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

Trial Status: Active

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.

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: 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
  • 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 * 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-retroviral therapy 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 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 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
  • 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: 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
  • 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
  • INCLUSION CRITERIA FOR 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
  • 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 * 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)
  • INCLUSION CRITERIA FOR STRATUM C: Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
  • INCLUSION CRITERIA FOR STRATUM C: HIV- infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • 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 CRITERIA FOR 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

Exclusion Criteria

  • EXCLUSION CRITERIA FOR STRATA A, B, D AND E
  • Concurrent Illness * Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except ** Patients with vitiligo or resolved asthma/atopy ** Patients with hypothyroidism stable on hormone replacement or Sjogren’s syndrome * History of or ongoing pneumonitis or significant interstitial lung disease Note: This would include non-infectious pneumonitis that required steroid use * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results * Patients with other current malignancies * Patients with known hypermutated brain tumors including those with CMMRD and Lynch 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 are encouraged to contact the study chair to request a rapid central imaging review to confirm 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 inversion recovery (FLAIR) * Tumor that in the opinion of the site investigator, shows significant mass effect in either 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 disease that is discrete from the primary lesion but that has a radiographic appearance consistent with leptomeningeal spread, rather than likely trans-parenchymal spread * Strata B, D and E – patients whose tumor has a significant component involving the brainstem or with significant fourth ventricular compression are ineligible
  • Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
  • Patients who have a known active hepatitis B or hepatitis C infection are ineligible; patient must have documented evidence of negative tests for the presence of hepatitis B surface antigen and hepatitis C (anti-hepatitis C virus [HCV] antibody OR hepatitis [Hep] C RNA-qualitative)
  • Patients who have received the last vaccination of a live vaccine =< 30 days prior to enrollment are ineligible; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and must meet timeline for live vaccine
  • Patients with a history severe (>= grade 3) hypersensitivity reaction to a monoclonal antibody are ineligible
  • Patients who have received previous therapy with an anti-CTLA4, anti-CD137, anti-PD-L1 or anti-PD-1 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Patients with uncontrolled seizures defined as seizures that require regular use of rescue medications or in the opinion of the investigator require increasing doses of anti-epileptic medications or would compromise the ability to tolerate study therapy or interfere with protocol therapy or procedures; patients with seizures that are well controlled are eligible and may be on antiepileptic medications if on a stable dose
  • Patients may not be on immunosuppressive therapy, including corticosteroids (with the exception of physiologic replacement, defined as 0.75 mg/m^2/day) at time of enrollment; however, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study
  • EXCLUSION CRITERIA FOR STRATUM C: Patients with diffuse intrinsic pontine or other brainstem high-grade glioma and those with primary spinal cord tumors
  • EXCLUSION CRITERIA FOR STRATUM C: Patients with bulky tumor on imaging are ineligible; treating physicians are encouraged to contact the study chair to request a rapid central imaging review to confirm fulfilment of these eligibility criteria, if they have concerns; bulky tumor is defined as: * Tumor with any evidence of clinically significant uncal herniation or midline shift * Tumor with diameter of > 5 cm in one dimension on T2/FLAIR * Tumor that in the opinion of the site investigator, shows significant mass effect * Metastatic disease: Patients with =< 5 separate foci of metastatic disease not causing mass effect on adjacent parenchyma and each measuring less than 0.5 cm in maximum diameter will be eligible for this arm of the study; patients with diffuse linear leptomeningeal spread are not eligible for this arm of the study * Multi-focal disease: Patients with multi-focal parenchymal disease will be eligible for stratum C if the sum of the product of the maximum perpendicular diameters of all measurable non-contiguous lesions is less than 16 cm^2; in such cases, a minimum of 2 and a maximum of 5 “target” non-contiguous lesions will be selected; the lower size limit of the target lesion(s) should be at least twice the thickness of the slices showing the tumor to decrease the partial volume effect (e.g., 8 mm lesion for a 4 mm slice)
  • EXCLUSION CRITERIA FOR STRATUM C: Concurrent illness * Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except ** Patients with vitiligo or resolved asthma/atopy ** Patients with hypothyroidism stable on hormone replacement or Sjogren’s syndrome * History of or ongoing pneumonitis or significant interstitial lung disease * Note: This would include non-infectious pneumonitis that required steroid use * Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results ** Exception to this is the presence of gastrointestinal polyps/adenomas and non-metastatic carcinomas, and history of any previous malignancies in patients with CMMRD and Lynch syndrome which will be allowed in this study * Patients who have received a solid organ transplant
  • EXCLUSION CRITERIA FOR STRATUM C: Patients who are receiving any other anti-cancer or investigational drug therapy are ineligible
  • EXCLUSION CRITERIA FOR STRATUM C: Patients who have a known active hepatitis B or hepatitis C infection are ineligible; patient must have documented evidence of negative tests for the presence of hepatitis B surface antigen and hepatitis C (anti-HCV antibody OR Hep C RNA-qualitative)
  • EXCLUSION CRITERIA FOR STRATUM C: Patients who have received the last vaccination of a live vaccine =< 30 days prior to enrollment are ineligible; examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella, yellow fever, rabies, BCG, and typhoid (oral) vaccine; seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated vaccines, and must meet timeline for live vaccine
  • EXCLUSION CRITERIA FOR STRATUM C: Patients with a history severe (>= grade 3) hypersensitivity reaction to a monoclonal antibody are ineligible
  • EXCLUSION CRITERIA FOR STRATUM C: Patients who have received previous therapy with an anti-CTLA4, anti-CD137, anti-PD-L1 or anti-PD-1 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • EXCLUSION CRITERIA FOR STRATUM C: Patients with uncontrolled seizures defined as seizures that require regular use of rescue medications or in the opinion of the investigator require increasing doses of antiepileptic medications or would compromise the ability to tolerate study therapy or interfere with protocol therapy or procedures; patients with seizures that are well controlled are eligible and may be on antiepileptic medications if on a stable dose
  • EXCLUSION CRITERIA FOR STRATUM C: Patients may not be on immunosuppressive therapy, including corticosteroids (with the exception of physiologic replacement, defined as =< 0.75 mg/m^2/day dexamethasone equivalent) at time of enrollment; however, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study

