Interleukin-1 in Vestibular Schwannoma (IL-VS): a biomarker development study
Vestibular schwannoma
The focus of this study is to validate a panel of biomarkers of response to IL-1 antagonism in patients with VS. Ten patients who are listed for surgical resection of a growing sporadic or NF2-related schwannomatosis (NF2-SWN) will be recruited via the Greater Manchester Skull Base Unit based at Salford Royal Hospital. Recruited patients will initially undergo a comprehensive 3T MRI scan protocol at Salford Royal Hospital (scan duration ~ 40 minutes). During this protocol patients will be administered a GBCA chelate (gadoterate meglumine; Dotarem, Guerbet S.A.) up to a maximum dose of 0.2 mmol/kg. From this baseline imaging, imaging parameters relevant to VS growth, such as tumoural diffusion metrics and dynamic contrast enhanced (DCE) MRI-derived measures such as the transfer constant Ktrans (min-1), will be derived. At the time of IV cannula insertion, baseline blood samples (≤20 ml) will also be obtained and blood plasma analysed using previously described multiplex assays to quantify the circulating concentrations of 48 distinct chemokines, cytokines and growth factors. Following these baseline tests, participants will receive 100 mg subcutaneous anakinra (Kineret©) once daily for 14 days, with the first dose being delivered at Salford Royal Hospital and subsequent doses delivered at the participant’s home by a trained member of the research team. This dose will be administered as a subcutaneous injection into the lower abdomen, and the first dose administration will be followed by a period of observation for 1 hour for any adverse effects. These injections will continue for a maximum of 14 days (including the first injection) and will be timed so that the final dose is given the day before the participant’s surgery. This duration and dose regimen is based upon prior pharmacokinetic model estimates of tumour penetration from our preclinical and clinical stroke trials. For each participant, 13 pre-filled 0.67 ml doses of anakinra will be delivered to the patient
1. Adult patient (>=18 years old) diagnosed with a growing VS, for whom surgical resection is planned
1. Uncertain diagnosis of VS 2. Known active tuberculosis or active hepatitis. 3. Known active malignancy. 4. Known Still’s Disease 5. Neutropenia (ANC <1.5 x 109 /L ) 6. Abnormal renal function (creatinine clearance or estimated Glomerular Filtration Rate (eGFR) <30 ml/minute) documented in the last 3 months 7. Live vaccinations within the last 10 days (please see Appendix 1) 8. Previous or concurrent treatment with IL-1Ra known at the time of study entry or previous participation in this study 9. Current treatment with TNF antagonists (please see below for the prohibited medication) 10. Known to have participated in a clinical trial of an investigational agent or device in the 30 days prior to study enrolment 11. Known to have participated in a clinical trial of an investigational agent or device within five half-lives (of the previous agent or device) 12. Known to be pregnant or breastfeeding or inability to reliably confirm that the patient is not pregnant (please see further guidance on pregnancy prevention below) 13. Clinically significant serious concurrent medical condition, pre-morbid illnesses, or concurrent serious infection (including confirmed or suspected COVID-19 infection), at the PI’s (or designee’s) discretion, which could affect the safety or tolerability of the intervention. Please see the precaution of use section for further guidance. 14. Known allergy to IL-1Ra or any of the excipients listed in the drug SmPC (please see section below) 15. Known allergy to other products that are produced by DNA technology using the microorganism E. coli (i.e., E. coli-derived protein) 16. Current treatment with IL-6 or IL-1 inhibitors or drugs affecting the IL-1 axis. Please see below for the prohibited medication 17. Current treatment with CYP450 substrates with a narrow therapeutic index (e.g., warfarin and phenytoin) 18. Previous active treatment for VS, including previous surgical resection; previous stereotactic radiosurgery or fractionated radiotherap