Pembrolizumab in Treating Younger Patients With Recurrent Progressive or Refractory High-Grade Gliomas Diffuse Intrinsic Pontine Gliomas Hypermutated Brain Tumors Ependymoma or Medulloblastoma

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  • sponsor
    National Cancer Institute (NCI)
Updated on 23 June 2021
stem cell transplantation
absolute neutrophil count
monoclonal antibodies
biologic agent
measurable disease
growth factor
glomerular filtration rate
biological factors
residual tumor
neutrophil count
tumor cells
blood transfusion
cancer treatment
diffusion tensor imaging
malignant glioma
brain tumor
tumor progression
cancer therapy
platelet transfusion
primary brain tumors
dyspnea at rest
diffuse intrinsic pontine glioma
investigational agent
cancer vaccine
brainstem tumor
craniospinal irradiation
allogeneic bone marrow transplant
cancer vaccines
brain stem tumor


This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.



I. To establish the safety and describe adverse effects associated with administration of the adult recommended dose of pembrolizumab (MK-3475) in each stratum separately.

II. To estimate the sustained objective response rate, (complete response [CR] + partial response [PR], sustained for at least 9 weeks) associated with pembrolizumab (MK-3475) treatment for pediatric patients with recurrent, progressive or refractory diffuse intrinsic pontine glioma (DIPG), non-brainstem high grade glioma (NB-HGG), ependymoma or medulloblastoma.

III. To establish the safety and describe adverse effects associated with administration of the adult recommended dose of pembrolizumab (MK-3475) in pediatric patients with progressive or recurrent hypermutated tumors, including those with constitutional mismatch-repair deficiency (CMMRD) syndrome.

IV. To estimate the sustained response rate of pediatric patients with progressive or recurrent hypermutated NB-HGG, including those with CMMRD syndrome, treated with pembrolizumab (MK-3475).

V. To determine changes in the immunophenotypic profile of PD-1hi CD8+ T cells from serial peripheral blood samples obtained before and during treatment with pembrolizumab (MK-3475) in pediatric patients with hypermutated brain tumors, including those with CMMRD syndrome.


I. To assess the relationship between outcome (response and progression-free survival) and potential biomarkers, including PD-L1 expression, patient immunophenotype, ribonucleic acid (RNA) signature profile, mutational profile, tumor gene expression and circulating tumor deoxyribonucleic acid (DNA) (ctDNA).

II. To estimate the duration of objective response in patients with measurable disease at baseline and estimate progression-free/event-free/overall survival for patients in each stratum treated with pembrolizumab (MK-3475).

III. To evaluate PD-L1 expression on archival tissue obtained from pediatric patients with eligible primary central nervous system (CNS) tumors.

IV. To examine the ability of quantitative magnetic resonance (MR) spectroscopy and diffusion/weighted imaging/apparent diffusion coefficient (ADC) mapping to provide early assessment of tumor behavior and specifically distinguish pseudoprogression/tumor inflammation from tumor progression.

V. To explore the use of serial MR permeability (dynamic contrast-enhanced [DCE]) and MR perfusion (dynamic susceptibility contrast [DSC]) to determine if elevated relative cerebral blood volume (rCBV) and transfer coefficient (ktrans) can distinguish pseudoprogression/tumor inflammation from tumor progression in tumors treated on this protocol.

VI. To characterize biomarkers, patient immunophenotyping, mutational load (as determined by whole exome sequencing), the tumor gene expression profile and ctDNA in patients receiving pembrolizumab (MK-3475).

VII. To estimate the duration of objective response, progression-free survival/event free survival and document overall survival of pediatric patients with progressive or recurrent hypermutated NB-HGG, including those with CMMRD syndrome, treated with pembrolizumab (MK-3475).

VIII. To estimate the progression-free survival (PFS) of all patients enrolled on stratum C and sustained objective response rate of pediatric patients with hypermutated progressive low grade gliomas including those with CMMRD, treated with pembrolizumab (MK-3475).

IX. To categorize the T-cell receptor repertoire in PD-1+ cells obtained from peripheral blood or from tumor tissue, when available, before and after treatment with pembrolizumab (MK-3475) in pediatric patients treated in stratum C (hypermutated brain tumors).

X. To define the specificity of T-cell receptors against tumor antigens identified in objective IX.

XI. To characterize functional features of T-cell populations after pembrolizumab (MK-3475) treatment and relate these findings to epigenetic programs within these cells.


Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for 34 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 1 year, then every 6 months for up to 3 years.

Condition Colorectal Cancer, Lynch Syndrome, Glioma, Hereditary Neoplastic Syndrome, Malignant neoplasm of brain, Colon Cancer Screening, Brain Tumor (Pediatric), Colon cancer; rectal cancer, High Grade Glioma, Recurrent Childhood Ependymoma, Refractory Brain Neoplasm, Constitutional Mismatch Repair Deficiency Syndrome, Recurrent Diffuse Intrinsic Pontine Glioma, Refractory Diffuse Intrinsic Pontine Glioma, Recurrent Medulloblastoma, Refractory Medulloblastoma, Progressive Ependymoma, Progressive Medulloblastoma, Refractory Ependymoma, Brain Cancer, Gliomas, Brain Tumor, Hereditary Cancer Syndromes, malignant glioma, recurrent brain tumors, hnpcc
Treatment laboratory biomarker analysis, Pembrolizumab, magnetic resonance spectroscopic imaging, Diffusion Tensor Imaging, dynamic contrast-enhanced magnetic resonance imaging, Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging, Diffusion Weighted Imaging, Perfusion Magnetic Resonance Imaging
Clinical Study IdentifierNCT02359565
SponsorNational Cancer Institute (NCI)
Last Modified on23 June 2021

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