PRIDE – PRotective VEGF Inhibition for Isotoxic Dose Escalation in Glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Tuebingen AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

10 Apr 2024 → ongoing

Decision date (initial)

2024-07-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514865-20-00

EudraCT number

2021-000565-32

ClinicalTrials.gov

NCT05871021

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Overall survival

Secondary objectives 6

1. Safety and tolerability of isotoxic dose escalation and bevacizumab
2. Progression-free survival after 6 months (PFS-6)
3. Progression-free survival (PFS)
4. Quality of life as determined by EORTC QLQ-C30 and the EORTC brain module QLQ-BN 20.
5. Cognitive function as determined by MMSE and MOCA
6. Exploratory objective: validation of 4-miRNA signature-based risk subgroups in FFPE material and plasma samples

Conditions and MedDRA coding

Glioblastoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 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
2. ≥ 18 and ≤ 70 years of age, smoking or non-smoking, of any ethnic origin
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0–2
4. 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.
5. 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.
6. 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)
7. Adequate liver function: Total bilirubin < 1.5 x upper limit of normal (ULN) AND aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5 x ULN.
8. 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.
9. 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.
10. 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.

Exclusion criteria 33

1. Positive test results for HbsAG, anti-HCV, anti-HIV-1/-2
2. Any other condition or treatment that, in the opinion of the Investigator, might interfere with the study or current drug.
3. Controlled substance abuse according to the German Narcotic Drugs Act (Betäubungsmittelgesetz, BtMG).
4. 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.
5. 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.
6. Pregnancy or breast feeding.
7. Patient is the investigator, research assistant, pharmacist, study coordinator, other staff or relative there of directly involved in the conduct of the study.
8. 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.
9. Any prior radiotherapy to the brain or prior radiotherapy resulting in a potential overlap in the radiation field.
10. 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.
11. Patients who previously participated in this trial.
12. Evidence for any active intracranial infection requiring hospitalization or i.v. antibiotics within 2 weeks prior to inclusion
13. 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).
14. Patients who possibly are dependent on the sponsor or investigator.
15. Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV).
16. History of chronic gastrointestinal disease with diarrhea; history of abdominal or pelvic radiotherapy.
17. 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.
18. Inability to undergo MRI.
19. Contraindication and/or hypersensitivity to bevacizumab or its excipients. For details check the Summary of Product Characteristics of Aybintio®.
20. Prior treatment with bevacizumab for any indication.
21. Parallel administration of any drug suspected to interfere with bevacizumab at the time of inclusion.
22. 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.
23. 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.
24. 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.
25. Significant vascular disease (e.g., aortic aneurysm, aortic dissection or recent peripheral arterial thrombosis) within 6 months prior to enrolment.
26. Evidence or history of recurrent thromboembolism (> 1 episode of deep venous thrombosis / peripheral embolism) during the past 2 years.
27. Evidence of bleeding diathesis of coagulopathy (in the absence of therapeutic anticoagulation).
28. Chronic daily intake of aspirin > 325 mg/day or clopidogrel > 75 mg/day.
29. History of intracranial abscess within 6 months prior to inclusion.
30. History of abdominal or tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to study enrolment.
31. History of ≥ grade 2 hemoptysis according to NCI-CTC criteria within 1 month prior to inclusion.
32. Serious non-healing wound, ulcer or bone fracture.
33. Placement of a central vascular access device (CVAD) within 2 days prior to bevacizumab administration.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival

Secondary endpoints 6

1. Safety and tolerability of isotoxic dose escalation and bevacizumab
2. Progression-free survival after 6 months (PFS-6)
3. Progression-free survival (PFS)
4. Quality of life as determined by EORTC QLQ-C30 and the EORTC brain module QLQ-BN 20
5. Cognitive function as determined by MMSE and MOCA
6. Exploratory objective: validation of 4-miRNA signature-based risk subgroups in FFPE material and plasma samples

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Tuebingen AöR

Sponsor organisation

Universitaetsklinikum Tuebingen AöR

Address

Geissweg 3, Innenstadt Innenstadt

City

Tuebingen

Postcode

72076

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Klinik für Radioonkologie

Public contact point

Organisation

Universitaetsklinikum Tuebingen AöR

Contact name

Klinik für Radioonkologie

Locations

1 EU/EEA country · 9 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 8 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