Regorafenib for recurrent meningioma. A multicenter, randomized phase II study (MIRAGE trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Istituto Oncologico Veneto

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Sep 2024 → ongoing

Decision date (initial)

2024-07-11

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Bayer S.p.A.

External identifiers

EU CT number

2024-510954-28-01

ClinicalTrials.gov

NCT06275919

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

This study aims to evaluate the role of Regorafenib in prolonging the progression-free survival in the population of grade 2 and grade 3 meningiomas who progressed after surgery and radiotherapy.
The primary aim of the study is to evaluate the progression-free survival (PFS) in the intention to treat (ITT) population.

Secondary objectives 5

1. Overall survival (OS)
2. Disease control rate (DCR), as percentage of patients achieving a complete response plus partial response plus stable disease
3. Toxicity during the treatment, graded according to the NCI-Common Terminology Criteria for Adverse Events (CTCAE) v.5
4. Quality of Life assessed by EORTC QLQ-C30 and QLQ-BN2
5. Objective response rate, as percentage of patients achieving a complete response plus partial response

Conditions and MedDRA coding

grade 1, 2 and 3 meningioma

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 20

1. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
2. 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.
3. Patients capable of taking oral medication
4. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
5. Histological diagnosis of meningioma according to the WHO 2021 classification
6. Radiologically documented progression of any existing tumor with an estimated planar growth >25% (bidirectional) in the last 12 months or appearance of new lesions
7. Ineligible for further surgery and/or radiotherapy
8. at least 1 Measurable lesion (minimum 10 x 10mm) on baseline MRI
9. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 (or KPS ³70)
10. Male or female ≥ 18 years of age
11. 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.
12. Subjects must have life expectancy of at least 6 months
13. Paraffin-embedded tumor tissue available (mandatory)
14. Dosage of dexamethasone or equivalent steroid within 7 days prior the randomization ≤4mg/die
15. Stable or decreasing dosage of steroids for 7 days prior to the randomization.
16. Adequate cardiac function and adequate liver, renal and hematological function
17. 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
18. 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.
19. 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.
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 25

1. 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)
2. Uncontrolled intercurrent illness including (e.g., symptomatic ascites), but not limited to ongoing or active infection.
3. Persistent ≥ Grade 3 Lipase (> 2.0 - 5.0 x upper limit of normal [ULN] with signs or symptoms; > 5.0 x ULN and asymptomatic).
4. Receiving additional, concurrent, active therapy for Meningioma outside of the trial.
5. Persistent proteinuria > 3.5 g/24 hours measured by urine protein creatinine ratio from a random urine sample (≥ Grade 3, CTCAE 5.0)
6. Have any malabsorbition condition
7. 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).
8. Disease outside the brain (ie. spinal cord or bone or metastasis to a distant organ)
9. Candidate for urgent palliative intervention for primary disease (e.g., impending herniation. as judged by the Investigator
10. History of allergy or hypersensitivity to any of the study treatments or any of their excipients.
11. 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)
12. Any cerebrovascular accident (including transient ischemic attacks. within the last 6 months prior to initiation of study treatment.
13. Unable or unwilling to undergo brain MRI scans with intravenous (IV) gadolinium
14. 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.
15. Serious, non-healing wound, ulcer, bone fracture, or abscess.
16. Subject incapacitated to understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
17. Are taking strong UGT1A9 inhibitors (e.g. mefenamic acid, diflunisal and niflumic acid)
18. Have an ongoing infection with severity of Grade 2 or above (CTCAE 5.0)
19. 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.
20. 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).
21. 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.
22. Active, known, or suspected auto-immune disease, including systemic lupus erythematosus, Hashimotos thyroiditis, scleroderma, polyarteritis nodosa, or auto-immune hepatitis.
23. 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.
24. History of bleeding diathesis (irrespective of severity).
25. Prior antineoplastic therapy for meningioma

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The progression free survival (PFS) will be determined as the time from the date of randomization to the date of disease progression determined using 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 last assessment.

Secondary endpoints 5

1. The overall survival (OS) will be determined as the time from the date of randomization to the date of death from any cause. Patients alive at the time of analysis will be censored at the date of last assessment.
2. 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.
3. 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.
4. Quality of life will be assessed by EORTC QLQ-C30 and the QLQBN20 questionnaires. Two HRQOL measures are selected for this study, EORTC QLQ-C30 and the QLQBN20 which have robust psychometric properties resulting from their use in several international cancer clinical trials. The EORTC QLQ-C30 is a core measure designed to be supplemented with the disease specific module. Both instruments are available in Italian and have followed rigorous forward-backward translation procedures.
5. Toxicity during the treatment will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5. Grade refers to the severity of the adverse event. A grading (severity) scale is provided for each adverse event term.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Istituto Oncologico Veneto

Sponsor organisation

Istituto Oncologico Veneto

Address

Via Gattamelata 64

City

Padova

Postcode

35128

Country

Italy

Scientific contact point

Organisation

Istituto Oncologico Veneto

Contact name

Clinical Research Unit

Public contact point

Organisation

Istituto Oncologico Veneto

Contact name

Clinical Research Unit

Locations

1 EU/EEA country · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications