Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; ...however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAFV600E Val600Glu mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% 95% CI 18–57) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% 21–61) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five 10%) and maculopapular rash (five 10%). No treatment-realted deaths were reported.
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct ...from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in ...Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) ...and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.
Selumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization.
Thirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles n = 13, 13 cycles n = 1) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.
Selumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.
Posterior Fossa Tumors Brandão, Lara A; Young Poussaint, Tina
Neuroimaging clinics of North America,
02/2017, Letnik:
27, Številka:
1
Journal Article
Recenzirano
Pediatric brain tumors are the leading cause of death from solid tumors in childhood. The most common posterior fossa tumors in children are medulloblastoma, atypical teratoid/rhabdoid tumor, ...cerebellar pilocytic astrocytoma, ependymoma, and brainstem glioma. Location, and imaging findings on computed tomography (CT) and conventional MR (cMR) imaging may provide important clues to the most likely diagnosis. Moreover, information obtained from advanced MR imaging techniques increase diagnostic confidence and help distinguish between different histologic tumor types. Here we discuss the most common posterior fossa tumors in children, including typical imaging findings on CT, cMR imaging, and advanced MR imaging studies.
Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and ...characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection.
Patients were enrolled in the phase I study according to a rolling 6 design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m
) for 7-10 days preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts.
Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9-20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2-17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 and 1.2 mg/m
for 21 and 28 days, respectively. Steady-state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations, and cerebrospinal fluid (CSF) samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range, 2.22-53.4).
Ribociclib and everolimus were well-tolerated and demonstrated pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.
A phase II study of bevacizumab (BVZ) plus irinotecan (CPT-11) was conducted in children with recurrent malignant glioma (MG) and intrinsic brainstem glioma (BSG).
Eligible patients received two ...doses of BVZ intravenously (10 mg/kg) 2 weeks apart and then BVZ plus CPT-11 every 2 weeks until progressive disease, unacceptable toxicity, or a maximum of 2 years of therapy. Correlative studies included diffusion weighted and T1 dynamic contrast-enhanced permeability imaging, BVZ pharmacokinetics, and estimation of vascular endothelial growth factor receptor 2 (VEGFR-2) phosphorylation in peripheral blood mononuclear cells (PBMC) after single-agent BVZ.
Thirty-one evaluable patients received a median of two courses of BVZ plus CPT-11 (range, 1 to 19). No sustained responses were observed in either stratum. Median time to progression for all 34 eligible patients enrolled was 127 days for MG and 71 days for BSG. Progression-free survival rates at 6 months were 41.8% and 9.7% for MG and BSG, respectively. Toxicities related to BVZ included grade 1 to 3 fatigue in seven patients, grade 1 to 2 hypertension in seven patients, grade 1 CNS hemorrhage in four patients, and grade 4 CNS ischemia in two patients. The mean diffusion ratio decreased after two doses of BVZ in patients with MG only. Vascular permeability parameters did not change significantly after therapy in either stratum. Inhibition of VEGFR-2 phosphorylation in PBMC was detected in eight of 11 patients after BVZ exposure.
BVZ plus CPT-11 was well-tolerated but had minimal efficacy in children with recurrent malignant glioma and brainstem glioma.
Equity, diversity, and inclusion (EDI) research is increasing, and there is a need for a more standardized approach for methodological and ethical review of this research. A supplemental review ...process for EDI-related human subject research protocols was developed and implemented at a pediatric academic medical center (AMC). The goal was to ensure that current EDI research principles are consistently used and that the research aligns with the AMC's declaration on EDI. The EDI Research Review Committee, established in January 2022, reviewed EDI protocols and provided recommendations and requirements for addressing EDI-related components of research studies. To evaluate this review process, the number and type of research protocols were reviewed, and the types of recommendations given to research teams were examined. In total, 78 research protocols were referred for EDI review during the 20-month implementation period from departments and divisions across the AMC. Of these, 67 were given requirements or recommendations to improve the EDI-related aspects of the project, and 11 had already considered a health equity framework and implemented EDI principles. Requirements or recommendations made applied to 1 or more stages of the research process, including design, execution, analysis, and dissemination. An EDI review of human subject research protocols can provide an opportunity to constructively examine and provide feedback on EDI research to ensure that a standardized approach is used based on current literature and practice.
Abstract
Background
Embryonal tumors of the CNS are the most common malignant tumors occurring in the first years of life. This study evaluated the feasibility and safety of incorporating novel ...non-cytotoxic therapy with vorinostat and isotretinoin to an intensive cytotoxic chemotherapy backbone.
Methods
PBTC-026 was a prospective multi-institutional clinical trial for children <48 months of age with newly diagnosed embryonal tumors of the CNS. Treatment included three 21-day cycles of induction therapy with vorinostat and isotretinoin, cisplatin, vincristine, cyclophosphamide, and etoposide; three 28-day cycles of consolidation therapy with carboplatin and thiotepa followed by stem cell rescue; and twelve 28-day cycles of maintenance therapy with vorinostat and isotretinoin. Patients with M0 medulloblastoma (MB) received focal radiation following consolidation therapy. Molecular classification was by DNA methylation array.
Results
Thirty-one patients with median age of 26 months (range 6-46) received treatment on study; 19 (61%) were male. Diagnosis was MB in 20 and supratentorial CNS embryonal tumor in 11. 24/31 patients completed induction therapy within a pre-specified feasibility window of 98 days. Five-year progression-free survival (PFS) and overall survival (OS) for all 31 patients were 55 ± 15 and 61 ± 13, respectively. Five-year PFS was 42 ± 13 for group 3 MB (n = 12); 80 ± 25 for SHH MB (n = 5); 33 ± 19 for embryonal tumor with multilayered rosettes (ETMR, n = 6).
Conclusion
It was safe and feasible to incorporate vorinostat and isotretinoin into an intensive chemotherapy regimen. Further study to define efficacy in this high-risk group of patients is warranted.
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