Phase IIa Multicenter Study of Isotoxic Radiochemotherapy with Bevacizumab in IDH Wild-Type, MGMT Unmethylated Glioblastoma

Trial ID: 2024-514865-20-00
Protocol: PRIDE
Sponsor: Universitaetsklinikum Tuebingen AöR

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Diseases & Conditions

Glioblastoma

Objectives

The primary objective of this study is to evaluate **overall survival** in patients with a first diagnosis of IDH wild-type, MGMT unmethylated **glioblastoma**. This objective is clinically relevant as it directly measures the efficacy of the treatment regimen in extending the lifespan of patients afflicted with this aggressive brain tumor.

Secondary objectives include:

Assessing the safety and tolerability of isotoxic dose escalation and **bevacizumab**.
Evaluating progression-free survival after 6 months (PFS-6) and overall progression-free survival (PFS).
Determining the quality of life using the EORTC QLQ-C30 and the EORTC brain module QLQ-BN 20.
Assessing cognitive function through the MMSE and MOCA tests.
Exploratory validation of a 4-miRNA signature-based risk subgroup in FFPE material and plasma samples.

Participants

The clinical trial involves participants diagnosed with **glioblastoma**, specifically IDH-wildtype and MGMT unmethylated status, confirmed histologically. The study population includes both male and female subjects, aged between 18 and 70 years, of any ethnic origin, and encompasses both smokers and non-smokers. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial population selection criteria include adequate hematological, liver, and renal function, as well as a healed craniotomy or intracranial biopsy site. Participants must have provided signed informed consent, including consent for data protection. The sponsor has not provided information regarding the total number of participants in the trial.

Plans and Procedures

The clinical trial is designed as a **phase IIa**, open-label, multicenter study focusing on the treatment of patients with a first diagnosis of **glioblastoma**, specifically those with IDH wild-type and MGMT unmethylated status. The primary objective is to assess overall survival, with secondary endpoints including safety and tolerability of isotoxic dose escalation and **bevacizumab**, progression-free survival, quality of life, and cognitive function. The trial is expected to commence recruitment on March 31, 2024, and conclude by March 31, 2027.

Participants will be administered **Aybintio 25 mg/ml concentrate for solution for infusion** via intravenous use. The maximum daily dose is 7.5 mg/kg, with a total dose not exceeding 15 mg/kg over a treatment period of up to 2 months. The study involves a sequence of visits, starting with a screening visit to confirm eligibility based on histological evidence of glioblastoma and other inclusion criteria such as age, performance status, and adequate organ function. Women of childbearing potential must have a negative pregnancy test and use adequate contraception throughout the study and for six months after.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor treatment response, safety, and any adverse events. These visits will include assessments of hematological, liver, and renal function, as well as imaging studies to evaluate disease progression. The end-of-study visit will occur after the completion of the treatment period, where final evaluations of the primary and secondary endpoints will be conducted.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up as required by the study protocol. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial is not categorized as low intervention, and all procedures will adhere to ethical guidelines and regulatory requirements.

Treatment

The clinical trial involves the administration of **Aybintio**, a **bevacizumab**-based medication, which is a **concentrate for solution for infusion**. The pharmaceutical form of Aybintio is a solution for infusion, specifically designed for **intravenous use**. The active substance, bevacizumab, is a protein of non-human origin, classified under the ATC code L01XC07. The medication is provided at a concentration of 25 mg/ml. The dosing regimen involves a maximum daily dose of 7.5 mg/kg, with a total maximum dose of 15 mg/kg. The treatment period is limited to a maximum of 2 cycles. The administration of Aybintio is conducted under controlled conditions to ensure participant safety and adherence to the dosing schedule.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the effects of Aybintio in the treatment of patients with a first diagnosis of IDH wild-type, MGMT unmethylated **glioblastoma**. Participant compliance with the treatment regimen is monitored through regular assessments and documentation of infusion sessions. The trial aims to evaluate the overall survival of participants receiving this treatment, with careful monitoring of any adverse effects or deviations from the protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the endpoint of overall survival in patients diagnosed with **glioblastoma**. Secondary endpoints include safety and tolerability of isotoxic dose escalation and bevacizumab, progression-free survival after 6 months (PFS-6), progression-free survival (PFS), quality of life as determined by the EORTC QLQ-C30 and the EORTC brain module QLQ-BN 20, and cognitive function as determined by the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MOCA). Additionally, an exploratory objective involves the validation of 4-miRNA signature-based risk subgroups in formalin-fixed paraffin-embedded (FFPE) material and plasma samples.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis of glioblastoma, IDH-wildtype and MGMT unmethylated status must be proven histologically (according to local neuro-pathology). MRI images must not be older than 2 weeks before initiating RT
≥ 18 and ≤ 70 years of age, smoking or non-smoking, of any ethnic origin
Eastern Cooperative Oncology Group (ECOG) Performance Status 0–2
Patient must have provided signed informed consent (obtained prior to any studyspecific procedure). This includes the willingness to give written informed consent, written consent for data protection (according to the German General Data Protection Regulation (Datenschutz-Grundverordnung, DSGVO) in addition to willingness to participate and comply with the study.
Craniotomy or intracranial biopsy site must be adequately healed, free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of inclusion.
Adequate hematological function: white blood cell (WBC) count  3x109/L, absolute neutrophil count > 1500/μl, platelet count  100.000/μl, hemoglobin ≥ 8 g/dl (may be obtained by the use of erythropoietin-stimulating agents or transfusion for anemia)
Adequate liver function: Total bilirubin < 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 x ULN.
Adequate renal function: Serum creatinine ≤ 1.5 x ULN AND patients with urine dipstick for proteinuria < 2+. Patients with ≥ 2+ proteinuria on dipstick urinalysis at baseline should show urine protein to creatinine ratio ≤ 1 or should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours.
International normalized ratio (INR) (in absence of anticoagulation treatment) ≤ 1.5 within 7 days prior to the first dose of study medication and radiotherapy. Anticoagulation is allowed if target INR is < 3 and if the patient is on a stable dose of anticoagulant (coumarin type, low molecular weight heparin (LMWH) or bivalirudin or argatroban) for >2 weeks at time of enrolment. Therefore, during the study, the preferred choice for anticoagulation treatment with therapeutic intent should be low molecular weight heparin as per ASCO guidelines.
Women of childbearing potential (i.e., a woman, who is biologically capable of becoming pregnant) must be non-lactating and must have a negative serum (β-HCG) EudraCT-No.: 2021-000565-32 EU CT-No.: 2024-514865-20-00 PRIDE Study Protocol, Version 2.0 18.08.2025 Page 28 of 60 pregnancy test within 7 days prior to the first dose of study medication and radiotherapy; adequate contraception should be applied for both male and female patients during the whole duration of the study treatment and 6 months after. This includes:  A woman who is not capable of bearing a child is defined as follows: postmenopausal (12 months natural (spontaneous) amenorrhea or 6 months spontaneous amenorrhea with serum-FSH-values (follicle-stimulating hormone) of > 40 mIU/mL); 6 weeks after a bilateral ovariectomy with or without hysterectomy or sterilization by means of tubal ligation.  A woman capable of bearing child is defined as follows: a woman who is physiologically capable of becoming pregnant, including women whose occupation, lifestyle or sexual orientation exclude sexual intercourse with a male partner and women whose partners have been sterilized by vasectomy or other measures.  Medically-approved acceptable methods of contraception with a low failure rate (i.e. less than 1% per year) when used consistently and correct can include the following: hormonal contraceptives, intrauterine device and double barrier method. Acceptable preventive measures can include total abstinence at the discretion of the investigator, in cases where compliance is ensured because of the study participant's age, occupation, lifestyle or sexual orientation. Periodical abstinence (e.g. calendar, ovulation, symptom-thermal methods or abstinence until the 4th day after the ovulation) as well as coitus interruptus are not acceptable methods of contraception.

