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

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 withoutchemotherapy

• Histologic diagnosis is not required for patients with typical imaging findingsof DIPG (defined as patients with a diffuse expansile mass centered in andinvolving at least 2/3 of the pons); patients with brainstem tumors who haveundergone biopsy with a diagnosis of high-grade glioma or diffuse infiltratingglioma are also eligible

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

• Stratum D: Patients must have a histologically confirmed diagnosis of ependymomathat is recurrent, progressive or refractory following therapy which includedradiotherapy

• Stratum E: Patients must have a histologically confirmed diagnosis ofmedulloblastoma that is recurrent, progressive or refractory following therapy whichincluded radiotherapy

• Patients must have adequate pre-trial formalin-fixed paraffin-embedded (FFPE) tumormaterial available for use in the biology studies mutational analysis and genomewide sequencing for each stratum

• Patients with DIPG who have tissue available are requested to submit similartissue as patients in other strata; however, this is not required foreligibility

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

• Patient must be >= 1 but =< 18 years of age at the time of enrollment during thesafety portion. Patients < 22 may be enrolled during the efficacy portion of thestudy.

• Patients must have received prior radiation therapy and/or chemotherapy andrecovered from the acute treatment related toxicities (defined as =< grade 1 if notdefined in eligibility criteria) of all prior chemotherapy, immunotherapy orradiotherapy prior to entering this study; there is no upper limit to the number ofprior therapies that is allowed

• Patients must have received their last dose of known myelosuppressive anticancertherapy at least three (3) weeks prior to study enrollment or at least six (6) weeksif prior nitrosourea

• Biologic or investigational agent (anti-neoplastic): Patient must have receivedtheir last dose of the investigational or biologic agent >= 7 days prior to studyenrollment

• For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during whichadverse events are known to occur; the duration must be discussed with andapproved by the study chair

• Monoclonal antibody treatment and/or agents with prolonged half-lives: Patient musthave recovered from any acute toxicity potentially related to the agent and receivedtheir last dose of the agent >= 28 days prior to study 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 priorto enrollment

• Patients must be fully recovered from all acute effects of prior surgicalintervention

• Both males and females of all races and ethnic groups are eligible for this study

• Patients with neurological deficits should have deficits that are completely stablefor 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 awheelchair, will be considered ambulatory for the purpose of assessing theperformance score

• Absolute neutrophil count >= 1000 cells/uL

• Platelets >= 75,000 cells /uL (unsupported, defined as no platelet transfusionwithin 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 xinstitutional upper limit of normal

• Albumin >= 2 g/dl

• Serum creatinine based on age/gender as noted below; patients that do not meet thecriteria 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

• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)

• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)

• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)

• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)

• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)

• Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)

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

• Human immunodeficiency virus (HIV)- infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

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

• Patients must be willing to use brief courses (at least 72 hours) of steroids asdirected for potential inflammatory side effects of the therapy if recommended bytheir 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 urinepregnancy test within 72 hours prior to receiving the first dose of studymedication; if the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required; pregnant women are excluded from this studybecause pembrolizumab (MK-3475) is an agent with the potential for teratogeniceffects; because there is unknown but potential risk for adverse events in nursinginfants secondary to treatment of the mother with pembrolizumab (MK-3475),breastfeeding should be discontinued if the mother is to be treated withpembrolizumab (MK-3475)

• Patients of childbearing or child fathering potential must be willing to use 2methods of birth control or be surgically sterile or abstain from heterosexualactivity while being treated on this study and for 4 months after the last dose ofstudy medication

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

• STRATUM C: Diagnosis of hypermutated brain tumors Patients with brain tumors andincreased 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 performedin a CLIA-certified laboratory and/or the use of Foundation One next generationsequence panel or another CLIA approved targeted sequencing lab with publiclyavailable correlations between number of mutations found in the panel andmutations per megabase and/or genome; for protocol purposes a high mutationburden will be defined as at least 180 non-synonymous coding-region mutationsby whole exome/genome sequencing (well above two standard deviations of thenumber of median similar mutations described in pediatric CNS cancers) AND/OR ahigh tumor mutation burden (TMB) or intermediate TMB based on the reportingparameters of the panel; TMB parameters provided for the Foundation One panelare as follows: high TMB is >= 20 mutations per megabase or intermediate TMB isbetween 6 to 19 mutations per megabase OR

