Ependymoma

This is a multisite, phase I/II clinical trial in children and young adults with newly-diagnosed high-grade glioma (HGG), diffuse midline glioma (DMG) and recurrent HGG/DMG, Medulloblastoma (MB), or ependymoma (EPN) to determine the safety, immunogenicity, and efficacy of a CMV-directed peptide vaccine plus checkpoint blockade.

This is an open-label phase 1 safety and feasibility study that will employ multi-tumor antigen specific cytotoxic T lymphocytes (TSA-T) directed against proteogenomically determined personalized tumor-specific antigens (TSA) derived from a patient's primary brain tumor tissues. Young patients with embryonal central nervous system (CNS) malignancies typically are unable to receive irradiation due to significant adverse effects and are treated with intensive chemotherapy followed by autologous stem cell rescue; however, despite intensive therapy, many of these patients relapse. In this study, individualized TSA-T cells will be generated against proteogenomically determined tumor-specific antigens after standard of care treatment in children less than 5 years of age with embryonal brain tumors. Correlative biological studies will measure clinical anti-tumor, immunological and biomarker effects.

Study in children and adolescents of 177Lu DOTATATE (Lutathera®) combined with the PARP inhibitor olaparib for treatment of recurrent or relapsed solid tumours expressing somatostatin receptors (SSTR) (LuPARPed)

The goal of this clinical trial is to learn if intratumoral administration of DNX-2401 works to treat recurrent and refractory high grade brain tumors in children and young adults. It will also learn about the safety of DNX-2401. The main questions it aims to answer are: * Does a single intratumoral administration of DNX-2401 elicit tumor response and improve survival? * Is a single intratumoral administration of DNX-2401 safe and well tolerated? Participants will: * Undergo surgery for tumor biopsy followed by a single intratumoral administration of DNX-2401 * Visit the clinic periodically for checkups and tests

This phase I trial studies the side effects of linear energy transfer (LET) optimized image modulated proton therapy (IMPT) in treating pediatric patients with ependymoma. Radiation therapy such as LET optimized IMPT, uses proton beams to kill tumor cells and shrink tumors without damaging surrounding normal tissues.

Background: About 90,000 new cases of brain and spinal cord tumors are diagnosed annually in the United States. Most of these tumors are benign; however, about 30% are malignant, and 35% of people with malignant tumors in the brain and spinal cord will die within 5 years. Many of these people have changes in certain genes (MYC or MYCN) that drive the development of their cancers. Objective: To test a study drug (PLX038) in people with tumors of the brain or spinal cord. Eligibility: People aged 18 years or older with a tumor of the brain or spinal cord. Some participants must also have tumors with changes in the MYC or MYCN genes. Design: Participants will be screened. They will have a physical exam and blood tests. They will have imaging scans and a test of their heart function. They may need to have a biopsy: A sample of tissue will be removed from their tumor. PLX038 is given through a tube attached to a needle inserted into a vein in the arm. All participants will receive PLX038 on the first day of each 21-day treatment cycle. They will take a second drug 3 days later to help reduce the risk of infection; for this drug, participants will be shown how to inject themselves under the skin at home. Blood tests, imaging scans, and other tests will be repeated during study visits. Hair samples will also be collected during these visits. Some participants may have an additional biopsy. Study treatment will continue up to 7 months. Follow-up visits will continue every few months for up to 5 years.

his is a single-center, prospective observational study in children and adolescents with central nervous system tumors who need whole-brain and whole-spine radiation therapy (craniospinal irradiation, CSI). The study uses proton therapy with a special vertebral body-sparing (VBS) technique to protect the front and center of the vertebrae, which helps preserve bone marrow function and growth. The main goals are to find safe dose limits for the vertebrae and check how often severe side effects occur. The study will also look at bone marrow preservation, spinal deformity, tumor control, survival, chemotherapy completion, neurocognitive function, quality of life, and growth and development for up to 5 years after treatment.

