scholarly journals LGG-02. A PHASE II PROSPECTIVE TRIAL OF SELUMETINIB IN CHILDREN WITH RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA (PLGG) WITH A FOCUS UPON OPTIC PATHWAY/HYPOTHALAMIC TUMORS AND VISUAL ACUITY OUTCOMES: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY, PBTC-029B

2019 ◽  
Vol 21 (Supplement_2) ◽  
pp. ii98-ii99 ◽  
Author(s):  
Jason Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Young Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Brain Tumor ◽  
Phase Ii ◽  
Prospective Trial ◽  
Pediatric Brain Tumor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Optic Pathway ◽  
Pediatric Brain

scholarly journals LGG-08. A PHASE II PROSPECTIVE STUDY OF SELUMETINIB IN CHILDREN WITH RECURRENT OR REFRACTORY LOW-GRADE GLIOMA (LGG): A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

2017 ◽  
Vol 19 (suppl_4) ◽  
pp. iv34-iv35 ◽  
Author(s):  
Jason Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Y Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Prospective Study ◽  
Phase Ii ◽  
Pediatric Brain Tumor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Pediatric Brain

scholarly journals 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

2021 ◽  
Author(s):  
Jason Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Young Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Visual Fields ◽  
Pediatric Brain Tumor ◽  
Progression Free Survival ◽  
Neurofibromatosis Type ◽  
Low Grade ◽  
Optic Pathway ◽  
Pediatric Brain

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.

scholarly journals LTBK-01. UPDATES ON THE PHASE II AND RE-TREATMENT STUDY OF AZD6244 (SELUMETINIB) FOR CHILDREN WITH RECURRENT OR REFRACTORY PEDIATRIC LOW GRADE GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i214-i214
Author(s):  
Jason R Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Young Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase Ii ◽  
Pediatric Brain Tumor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Pediatric Brain

A phase II prospective study of selumetinib in children with recurrent or refractory low-grade glioma (LGG): A Pediatric Brain Tumor Consortium (PBTC) study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10504-10504 ◽  
Author(s):  
Jason R. Fangusaro ◽  
Arzu Onar-Thomas ◽  
Tina Young-Poussaint ◽  
Shengjie Wu ◽  
Azra H Ligon ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pediatric Brain Tumor ◽  
Braf V600e Mutation ◽  
Low Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
Optic Pathway ◽  
Grade 3 ◽  
Molecular Aberrations

10504 Background: A greater understanding of the Ras-MAP kinase-signaling pathway in pediatric low-grade glioma (LGG) paired with the availability of potent selective inhibitors has enhanced the ability to target this pathway with therapeutic intent. Methods: The PBTC conducted a multi-institutional phase II study (NCT01089101) evaluating selumetinib (AZD6244, ARRY-142886), a MEK I/II inhibitor, in children with recurrent/refractory LGG assigned to 6 strata and treated at 25 mg/m2/dose PO BID for up to two years. Here we present the data from three of these strata. The remaining strata are still accruing patients. Results: Stratum I included children with non-NF-1 and non-optic pathway recurrent/refractory pilocytic astrocytoma (PA) harboring BRAF aberrations (BRAF V600e mutation or the BRAF-KIAA 1549 fusion). Eight of 25 (32%) patients achieved a partial response (PR) with 2-year PFS of 66+/-11%. Two of 7 (29%) patient tumors with a BRAF V600e mutation and 6/18 (33%) with a BRAF KIAA-1549 fusion had a PR. Stratum 3 enrolled NF-1-associated LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Ten of 25 (40%) achieved PR with a 2-year PFS of 96+/-4%. Only one patient progressed while on treatment. Stratum 4 included children with non-NF-1 optic pathway/hypothalamic LGG. Tissue for tumor BRAF evaluation was not required for eligibility. Two of 16 (12.5%) had a PR with a 2-year PFS of 65+/-13%. The BRAF aberration status of the responders in strata 3 and 4 is mostly unknown. All responses were confirmed centrally and seven patients remain on treatment. The most common toxicities were grade 1/2 CPK elevation, diarrhea, hypoalbuminemia, elevated AST and rash. Rare grade 3/4 toxicities included elevated CPK, rash, neutropenia, emesis and paronychia. Conclusions: Selumetinib was effective in treating children with recurrent/refractory LGG, including those with NF-1 associated LGG and PA harboring BRAF V600e mutation or BRAF-KIAA 1549 fusion. Larger prospective studies are necessary to determine the future, specific role of this agent in treating children with LGG harboring specific molecular aberrations. Clinical trial information: NCT01089101.

