TY - JOUR
T1 - Selumetinib in children with inoperable plexiform neurofibromas
AU - Gross, Andrea M.
AU - Wolters, Pamela L.
AU - Dombi, Eva
AU - Baldwin, Andrea
AU - Whitcomb, Patricia
AU - Fisher, Michael J.
AU - Weiss, Brian
AU - Kim, Ae Rang
AU - Bornhorst, Miriam
AU - Shah, Amish C.
AU - Martin, Staci
AU - Roderick, Marie C.
AU - Pichard, Dominique C.
AU - Carbonell, Amanda
AU - Paul, Scott M.
AU - Therrien, Janet
AU - Kapustina, Oxana
AU - Heisey, Kara
AU - Wade Clapp, D.
AU - Zhang, Chi
AU - Peer, Cody J.
AU - Figg, William D.
AU - Smith, Malcolm
AU - Glod, John
AU - Blakeley, Jaishri O.
AU - Steinberg, Seth M.
AU - Venzon, David J.
AU - Austin Doyle, L.
AU - Widemann, Brigitte C.
N1 - Funding Information:
Supported by the Intramural Research Program of the National Institutes of Health; the Center for Cancer Research of the National Cancer Institute (NCI); the NCI Cancer Therapy Evaluation Program (CTEP); AstraZeneca through a Cooperative Research and Development Agreement with the NCI CTEP (provision of selumetinib and funding for the pharmacokinetic analysis and clinical-trial support); a grant (U54 CA196519-04) from the Developmental and Hyperactive Ras Tumor (DHART) Specialized Program of Research Excellence (funding for the pharmacodynamic studies); and the Neurofibromatosis Therapeutic Acceleration Program (NTAP) (funding for trial conduct at the Children’s Hospital of Philadelphia and Cincinnati Children’s Hospital Medical Center).
Funding Information:
In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.)
Funding Information:
Supported by the Intramural Research Program of the National Institutes of Health; the Center for Cancer Research of the National Cancer Institute (NCI); the NCI Cancer Therapy Evaluation Program (CTEP); AstraZeneca through a Cooperative Research and Development Agreement with the NCI CTEP (provision of selumetinib and funding for the pharmacokinetic analysis and clinical-trial support); a grant (U54 CA196519-04) from the Developmental and Hyperactive Ras Tumor (DHART) Specialized Program of Research Excellence (funding for the pharmacodynamic studies); and the Neurofibromatosis Therapeutic Acceleration Program (NTAP) (funding for trial conduct at the Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center). Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. We thank the patients and families who participated in this trial; our collaborators and teams at the participating sites who provided guidance and advice and helped make this trial possible, including Joseph Andress, Lori Backus, Alessandra Brofferio, Ashura Buckley, Victoria Collier, Kathy Farrell, Joseph Fontana, Alexis Franklin, Andrea Gillespie, Ann Harrington, Marielle Holmblad, Jason Levine, Jonas Okafor, Ratnakar Patti, Scott Plotkin, Katie Smith, Michaele Smith, Jeffrey Solomon, Kari Struemph, Mary Anne Tamula, and Megan Westendorf; and the staffs of the CTEP, AstraZeneca, the NTAP, and the Children's Tumor Foundation for their help throughout this project.
Funding Information:
This trial was coordinated by the National Cancer Institute (NCI), Center for Cancer Research, Pediatric Oncology Branch (POB), and sponsored by the Cancer Therapy Evaluation Program (CTEP). The trial was conducted at four participating sites: NCI POB, Children’s Hospital of Philadelphia, Cincinnati Children’s Hospital, and Chil- dren’s National Hospital. The trial protocol (available with the full text of this article at NEJM.org) was designed and written by the NCI investigators. AstraZeneca provided selumetinib for the trial, approved the trial protocol, and provided financial support for the analysis of selumetinib in plasma samples and for the conduct of the clinical trial through a Cooperative Research and Development Agreement with the NCI CTEP. AstraZeneca did not have a role in patient recruitment, data analysis, or manuscript preparation but participated in the review and approval of the manuscript for submission. The protocol was approved by the institutional review board at each participating site. All the patients or their legal guardians provided written informed consent. The authors vouch for the accuracy and completeness of the data reported and for the fidelity of the trial to the protocol.
Publisher Copyright:
© 2020 Massachusetts Medical Society.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - BACKGROUND No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib.
AB - BACKGROUND No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib.
UR - http://www.scopus.com/inward/record.url?scp=85082768289&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa1912735
DO - 10.1056/NEJMoa1912735
M3 - Article
C2 - 32187457
AN - SCOPUS:85082768289
SN - 0028-4793
VL - 382
SP - 1430
EP - 1442
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 15
ER -