Evaluation of 177Lu-PSMA Theranostics in Recurrent Grade 3 and Grade 4 Glioma: Safety, Tolerability, and Efficacy Analysis

The primary objective of this study is to evaluate the **safety** and **tolerability** of **177Lu-PSMA** in patients with recurrent or progressed grade 3 and grade 4 **glioma**. Additionally, the study aims to assess the **efficacy** of 177Lu-PSMA in treating these patients. This is clinically relevant as it addresses the need for effective and safe treatment options for high-grade gliomas, which are aggressive brain tumors with limited therapeutic options.

Secondary objectives include:

• Evaluating the **radiation dose** delivered to the tumor and critical organs.
• Assessing the **efficacy** and **side effects** of the treatment based on patient-reported outcomes, physician assessments, and radiological parameters.
• Investigating the **diagnostic** and **theranostic** properties of **68Ga-PSMA**.

The clinical trial involves participants diagnosed with **recurrent grade 3 and grade 4 glioma**. The study population includes both male and female subjects, aged 18 years and older, with a **Karnofsky performance status** of at least 70%, indicating they must be able to care for themselves after radionuclide therapy. Participants are required to have a life expectancy greater than 12 weeks and must not be receiving any other tumor-directed treatment during a treatment cycle. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the requirement for women of childbearing potential to use adequate contraception. Participants must have a high tumor uptake on diagnostic imaging with 68Ga-PSMA and their tumors should not be amenable to radiotherapy or surgery, with no preferable systemic therapy options available. The selection criteria ensure that participants have a previous diagnosis of histologically confirmed WHO grade 3 or grade 4 glioma, with radiologically confirmed tumor relapse or progression at least 12 weeks post-radiotherapy.

The clinical trial is designed to evaluate the **safety** and **efficacy** of **177Lu-PSMA** in patients with recurrent grade 3 and grade 4 glioma. This is a phase II, randomized, double-blind, controlled study. The trial will assess the therapeutic potential of **177Lu-PSMA** administered as a **solution for injection** via **intravenous infusion**. The study is expected to run until December 31, 2025, with recruitment having commenced on April 4, 2023. Participants will be involved in the study for a maximum treatment period of 12 months, with each treatment cycle lasting between 6 to 8 weeks.

The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as a previous diagnosis of histologically confirmed WHO grade 3 or grade 4 glioma, a life expectancy greater than 12 weeks, and a Karnofsky performance status of at least 70%. Participants must also have a negative pregnancy test within 14 days prior to enrollment and provide written informed consent. The screening visit will also ensure that the tumor is not amenable to radiotherapy or surgery and that no other preferable systemic therapy options are available.

Following the screening, participants will undergo regular follow-up visits to monitor the **safety** and **tolerability** of the treatment, as well as to evaluate the **efficacy** of **177Lu-PSMA**. Primary endpoints include the type, frequency, and severity of adverse events, assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and changes in the modified RAI-6 questionnaire score. Secondary endpoints will assess radiation dose to the tumor and critical organs, tumor responses, neurologic exam scores, health-related quality of life, and diagnostic properties of **68Ga-PSMA**.

The end-of-study visit will conclude the participant's involvement, with assessments to determine progression-free survival at 6 months and overall survival at 1 year from the commencement of therapy. Participants may be terminated early from the study if they experience unacceptable adverse events, withdraw consent, or if the treating oncologist deems it necessary due to lack of efficacy or other medical reasons. The study aims to provide comprehensive data on the potential benefits and risks associated with **177Lu-PSMA** therapy in this patient population.

The clinical trial involves the administration of **177Lu PSMA I&T solution for injection**, which is an experimental medication used in the treatment of recurrent grade 3 and grade 4 glioma. The active substance in this medication is **lutetium (177Lu) zadavotide guraxetan**, classified under the ATC code V10 as a therapeutic radiopharmaceutical. The pharmaceutical form of the medication is a solution for injection, and it is administered via **intravenous infusion**. The maximum daily dose is 7.4 GBq, with a total maximum dose of 59.2 GBq over a treatment period not exceeding 12 months. The medication is produced by Curium Finland Oy and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial focuses solely on the administration of the experimental medication. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the safety, tolerability, and efficacy of the 177Lu PSMA I&T solution for injection in the specified patient population.

The efficacy of **177Lu-PSMA** in the treatment of recurrent or progressed grade 3 and grade 4 glioma will be assessed through several primary and secondary endpoints. The primary efficacy endpoints include progression-free survival at 6 months and overall survival at 1 year, measured from the date of commencement of **177Lu-PSMA** therapy. These endpoints will provide critical data on the duration patients remain free from disease progression and their overall survival following treatment.

Secondary efficacy assessments will involve evaluating tumor responses using contrast-enhanced MRI according to the Response Assessment in Neuro-Oncology (RANO) criteria and volume measurements. Additionally, neurologic examinations will be conducted using the nano score, and health-related quality of life will be assessed with EQ-5D scores. The Karnofsky performance status will also be evaluated to determine the patient's ability to care for themselves post-treatment. These assessments will be conducted from baseline to the end of each treatment cycle and during follow-up examinations.

Furthermore, the study will calculate absorbed radiation doses to the tumor and critical organs, including the kidneys, parotid glands, sublingual glands, submandibular glands, lacrimal glands, liver, spleen, and red marrow, for each therapy cycle and accumulated doses for all therapy cycles. This will help in understanding the distribution and potential impact of the radiopharmaceutical on both the tumor and surrounding tissues.