Protective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma

Official title

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

Overview

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.

Interventions

• Radiation Dose escalation of radiation dose beyond the therapeutic standard
  Dose escalation to 75 Gy with concomitant radioprotectant bevacizumab

Primary outcome measures

• OS [Time frame: Date of study inclusion (informed consent) to death or end of F/U]

Secondary outcome measures (6)

• Safety and tolerability [Time frame: Date of study inclusion (informed consent) to death or end of F/U]
• PFS-6 [Time frame: 6 months after the date of study inclusion (informed consent)]
• PFS [Time frame: Date of study inclusion (informed consent) to death or progression]
• QoL [Time frame: Date of study inclusion (informed consent) to death or end of F/U]
• Cognitive function [Time frame: Date of study inclusion (informed consent) to death or end of F/U]
• Exploratory objective [Time frame: Date of study inclusion (informed consent) to death or end of F/U]

Eligibility criteria

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 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
• 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
• Contraindication and/or hypersensitivity to bevacizumab or its excipients. For details check the Summary of Product Characteristics Aybintio®
• 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 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 9 centers

• Department of Radiation Oncology, University Hospital Augsburg — Augsburg
• Department of Radiation Oncology, University Hospital Köln — Cologne
• Department of Radiation Oncology, University Hospital Frankfurt — Frankfurt
• Department of Radiation Oncology, University Hospital Freiburg — Freiburg im Breisgau
• Department of Radiation Oncology, University Hospital Leipzig — Leipzig
• Department of Radiation Oncology, Medical Faculty Mannheim — Mannheim
• Department of Radiation Oncology, University Hospital, LMU Munich — Munich
• Department of Neurology, University Hospital Regensburg — Regensburg
• … and 1 more center

Publications

• Maier SH, Schonecker S, Anagnostatou V, Garny S, Nitschmann A, Fleischmann DF, Buttner M, Kaul D, Imhoff D, Fokas E, Seidel C, Hau P, Kolbl O, Popp I, Grosu AL, Haussmann J, Budach W, Celik E, Kahl KH, Hoffmann E, Tabatabai G, Paulsen F, Holzgreve A, Albert NL, Mansmann U, Corradini S, Belka C, Niyazi M, Bodensohn R. Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblast PMID 38765202

Identifiers

NCT: NCT05871021 · 2021-000565-32

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