements taken from the 24 children in the multicenter early phase I clinical trial, described here and led by Brigitte C. Widemann MD, acting chief of the National Cancer Institute's (NCI) Pediatric Oncology Branch, and sponsored by NCI's Cancer Therapy Evaluation Program.

The Widemann study was conducted at the National Institutes of Health Clinical Center and three participating sites. All took advantage of techniques developed by Dr. Widemann's team enabling very precise measurement of the plexiform neurofibromas.

Experiments were conducted on mice which had developed neurofibromas as a result of genetic modifications performed at Cincinnati Children's Hospital in the laboratory of Nancy Ratner PhD. The National Cancer Institute (NCI) is part of the National Institutes of Health.

Study results appeared Dec. 29, 2016, in the New England Journal of Medicine.

Effective medical therapies are lacking for the treatment of neurofibromatois type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling.

A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.

Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.)

Reference: Widemann BC, et al. Activity of Selumetinib in Neurofibromatosis Type 1 Plexiform Neurofibromas. December 29, 2016. NEJM. DOI: 10.1056/NEJMoa1605943.

This research was supported by NCI's Center for Cancer Research and the Cancer Therapy Evaluation Program; by the Children's Tumor Foundation to Michael Fisher to support participating sites other than the NCI; and by AstraZeneca providing selumetinib and funding for the pharmacokinetic analysis.

About the National Cancer Institute (NCI): NCI leads the National Cancer Program and the NIH's efforts to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit nih.gov.
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Plexiform neurofibromas develop in up to 50 percent
of people with neurofibromatosis type 1(NF1).
Image Credit: MouseWorks



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