Protective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma

Study Overview
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Brief Summary
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Glioblastoma is the most aggressive brain tumor and often recurs locally despite intensive treatment. Standard chemoradiotherapy with 60 Gy may not be sufficient to control the tumor, and dose escalation seems to be warranted, but causes more toxicity. To address this, the multicentric PRIDE trial employs two cycles of bevacizumab to achieve dose escalation isotoxically. The goal is improved survival without significantly increasing side effects. The study uses a simultaneous integrated boost with a total dose of 75 Gy in 2.5 Gy per fraction.

Official Title
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A Phase IIa, Open-label, Multicenter Study of Radiochemotherapy With Isotoxic Dose Escalation and Protective VEGF Inhibition Using Bevacizumab in the Treatment of Patients With First Diagnosis of IDH Wild-type, MGMT Unmethylated Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Radiation: Dose escalation of radiation dose beyond the therapeutic standard


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: IDH wild-type, MGMT unmethylated glioblastoma patients Informed consent Age ≥18 and ≤ 70 years, smoking or non-smoking, of any ethnic origin ECOG 0-2 Neutrophil counts > 1500/μl; Platelet counts > 100.000/μl; Hemoglobin > 8 g/dl; Serum creatinine < 1.5-fold upper limit of normal (ULN); Bilirubin, AST or ALT < 2.5-fold ULN unless attributed to anticonvulsants; Alkaline phosphatase < 2.5-fold ULN Adequate contraception 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 Exclusion Criteria: Evidence of recent hemorrhage on postoperative MRI of the brain Subjects on any drug suspected to interfere with bevacizumab at the time of study inclusion Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV) Known hypersensitivity to any component of the investigational drugs or excipients (allergy to or other intolerability of bevacizumab or excipients) 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 Incapability to undergo MRI Prior treatment with bevacizumab for any indication 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 (de-fined 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 stroke or transient ischemic attack within 6 months prior to enrolment 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 or 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 tracheo-oesophageal 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 75 Gy with two cycles of bevacizumab<br> | Radiation: Dose escalation of radiation dose beyond the therapeutic standard<br>* Dose escalation to 75 Gy with concomitant radioprotectant bevacizumab<br>* Other names: bevacizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall Survival | Date of study inclusion (informed consent) to death or end of F/U | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability | Safety and tolerability of dose escalation with bevacizumab according to CTCAE v5.0 | Date of study inclusion (informed consent) to death or end of F/U | 
| PFS-6 | 6 months rate of progression-free survival | 6 months after the date of study inclusion (informed consent) | 
| PFS | Progression-free survival | Date of study inclusion (informed consent) to death or progression | 
| QoL | Quality of life as determined by EORTC QLQ-C30/QLQ-BN 20 | Date of study inclusion (informed consent) to death or end of F/U | 
| Cognitive function | Cognitive function determined by standard test batteries | Date of study inclusion (informed consent) to death or end of F/U | 
| Exploratory objective | Validation of prognostic 4-miRNA signature-based risk score | Date of study inclusion (informed consent) to death or end of F/U | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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bevacizumab, Dose escalation, VEGF inhibition, FET PET, VMAT