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

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

• STRATUM C: Patients must have a histologically confirmed primary brain tumor that isrecurrent, progressive or refractory; inclusion criteria encompasses all types ofbrain tumors (e.g. gliomas, embryonal tumors or any other type of brain tumor aslong 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 tumorprogression/recurrence as long as they are not enrolled on any othertherapeutic clinical trial and there is macroscopic residual disease

• Patients with other concomitant tumors associated with CMMRD and Lynch syndromeincluding gastrointestinal polyps/adenomas and carcinomas, lymphomas andleukemias will be eligible as long as they are not requiring anticancer therapydirected against these other cancers and meet all other eligibility criteria

• STRATUM C: Patients must have adequate pre-trial FFPE tumor material available andbe 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 10unstained slides for the planned analysis

• STRATUM C: Subjects must have measurable disease in 2-dimensions on MRI scan of thebrain and/or spine with the exception allowed for non-progressed HGGs; diseaseshould be consistently measured with the two largest perpendicular dimensions

• STRATUM C: Patient should be < 30 years at the time of enrollment

• STRATUM C: Patients must have received prior radiotherapy and/or chemotherapy withthe following exceptions:

• Patients with secondary CNS cancers after a previous medical problem/malignancywho cannot receive full dose of radiotherapy (> 50 Gy) as long as they meet allother eligibility criteria

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

• STRATUM C: Patients must have received their last dose of known myelosuppressiveanticancer therapy at least three (3) weeks prior to study enrollment or at leastsix (6) weeks if prior nitrosourea

• STRATUM C: Patient must have received their last dose of the investigational orbiologic agent >= 7 days prior to study enrollment

• For agents that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during whichadverse events are known to occur; the duration must be discussed with andapproved by the study chair

• STRATUM C: Monoclonal antibody treatment and/or agents with prolonged half-lives:Patient must have recovered from any acute toxicity potentially related to the agentand received their last dose of the agent >= 28 days prior to study enrollment

• STRATUM C: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolyticviruses, etc.) at least 42 days prior to enrollment

• 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 XRT (small port) >= 2 weeks

• STRATUM C: Patient must be:

• >= 12 weeks since autologous bone marrow/stem cell transplant prior toenrollment

• >= 5 years since allogeneic stem cell transplant prior to enrollment with noevidence of active graft versus (vs.) host disease

• STRATUM C: Patients must be fully recovered from all acute effects of prior surgicalintervention

• STRATUM C: Both males and females of all races and ethnic groups are eligible forthis study

• STRATUM C: Patients with neurological deficits should have deficits that arecompletely stable for a minimum of 1 week (7 days) prior to enrollment

• STRATUM C: Karnofsky performance scale (KPS for > 16 years of age) or Lanskyperformance score (LPS for =< 16 years of age) assessed within two weeks ofenrollment must be >= 60; patients who are unable to walk because of neurologicdeficits, but who are up in a wheelchair, will be considered ambulatory for thepurpose of assessing the performance score

• STRATUM C: Absolute neutrophil count >= 1000 cells/uL

• STRATUM C: Platelets >= 75,000 cells/uL (unsupported, defined as no platelettransfusion within 7 days)

• STRATUM C: Hemoglobin >= 8 g/dl (may receive transfusions)

• STRATUM C: Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)

• STRATUM C: ALT (SGPT) =< 3 x institutional upper limit of normal

• STRATUM C: Albumin >= 2 g/dl

• STRATUM C: Serum creatinine based on age/gender as noted below; patients that do notmeet the criteria below but have a 24 hour creatinine clearance or GFR (radioisotopeor iothalamate) >= 70 ml/min/1.73 m^2 are eligible

• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)

• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)

• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)

• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)

• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)

• Age: >= 16 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)

• STRATUM C: Pulse oximetry > 93% on room air and no evidence of dyspnea at rest

• STRATUM C: HIV- infected patients on effective anti-retroviral therapy withundetectable viral load within 6 months are eligible for this trial

