High Grade Gliomas

The goal of this clinical research study is to learn about the safety and effects of G207 combined with radiation therapy in patients with recurrent or progressive high-grade glioma (HGG).

This is an open-label phase 1 safety and feasibility study evaluating a novel combination therapy for progressive and relapsed diffuse midline glioma (DMG) and other progressive and relapsed high-grade brain tumors. This study combines intravenous nivolumab therapy infused following transient blood-brain barrier opening (BBBO) using low-intensity focused ultrasound with microbubble (LIFU-MB) treatment using NeuroNavigation-Guided Focused Ultrasound (NgFUS). There are two groups in this study: * Group A: Patients with relapsed or progressive diffuse midline glioma in the brainstem * Group B: Patients with relapsed or progressive high grade brain tumor that clinically require surgical resection The primary outcome is to evaluate the safety and feasibility of 3 cycles of nivolumab with BBB disruption using NgFUS with microbubbles in pediatric patients with progressive or relapsed brainstem DMG or with high grade brain tumors after surgery. Secondary outcomes include preliminary efficacy and immunological effects.

The goal of this clinical trial is to learn if preopearative proton therapy (PPT) is tolerable in patients with High-grade brain gliomas. It will also learn about the influence on surgical procedure, clinical effects and safety of regular treatment. The main questions it aims to answer are: Does preoprative proton therapy well-tolerated? What maximal dose of PPT is safe? Proposed Treatment Stages 1. Multidisciplinary board (neurosurgeon, radiation therapist, and medical oncologist) decision of patient enrollment. 2. Course of preoperative proton stereotactic radiotherapy (PSRT) directed at the tumor only: GTV=contrast-part of brain giloma, CTV=GTV. Dose regimens: first 3 patients - 4 Gy(RBE) × 5 fractions; subsequent 3 patients - 5 Gy(RBE) × 5 fractions; subsequent 3 patients - 6 Gy(RBE) × 5 fractions. RBE = Relative biological efficacy, equal 1.1 for protons. Should any information regarding unacceptable treatment toxicity emerge, the study will be terminated. 3. Microsurgical resection of the contrast-enhancing portion of the tumor using fluorescence microscopy and, when indicated, neurophysiological monitoring. 4. Contrast-enhanced MRI to assess the resection volume within the first 24-48 hours after surgery. 5. Follow-up evaluation - clinical, morphological, and radiological assessment of the effects of the preoperative and surgical treatment stages, performed 3-4 weeks after the surgical phase. 6. Standard treatment and follow-up: Chemoradiotherapy with a scanned proton beam combined with temozolomide 75 mg/m², given at 2 Gy × 30 fractions, to commence 4-6 weeks after surgery. Adjuvant chemotherapy with temozolomide 150-200 mg/m² on a 5/23 schedule (maintenance chemotherapy), for 12 cycles or until disease progression/unacceptable toxicity. 7. Follow-up - control examinations every 1 month after completion of chemoradiotherapy, then every 3 months for the first year.

High-grade gliomas (HGGs) are among the most aggressive and treatment-resistant brain tumors. Immunotherapy with checkpoint inhibitors like nivolumab has shown promise, but its efficacy remains variable and poorly understood in this patient population. This clinical trial investigates a novel imaging-enabled formulation of nivolumab-IRDye800 (nivo800) which incorporates a near-infrared (NIR) fluorescent dye to enable real-time visualization of drug distribution within tumor tissue.

High-grade gliomas (HGGs) are the most common type of brain cancer in adults. Life expectancy for patients with HGGs is low. Radiotherapy aims to cure the tumour, but this is hard because HGGs are resistant to treatment. Among the possible causes of resistance may be tumour cells with low-oxygen levels (hypoxia). The investigators know that hypoxia reduces tumour sensitivity to radiotherapy. Using a special imaging technique called oxygen-enhanced MRI (OE-MRI), the investigators can try to identify areas of the tumour with hypoxia. The investigators could then give those areas a higher dose of radiotherapy. This might improve tumour control. This study aims to see if OE-MRI can find low-oxygen areas in HGGs. The study will also assess whether higher radiotherapy doses can be simulated in these regions. Project summary: 1. Set up the OE-MRI process at Leeds Cancer Centre (LCC). OE-MRI settings will be tested on healthy volunteer participants to ensure the images are as good as possible. 2. Participant Imaging. Patient participants with HGG will be recruited to take part. OE-MRI will be used to image participants during their treatment and track low-oxygen areas before treatment, halfway through treatment and 3 months after treatment has finished. 3. Dose Escalation Assessment. Computer programs will be used to design radiotherapy treatments to test if higher radiation doses to the tumour's low-oxygen areas can better control the cancer. This will help understand if this targeted approach has potential benefits. This is modelling and will not alter routine clinical patient participant management.