This is a multi-arm phase II platform-basket screening study designed to test multiple experimental therapies simultaneously in patients with NF2-related schwannomatosis (NF2-SWN, formerly known as neurofibromatosis type 2) with associated progressive tumors of vestibular schwannomas (VS), non-vestibular schwannomas (non-VS), meningiomas, and ependymomas. This Master Study is being conducted as a "basket" study that may allow people with multiple tumor types associated with NF2-SWN to receive new drugs throughout this study. Embedded within the Master Study are individual drug substudies. * Investigational Drug Sub-study A: Brigatinib * Investigational Drug Sub-study B: Neratinib * Investigational Drug Sub-study C: Retifanlimab plus bevacizumab

Loc3CAR is a Phase I clinical trial evaluating the use of autologous B7-H3-CAR T cells for participants ≤ 21 years old with primary CNS neoplasms. B7-H3-CAR T cells will be locoregionally administered via a CNS reservoir catheter. Study participants will be divided into two cohorts: cohort A with B7-H3-positive relapsed/refractory non-brainstem primary CNS tumors, and cohort B with diffuse midline gliomas (DMG). Participants will receive four (4) B7-H3-CAR T cell infusions over a 4 week period. The purpose of this study is to find the maximum (highest) dose of B7-H3-CAR T cells that are safe to give patients with primary brain tumors. Primary objectives * To determine the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for the locoregional delivery of autologous B7-H3-CAR T cells in patients ≤ 21 years of age with recurrent/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B). Secondary objectives * To assess the efficacy, defined as sustained objective response, a partial response (PR) or complete response (CR) observed anytime on active treatment with B7-H3-CAR T cells in patients with relapsed/refractory B7-H3+ primary CNS tumors (Cohort A) or DMG (Cohort B). * To characterize and monitor neurologic toxicities in patients while on study (Cohort A and B).

Advanced technology of ex vivo drug profiling referred to as pharmacoscopy may allow to identify novel drugs for the treatment of glioblastoma and other refractory brain tumors at an individual patient level. This personalized therapeutic approach was developed and validated in pre-clinical glioma models. With the current research proposal, we seek to establish feasibility for a clinical interventional trial for patients with refractory primary brain tumors that is based on pharmacoscopy-guided selection of treatment. The study is supported by an unrestricted grant from Anti Cancer Fund.

The current study will use a new treatment approach based on the molecular characteristics of each participant's tumor. The study will test the feasibility in the pilot phase of performing real-time drug screening on tissue taken during surgery in patients with relapsed medulloblastoma or ependymoma and of having a specialized tumor board assign a treatment plan based on the results of this screening and genomic sequencing. The aim of this trial is to allow every child and young adult with relapsed medulloblastoma and ependymoma to receive the most effective and least toxic therapies currently available and will pave the way for improved understanding and treatment of these tumors in the future. Moreover, if successful, it could serve as a paradigm for personalized medicine programs for other types of cancer.

