Using Regorafenib to treat recurrent grade 2 and 3 meningiomas

Regorafenib for Recurrent Meningioma. A Multicenter, Randomized Phase II Study (MIRAGE Trial)

This study is testing if the medication Regorafenib can help people with recurring grade II or III meningiomas by slowing down tumor growth and improving their health.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 104 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Istituto Oncologico Veneto IRCCS (other)
• Drugs / interventions: bevacizumab, radiation, sunitinib, valatinib
• Locations: 17 sites (Meldola, Forlì-Cesena and 16 other locations)
• Trial ID: NCT06275919 on ClinicalTrials.gov

What this trial studies

This study investigates the effectiveness of Regorafenib, a medication that inhibits specific receptors involved in tumor growth, for patients with recurrent grade II or III meningiomas. The trial aims to determine if Regorafenib can demonstrate antitumor activity by analyzing its impact on tumor progression and patient outcomes. Participants will receive Regorafenib alongside local standard care, and their progress will be monitored through imaging and clinical assessments. The study is based on previous findings that suggest Regorafenib may reduce tumor cell motility and invasion.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with a confirmed diagnosis of recurrent grade II or III meningioma who are not eligible for further surgery or radiotherapy.

Not a fit: Patients with grade I meningiomas or those who have not experienced tumor progression may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with recurrent meningiomas, potentially improving their prognosis.

How similar studies have performed: Previous studies have shown promising results with other VEGF inhibitors in treating meningiomas, suggesting potential success for this approach with Regorafenib.

Eligibility criteria

Inclusion Criteria:

* Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
* Patients capable of taking oral medication
* Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
* Histological diagnosis of meningioma according to the WHO 2021 classification
* Radiologically documented progression of any existing tumor with an estimated planar growth \>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 before starting Regorafenib:
* Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support for 7 days (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) and serum glutamate pyruvic transaminase (SGPT)/alanine aminotransferase (ALT) ≤ 3.0 x Upper Limit of Normal (ULN).
* Serum total bilirubin ≤ 1.5 x ULN
* Serum creatinine ≤ 1.5 x ULN or measured glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m2 using an exogenous filtration marker such as iohexol, inulin, 51Cr EDTA or 1125 iothalamate, or creatinine clearance of ≥ 50 mL/min using Cockroft-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) or surgically 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 conjunction with spermicidal jelly) during the Treatment period and for at least 6 months after the last dose of study drug.
* For male patients who are partners of premenopausal women: agreement to use a barrier method of contraception during the Treatment period and for at least 6 months after the last dose of study drug.
* Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to participate.
* 19\. Patients with measurable, progressive meningioma who received radiation therapy are potentially eligible but need to show evidence of progression at least 24 weeks from completion of radiation therapy.
* 20\. Possible prior use of bevacizumab in the treatment of radionecrosis (3-24 months after radiosurgery or radiotherapy; 5mg/kg q14w, 4-6 cycles)

Exclusion Criteria:

* Prior antineoplastic therapy for meningioma
* Subject incapacitated to understand and voluntarily sign an ICF prior to any study-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 niflumic acid)
* Receiving additional, concurrent, active therapy for Meningioma outside of the trial.
* 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., impending herniation) as judged by the Investigator
* History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
* In the presence of therapeutic intent to anticoagulate the patient:,INR or PT and aPTT not within therapeutic limits (according to the medical standard in the institution)
* 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 interval of\< 3 years. Patients with prior history of in situ cancer or basal or squamous cell skin 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 Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE), Grade 2 intracranial hemorrhage, or persistent thrombotic/embolic event within 4 weeks prior to the start of study medication.
* Uncontrolled or severe cardiac disease (e.g., history of unstable angina, myocardial infarction, coronary stenting, or bypass surgery within the last 6 months prior to initiation of study treatment), symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation), requirement for inotropic support or use of devices for cardiac conditions (e.g.,pacemakers/defibrillators), or hypertension (participants with systolic blood pressure\[BP\] of \> 160 mmHg or diastolic BP of \> 100 mmHg despite optimal medical management are to be excluded).
* History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or symptomatic pleural effusion.
* Active, known, or suspected auto-immune disease, including systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or auto-immune hepatitis.
* Known history of hepatitis B, human immunodeficiency virus (HIV), or active hepatitis C infection requiring treatment with antiviral therapy. Note: HIV testing is not required in the absence of clinical suspicion.
* History of bleeding diathesis (irrespective of severity).
* Uncontrolled intercurrent illness including (e.g., symptomatic ascites), but not limited to ongoing or active infection.
* Persistent ≥ Grade 3 Lipase (\> 2.0 - 5.0 x upper limit of normal \[ULN\] with signs or symptoms; \> 5.0 x ULN and asymptomatic).
* Persistent proteinuria \> 3.5 g/24 hours measured by urine protein creatinine ratio from a random urine sample (≥ Grade 3, CTCAE 5.0)
* Have any malabsorbition condition
* Any condition that could make the subject noncompliant with the study procedures and/or study requirements, as judged by the Investigator (for example: cognitive impairment, psychiatric illness, etc).

Where this trial is running

Meldola, Forlì-Cesena and 16 other locations

• IRST Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" — Meldola, Forlì-Cesena, Italy (RECRUITING)
• Azienda Ospedaliera Universitaria Gaetano Martino — Messina, Italia/Messina, Italy (RECRUITING)
• Humanitas Cancer Center — Rozzano, Milano, Italy (RECRUITING)
• A.O.U. Policlinico di Bari — Bari, Italy (RECRUITING)
• Ospedale San Paolo — Bari, Italy (COMPLETED)
• Ospedale Bellaria - AUSL Bologna — Bologna, Italy (RECRUITING)
• Azienda Ospedaliero Universitaria Careggi — Florence, Italy (RECRUITING)
• Policlinico San Martino — Genova, Italy (RECRUITING)
• Spedali Riuniti — Livorno, Italy (RECRUITING)
• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan, Italy (RECRUITING)
• IRCCS Ospedale San Raffaele — Milan, Italy (RECRUITING)
• Ospedale del Mare — Naples, Italy (RECRUITING)
• Istituto Oncologico Veneto — Padova, Italy (RECRUITING)
• Fondazione Policlinico Universitario Agostino Gemelli IRCCS — Roma, Italy (RECRUITING)
• IRCCS Istituto Tumori Regina Elena — Roma, Italy (RECRUITING)
• Policlinico Umberto I - Università Sapienza Roma — Roma, Italy (NOT_YET_RECRUITING)
• A.O.U. Città della Salute e della Scienza di Torino — Torino, Italy (RECRUITING)

Study contacts

• Principal investigator: Giuseppe Lombardi, MD — Istituto Oncologico Veneto IOV IRCCS
• Study coordinator: Gian Luca De Salvo, MD

Conditions: Meningioma, Malignant