Phase 2a Immune Modulation With Ultrasound for Newly Diagnosed Glioblastoma

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.

This is a multicenter, two-arm, randomized, double-blind, placebo-controlled study of Optune® (Tumor Treating Fields at 200 kHz) together with maintenance Temozolomide (TMZ) chemotherapy agent and pembrolizumab compared to Optune® together with maintenance TMZ and placebo in newly diagnosed Glioblastoma (GBM) patients. The primary objective of the study is to evaluate the Overall Survival (OS).

Approximately 30% of cancer patients may experience psychopathological disorders. The most common psychopathological disorders in cancer patients are mood disorders, anxiety, depression, adjustment disorders, and suicidal ideation. Among depressive disorders, mixed depression, with the simultaneous presence of symptoms of both depressive and manic polarity, is associated to higher levels of chronicity, functional impairment and suicidality. These disorders can also be worsened by loneliness and demoralization. Patients with head and neck cancer (H\&N-C) and Glioblastoma multiforme (GBM) have high psychological and sometimes psychiatric comorbidity probably due to the severity, poor prognosis of these cancers and harsh treatment toxicities. The most important protective factor for psychopathology is psychological resilience, which is "the capacity of a person to protect themselves and their mental health when facing life adversities," such as a GBM or H\&N-C diagnosis. Resilience is influenced by the affective temperament, which refers to basic personality traits related to behavioral and emotional reactivity to environmental stimuli. It is believed to be biologically determined and relatively stable throughout life. To date, the literature does not clarify the role of resilience and temperament in mediating the psychological profile of cancer patients. Furthermore, extensive profiling of the psychological and psychiatric profile of these patients at such a critical and pivotal moment in their journey is currently lacking in the literature. Aim of this study is to evaluate global psychological and psychiatric profile of patients affected by GBM and H\&N-C and the eventual fluctuation over time during RT course. Conducting an early and accurate screening for potential psychopathological issues will give the opportunity to avoid factors that could: worsen patient compliance, lead to suicidal risk, and increase hospitalizations. The results obtained will be utilized for planning precocious psychological or psychiatric take-in-charge aimed at promoting psychological well-being of H\&N-C and GBM patients.

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.