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Exclusion Criteria

Positive test results for HbsAG, anti-HCV, anti-HIV-1/-2
Any other condition or treatment that, in the opinion of the Investigator, might interfere with the study or current drug.
Controlled substance abuse according to the German Narcotic Drugs Act (Betäubungsmittelgesetz, BtMG).
Past medical history of diseases with poor prognosis according to the judgement of the investigator, e.g. severe coronary heart disease, severe diabetes, immune deficiency, residual deficits after stroke, severe mental retardation.
Foreseeable non-compliance with the protocol requirements, instructions and study-related restrictions, e.g. uncooperative attitude, inability to return for follow-up visits, and low probability of completing the study.
Pregnancy or breast feeding.
Patient is the investigator, research assistant, pharmacist, study coordinator, other staff or relative there of directly involved in the conduct of the study.
Evidence of significant hemorrhage on postoperative MRI of the brain. Patients with asymptomatic, minor hemosiderin deposition, resolving postsurgical hemorrhagic changes, or punctate intratumoral hemorrhage (e.g., related to biopsy or surgery) are not excluded.
Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field.
Patients simultaneously enrolled in another clinical trial or patients who participated in another clinical trial during the 28 days (or five-half lives of the respective investigational product, whichever is longer) before enrolment.
Patients who previously participated in this trial.
Evidence for any active intracranial infection requiring hospitalization or i.v. antibiotics within 2 weeks prior to inclusion
Patients who are underage or patients who are incapable to understand the aim, importance and consequences of the study and to give legal informed consent (according to § 40b AMG).
Patients who possibly are dependent on the sponsor or investigator.
Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV).
History of chronic gastrointestinal disease with diarrhea; history of abdominal or pelvic radiotherapy.
Any other significant medical illness or medically significant laboratory finding that would, in the investigator’s judgement, make the patient inappropriate for this study, or would increase the risk associated with the patients’ participation in the study.
Inability to undergo MRI.
Contraindication and/or hypersensitivity to bevacizumab or its excipients. For details check the Summary of Product Characteristics of Aybintio®.
Prior treatment with bevacizumab for any indication.
Parallel administration of any drug suspected to interfere with bevacizumab at the time of inclusion.
Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, III, IV), unstable angina pectoris or myocardial infarction within 6 months prior to enrolment.
Inadequately controlled hypertension (defined as a blood pressure of > 150 mmHg systolic and/or >100 mmHg diastolic on medication) or any prior history of hypertensive crisis or hypertensive encephalopathy.
History of clinically significant cerebrovascular events within 6 months prior to enrolment. This includes ischemic stroke or transient ischemic attack. Small, clinically silent perioperative ischemic changes are not exclusionary.
Significant vascular disease (e.g., aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to enrolment.
Evidence or history of recurrent thromboembolism (> 1 episode of deep venous thrombosis / peripheral embolism) during the past 2 years.
Evidence of bleeding diathesis of coagulopathy (in the absence of therapeutic anticoagulation).
Chronic daily intake of aspirin > 325 mg/day or clopidogrel > 75 mg/day.
History of intracranial abscess within 6 months prior to inclusion.
History of abdominal or tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to study enrolment.
History of ≥ grade 2 hemoptysis according to NCI-CTC criteria within 1 month prior to inclusion.
Serious non-healing wound, ulcer or bone fracture.
Placement of a central vascular access device (CVAD) within 2 days prior to bevacizumab administration.