The goal of this clinical trial is to first define the Safety and Optimal Biological Dose (OBD) of study drug TGX-007 and to then further investigate the safety and efficacy in patients with newly diagnosed or recurrent Glioblastoma. TGX-007 is a gene therapy drug delivered by a harmless adeno-associated virus (AAV) vector which delivers two combined therapeutic payloads to enable killing of proliferative cells and activation of an anti-tumour immune response. One is herpes simplex virus thymidine kinase (HSV-tk), which converts the pro-drug valaciclovir into an active drug that can kill tumour cells and the other is interleukin 12 (IL-12), which activates the body's immune system to recognise and fight the tumour. Patients newly diagnosed with glioblastoma suitable for standard of care surgery and chemoradiotherapy or patients with recurrent glioblastoma suitable for further surgery may be eligible for the study. Patients will receive TGX-007 by a direct intratumoural injection and will then take the pro-drug valacyclovir orally for up to 21 days before proceeding to standard of care surgery. The study is split into two phases. Phase I will treat patients at different dose levels of TGX-007 to identify the Optimal Biological Dose that will be used to further expand the study into Phase II. Phase II will expand the number of patients treated at the selected OBD to investigate how effective TGX-007 is at treating newly diagnosed and recurrent GBM. Approximately 68 people aged 18-70 will take part in the study.

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)

This clinical trial is studying a drug called SGT-53 along with radiation and another drug called Nivolumab. It's for children with brain tumors that have come back, gotten worse, or didn't get better with earlier treatments. The main questions it aims to answer are: What is the right dose of SGT-53 that children can safely receive when it is used with radiation and Nivolumab? This dose will be used in the second phase of the trial. What side effects are there of SGT-53 when it is used with radiation and Nivolumab? How does SGT-53 move through the body when given with radiation and Nivolumab? How much of the SGT-53 drug is found in the tumor tissue? This will be tested in a small group of patients? Participants will: For the first treatment cycle: Get SGT-53 twice per week Get Nivolumab every 2 weeks Receive radiation therapy during week 2 For Cycles 2-6: Get SGT-53 once per week during even cycles and twice per week during odd cycles Get Nivolumab every 2 weeks For Cycles 7+ Get both SGT-53 and Nivolumab every 2 weeks In the phase 0 part of the study, 4 participants will have genetic testing performed on their tumor tissue after receiving SGT-53. These samples will be compared to another sample taken from the skin.

This is a draft, ClinicalTrials.gov-style example record for a first-in-human Phase 1 study evaluating locoregional administration of dual-targeting chimeric antigen receptor natural killer (CAR-NK) cells in adults with recurrent or progressive glioblastoma (GBM) or other high-grade glioma (HGG). Participants will undergo tumor antigen profiling for IL13Rα2, EGFR/EGFRvIII, and B7-H3 (CD276). Based on this assessment, each participant will receive the most suitable dual-target CAR construct to reduce antigen-escape risk.

Better treatments are needed for high-grade gliomas (HGG), and new ways of treating this disease should be tested. The investigators want to see if giving medicine before radiation works well. After radiation, MRI scans can be harder to understand because radiation changes how the brain looks on the scan. If new medicines are given before radiation, the scans are easier to read. First, the investigators need to find out if giving chemotherapy early works using a drug we already know can treat gliomas. The investigators will start with temozolomide, which is the only chemotherapy approved by the FDA for HGG. If this approach is successful, the investigators can then test new drugs using this screening method.

