Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

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

Summary: This clinical 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), or brain tumors with a high number of genetic mutations that have come back, progressed, or have not responded to previous treatment. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells.

Detailed description: PRIMARY OBJECTIVES:
  I. To establish the safety and describe adverse effects associated with administration of the adult recommended dose of pembrolizumab (MK-3475) in children with recurrent, progressive or refractory non-brainstem high grade glioma (NB-HGG) and diffuse intrinsic pontine glioma (DIPG).
  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 NB-HGG or DIPG.
  III. To establish the safety and describe adverse effects associated with administration of the adult recommended dose of MK-3475 (pembrolizumab) in pediatric patients with progressive or recurrent hypermutated tumors, including those with conditional 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 MK-3475 (pembrolizumab).
  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 MK-3475 (pembrolizumab) 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 [PFS]) and potential biomarkers, including programmed cell death (PD)-ligand 1 (L1) expression, patient immunophenotype, ribonucleic acid (RNA) signature profile, and tumor gene expression profile.
  II. To estimate the duration of objective response, progression-free/event-free survival and document overall survival for patients with NB-HGG and DIPG treated with MK-3475 (pembrolizumab).
  III. To evaluate PD-L1 expression on archival tissue obtained from patients with non-brainstem high-grade glioma.
  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) and the tumor gene expression profile in patients with HGG receiving MK-3475 (pembrolizumab).
  VII. To estimate the duration of objective response, PFS/event free survival and document overall survival of pediatric patients with progressive or recurrent hypermutated NB-HGG, including those with CMMRD syndrome, treated with MK-3475 (pembrolizumab).
  VIII. To estimate the PFS and sustained objective response rate of pediatric patients with hypermutated progressive low grade gliomas including those with CMMRD, treated with MK-3475 (pembrolizumab).
  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 MK-3475 (pembrolizumab) 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 MK-3475 (pembrolizumab) 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.

Eligibility: Inclusion Criteria:
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Tumor:
  -  A diffuse intrinsic pontine glioma (DIPG) that is recurrent, progressive or refractory; 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients with DIPG who have tissue available are requested to submit similar tissue as patients with NB-HGG; however, this is not required for eligibility
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Patients must be fully recovered from all acute effects of prior surgical intervention
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): All races and ethnic groups are eligible for this study
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Absolute neutrophil count >= 1.0 x 10^9 cells/L
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days)
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Hemoglobin >= 8 g/dl (may receive transfusions)
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Albumin >= 2 g/dl
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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)
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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
  -  INCLUSION CRITERIA FOR DIPG (STRATUM A - CURRENTLY CLOSED TO ACCRUAL): 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 NB-NGG (STRATUM B): Tumor:
  -  Patients must have a histologically confirmed diagnosis of a non-brainstem high-grade glioma that is recurrent, progressive or refractory; spinal primary disease is eligible
  -  NCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients with non-brainstem high grade glioma must have adequate pre-trial FFPE tumor material available for use in the biology studies and genome wide sequencing; while tissue is required for PD-1, PD-L1 and immunophenotyping, patients will be deemed eligible for the study with a minimum of 10 unstained slides for the PD-1/PD-L1 immunohistochemical analysis
  -  NCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Patients must be fully recovered from all acute effects of prior surgical intervention
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): All races and ethnic groups are eligible for this study
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Absolute neutrophil count >= 1.0 x 10^9 cells/L
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Platelets >= 100,000/mm^3 (unsupported, defined as no platelet transfusion within 7 days)
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Hemoglobin >= 8 g/dl (may receive transfusions)
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): ALT (SGPT) =< 3 x institutional upper limit of normal
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): Albumin >= 2 g/dl
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): Pulse oximetry > 93% on room air and no evidence of dyspnea at rest
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): 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 NB-NGG (STRATUM B): 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
  -  INCLUSION CRITERIA FOR NB-NGG (STRATUM B): 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 HYPERMUTATED BRAIN TUMORS (STRATUM C): Patients with brain tumors and increased tumor mutation burden as determined by
  -  Confirmed diagnosis of CMMRD syndrome by 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 central nervous system [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

Relevance to patient case: not relevant