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

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 21 days for 34 courses 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.

Inclusion Criteria:

- INCLUSION CRITERIA FOR STRATA A, B, D AND E

- Tumor: patient must have one of the following diagnoses to be eligible:

- Stratum A, currently closed to enrollment: Patients must have a recurrent, progressive
or refractory DIPG following radiation therapy with or without chemotherapy

- Histologic diagnosis is not required for patients with typical imaging findings
of DIPG (defined as patients with a diffuse expansile mass centered in and
involving at least 2/3 of the pons); patients with brainstem tumors who have
undergone biopsy with a diagnosis of high-grade glioma or diffuse infiltrating
glioma are also eligible

- Stratum B: Patients must have a histologically confirmed diagnosis of a non-brainstem
high-grade glioma (NB-HGG) that is recurrent, progressive or refractory following
therapy which included radiotherapy; spinal primary disease is eligible

- Stratum D: Patients must have a histologically confirmed diagnosis of ependymoma that
is recurrent, progressive or refractory following therapy which included radiotherapy

- Stratum E: Patients must have a histologically confirmed diagnosis of medulloblastoma
that is recurrent, progressive or refractory following therapy which included
radiotherapy

- Patients must have adequate pre-trial formalin-fixed paraffin-embedded (FFPE) tumor
material available for use in the biology studies mutational analysis and genome wide
sequencing for each stratum

- Patients with DIPG who have tissue available are requested to submit similar
tissue as patients in other strata; however, this is not required for eligibility

- All subjects must have measurable disease in 2-dimensions on MRI scan of the brain;
disease should be consistently measured with the two largest perpendicular dimensions

- Patients must have received prior radiation therapy and/or chemotherapy and recovered
from the acute treatment related toxicities (defined as =< grade 1 if not defined in
eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior
to entering this study; there is no upper limit to the number of prior therapies that
is allowed

- Patients must have received their last dose of known myelosuppressive anticancer
therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks
if prior nitrosourea

- Biologic or investigational agent (anti-neoplastic): Patient must have received their
last dose of the investigational or biologic agent >= 7 days prior to study enrollment

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration must be discussed with and approved by
the study chair

- Monoclonal antibody treatment and/or agents with prolonged half-lives: at least
three half-lives must have elapsed prior to enrollment

- Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses,
etc.) at least 42 days prior to enrollment

- Patients must have had their last fraction of:

- Craniospinal irradiation >= 3 months prior to enrollment

- Other substantial bone marrow irradiation >= 6 weeks prior to enrollment

- Local palliative radiation therapy (XRT) (small port) >= 2 weeks

- Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to
enrollment

- Patients must be fully recovered from all acute effects of prior surgical intervention

- All races and ethnic groups are eligible for this study

- Patients with neurological deficits should have deficits that are completely stable
for a minimum of 1 week (7 days) prior to enrollment

- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score
(LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 70;
patients who are unable to walk because of neurologic deficits, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score

- Absolute neutrophil count >= 1000 cells/uL

- Platelets >= 75,000 cells /uL (unsupported, defined as no platelet transfusion within
7 days)

- Hemoglobin >= 8 g/dl (may receive transfusions)

- Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)

- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
institutional upper limit of normal

- Albumin >= 2 g/dl

- Serum creatinine based on age/gender as noted below; patients that do not meet the
criteria below but have a 24 hour creatinine clearance or glomerular filtration rate
(GFR) (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible

- 1 to < 2 years: 0.6 mg/dl

- 2 to < 6 years: 0.8 mg/dl

- 6 to < 10 years: 1 mg/dl

- 10 to < 13 years: 1.2 mg/dl

- 13 to < 16 years: 1.5 mg/dl (male), 1.4 mg/dl (female)

- >= 16 years: 1.7 mg/dl (male), 1.4 mg/dl (female)

- Pulse oximetry > 93% on room air and no evidence of dyspnea at rest

- Patients must be off all colony-forming growth factor(s) for at least 1 week prior to
registration (e.g. filgrastim, sargramostim, erythropoietin); 2 weeks must have
elapsed for long-acting formulations

- Patients must be willing to use brief courses (at least 72 hours) of steroids as
directed for potential inflammatory side effects of the therapy if recommended by
their treating physician