This is a Phase 1 study of central nervous system (CNS) locoregional adoptive therapy with autologous CD4+ and CD8+ T cells lentivirally transduced to express a B7H3-specific chimeric antigen receptor (CAR) and EGFRt. CAR T cells are delivered via an indwelling catheter into the tumor resection cavity or ventricular system in children and young adults with diffuse intrinsic pontine glioma (DIPG), diffuse midline glioma (DMG), and recurrent or refractory CNS tumors. A child or young adult meeting all eligibility criteria, including having a CNS catheter placed into the tumor resection cavity or into their ventricular system, and meeting none of the exclusion criteria, will have their T cells collected. The T cells will then be bioengineered into a second-generation CAR T cell that targets B7H3-expressing tumor cells. Patients will be assigned to one of 3 treatment arms based on location or type of their tumor. Patients with supratentorial tumors will be assigned to Arm A, and will receive their treatment into the tumor cavity. Patients with either infratentorial or metastatic/leptomeningeal tumors will be assigned to Arm B, and will have their treatment delivered into the ventricular system. The first 3 patients enrolled onto the study must be at least 15 years of age and assigned to Arm A or Arm B. Patients with DIPG will be assigned to Arm C and have their treatment delivered into the ventricular system. The patient's newly engineered T cells will be administered via the indwelling catheter for two courses. In the first course patients in Arms A and B will receive a weekly dose of CAR T cells for three weeks, followed by a week off, an examination period, and then another course of weekly doses for three weeks. Patients in Arm C will receive a dose of CAR T cells every other week for 3 weeks, followed by a week off, an examination period, and then dosing every other week for 3 weeks. Following the two courses, patients in all Arms will undergo a series of studies including MRI to evaluate the effect of the CAR T cells and may have the opportunity to continue receiving additional courses of CAR T cells if the patient has not had adverse effects and if more of their T cells are available. The hypothesis is that an adequate amount of B7H3-specific CAR T cells can be manufactured to complete two courses of treatment with 3 or 2 doses given on a weekly schedule followed by one week off in each course. The other hypothesis is that B7H3-specific CAR T cells can safely be administered through an indwelling CNS catheter or delivered directly into the brain via indwelling catheter to allow the T cells to directly interact with the tumor cells for each patient enrolled on the study. Secondary aims of the study will include evaluating CAR T cell distribution with the cerebrospinal fluid (CSF), the extent to which CAR T cells egress or traffic into the peripheral circulation or blood stream, and, if tissues samples from multiple timepoints are available, also evaluate disease response to B7-H3 CAR T cell locoregional therapy.

The purpose of this research study is to test the safety and effectiveness of a cell therapy at different doses for children and young adults with recurrent or progressive brain tumors. Recurrent/recurred means a tumor that has gone away and then came back. This cell therapy is called B7- H3.CD28Z.CART, referred to as B7-H3 CAR T cells. B7-H3 is a protein that is over-expressed on many tumor cells, making it a good target for cancer cell therapy. The names of the study investigational therapies involved in this study are: * Fludarabine (a type of chemotherapy) * Cyclophosphamide (a type of chemotherapy) * B7-H3 CAR T cells (a type of cellular therapy)

Recent lab-based discoveries suggest that IDO (indoleamine 2,3-dioxygenase) and BTK (Bruton's tyrosine Kinase) form a closely linked metabolic checkpoint in tumor-associated antigen-presenting cells. The central clinical hypothesis for the GCC2020 study is that combining ibrutinib (BTK-inhibitor) with indoximod (IDO-inhibitor) during chemotherapy will synergistically enhance anti-tumor immune responses, leading to improvement in clinical response with manageable overlapping toxicity. The GCC2020 trial is a prospective open-label phase 1 trial to determine the best safe dose of the BTK-inhibitor ibrutinib to use in combination with previously studied chemo-immunotherapy regimens comprised of the investigational IDO-inhibitor indoximod plus oral palliative chemotherapy for participants, age 6 to 25 years, with relapsed or refractory primary brain cancer. Those previously treated with indoximod-based therapy may be eligible, including prior treatment via the phase 2 indoximod study (GCC1949, NCT04049669), the now closed phase 1 study (NLG2105, NCT02502708), or any expanded access (compassionate use) protocols. Ibrutinib will be combined with either indoximod plus oral cyclophosphamide and etoposide (Regimen A) or indoximod plus oral temozolomide (Regimen B). No cross-over between these two regimens will be allowed. Dose-escalation cohorts will determine the best safe dose of ibrutinib for each of these regimens. This will be followed by expansion cohorts, using ibrutinib at the best safe dose for each regimen, to allow assessment of preliminary evidence of efficacy.

The primary objective of this Phase 1, open-label, dose-escalation, and exploratory study is to evaluate the safety and tolerability profile (establish the maximum-tolerated dose) and evaluate the occurrence of dose-limiting toxicities (DLTs) following single weekly or multiple-day weekly dose regimens of single-agent, oral ONC206 in patients with recurrent, primary central nervous system (CNS) neoplasms.