scholarly journals A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

2017 ◽  
Vol 19 (8) ◽  
pp. 1135-1144 ◽  
Author(s):  
Anuradha Banerjee ◽  
Regina I. Jakacki ◽  
Arzu Onar-Thomas ◽  
Shengjie Wu ◽  
Theodore Nicolaides ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Phase I Trial ◽  
Pediatric Patients ◽  
Pediatric Brain Tumor ◽  
Mek Inhibitor ◽  
Low Grade Glioma ◽  
Low Grade ◽  
Pediatric Brain

scholarly journals PATH-21. TELOMERE LENGTH ANALYSIS OF CNS TUMORS IN THE PEDIATRIC BRAIN TUMOR ATLAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii428-iii428
Author(s):  
Jo Lynn Rokita ◽  
Krutika Gaonkar ◽  
Heba Ijaz ◽  
Daniel Miller ◽  
Tasso Karras ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Gene Mutations ◽  
Pediatric Brain Tumor ◽  
High Grade Glioma ◽  
Pediatric Brain Tumors ◽  
Low Grade ◽  
Alternative Lengthening ◽  
Length Analysis ◽  
Telomere Lengthening ◽  
Pediatric Brain

Abstract Subsets of pediatric cancers, including high grade glioma (pHGG), have high rates of uniquely long telomeres, associated with ATRX gene mutations and alternative lengthening of telomeres (ALT). Ultimately, these cancers may benefit from a therapy stratification approach. In order to identify and further characterize pediatric brain tumors with telomere lengthening (TL), we determined the intratelomeric content in silico from paired WGS of 918 tumors from CBTTC Pediatric Brain Tumor Atlas (PBTA). The results were highly concordant with experimental assays to determine ALT in a subset of 45 pHGG tumors from the set. Overall, 13% of the PBTA cohort had telomere lengthening. We confirmed the highest rate of TL (37%) in the pHGG cohort (37/100 tumors; 30/82 patients). There was no statistical difference in age, gender or survival in subset analysis. As expected, the patient pHGG tumors with telomere lengthening were enriched for ATRX mutations (60%, q= 1.76e-3). However, 6 tumors without ATRX mutation also had normal protein expression, suggesting a different mechanism of inactivation or TL. The pHGG tumors with telomere lengthening had increased mutational burden (q=8.98e-3) and included all known pHGG cases (n=6) in the cohort with replication repair deficiencies. Of interest, the second highest rate of telomere lengthening was 9 subjects (24%) in the craniopharyngioma cohort. None of the craniopharyngioma tumors had ATRX mutations or low ATRX expression, and 55% of those with TL had CTNNB1 mutations. Finally, lower rates of telomere lengthening were found in medulloblastoma (10%), ependymoma (10%), low grade astrocytoma (8%) and ganglioglioma (7/47, 15%).

Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors

2016 ◽  
pp. e540-e546 ◽  
Author(s):  
Giles W. Robinson ◽  
Hendrik Witt ◽  
Adam Resnick
Keyword(s):  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Low Grade ◽  
Short Period ◽  
Tumor Management ◽  
The Impact ◽  
Pediatric Brain

Over a relatively short period of time, owing to improvements in biotechnology, our ability to identify the molecular mechanisms within pediatric brain tumors has dramatically increased. These findings have reshaped the way that we describe these diseases and have provided insights into how to better treat these often devastating diseases. Although still far from reaching the full therapeutic potential these advancements hold, the impact of these findings is steadily taking hold of pediatric brain tumor management. In this article, we summarize the major discoveries within three common pediatric brain tumor categories; medulloblastoma, ependymoma, and low-grade glioma. We discuss the current impact of these findings on treatment and the direction these findings may take the field of pediatric neuro-oncology.

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