- Female subjects of childbearing potential must not be pregnant or breast-feeding;
female patients of childbearing potential must have a negative serum or urine
pregnancy test within 72 hours prior to receiving the first dose of study medication;
if the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required; pregnant women are excluded from this study; breastfeeding
should be discontinued if the mother is to be treated with MK-3475 (pembrolizumab)

- Patients of childbearing or child fathering potential must be willing to use 2 methods
of birth control or be surgically sterile or abstain from heterosexual activity while
being treated on this study and for 6 months after the last dose of study medication

- The patient or parent/guardian is able to understand the consent and is willing to
sign a written informed consent document, inclusive of assent where appropriate,
according to institutional guidelines

- INCLUSION CRITERIA FOR STRATUM C: Diagnosis of hypermutated brain tumors Patients with
brain tumors and increased tumor mutation burden as determined by

- Confirmed diagnosis of CMMRD syndrome by Clinical Laboratory Improvement Act
(CLIA)-certified germline gene sequencing OR

- Confirmation of high mutation burden by whole genome/exome sequencing performed
in a CLIA-certified laboratory and/or the use of Foundation One next generation
sequence panel or another CLIA approved targeted sequencing lab with publicly
available correlations between number of mutations found in the panel and
mutations per megabase and/or genome; for protocol purposes a high mutation
burden will be defined as at least 100 non-synonymous coding-region mutations by
whole exome/genome sequencing (well above two standard deviations of the number
of median similar mutations described in pediatric CNS cancers) AND/OR a high
tumor mutation burden (TMB) or intermediate TMB based on the reporting parameters
of the panel; TMB parameters provided for the Foundation One reports are high
tumor mutation burden is >= 20 mutations per megabase or intermediate TMB is
between 6 to 19 mutations per megabase

- Confirmed diagnosis of Lynch syndrome by CLIA-certified germline gene sequencing;
patients with Lynch syndrome will not be accounted for in primary objective
unless their tumors are determined to have the minimum number of mutations
described above but they will still be eligible for this study

- Low-grade tumors in patients with CMMRD or Lynch syndrome do not have to reach
the threshold of 100 mutations for study inclusion

- INCLUSION CRITERIA FOR STRATUM C: Patients must have a histologically confirmed
primary brain tumor that is recurrent, progressive or refractory; inclusion criteria
encompasses all types of brain tumors (e.g. gliomas, embryonal tumors or any other
type of brain tumor as long as other eligibility criteria are met;

- Patients with high-grade gliomas are eligible for this clinical trial at least 2
weeks after completion of radiotherapy independent of tumor
progression/recurrence as long as they are not enrolled on any other therapeutic
clinical trial and there is macroscopic residual disease

- Patients with other concomitant tumors associated with CMMRD syndrome including
gastrointestinal polyps/adenomas and carcinomas, lymphomas and leukemias will be
eligible as long as they are not requiring anticancer therapy directed against
these other cancers and meet all other eligibility criteria

- INCLUSION CRITERIA FOR STRATUM C: Patients must have adequate pre-trial FFPE tumor
material available and be willing to provide a blood sample for use in the genome wide
sequencing studies; while tissue is required for genome-wide sequencing of tumor and
germline samples, patients will be deemed eligible for the study with a minimum of
approximately 10 unstained slides for the planned analysis

- INCLUSION CRITERIA FOR STRATUM C: All subjects must have measurable disease in
2-dimensions on MRI scan of the brain and/or spine; disease should be consistently
measured with the two largest perpendicular dimensions

- INCLUSION CRITERIA FOR STRATUM C: Patients must have received prior radiotherapy
and/or chemotherapy with the following exceptions:

- Patients with secondary CNS cancers after a previous medical problem/malignancy
who cannot receive full dose of radiotherapy (> 50 Gy) as long as they meet all
other eligibility criteria

- Patients with progressive low-grade gliomas and CMMRD or Lynch syndrome Patients
must have recovered from the acute treatment related toxicities (defined as =<
grade 1 if not defined in eligibility criteria) of all prior chemotherapy,
immunotherapy or radiotherapy prior to entering this study; there is no upper
limit to the number of prior therapies that is allowed

- INCLUSION CRITERIA FOR STRATUM C: Patients must have received their last dose of known
myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment
or at least six (6) weeks if prior nitrosourea

- INCLUSION CRITERIA FOR STRATUM C: Patient must have received their last dose of the
investigational or biologic agent >= 7 days prior to study enrollment

