Phase IIb Trial of Everolimus and Lutetium (177Lu) Oxodotreotide in Refractory Grade 2 and 3 Meningioma

The primary objective of this phase IIb clinical trial is to evaluate the efficacy of combining **everolimus** with 177Lu-DOTATATE on progression-free survival at 6 months (PFS-6) in patients with grades 2 and 3 refractory **meningioma**. This is clinically relevant as it aims to determine the potential of this combination therapy to improve disease control in a population with limited treatment options.

Secondary objectives include evaluating the efficacy of the everolimus-PRRT with 177Lu-DOTATATE combination on overall survival at 12 months (OS-12), tumor growth rate, and tolerance/toxicity in the same patient population. Additionally, the study will assess the impact of tumor dosimetry on PFS-6 and OS-12, and describe the evolution of patients' health-related quality of life (HRQoL) over a 6-month period. These secondary objectives are important for understanding the broader impact of the treatment on patient outcomes and quality of life.

The clinical trial focuses on evaluating the efficacy of combining everolimus-PRRT with 177Lu-DOTATATE in patients with **meningioma**, specifically targeting grades 2 and 3 refractory cases. The study population includes both male and female participants, with an age range of adult patients under 80 years old. Participants are required to have a WHO performance status of 3 or less and must have a histologically confirmed diagnosis of grade 2 or 3 meningioma that is not amenable to surgery or radiotherapy, with evidence of clinical or radiological progression. The trial does not involve a vulnerable population. Participants must have undergone a brain MRI and 68Ga-DOTATOC PET within the last two months and must express somatostatin receptors as determined by PET imaging. Effective contraception is required for women of childbearing age. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of combining **everolimus** with **177Lu-DOTATATE** in the treatment of grades 2 and 3 refractory **meningioma**. This is a phase IIb, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on March 1, 2024, and conclude by May 1, 2028. Participants will be involved in the study for a maximum treatment period of 9 months, with the primary endpoint being progression-free survival at 6 months (PFS-6) according to the RANO criteria.

The trial will include several study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and tumor characteristics. Eligible participants will then be randomized to receive either the investigational treatment or a control. Follow-up visits will occur at regular intervals to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the final outcomes and any long-term effects of the treatment.

Participants are expected to adhere to the study protocol, including attending all scheduled visits and undergoing required assessments such as MRI and PET scans. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial aims to provide valuable insights into the potential benefits of this combination therapy for patients with refractory meningioma.

The clinical trial involves the administration of **Lutathera** 370 MBq/mL solution for infusion, which contains the active substance **lutetium (177Lu) oxodotreotide**. This pharmaceutical form is a solution for infusion, administered via the **intravenous route**. The maximum daily dose is 7400 MBq, with a total maximum dose of 7400 MBq over a treatment period of up to 9 months. The product is manufactured by Advanced Accelerator Applications and is authorized for use in the European Union. In this study, it is being evaluated for the treatment of meningioma.

Additionally, the trial includes the use of **Everolimus** in various formulations. **Everolimus PUREN 5 mg Tabletten** and **Everolimus PUREN 2.5 mg Tabletten** are both oral tablets containing the active substance **everolimus**. The maximum daily doses for these formulations are 5 mg and 2.5 mg, respectively, with a treatment period of up to 7 days. These products are manufactured by Eugia Pharma (Malta) Ltd and are not authorized for the indication of meningioma.

Furthermore, the trial utilizes **Everolimus beta 5 mg Tabletten** and **Everolimus beta 2.5 mg Tabletten**, also oral tablets containing **everolimus**. The maximum daily dose for both formulations is 7.5 mg, with a treatment period of up to 7 days. These products are manufactured by Betapharm Arzneimittel GmbH. The administration of these tablets is oral, and they are not specifically authorized for meningioma treatment.

Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy of combining everolimus with 177Lu-DOTATATE in the treatment of grades 2 and 3 refractory meningioma.

The efficacy of the clinical trial evaluating the combination of everolimus and **177Lu-DOTATATE** in the treatment of grades 2 and 3 refractory meningioma will be assessed using several endpoints. The primary endpoint is Progression-Free Survival at 6 months (PFS-6) from the start of treatment, evaluated according to the RANO criteria. Secondary endpoints include Overall Survival at 12 months (OS-12), tumor growth rate, and dosimetry of the dose delivered to the tumor. Tumor growth rate will be determined by comparing the product of the two largest diameters of the target lesion from MRI scans at months 3 or 6 to baseline measurements. Dosimetry will be calculated using at least two skull scans with **177Lu-DOTATATE** SPECT-CT on days 1 and 7 after the first treatment cycle.

Additional secondary endpoints include the number and types of adverse events classified according to the CTCAE criteria, recorded from the start of treatment until 180 days post-treatment. Health-Related Quality of Life (HRQoL) will be assessed using the EORTC QLQ-C30 questionnaire at inclusion and at 6 months. These efficacy parameters will be measured and collected at specified timepoints throughout the trial to ensure comprehensive evaluation of the treatment's impact on patients with refractory meningioma.