A Safety and Preliminary Efficacy Trial of Pembrolizumab (MK-3475) in Children With Recurrent, Progressive or Refractory Diffuse Intrinsic Pontine Glioma (DIPG), Non-Brainstem High-Grade Gliomas (NB-HGG), Ependymoma, Medulloblastoma or Hypermutated Brain Tumors

  • STATUS
    Recruiting
  • End date
    Dec 31, 2024
  • participants needed
    110
  • sponsor
    National Cancer Institute (NCI)
Updated on 15 September 2022
cancer
stem cell transplantation
lymphoma
filgrastim
absolute neutrophil count
monoclonal antibodies
biologic agent
nitrosoureas
measurable disease
sargramostim
ependymoma
adenoma
growth factor
MRI
glomerular filtration rate
biological factors
erythropoietin
residual tumor
neutrophil count
tumor cells
pembrolizumab
blood transfusion
cancer treatment
diffusion tensor imaging
malignant glioma
brain tumor
tumor progression
cancer therapy
platelet transfusion
mk-3475
biologics
primary brain tumors
dipg
medulloblastoma
dyspnea at rest
diffuse intrinsic pontine glioma
investigational agent
cancer vaccine
brainstem tumor
craniospinal irradiation
allogeneic bone marrow transplant
cancer vaccines
brain stem tumor

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.

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 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.

Details
Condition Constitutional Mismatch Repair Deficiency Syndrome, Lynch Syndrome, Malignant Glioma, Recurrent Brain Neoplasm, Recurrent Childhood Ependymoma, Recurrent Diffuse Intrinsic Pontine Glioma, Recurrent Medulloblastoma, Refractory Brain Neoplasm, Refractory Diffuse Intrinsic Pontine Glioma, Refractory Ependymoma, Refractory Medulloblastoma
Treatment laboratory biomarker analysis, Pembrolizumab, magnetic resonance spectroscopic imaging, Diffusion Tensor Imaging, dynamic contrast-enhanced magnetic resonance imaging, Dynamic Susceptibility Contrast-Enhanced Magnetic Resonance Imaging, Diffusion Weighted Imaging, Perfusion Magnetic Resonance Imaging
Clinical Study IdentifierNCT02359565
SponsorNational Cancer Institute (NCI)
Last Modified on15 September 2022

Eligibility

Yes No Not Sure

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
Stratum D: Patients must have a histologically confirmed diagnosis of ependymoma that is recurrent, progressive or refractory following therapy which included radiotherapy
high-grade glioma (NB-HGG) that is recurrent, progressive or refractory
Stratum E: Patients must have a histologically confirmed diagnosis of medulloblastoma that is recurrent, progressive or refractory following therapy which included radiotherapy
following therapy which included radiotherapy; spinal primary disease is
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
eligible
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
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
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
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
All subjects must have measurable disease in 2-dimensions on MRI scan of the brain
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
disease should be consistently measured with the two largest perpendicular
dimensions
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
Monoclonal antibody treatment and/or agents with prolonged half-lives: Patient must
Patients must be fully recovered from all acute effects of prior surgical intervention
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
Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
Both males and females of all races and ethnic groups are eligible for this study
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)
Patient must be >= 12 weeks since autologous bone marrow/stem cell transplant prior to
Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
enrollment
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 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)
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
Confirmed diagnosis of CMMRD syndrome by Clinical Laboratory Improvement Act (CLIA)-certified germline gene sequencing OR
STRATUM C: Diagnosis of hypermutated brain tumors Patients with brain tumors and increased tumor mutation burden as determined by
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 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
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
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
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
STRATUM C: Patients must have received prior radiotherapy and/or chemotherapy with the following exceptions
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
STRATUM C: Patient should be < 30 years at the time of enrollment
STRATUM C: Patients must have a histologically confirmed primary brain tumor that is
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
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
recurrent, progressive or refractory; inclusion criteria encompasses all types
STRATUM C: Patient must have received their last dose of the investigational or biologic agent >= 7 days prior to study enrollment
of brain tumors (e.g. gliomas, embryonal tumors or any other type of brain
tumor as long as other eligibility criteria are met
Craniospinal irradiation >= 3 months prior to enrollment
STRATUM C: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses, etc.) at least 42 days prior to enrollment
Other substantial bone marrow irradiation >= 6 weeks prior to enrollment
STRATUM C: Patients must have had their last fraction of
STRATUM C: Patients must have adequate pre-trial FFPE tumor material available and be
Local palliative radiation therapy (XRT) (small port) >= 2 weeks
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
>= 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment
germline samples, patients will be deemed eligible for the study with a
>= 5 years since allogeneic bone marrow transplant prior to enrollment with no evidence of active graft versus (vs.) host disease
STRATUM C: Patient must be
minimum of approximately 10 unstained slides for the planned analysis
STRATUM C: All races and ethnic groups are eligible for this study
STRATUM C: Patients with neurological deficits should have deficits that are completely stable for a minimum of 1 week (7 days) prior to enrollment
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
STRATUM C: Absolute neutrophil count >= 1000 cells/uL
STRATUM C: Platelets >= 75,000 cells/uL (unsupported, defined as no platelet transfusion within 7 days)
STRATUM C: Hemoglobin >= 8 g/dl (may receive transfusions)
STRATUM C: Monoclonal antibody treatment and/or agents with prolonged half-lives
STRATUM C: Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
Patient must have recovered from any acute toxicity potentially related to the
STRATUM C: ALT (SGPT) =< 3 x institutional upper limit of normal
agent and received their last dose of the agent >= 28 days prior to study
Age: 1 to < 2 years; maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
STRATUM C: Albumin >= 2 g/dl
enrollment
Age: 2 to < 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
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: 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 with undetectable viral load within 6 months are eligible for this trial
STRATUM C: Patients must be fully recovered from all acute effects of prior surgical
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-ac
intervention
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