Evaluation of [^89Zr]-Bevacizumab PET/CT Imaging as a Biomarker for Predicting Bevacizumab Efficacy in NF2-Related Vestibular Schwannomas

The primary objective of this study is to validate pre-treatment **[89Zr]-bevacizumab PET/CT** as an imaging biomarker for predicting a hearing response to bevacizumab treatment in patients with NF2-related vestibular schwannomas. This is clinically relevant as it aims to enhance the precision of treatment planning for individuals with **NF2-related schwannomatosis**, potentially improving therapeutic outcomes and reducing unnecessary exposure to ineffective treatments.

The clinical trial involves participants diagnosed with **NF2-related schwannomatosis**, specifically targeting those with vestibular schwannomas. The study population includes both male and female subjects aged 18 years or older. Participants are required to have a confirmed diagnosis of NF2 according to the revised Manchester criteria and must provide written informed consent. They should have measurable disease, defined as at least one vestibular schwannoma greater than 0.4 ml, as determined by volumetric analysis on a contrast-enhanced T1-weighted cranial MRI scan. Additionally, participants must be eligible and planned for bevacizumab treatment. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations. The trial does not include a vulnerable population.

The clinical trial is designed to evaluate the efficacy of **89Zr-Bevacizumab** as a biomarker for predicting the treatment response in patients with **NF2-related schwannomatosis**. This is a phase II, randomized, double-blind, controlled study. The trial aims to validate pre-treatment **89Zr-Bevacizumab** PET/CT imaging as a predictive tool for hearing response to bevacizumab therapy. The study is expected to run from July 2022 to December 2025, with participant involvement lasting up to one year.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as age (18 years or older), confirmed diagnosis of NF2, and measurable disease. Written informed consent is required. The inclusion visit will involve a comprehensive screening process, including a contrast-enhanced T1-weighted cranial MRI scan to ensure measurable vestibular schwannomas are present. Following the inclusion visit, participants will receive **89Zr-Bevacizumab** via intravenous injection, with the maximum daily dose not exceeding 5 mg.

Subsequent follow-up visits will be scheduled to monitor the correlation between pre-treatment imaging results and clinical outcomes, including hearing response and radiographic response to bevacizumab therapy. Secondary endpoints will assess correlations with patient-reported outcomes, vestibular function, cranial nerve function, kidney function, and non-target schwannoma response. The end-of-study visit will conclude the trial, where final assessments and data collection will occur.

Participants may be withdrawn from the study if they experience adverse reactions, fail to comply with study procedures, or if the investigator deems it necessary for safety reasons. The trial's primary endpoint is the correlation of pre-treatment **89Zr-Bevacizumab** imaging with hearing and radiographic responses, while secondary endpoints include various functional and patient-reported outcomes. The study is not classified as low intervention and is conducted under the auspices of Amsterdam UMC.

The clinical trial involves the administration of **89Zr-Bevacizumab**, an experimental medication designed for imaging purposes. The active substance in this medication is **bevacizumab zirconium ZR-89**, a radiolabeled monoclonal antibody. The pharmaceutical form of this product is an **injection**, and it is administered via **intravenous injection**. The maximum daily dose is 5 mg, with a total dose not exceeding 5 mg over the treatment period. The maximum treatment period is limited to one day. This formulation is not a pediatric formulation and is not classified as an orphan drug. The product is developed by Amsterdam UMC and is intended to serve as a test agent in the trial.

In this study, **89Zr-Bevacizumab** is utilized to validate pre-treatment PET/CT imaging as a biomarker for predicting the hearing response to bevacizumab treatment in patients with symptomatic **neurofibromatosis type 2** (NF2) related vestibular schwannomas. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The administration of the drug is carefully controlled to maintain the integrity of the study and ensure the safety of the participants.

Efficacy in this clinical trial will be assessed by evaluating the correlation between pre-treatment **89Zr-Bevacizumab** PET/CT imaging and the proportion of patients with confirmed hearing response (HR) and radiographic response (RR) to bevacizumab therapy. The primary endpoint focuses on these correlations to determine the predictive value of the imaging biomarker for treatment outcomes in patients with neurofibromatosis type 2 (NF2) related vestibular schwannomas.

Secondary endpoints include the correlations of pre-treatment **89Zr-Bevacizumab** PET/CT imaging with various patient-reported outcome measures (PROM), vestibular function, cranial nerve (dys)function, kidney function, and non-target schwannoma response following bevacizumab treatment. These assessments aim to provide a comprehensive evaluation of the treatment's impact on multiple aspects of patient health and disease progression.