In this study, we want to find out more about the side effects of an investigational drug for relapsed or refractory atypical teratoid rhabdoid tumor and high-grade glioma, Gallium Maltolate (GaM) and what doses of GaM are safe for people to take. Everyone in this study will receive GaM which is still experimental and is not approved by the U.S. Food and Drug Administration. We do not know all the ways that this drug may affect people. We hope the information from this study will help us develop a better treatment for relapsed or refractory atypical teratoid rhabdoid tumor and high-grade glioma in the future.

B7-H3 is expressed at low levels in normal tissues but overexpressed in various tumor tissues. The ubiquitous expression of B7-H3 in tumors of different grades is a key feature for brain gliomas. The immunohistochemistry study showed that B7-H3 is abundantly expressed on both glioma (especially high-grade glioma) cells and tumor-associated endothelial cells. For GBM, the expression of B7-H3 is intensely positive, especially on tumor cells and vascular endothelial cells, which makes B7-H3 a potential immunotherapeutic target. γδ T cells recognize tumor cells without being restricted by MHC molecules, and thus can be used in allogeneic therapy without the risk of causing graft-versus-host disease. This study is an open-label, single-arm, dose-escalation and dose-expansion clinical study aimed at evaluating the safety and efficacy of allogeneic B7-H3 CAR γδT in patients with malignant glioma.

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.

Brain tumors account for 1.35% of all cancers and cause 2.2% of cancer-related deaths. Gliomas are the most common type, comprising 40-90% of central nervous system tumors in different age groups. The incidence of malignant gliomas is approximately 0.5-2 per 100,000 people annually. Standard treatments include surgical resection, radiotherapy, and chemotherapy, yet overall survival remains low, typically 1-3 years post-diagnosis. The study highlights the pressing need for novel treatment strategies, particularly given the infiltrative nature of gliomas and the potential for targeted therapies using neuropeptides. The aim of this study is to assess the efficacy and safety of local targeted therapy with \[225Ac\]Ac-DOTA-SP in recurrent glioblastoma. It is an interventional study without a control group, initiated by the researcher. Patients included are aged 18-80 with recurrent WHO G3-G4 glioma post-first-line treatment, not requiring immediate surgery and meeting specific MRI progression criteria. Patients will receive a maximum of six cycles of \[225Ac\]Ac-DOTA-SP, involving pre-treatment assessments, local administration of the agent after ensuring catheter patency, and continuous monitoring. Blood tests and neurological evaluations will be performed regularly. Outcome will be assessed by measuring overall survival (OS) and progression-free survival (PFS). The study anticipates improvements in both OS and PFS when compared to current treatments, contributing to critical insights into targeted alpha therapy's effectiveness in glioblastoma. Treatment with \[225Ac\]Ac-DOTA-SP previously indicated few significant side effects, primarily transient issues like seizures. Patients will be closely monitored throughout the study to identify any adverse effects promptly. The estimated study duration is three years, with biological material collected for histopathological and genetic analysis during surgical reoperation. Data will be anonymized to protect patient confidentiality, stored securely, and made available only for the scope of the study. Led by Prof. Przemysław Kunert, the research team includes multiple co-investigators from neurosurgery and nuclear medicine departments.

A Phase I Study Evaluating the Safety, Tolerability, Biodistribution and Shedding of the Virus, Pharmacodynamics, Immunogenicity, and Antitumor Activity of GC001 Oncolytic Vaccinia Virus Injection in Patient With Recurrent or Progressive Gliomas .

Gliomas are tumors that occur in all ages; they include the most common malign primary central nervous system tumors in developed countries. Gliomas are often aggressive, and their recommended treatment is surgical resection and chemoradiation. Complete tumor removal is challenging because of diffuse cell growth and the proximity of functionally critical tissues. Surgeons use 5-aminolevulinic acid (5-ALA) drug-induced fluorescence to visually detect tumor cells, which improves resection rates and delays tumor progression. Tumor cells are often left unnoticed because of visual obstacles or weak fluorescence, which may lead to local recurrence and reoperations. Surgical suction devices are used to remove cancerous tissues, but so far the suction aspirate tissues have not been routinely used in tissue detection. This multicenter controlled clinical trial investigates the clinical performance and outcomes of a new method for detecting tumor from the suction aspirates in near-real time based on 5-ALA induced fluorescence. The feedback from the aspirate tissue monitor (ATM) is expected to improve the identification of tumors, leading to fewer reoperations and better treatment outcomes.