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

• STRATUM C: Patients must be willing to use brief courses (at least 72 hours) ofsteroids as directed for potential inflammatory side effects of the therapy ifrecommended by their treating physician

• STRATUM C: Female subjects of childbearing potential must not be pregnant orbreast-feeding; female patients of childbearing potential must have a negative serumor urine pregnancy test within 72 hours prior to receiving the first dose of studymedication; if the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required; pregnant women are excluded from this studybecause pembrolizumab (MK-3475) is an agent with the potential for teratogeniceffects; because there is unknown but potential risk for adverse events in nursinginfants secondary to treatment of the mother with pembrolizumab (MK-3475),breastfeeding should be discontinued if the mother is to be treated withpembrolizumab (MK-3475)

• STRATUM C: Patients of childbearing or child fathering potential must be willing touse 2 methods of birth control or be surgically sterile or abstain from heterosexualactivity while being treated on this study and for 4 months after the last dose ofstudy medication

• STRATUM C: The patient or parent/guardian is able to understand the consent and iswilling to sign a written informed consent document, inclusive of assent whereappropriate, according to institutional guidelines

Exclusion Criteria:

• EXCLUSION CRITERIA FOR STRATA A, B, D AND E

• Concurrent Illness

• Patients with active autoimmune disease or documented history of autoimmunedisease/syndrome that requires ongoing systemic steroids or systemicimmunosuppressive agents, except

• Patients with vitiligo or resolved asthma/atopy

• Patients with hypothyroidism stable on hormone replacement or Sjogren'ssyndrome

• History of or ongoing pneumonitis or significant interstitial lung diseaseNote: This would include non-infectious pneumonitis that required steroid use

• Patients with any clinically significant unrelated systemic illness (seriousinfections or significant cardiac, pulmonary, hepatic or other organdysfunction), that in the opinion of the investigator would compromise thepatient's ability to tolerate protocol therapy, put them at additional risk fortoxicity or would interfere with the study procedures or results

• Patients with other current malignancies

• Patients with known hypermutated brain tumors including those with CMMRD andLynch syndrome are ineligible for enrollment in Strata A, B, D and E

• Patients who have received a solid organ transplant

• Patients with bulky tumor on imaging are ineligible; treating physicians areencouraged to contact the study chair to request a rapid central imaging review toconfirm fulfilment of these eligibility criteria, if they have concerns

Bulk tumor is defined as:

• Tumor with evidence of clinically significant uncal herniation or midline shift

• Tumor with diameter of > 5 cm in one dimension on T2/fluid attenuated inversionrecovery (FLAIR)

• Tumor that in the opinion of the site investigator, shows significant mass effect ineither the brain or spine

• Multi-focal/ metastatic disease:

Note: Multiple foci of enhancement in a single FLAIR abnormality is permissible and will not exclude the subject

• Patients with multi-focal parenchymal disease are ineligible

• Patients with leptomeningeal metastatic disease are eligible; this includes diseasethat is discrete from the primary lesion but that has a radiographic appearanceconsistent with leptomeningeal spread, rather than likely trans-parenchymal spread

• Strata B, D and E - patients whose tumor has a significant component involvingthe brainstem or with significant fourth ventricular compression are ineligible

• Patients who are receiving any other anti-cancer or investigational drugtherapy are ineligible

• Patients who have a known active hepatitis B or hepatitis C infection areineligible; patient must have documented evidence of negative tests forthe presence of hepatitis B surface antigen and hepatitis C (anti-hepatitis C virus [HCV] antibody OR hepatitis [Hep] CRNA-qualitative)

• Patients who have received the last vaccination of a live vaccine =< 30days prior to enrollment are ineligible; examples of live vaccinesinclude, but are not limited to, the following: measles, mumps, rubella,varicella, yellow fever, rabies, bacillus Calmette-Guerin (BCG), andtyphoid (oral) vaccine; seasonal influenza vaccines for injection aregenerally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (e.g. Flu-Mist [registered trademark]) are liveattenuated vaccines, and must meet timeline for live vaccine

• Patients with a history severe (>= grade 3) hypersensitivity reaction to amonoclonal antibody are ineligible

• Patients who have received previous therapy with an anti-CTLA4, anti-CD137