California

Los Angeles
Children's Hospital Los Angeles
Status: ACTIVE
Contact: Site Public Contact
Phone: 323-361-4110
Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 800-694-0012

Colorado

Aurora
Children's Hospital Colorado
Status: ACTIVE
Contact: Site Public Contact
Phone: 303-764-5056

District of Columbia

Washington
Children's National Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 202-884-2549

Georgia

Atlanta
Children's Healthcare of Atlanta - Egleston
Status: ACTIVE
Contact: Site Public Contact
Phone: 404-785-2025

Illinois

Chicago
Lurie Children's Hospital-Chicago
Status: ACTIVE
Contact: Site Public Contact
Phone: 773-880-4562

New York

New York
Memorial Sloan Kettering Cancer Center
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 212-639-7592

Ohio

Cincinnati
Cincinnati Children's Hospital Medical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 513-636-2799

Pennsylvania

Pittsburgh
Children's Hospital of Pittsburgh of UPMC
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-692-8570

Tennessee

Memphis
Saint Jude Children's Research Hospital
Status: TEMPORARILY_CLOSED_TO_ACCRUAL
Contact: Site Public Contact
Phone: 888-226-4343

Texas

Houston
Texas Children's Hospital
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-823-5923

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.

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.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Pediatric Brain Tumor Consortium

Principal Investigator
Eugene Ickjin Hwang

  • Primary ID PBTC-045
  • Secondary IDs NCI-2015-00130
  • Clinicaltrials.gov ID NCT02359565