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Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pembrolizumab 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 MRI, DCE permeability MRI, DTI, DSC perfusion MRI, MR diffusion imaging and may undergo MR spectroscopy as well as CSF and blood sample collection during screening and on study.

Biospecimen Collection

Conventional Magnetic Resonance Imaging

Diffusion Tensor Imaging

Diffusion Weighted Imaging

Dynamic Contrast-enhanced MR Perfusion

Dynamic Susceptibility Contrast-Perfusion-Weighted Imaging

Magnetic Resonance Spectroscopic Imaging

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Nathan J. Robison

Sonia Partap

Kathleen M. Dorris

Jason R. Fangusaro

Ira J. Dunkel

Natasha Pillay Smiley

James T. Felker

Patricia A. Baxter

Vijay Ramaswamy

Eugene I Hwang

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.

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.

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

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

Will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events observed during the dose finding period as well as during later courses will be summarized by stratum and by dose (if applicable). Separate tables for adverse events attributable to pembrolizumab will also be provided for each of the three strata.

Stratum specific exact confidence interval estimates will be provided for the sustained objective response rates. In addition, if adequate number of responses is observed to make such analyses meaningful, stratum-specific confirmed sustained objective response rates observed during treatment will be estimated by cumulative incidence functions.

A 1-sample t-distribution-based confidence interval (or its non-parametric counterparts, as needed) will be used to estimate the average change in the percentage of CD8+ T cells that are PD-1+ due to treatment with pembrolizumab.

Log-ranks tests or Cox regression models will be used to explore associations between biomarkers and PFS and OS.

Kaplan-Meier estimates of event free survival distribution for all evaluable patients within each stratum will be provided.

Kaplan-Meier estimates of OS distribution for all evaluable patients within each stratum will be provided. Log-ranks tests or Cox regression models will be used to explore associations between biomarkers and progression free survival (PFS) and OS.

Will report any objective radiological responses observed in subjects who were not part of the primary cohort of progressive/recurrent high-grade gliomas (HGGs).

The biomarker data generated as part of this study will be summarized via descriptive statistics and plots. The association between response and potential biomarkers will be evaluated by Fisher's exact or Chi-square test for categorical outcomes and two sample t-tests (or appropriate non-parametric counterparts) for continuous outcomes. Log-ranks tests or Cox regression models will also be used to explore associations between biomarkers and PFS and OS. These analyses will be done in a stratum specific fashion.

Observed values of the proposed quantitative imaging parameters as well as changes in these parameters across time will be described and summarized via descriptive statistics and plots. Mixed effects models will be used to explore differences in estimated slope parameters of the quantitative imaging. Pairwise changes in these imaging parameters across various time points will also be described. T-tests (or their non-parametric equivalent) will be used to compare differences in pairwise changes between patients with progression vs. pseudoprogression/tumor inflammation.

National Cancer Institute (NCI)

Neoplasm Metastasis

Neoplastic Processes

Chelating Agents

Patients undergo conventional and advanced MRI over 60 minutes within 14 days before the start of scheduled brain radiation treatment. Patients then undergo 7 additional MRI over 60 minutes each between 4-16 weeks apart. Patients may receive gadolinium and/or iopamidol during MRI scans.

Advanced Magnetic Resonance Imaging

Gadolinium-Chelate

Iopamidol

Jason M Johnson

This clinical trial studies the different types of investigational imaging techniques called sequences during magnetic resonance imaging (MRI) of the head before and after radiation therapy in patients with cancer that has spread to the brain (intracranial metastases). This clinical trial also compares these new techniques with standard MRI imaging to see if sequences provide better images. Diagnostic procedures, such as MRI, may help find and diagnose solid organ cancer and find out how far the disease has spread.

