A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study

Jason Fangusaro; Arzu Onar-Thomas; Tina Young Poussaint; Shengjie Wu; Azra H Ligon; Neal Lindeman; Olivia Campagne; Anu Banerjee; Sridharan Gururangan; Lindsay B Kilburn; Stewart Goldman; Ibrahim Qaddoumi; Patricia Baxter; Gilbert Vezina; Corey Bregman; Zoltan Patay; Jeremy Y Jones; Clinton F Stewart; Michael J Fisher; Laurence Austin Doyle; Malcolm Smith; Ira J Dunkel; Maryam Fouladi

doi:10.1093/neuonc/noab047

A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study

Neuro Oncol. 2021 Oct 1;23(10):1777-1788. doi: 10.1093/neuonc/noab047.

Authors

Jason Fangusaro¹, Arzu Onar-Thomas², Tina Young Poussaint^{3

4}, Shengjie Wu², Azra H Ligon⁵, Neal Lindeman⁵, Olivia Campagne⁶, Anu Banerjee⁷, Sridharan Gururangan⁸, Lindsay B Kilburn⁹, Stewart Goldman^{10

11}, Ibrahim Qaddoumi¹², Patricia Baxter^{13

14}, Gilbert Vezina¹⁵, Corey Bregman¹⁶, Zoltan Patay¹⁷, Jeremy Y Jones¹⁸, Clinton F Stewart⁶, Michael J Fisher^{19

20}, Laurence Austin Doyle²¹, Malcolm Smith²², Ira J Dunkel^{23

24}, Maryam Fouladi²⁵

Affiliations

¹ Department of Hematology, Oncology, and Stem Cell Transplantation, Children's Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA.
² Department of Biostatistics St. Jude Children's Research Center, Memphis, Tennessee, USA.
³ St. Jude Children's Research Center, Memphis, Tennessee, USA.
⁴ Department of Radiology, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Department of Pharmaceutical Sciences St. Jude Children's Research Center, Memphis, Tennessee, USA.
⁷ Center for Cancer and Blood Disorders, University of California, San Francisco, California, USA.
⁸ Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.
⁹ Division of Oncology Children's National Hospital , Washington DC, USA.
¹⁰ Children's National Hospital, Washington DC, USA.
¹¹ Department of Hematology, Oncology, Neuro-Oncology and Stem Cell Transplantation.
¹² Department of Oncology St. Jude Children's Research Center, Memphis, Tennessee, USA.
¹³ Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.
¹⁴ Department of Hematology and Oncology, Texas Children's Hospital, Houston, Texas, USA.
¹⁵ Department of Radiology Children's National Hospital , Washington DC, USA.
¹⁶ Department of Medical Imaging.
¹⁷ Department of Diagnostic Imaging St. Jude Children's Research Center, Memphis, Tennessee, USA.
¹⁸ Department of Radiology Nationwide Children's Hospital, Columbus, Ohio, USA.
¹⁹ Nationwide Children's Hospital, Columbus, Ohio, USA.
²⁰ Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
²¹ Investigational Drug Branch, National Cancer Institute and Cancer Therapy Evaluation Program, Rockville, Maryland, USA.
²² Clinical Investigation Branch, National Cancer Institute and Cancer Therapy Evaluation Program, Rockville, Maryland, USA.
²³ National Cancer Institute and Cancer Therapy Evaluation Program, Rockville, Maryland, USA.
²⁴ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
²⁵ Department of Hematology and Oncology Nationwide Children's Hospital, Columbus, Ohio, USA.

Abstract

Background: Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes.

Methods: We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses.

Results: Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash.

Conclusions: Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.

Keywords: MEK-1/2; hypothalamic glioma; optic pathway glioma; pediatric low-grade glioma; selumetinib.

Publication types

Clinical Trial, Phase II
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Benzimidazoles
Brain Neoplasms* / drug therapy
Child
Humans
Neurofibromatosis 1*
Optic Nerve Glioma* / drug therapy

Substances

AZD 6244
Benzimidazoles

Abstract

Publication types

MeSH terms

Substances

Grants and funding