Phase II Multicenter Randomized Study of Regorafenib in Recurrent Grade 2 and 3 Meningioma Post-Surgery and Radiotherapy

Trial ID: 2024-510954-28-01
Protocol: MIRAGE
Sponsor: Istituto Oncologico Veneto

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Diseases & Conditions

Meningioma malignant

Objectives

The primary objective of this study is to evaluate the efficacy of **Regorafenib** in prolonging progression-free survival (PFS) in patients with recurrent grade 2 and grade 3 meningiomas who have experienced progression following surgery and radiotherapy. This is clinically relevant as it addresses the need for effective treatment options in this patient population, potentially improving disease management and patient outcomes.

Secondary objectives include:

Overall survival (OS)
Disease control rate (DCR), defined as the percentage of patients achieving a complete response, partial response, or stable disease
Toxicity during treatment, assessed according to the NCI-Common Terminology Criteria for Adverse Events (CTCAE) v.5
Quality of Life, evaluated using the EORTC QLQ-C30 and QLQ-BN2 questionnaires
Objective response rate, measured as the percentage of patients achieving a complete or partial response

These secondary objectives aim to provide a comprehensive assessment of the treatment's impact on survival, disease control, safety, and patient quality of life.

Participants

The clinical trial involves a study population of **adult** participants, both **male** and **female**, aged **18 years and older**. The trial focuses on individuals diagnosed with **grade 2 and grade 3 meningioma** who have experienced progression following surgery and radiotherapy. The sponsor has not provided the total number of participants. Participants were selected based on specific criteria, including the ability to take oral medication, a life expectancy of at least six months, and adequate cardiac, liver, renal, and hematological function. The trial includes individuals with a histological diagnosis of grade 2 or grade 3 meningioma, as per the WHO 2021 classification, and those with radiologically documented tumor progression. Participants must have an Eastern Cooperative Oncology Group performance status of 0 to 1 and must not be eligible for further surgery or radiotherapy. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to a stable or decreasing dosage of steroids prior to randomization. The trial also includes vulnerable populations, and both male and female participants are required to use adequate contraception during the treatment period and for at least six months after the last dose of the study drug.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **regorafenib** in prolonging progression-free survival in patients with grade 2 and 3 meningioma who have experienced progression following surgery and radiotherapy. This is a multicenter, randomized, phase II study. The trial employs a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from June 2024 to December 2026, with participant involvement expected to last up to 18 months, depending on individual response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as histological diagnosis and radiological progression. Following randomization, participants will attend regular follow-up visits to monitor disease progression, treatment response, and any adverse events. These visits will include assessments using the RANO criteria for progression-free survival and the modified Macdonald criteria for objective response rate and disease control rate. Quality of life will be evaluated using the EORTC QLQ-C30 and QLQBN20 questionnaires. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participants are expected to adhere to the study schedule and protocol requirements. Conditions that may lead to early termination from the study include significant disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is progression-free survival, while secondary endpoints include overall survival, objective response rate, disease control rate, quality of life, and treatment-related toxicity. The trial aims to provide valuable insights into the potential benefits of regorafenib for this patient population.

Treatment

The clinical trial involves the administration of **Stivarga** (regorafenib) 40 mg film-coated tablets, which is the experimental medication under investigation. **Regorafenib** is a multi-kinase inhibitor, chemically synthesized, and is provided in the form of film-coated tablets. The pharmaceutical form is specifically designed for oral administration. The dosage regimen for this trial is a maximum daily dose of 160 mg, which equates to four tablets per day. The treatment period is set for a maximum of 18 cycles, with each cycle lasting 28 days. Participants are required to take the medication orally, once daily, with a full glass of water after a low-fat meal to ensure optimal absorption and efficacy. Compliance with the dosing schedule is monitored through regular follow-ups and pill counts to ensure adherence to the treatment protocol.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of **regorafenib** in prolonging progression-free survival in patients with recurrent grade 2 and 3 meningiomas who have previously undergone surgery and radiotherapy. The trial is designed to assess the primary objective of progression-free survival in the intention-to-treat population. Participants' adherence to the medication regimen is crucial for the integrity of the study results, and measures are in place to monitor and encourage compliance throughout the trial duration.

Efficacy

Efficacy in the clinical trial evaluating **regorafenib** for recurrent grade 2 and 3 meningioma will be assessed using several key endpoints. The primary endpoint is progression-free survival (PFS), which will be measured from the date of randomization to the date of disease progression, as determined by the RANO criteria, or to the date of death, whichever occurs first. Patients without a PFS event at the time of analysis will be censored at the date of the last assessment.

Secondary endpoints include overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life, and treatment toxicity. OS will be determined from the date of randomization to the date of death from any cause, with patients alive at the time of analysis censored at the date of the last assessment. ORR and DCR will be evaluated using the modified Macdonald criteria, with ORR defined as the percentage of patients achieving complete response (CR) and partial response (PR), and DCR including CR, PR, and stable disease (SD).

Quality of life will be assessed using the EORTC QLQ-C30 and QLQBN20 questionnaires, which are validated tools with robust psychometric properties. These instruments are designed to measure health-related quality of life (HRQOL) in cancer patients and have been translated into Italian following rigorous procedures. Treatment toxicity will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5, which provides a severity scale for each adverse event term.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
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.
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
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.
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: a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L without growth factor support for 7 days (14 days if subject received pegfilgrastim). b. Hemoglobin (Hgb) ≥10 g/dL c. Platelet count (plt) ≥100x 109/L d. Serum potassium concentration within normal range, or correctable with supplements e. 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). f. Serum total bilirubin ≤ 1.5 x ULN g. 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. h. Serum albumin > 3.5 g/dL i. 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.
Possible prior use of bevacizumab in the treatment of radionecrosis (3-24 months after radiosurgery or radiotherapy; 5mg/kg q14w, 4-6 cycles)

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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)
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).
Receiving additional, concurrent, active therapy for Meningioma outside of the trial.
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).
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)
Any cerebrovascular accident (including transient ischemic attacks. within the last 6 months prior to initiation of study treatment.
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.
Subject incapacitated to understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
Are taking strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal and niflumic acid)
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).
Prior antineoplastic therapy for meningioma