Regorafenib for Recurrent Grade 2 and 3 Meningioma (MIRAGE Trial)

Inclusion Criteria:

• Subject must understand and voluntarily sign an ICF prior to any study-relatedassessments/procedures being conducted

• Patients capable of taking oral medication

• Subject is willing and able to adhere to the study visit schedule and other protocolrequirements.

• Histological diagnosis of grade 2 or grade 3 meningioma according to the WHO 2021classification

• Radiologically documented progression of any existing tumor with an estimated planargrowth >25% (bidirectional) in the last 12 months or appearance of new lesions

• Ineligible for further surgery and/or radiotherapy

• at least 1 Measurable lesion (minimum 10 x 10mm) on baseline MRI

• Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 (or KPS ³70)

• Male or female ≥ 18 years of age

• Subjects must have life expectancy of at least 6 months

• Paraffin-embedded tumor tissue available (mandatory)

• Dosage of dexamethasone or equivalent steroid within 7 days prior the randomization ≤4mg/die

• Stable or decreasing dosage of steroids for 7 days prior to the randomization.

• Adequate cardiac function and adequate liver, renal and hematological function

• Subject must have the following laboratory values at screening within 14 days beforestarting Regorafenib:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support for 7days (14 days if subject received pegfilgrastim).

• Hemoglobin (Hgb) ≥10 g/dL

• Platelet count (plt) ≥100x 109/L

• Serum potassium concentration within normal range, or correctable with supplements

• Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) andserum glutamate pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 3.0 xUpper Limit of Normal (ULN).

• Serum total bilirubin ≤ 1.5 x ULN

• Serum creatinine ≤ 1.5 x ULN or measured glomerular filtration rate (GFR) ≥ 50mL/min/1.73 m2 using an exogenous filtration marker such as iohexol, inulin, 51CrEDTA or 1125 iothalamate, or creatinine clearance of ≥ 50 mL/min usingCockroft-Gault equation.

• Serum albumin > 3.5 g/dL

• PT (or INR) and APTT within normal range

• For women who are not postmenopausal (i.e., < 2 years after last menstruation) orsurgically sterile (absence of ovaries and/or uterus) and who are sexually active:agreement to use an adequate method of contraception (oral contraceptives,intrauterine contraceptive device, or barrier method of contraception in conjunctionwith spermicidal jelly) during the Treatment period and for at least 6 months afterthe last dose of study drug.

• For male patients who are partners of premenopausal women: agreement to use abarrier method of contraception during the Treatment period and for at least 6months after the last dose of study drug.

• Participants with type I diabetes mellitus, hypothyroidism only requiring hormonereplacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to participate.

19. Patients with measurable, progressive meningioma who received radiation therapyare potentially eligible but need to show evidence of progression at least 24weeks from completion of radiation therapy.

Exclusion Criteria:

• Prior antineoplastic therapy for meningioma

• Subject incapacitated to understand and voluntarily sign an ICF prior to anystudy-related assessments/procedures being conducted

• Are taking strong cytochrome P (CYP) CYP3A4 inhibitors (eg, clarithromycin,indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole,ritonavir, saquinavir, telithromycin, voriconazole) or strong CYP3A4 inducers (eg,carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort)

• Are taking strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal and niflumicacid)

• Receiving additional, concurrent, active therapy for Meningioma outside of thetrial.

• Disease outside the brain (ie. spinal cord or bone or metastasis to a distant organ)

• Candidate for urgent palliative intervention for primary disease (e.g., impendingherniation) as judged by the Investigator

• History of allergy or hypersensitivity to any of the study treatments or any oftheir excipients.

• In the presence of therapeutic intent to anticoagulate the patient:,INR or PT andaPTT not within therapeutic limits (according to the medical standard in theinstitution)

• Unable or unwilling to undergo brain MRI scans with intravenous (IV) gadolinium

• History of another malignancy in the previous 3 years, with a disease-free intervalof< 3 years. Patients with prior history of in situ cancer or basal or squamous cellskin cancer are eligible.

• Serious, non-healing wound, ulcer, bone fracture, or abscess.

• Any cerebrovascular accident (including transient ischemic attacks) within the last 6 months prior to initiation of study treatment.

• Have an ongoing infection with severity of Grade 2 or above (CTCAE 5.0)

• Any hemorrhage or bleeding event that is ≥ Grade 3 based on the National CancerInstitute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), Grade 2intracranial hemorrhage, or persistent thrombotic/embolic event within 4 weeks priorto the start of study medication.

• Uncontrolled or severe cardiac disease (e.g., history of unstable angina, myocardialinfarction, coronary stenting, or bypass surgery within the last 6 months prior toinitiation of study treatment), symptomatic congestive heart failure, seriousuncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirementfor inotropic support or use of devices for cardiac conditions (e.g.,pacemakers/defibrillators), or hypertension (participants with systolic bloodpressure[BP] of > 160 mmHg or diastolic BP of > 100 mmHg despite optimal medicalmanagement are to be excluded).

• History of interstitial lung disease, history of slowly progressive dyspnea andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonaryhypersensitivity pneumonitis, or symptomatic pleural effusion.

• Active, known, or suspected auto-immune disease, including systemic lupuserythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, orauto-immune hepatitis.

• Known history of hepatitis B, human immunodeficiency virus (HIV), or activehepatitis C infection requiring treatment with antiviral therapy. Note: HIV testingis not required in the absence of clinical suspicion.

• History of bleeding diathesis (irrespective of severity).

• Uncontrolled intercurrent illness including (e.g., symptomatic ascites), but notlimited to ongoing or active infection.

• Persistent ≥ Grade 3 Lipase (> 2.0 - 5.0 x upper limit of normal [ULN] with signs orsymptoms; > 5.0 x ULN and asymptomatic).

• Persistent proteinuria > 3.5 g/24 hours measured by urine protein creatinine ratiofrom a random urine sample (≥ Grade 3, CTCAE 5.0)

• Have any malabsorbition condition

• Any condition that could make the subject noncompliant with the study proceduresand/or study requirements, as judged by the Investigator (for example: cognitiveimpairment, psychiatric illness, etc).