The following article in The New England Journal of Medicine shows promising results from a clinical trial that was conducted at the National Institutes of Health. At the bottom of the page see a video of Dr. Brigitte Widemann, acting chief of the National Cancer Institute’s (NCI) Pediatric Oncology Branch, who led the phase 1 clinical trial.
Activity of Selumetinib in Neurofibromatosis Type 1–Related Plexiform Neurofibromas
Eva Dombi, M.D., Andrea Baldwin, C.P.N.P., Leigh J. Marcus, M.D., Michael J. Fisher, M.D., Brian Weiss, M.D., AeRang Kim, M.D., Ph.D., Patricia Whitcomb, R.N., Staci Martin, Ph.D., Lindsey E. Aschbacher-Smith, M.S., Tilat A. Rizvi, Ph.D., Jianqiang Wu, M.D., Rachel Ershler, M.D., Pamela Wolters, Ph.D., Janet Therrien, B.S., John Glod, M.D., Ph.D., Jean B. Belasco, M.D., Elizabeth Schorry, M.D., Alessandra Brofferio, M.D., Amy J. Starosta, Ph.D., Andrea Gillespie, R.N., Austin L. Doyle, M.D., Nancy Ratner, Ph.D., and Brigitte C. Widemann, M.D.
N Engl J Med 2016; 375:2550-2560December 29, 2016DOI: 10.1056/NEJMoa1605943
Effective medical therapies are lacking for the treatment of neurofibromatosis type 1–related plexiform neurofibromas, which are characterized by elevated RAS–mitogen-activated protein kinase (MAPK) signaling.
We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1–related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.
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.)