Every new classification depends on its prognostic power and on the type of treatment given. With the rapid evolution of diagnostic methods and the advance in new treatments, there is much less reliable information available on how patients with newly defined brain tumour entities should be treated and what to expect from the current treatments. The goal is to determine whether the new 2021 WHO classification, based on cIMPACT-NOW recommendations, results in more homogeneous patient groups than the old 2016 classification. Furthermore, it will help derive provisional guidelines on how patients with these newly defined tumour entities are best treated. These recommendations will be based on the experience of EORTC investigators with chosen treatments and their experience as reported in this data collection report.

Pediatric patients 6-21 years of age with supratentorial recurrent, refractory, or progressive pediatric ependymoma and high-grade glioma (HGG) will be included in this study of treatment with Rhenium-186 Nanoliposome (186RNL). Phase 1 of the study will look to determine the maximum tolerated dose (MTD) of 186RNL in this patient population. Phase 2 of the study will use the recommended dose determined in Phase 1 to continue to look at overall response rate and progression-free survival following 186RNL treatment.

Radiation constitutes an integral component in the management of primary brain tumors in pediatric and young adults like medulloblastoma, ependymoma, low-grade glioma, pituitary tumors, etc. A decline in neurocognitive outcomes is a multifactorial effect occurring from the primary disease as well as associated with treatments, including radiation. Since many of these tumors are highly curable, it is crucial to reduce long-term side effects, including memory loss, to improve the quality of life in these patients, leading to better rehabilitation. Radiation-induced neurocognitive deterioration is postulated to occur from multiple factors like neuroinflammation, vascular damage, and depletion of neural stem cells. The proposed study will prospectively evaluate 200 pediatric and young adults with brain tumors treated with radiotherapy. Biological samples (peripheral blood and cerebrospinal fluid) will be procured during routine investigations (an additional amount will be collected for study purposes without the need for additional investigations). Serial blood markers (whenever available pre-operative and before, during, and after completion of radiation) of neuroinflammation and neural markers will be tested in patients undergoing radiation as part of their standard treatment, and correlate with the neurocognitive outcomes measured by age-appropriate Wechsler intelligence scales. Also, the impact of clinical (e.g. age) and radiotherapy parameters like volume, dose of radiation, and technique (photon versus proton therapy) on acute (during radiotherapy) and late systemic inflammatory markers will be analyzed. The study will even provide the opportunity to know the influence of radiation on systemic neuroinflammatory markers in the human population, providing better biological insights into the neurocognitive decline. If proven successful, these biomarkers can be used in routine clinical practice for early intervention to improve neurocognitive function in patients receiving radiation (even for other histology or other patients receiving radiation like brain metastasis).

The treatment of adolescents and young adults (AYA, 15 to 39 years) with malignant intra-axial CNS parenchymal tumors such as IDH-mutated gliomas, medulloblastomas and ependymomas is still not curative in all cases. The tumor biology and clinical needs to diagnose and treat these tumors are comparable across all age groups, so an integrated treatment environment overseen by adult and pediatric neuro-oncology specialists seems promising to leverage synergisms and advance diagnostic and therapeutic development in these tumors. A comprehensive, prospective and integrated biomaterial and imaging-based pipeline for the multi-faceted evaluation of AYAs has not yet been established for AYA patients with brain tumors in Germany. Current diagnostic platforms neglect the integrative processing of data from MRI and FET-PET imaging, radiotherapy plans, tumor tissue, liquid biopsies and clinical data as well as prognostic markers. A prospective AYA pipeline can therefore enable a better understanding of the aforementioned high-risk CNS malignancies and promises clinical advances for AYA patients and the clinical and scientific research landscape.

