A Safety and Preliminary Efficacy Trial of Pembrolizumab (MK-3475) in Children With Recurrent, Progressive or Refractory Diffuse Intrinsic Pontine Glioma (DIPG), Non-Brainstem High-Grade Gliomas (NB-HGG), Ependymoma, Medulloblastoma or Hypermutated Brain Tumors
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
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
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
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
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
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.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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