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

Meningioma, Malignant Clinical Trial

— MIRAGE  

Official title:

Regorafenib for Recurrent Grade 2 and 3 Meningioma. A Multicenter, Randomized Phase II Study (MIRAGE Trial)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06275919
• Other study ID #: IOV-BT-1-2023 MIRAGE
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: June 2024
• Est. completion date: March 2027

Study information

• Verified date: March 2024
• Source: Istituto Oncologico Veneto IRCCS
• Contact: Gian Luca De Salvo, MD
• Phone: 049 8215704
• Email: gianluca.desalvo[@]iov.veneto.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The focus of this study will be to investigate whether Regorafenib demonstrates antitumor activity against recurrent grade II or III meningiomas.

Small trials and case series suggest clinical relevant activity of several VEGF inhibitors such as sunitinib, bevacizumab and valatinib reporting a 6m-PFS rate of 42-64%. Indeed, VEGF and VEGF receptors (VEGFR) are regularly overexpressed in meningiomas and can correlate with outcome.

Regorafenib inhibits angiogenic receptor tyrosine kinases (RTKs) and is highly selective for VEGFR1/2/3; moreover Regorafenib inhibits PDGFRB, FGFR1 and oncogenic intracellular signalling cascades involving c-RAF/RAF1 and BRAF highly expressed in meningiomas.

Noteworthy, Regorafenib showed antitumor activity in vitro and in vivo in a recent study; indeed, Regorafenib showed significant inhibition of meningioma cell motility and invasion and in vivo, mice with orthotopic meningioma xenografts showed a reduced volume of signal enhancement in MRI following Regorafenib therapy; this translated in a significantly increased overall survival time (p<0.05) for Regorafenib treated mice.

Moreover, Regorafenib showed good efficacy in different cancer types, such as colorectal cancer, GIST, hepatocellular carcinoma and glioblastoma (REGOMA trial) , maintainingmaintaining a good quality of life.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 104
• Est. completion date: March 2027
• Est. primary completion date: December 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 grade 2 or grade 3 meningioma according to the WHO 2021 classification

• Radiologically documented progression (estimated planar growth >15%- measured in two dimensional tumor area- within the prior 6 months or a new lesion develops)

• 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.

Exclusion Criteria:

• 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)

• 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).

Related Conditions & MeSH terms

• Meningioma
• Meningioma, Malignant

Intervention

Drug:
• Regorafenib 40 MG Oral Tablet
REGORAFENIB 40 mg tablets once daily (160 mg/die), 3 weeks on, 1 week off, until disease progression or unacceptable toxicity
• Local Standard of Care
In this setting there are not drugs with indication. Every site will treat patients as per their experience.

Locations

Country	Name	City	State
Italy	Ospedale San Paolo	Bari
Italy	Ospedale Bellaria - AUSL Bologna	Bologna
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Italy	Policlinico San Martino	Genova
Italy	Spedali Riuniti	Livorno
Italy	IRST Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori"	Meldola	Forlì-Cesena
Italy	Azienda Ospedaliero Universitaria G. Martino	Messina
Italy	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano
Italy	IRCCS Ospedale San Raffaele	Milano
Italy	Ospedale del Mare	Napoli
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Italy	IRCCS Istituto Tumori Regina Elena	Roma
Italy	Policlinico Umberto I - Università Sapienza Roma	Roma
Italy	Humanitas Cancer Center	Rozzano	Milano
Italy	A.O.U. Città della Salute e della Scienza di Torino	Torino

Sponsors (2)

Lead Sponsor	Collaborator
Istituto Oncologico Veneto IRCCS	Bayer

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression free survival (PFS)	The progression free survival (PFS) will be determined as the time from the date of enrolment to the date of disease progression determined using RANO criteria or to the date of death, whichever occurs first.	Up to 36 months
Secondary	Overall survival (OS)	The overall survival (OS) will be determined as the time from the date of enrolment to the date of death from any cause.	Up to 30 months
Secondary	Objective response rate (ORR)	The objective response rate (ORR) will be defined as the percentage of patients with complete response (CR) and partial response (PR) determined using modified Macdonald criteria.	Up to 30 months
Secondary	Patient Reported Outcomes (PROs)	Quality of life will be assessed by EORTC QLQ-C30 questionnaire.	Up to 30 months
Secondary	Patient Reported Outcomes (PROs)	Quality of life will be assessed by the QLQBN20 questionnaire.	Up to 30 months
Secondary	Toxicity during treatment	Toxicity during the treatment will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5.	Up to 30 months
Secondary	Disease control rate (DCR)	The disease control rate (DCR) will be defined as the percentage of patients with complete response (CR), partial response (PR) and stable disease (SD) determined using modified Macdonald criteria.	Up to 30 months