- For agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration must be discussed with and approved by
the study chair

- Monoclonal antibody treatment and/or agents with prolonged half-lives: at least
three half-lives must have elapsed prior to enrollment

- INCLUSION CRITERIA FOR STRATUM C: Patient must have completed immunotherapy (e.g.
tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment

- INCLUSION CRITERIA FOR STRATUM C: Patients must have had their last fraction of:

- Craniospinal irradiation >= 3 months prior to enrollment

- Other substantial bone marrow irradiation >= 6 weeks prior to enrollment

- Local palliative radiation therapy (XRT) (small port) >= 2 weeks

- INCLUSION CRITERIA FOR STRATUM C: Patient must be:

- >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment

- >= 5 years since allogeneic bone marrow transplant prior to enrollment with no
evidence of active graft versus (vs.) host disease

- INCLUSION CRITERIA FOR STRATUM C: Patients must be fully recovered from all acute
effects of prior surgical intervention

- INCLUSION CRITERIA FOR STRATUM C: All races and ethnic groups are eligible for this
study

- INCLUSION CRITERIA FOR STRATUM C: Patients with neurological deficits should have
deficits that are completely stable for a minimum of 1 week (7 days) prior to
enrollment

- INCLUSION CRITERIA FOR STRATUM C: Karnofsky performance scale (KPS for > 16 years of
age) or Lansky performance score (LPS for =< 16 years of age) assessed within two
weeks of enrollment must be >= 60; patients who are unable to walk because of
neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for
the purpose of assessing the performance score

- INCLUSION CRITERIA FOR STRATUM C: Absolute neutrophil count >= 1000 cells/uL

- INCLUSION CRITERIA FOR STRATUM C: Platelets >= 75,000 cells/uL (unsupported, defined
as no platelet transfusion within 7 days)

- INCLUSION CRITERIA FOR STRATUM C: Hemoglobin >= 8 g/dl (may receive transfusions)

- INCLUSION CRITERIA FOR STRATUM C: Total bilirubin =< 1.5 times institutional upper
limit of normal (ULN)

- INCLUSION CRITERIA FOR STRATUM C: ALT (SGPT) =< 3 x institutional upper limit of
normal

- INCLUSION CRITERIA FOR STRATUM C: Albumin >= 2 g/dl

- INCLUSION CRITERIA FOR STRATUM C: Serum creatinine based on age/gender as noted below;
patients that do not meet the criteria below but have a 24 hour creatinine clearance
or GFR (radioisotope or iothalamate) >= 70 ml/min/1.73 m^2 are eligible

- 1 to < 2 years: 0.6 mg/dl

- 2 to < 6 years: 0.8 mg/dl

- 6 to < 10 years: 1 mg/dl

- 10 to < 13 years: 1.2 mg/dl

- 13 to < 16 years: 1.5 mg/dl (male), 1.4 mg/dl (female)

- >= 16 years: 1.7 mg/dl (male), 1.4 mg/dl (female)

- INCLUSION CRITERIA FOR STRATUM C: Pulse oximetry > 93% on room air and no evidence of
dyspnea at rest

- INCLUSION CRITERIA FOR STRATUM C: Patients must be off all colony-forming growth
factor(s) for at least 1 week prior to registration (i.e. filgrastim; sargramostim;
erythropoietin); 2 weeks must have elapsed for long-acting formulations

- INCLUSION CRITERIA FOR STRATUM C: Patients must be willing to use brief courses (at
least 72 hours) of steroids as directed for potential inflammatory side effects of the
therapy if recommended by their treating physician

- INCLUSION CRITERIA FOR STRATUM C: Female subjects of childbearing potential must not
be pregnant or breast-feeding; female patients of childbearing potential must have a
negative serum or urine pregnancy test within 72 hours prior to receiving the first
dose of study medication; if the urine test is positive or cannot be confirmed as
negative, a serum pregnancy test will be required; pregnant women are excluded from
this study; breastfeeding should be discontinued if the mother is to be treated with
MK-3475 (pembrolizumab)

- INCLUSION CRITERIA FOR STRATUM C: Patients of childbearing or child fathering
potential must be willing to use 2 methods of birth control or be surgically sterile
or abstain from heterosexual activity while being treated on this study and for 6
months after the last dose of study medication

- INCLUSION C