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

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.

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Faculty Opinions recommendation of Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725633683.793530280 ◽

2017 ◽

Author(s):

Scott Pomeroy ◽

Soma Sengupta

Keyword(s):

Brain Tumor ◽

Sonic Hedgehog ◽

Phase Ii ◽

Pediatric Brain Tumor ◽

Pediatric Brain

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EPT-06OUTCOMES FOR PATIENTS WITH RECURRENT MEDULLOBLASTOMA OR EPENDYMOMA ENROLLED ON PHASE II CLINICAL TRIALS: AN ANALYSIS OF CONTEMPORARY CHILDREN'S ONCOLOGY GROUP (COG) AND PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) TRIALS

Neuro-Oncology ◽

10.1093/neuonc/now069.05 ◽

2016 ◽

Vol 18 (suppl 3) ◽

pp. iii25.1-iii25

Author(s):

Eugene Hwang ◽

Catherine Billups ◽

Arzu Onar-Thomas ◽

Katherine Warren ◽

Oren Beaty ◽

...

Keyword(s):

Clinical Trials ◽

Brain Tumor ◽

Phase Ii ◽

Pediatric Brain Tumor ◽

Oncology Group ◽

Phase Ii Clinical Trials ◽

Pediatric Brain

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

Neuro-Oncology ◽

10.1093/neuonc/noaa222.656 ◽

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%).

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HG-41OUTCOMES FOR PATIENTS WITH RECURRENT MALIGNANT GLIOMA ENROLLED ON PHASE II CLINICAL TRIALS: AN ANALYSIS OF CONTEMPORARY CHILDREN'S ONCOLOGY GROUP (COG) AND PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) TRIALS

Neuro-Oncology ◽

10.1093/neuonc/now073.38 ◽

2016 ◽

Vol 18 (suppl 3) ◽

pp. iii56.4-iii56

Author(s):

Eugene Hwang ◽

Catherine Billups ◽

Arzu Onar-Thomas ◽

Sridharan Gururangan ◽

Katherine Warren ◽

...

Keyword(s):

Clinical Trials ◽

Brain Tumor ◽

Malignant Glioma ◽

Phase Ii ◽

Pediatric Brain Tumor ◽

Recurrent Malignant Glioma ◽

Oncology Group ◽

Phase Ii Clinical Trials ◽

Pediatric Brain

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

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_159149 ◽

2016 ◽

pp. e540-e546 ◽

Cited By ~ 2

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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