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

Banerjee, Anuradha; Jakacki, Regina I.; Onar‐Thomas, Arzu; Wu, Shengjie; Nicolaides, Theodore; Poussaint, Tina Young; Fangusaro, Jason; Phillips, Joanna J.; Perry, Arie; Turner, David C.; Prados, Michael D.; Packer, Roger J.; Qaddoumi, Ibrahim; Gururangan, Sridharan; Pollack, Ian F.; Goldman, Stewart; Doyle, L. Austin; Stewart, Clinton F.; Boyett, James M.; Kun, Larry E.; Fouladi, Maryam

doi:10.1093/neuonc/now282

Cited by 255 publications

(238 citation statements)

References 43 publications

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“…A phase I trial has been completed using MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory LGGs. Three of the five patients with NF1 completed 26, 20, and four cycles, respectively . The results of the phase II study using the same agent has been published in an abstract form in 25 children with NF1.…”

Section: Clinical Trialsmentioning

confidence: 99%

Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights

Khatua

Gutmann

Packer

2017

Pediatric Blood & Cancer

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Children with neurofibromatosis type 1 (NF1) are predisposed to develop central nervous system neoplasms, the most common of which are low-grade gliomas (LGGs). The absence of human NF1 associated LGG-derived cell lines, coupled with an inability to generate patient-derived xenograft models, represents barriers to profile molecularly targeted therapies for these tumors. Thus, genetically engineered mouse models have been identified to evaluate the interplay between Nf1-deficient tumor cells and nonneoplastic stromal cells to evaluate potential therapies for these neoplasms. Future treatments might also consider targeting the nonneoplastic cells in NF1-LGGs to reduce tumor growth and neurologic morbidity in affected children.

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Section: Clinical Trialsmentioning

confidence: 99%

Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights

Khatua

Gutmann

Packer

2017

Pediatric Blood & Cancer

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“…Agents that target and inhibit the MAPK (RAS–RAF–MEK–ERK–MAP) pathway and the mTOR pathway are demonstrating unique efficacy in children with central nervous system (CNS) tumors . Therapeutic inhibition of these pathways is associated with a high incidence of cutaneous reactions in adults .…”

Section: Introductionmentioning

confidence: 99%

“…Agents that target and inhibit the MAPK (RAS-RAF-MEK-ERK-MAP) pathway and the mTOR pathway are demonstrating unique efficacy in children with central nervous system (CNS) tumors. [1][2][3][4] Abbreviation: CNS, central nervous system Therapeutic inhibition of these pathways is associated with a high incidence of cutaneous reactions in adults. 5,6 The most common cutaneous adverse events to BRAF inhibitors include follicular eruptions, verrucous papillomas, hand-foot skin reaction, photosensitivity, and alopecia.…”

Section: Introductionmentioning

confidence: 99%

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross‐sectional study

Song

Zhong

Kieran

et al. 2019

Pediatric Blood & Cancer

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Background MAPK (RAS–RAF–MEK–ERK–MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. Methods In this cross‐sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one‐year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow‐up skin examinations were recommended every three months. Results Twenty‐two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3–19). Median time from treatment initiation to skin examination was 4.5 months (range, 0–43). Ninety‐six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions. Conclusions Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life‐saving therapy.

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“…The effectiveness, and the effects, of these therapies continue to be defined. [1][2][3][4] We report here a child with an unresectable low-grade glioma who progressed through, or after, four sequential chemotherapy regimens but then had a remarkable response to his fifth regimen, Tissue from his initial diagnostic surgery was then re-sent for molecular testing. Testing revealed a NACC2-NTRK fusion.…”

Section: Larotrectinib Imaging Response In Low-grade Gliomamentioning

confidence: 99%

“…The treatment of low‐grade gliomas is rapidly changing due to the availability of recently introduced and remarkable targeted therapies. The effectiveness, and the effects, of these therapies continue to be defined . We report here a child with an unresectable low‐grade glioma who progressed through, or after, four sequential chemotherapy regimens but then had a remarkable response to his fifth regimen, targeted therapy with larotrectinib, accompanied by loss of contrast enhancement on magnetic resonance imaging (MRI).…”

mentioning

confidence: 99%

Larotrectinib imaging response in low‐grade glioma

Walter

Kandula

Shah

2019

Pediatric Blood & Cancer

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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

Abstract: Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

Cited by 255 publications

References 43 publications

Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights

Neurofibromatosis type 1 and optic pathway glioma: Molecular interplay and therapeutic insights

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross‐sectional study

Larotrectinib imaging response in low‐grade glioma

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