Summary

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.

Objectives

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 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo standard magnetic resonance imaging (MRI), dynamic contrast-enhanced magnetic resonance (MR) perfusion (DCE permeability) MRI, diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion-weighted imaging (DSC perfusion) MRI, diffusion weighted imaging (MR diffusion imaging) and may undergo MR spectroscopy as well as cerebrospinal fluid (CSF) and blood sample collection during screening and on study.

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.

Eligibility

1. INCLUSION CRITERIA FOR STRATA A, B, D AND E
2. Tumor: patient must have one of the following diagnoses to be eligible:
3. 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
4. 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
5. Stratum D: Patients must have a histologically confirmed diagnosis of ependymoma that is recurrent, progressive or refractory following therapy which included radiotherapy
6. Stratum E: Patients must have a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive or refractory following therapy which included radiotherapy
7. 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
8. 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
9. Patient must be >= 1 but =< 18 years of age at the time of enrollment during the safety portion. Patients < 22 may be enrolled during the efficacy portion of the study.
10. 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
11. 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
12. 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
13. Monoclonal antibody treatment and/or agents with prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
14. Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
15. 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
16. Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
17. Patients must be fully recovered from all acute effects of prior surgical intervention
18. Both males and females of all races and ethnic groups are eligible for this study
19. Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
20. 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
21. Absolute neutrophil count >= 1000 cells/uL
22. Platelets >= 75,000 cells /uL (unsupported, defined as no platelet transfusion within 7 days)
23. Hemoglobin >= 8 g/dl (may receive transfusions)
24. Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
25. Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
26. Albumin >= 2 g/dl
27. 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 * 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)
28. Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
29. Human immunodeficiency virus (HIV)- infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
30. 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
31. 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
32. 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 because pembrolizumab (MK-3475) is an agent with the potential for teratogenic effects; because there is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab (MK-3475), breastfeeding should be discontinued if the mother is to be treated with pembrolizumab (MK-3475)
33. 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 4 months after the last dose of study medication
34. 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
35. 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 180 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 panel are as follows: high TMB is >= 20 mutations per megabase or intermediate TMB is between 6 to 19 mutations per megabase OR * 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
36. 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 and Lynch 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
37. 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
38. STRATUM C: Subjects must have measurable disease in 2-dimensions on MRI scan of the brain and/or spine with the exception allowed for non-progressed HGGs; disease should be consistently measured with the two largest perpendicular dimensions
39. STRATUM C: Patient should be < 30 years at the time of enrollment
40. 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
41. 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
42. 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
43. STRATUM C: Monoclonal antibody treatment and/or agents with prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment
44. STRATUM C: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
45. 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
46. STRATUM C: Patient must be: * >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment * >= 5 years since allogeneic stem cell transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
47. STRATUM C: Patients must be fully recovered from all acute effects of prior surgical intervention
48. STRATUM C: Both males and females of all races and ethnic groups are eligible for this study
49. STRATUM C: Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
50. 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
51. STRATUM C: Absolute neutrophil count >= 1000 cells/uL
52. STRATUM C: Platelets >= 75,000 cells/uL (unsupported, defined as no platelet transfusion within 7 days)
53. STRATUM C: Hemoglobin >= 8 g/dl (may receive transfusions)
54. STRATUM C: Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
55. STRATUM C: ALT (SGPT) =< 3 x institutional upper limit of normal
56. STRATUM C: Albumin >= 2 g/dl
57. 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 * 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)
58. STRATUM C: Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
59. STRATUM C: HIV- infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
60. 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
61. 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
62. 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 because pembrolizumab (MK-3475) is an agent with the potential for teratogenic effects; because there is unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab (MK-3475), breastfeeding should be discontinued if the mother is to be treated with pembrolizumab (MK-3475)
63. 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 4 months after the last dose of study medication
64. STRATUM C: 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

Treatment Sites in Georgia