PRIMARY OBJECTIVES:

I. Conspicuity:

Ia. To assess the conspicuity of idealized T1 and T2 imaging at detecting brain metastases at baseline. (Quantitative MRI) Ib. To assess the conspicuity (CNR) of chemical exchange saturation transfer (CEST) imaging at detecting brain metastases at baseline. (CEST MRI) Ic. To assess the conspicuity (CNR) of advances in difference equations (Adv Diff) at detecting brain metastases at baseline. (Multiple B Value Diffusion Imaging \[Adv Diff\]) Id. To assess the conspicuity of gradient- and spin-echo (GESE) dynamic susceptibility contrast (DSC) and standard Gradient Echo (GE) DSC at detecting brain metastases at baseline. (GESE DSC perfusion imaging)

SECONDARY OBJECTIVES:

I. Conspicuity:

Ia. To assess the conspicuity of T2 imaging at detecting brain metastases on a per-patient basis at follow-up scans and on a per-lesion basis at baseline and at follow-up time points. (Quantitative MRI) Ib. To assess the conspicuity (CNR) of CEST imaging at detecting brain metastases on a per-patient basis at follow-up scans and on a per-lesion basis at baseline and at follow-up time points. (CEST MRI) Ic. To assess the conspicuity (CNR) of Adv Diff at detecting brain metastases on a per-patient basis at follow-up scans and on a per-lesion basis at baseline and at follow-up time points. (Multiple B Value Diffusion Imaging \[Adv Diff\]) Id. To assess the conspicuity of GESE DSC and standard Gradient Echo (GE) DSC at detecting brain metastases on a per-patient basis at follow-up scans and on a per-lesion basis at baseline and at follow-up time points. (GESE DSC perfusion imaging) II. Treatment response. IIa. To assess the trend of idealized quantitative T1 and T2 values of brain metastases compared to normal brain parenchyma following treatment with stereotactic radiosurgery. (Quantitative MRI) IIb. To assess the ability of CEST imaging to differentiate radiation necrosis from progressive disease in brain metastases following stereotactic radiosurgery. (CEST MRI) IIc. To assess whether Adv Diff can differentiate radiation necrosis from progressive disease in brain metastases following stereotactic radiosurgery. (Multiple B Value Diffusion Imaging \[Adv Diff\]) IId. To assess whether GESE DSC improves differentiation of radiation necrosis from progressive disease in brain metastases following stereotactic radiosurgery compared to standard GE DSC. (GESE DSC perfusion imaging) IIe. To assess the ability of Adv arterial spin labeling (ASL) to differentiate radiation necrosis from progressive disease in brain metastases following stereotactic radiosurgery. (Multiple inversion time \[TI\] ASL "Adv ASL" perfusion)

OUTLINE:

Patients undergo conventional and advanced MRI scans over 60 minutes within 14 days before the start of scheduled brain radiation treatment. Patients then undergo 7 additional MRI scans over 60 minutes each between 4-16 weeks apart. Patients may receive gadolinium and/or iopamidol during MRI scans.

Advanced MRI Scan Before and After Radiation Therapy for the Detection of Intracranial Metastasis

Advanced MRI for Intracranial Metastasis Treated With Stereotactic Radiosurgery

Will be performed on the largest lesion within each patient at baseline, and the analysis will be repeated considering all lesions.

The sensitivity of each method at detecting lesions as determined by T1 weighting will be reported with 95% confidence intervals. Analyses will also be performed at the subsequent scans as numbers permit.

Brain metastases "treatment response" will be defined by size and contrast to noise ratio (CNR). Size: treatment response in a lesion will be considered as a decrease in size of 30%. CNR: treatment response will be considered as a decrease in T1 post-contrast CNR of at least 20%. Metastases that do not meet these criteria for treatment response will be considered treatment failure. Will calculate the CNR in patients with lesions that respond to treatment and in patients with local failure and will compare these by using a Wilcoxon rank-sum test. If numbers permit, analyses may be repeated using all lesions. The CNR will be compared between lesions with treatment change and those that are progressive disease using a Wilcoxon rank-sum test.

M.D. Anderson Cancer Center

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma	NCT02359565	Constitutional ... Lynch Syndrome Malignant Gliom... Recurrent Brain... Recurrent Child... Recurrent Diffu... Recurrent Medul... Refractory Brai... Refractory Diff... Refractory Epen... Refractory Medu...	Biospecimen Col... Conventional Ma... Diffusion Tenso... Diffusion Weigh... Dynamic Contras... Dynamic Suscept... Magnetic Resona... Pembrolizumab	1 Year - 30 Years	National Cancer Institute (NCI)
Advanced MRI Scan Before and After Radiation Therapy for the Detection of Intracranial Metastasis	NCT04870645	Malignant Solid...	Advanced Magnet... Conventional Ma... Gadolinium-Chel... Iopamidol	18 Years -	M.D. Anderson Cancer Center

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