The first proton therapy treatments in the Netherlands have taken place in 2018. Due to the physical properties of protons, proton therapy has tremendous potential to reduce the radiation dose to the healthy, tumour-surrounding tissues. In turn, this leads to less radiation-induced complications, and a decrease in the formation of secondary tumours. The Netherlands has spearheaded the development of the model-based approach (MBA) for the selection of patients for proton therapy when applied to prevent radiation-induced complications. In MBA, a pre-treatment in-silico planning study is done, comparing proton and photon treatment plans in each individual patient, to determine (1) whether there is a significant difference in dose in the relevant organs at risk (ΔDose), and (2) whether this dose difference translates into an expected clinical benefit in terms of NormalTissue Complication Probabilities (ΔNTCP). To translate ΔDose into ΔNTCP, NTCP-models are used, which are prediction models describing the relation between dose parameters and the likelihood of radiation-induced complications. The Dutch Society for Radiotherapy and Oncology (NVRO) setup the selection criteria for proton therapy in 2015, taking into account toxicity and NTCP. However, NTCP-models can be affected by changes in the irradiation technique. Therefore, it is paramount to continuously update and validate these NTCP-models in subsequent patient cohorts treated with new techniques. In ProTRAIT, a Findable, Accessible, Interoperable and Reusable (FAIR)data infrastructure for both clinical and 3D image and 3D dose information has been developed and deployed for proton therapy in the Netherlands. It allows for a prospective, standardized, multi-centric data from all Dutch proton and a representative group of photon therapy patients.

Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research are necessary to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. The majority of malignant CNS tumors in children and adolescents belong to two broad histologic tumor entities: those of glial origin, such as high-grade glioma (HGG)and ependymoma (EPN), and those of neuronal origin, also identified as embryonal tumors, that include medulloblastoma and AT/RT(1). Over the last few years, whole-genome sequencing, gene-expression profiling and genome-wide methylation studies have greatly deepened our understanding of the biology and genetics of these tumors, allowing for robust stratification in clinically relevant molecular subgroups. The advancement of single-cell omics over the last decade have highlighted the enormous heterogeneity of tumors, a complex mixture of co-existing cancer subclones and supportive normal cell populations. However, current treatments have remained largely static, and 5-year survival rate for children with malignant CNS tumors only achieves a modest 57.5%. More effective treatment strategies should include novel chemotherapeutic agents that take into account high intrinsic tumor heterogeneity as well as the complex regulations of transcriptional and translational mechanisms that control protein expression. Identification of novel drugs and treatment strategies is further limited by the paucity of appropriate preclinical models, which mirror the molecular characteristics of distinct tumor subgroups. We propose to establish patient-derived in vitro models to predict chemotherapeutic drug sensitivity/resistance in malignant pediatric CNS tumors. Next, we propose to perform molecular analyses in tissues of pediatric CNS tumors to determine whether in vitro findings have clinical correlates.

It is an open multicentric phase I/II trial with axitinib (Inlyta®) and metronomic delivery of etoposide for children, adolescent and young adults (AYA) with refractory/ relapsing solid tumors. It is a two-stage trial: First stage: To determine the Maximum Tolerated Dose (MTD) of the combination of axitinib and oral metronomic etoposide for patient with medulloblastoma or ependymoma Second stage: Extension cohort evaluating the preliminary efficacy at the recommended dose for the phase II (RDP2) of the combination. The 2nd stage will start after a meeting of independent data monitoring committee (IDMC). Two cohorts of 9 patients with ependymoma and medulloblastoma Patients treated at first stage won't be included in the second stage.

Primary malignant central nervous system (CNS) tumors are the second most common childhood malignancies. Amongst, medulloblastomas are the most common malignant brain tumor of childhood and occur primarily in the cerebellum. According to molecular characteristics, medulloblastomas were classified into four subtypes: WNT, SHH, Group3 and Group4 and different prognosis were noticed between subgroups. Several genetic predispositions related to clinical outcome were also discovered and might influence the treatment of medulloblastomas as novel pharmaceutical targets. This study aims to investigate genetic and cellular profiles of pediatric brain malignancies, mostly medulloblastomas, and other central nervous system tumor based on WGS, RNA-seq, single-cell sequencing and spatial transcriptomics. We also aim to investigate the correlation between genetic characteristics and clinical prognosis.