Efficacy and Safety of SCAI of Bevacizumab Combined With IC of Tislelizumab in the Treatment of Recurrent Glioblastoma.

Efficacy and Safety of Superselective Cerebral Arterial Infusion of Bevacizumab Combined With Intrathecal Injection of Tislelizumab in the Treatment of Recurrent Glioblastoma

To investigate the efficacy, safety and tolerability of superselective cerebral arterial infusion of Bevacizumab combined with intrathecal injection of Tislelizumab in the treatment of recurrent glioblastoma

Study Overview

• Status: Not yet recruiting
• Conditions: Glioblastoma
• Intervention / Treatment: Drug: Tislelizumab and Bevacizumab

Detailed Description

Glioblastoma multiforme (GBM) is a highly malignant intracranial tumor with a median survival of only about 15-17 months after standard treatment. Patients with GBM often experience disease recurrence, and once recurrence occurs, treatment options are very limited, with a median overall survival of only about 6 months. Results of a phase II clinical trial of nivolumab combined with standard or reduced-dose bevacizumab iv therapy for recurrent GBM showed that the median PFS for the two groups was 5.6 months vs. 4.6 months, respectively. The aim of this study is to improve the outcome of recurrent GBM patients by changing the route of administration of the two drugs, such as delivering Bevacizumab via intra-arterial infusion and administering PD-1 monoclonal antibodies via intrathecal injection.

• Study Type: Interventional
• Enrollment (Anticipated): 36
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xingen Zhu, Dr.; Phone Number: 18679136068; Email: zxg2008vip@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 1, 18 ≤ age ≤ 75 years. 2. Recurrent glioblastoma who failed first-line therapy, with no more than 3 prior episodes of disease progression and at least one confirmed and evaluable lesion.

  3. ECOG score 0-2 points, expected survival time ≥ 3 months; 4. Stable neurological symptoms for more than 7 days; 5. If the previous surgical resection interval is at least 4 weeks, after receiving chemotherapy for 3 weeks, after receiving radiotherapy including whole brain radiotherapy, stereotactic radiotherapy and other radiotherapy for 3 months, if receiving other intrathecal treatment drugs washout period of 7 days.

  6. Neutrophil count ≥ 1.5 × 10 ^ 9/L, hemoglobin ≥ 80 g/L, platelets ≥ 75 × 10 ^ 9/L.

  7. Prothrombin time/international normalized ratio and partial thromboplastin time ≤ 1.5 × upper limit of normal; 8. Total bilirubin ≤ 1.5 × ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ×ULN, albumin ≥ 30 g/L, creatinine ≤ 2 × ULN, calculated creatinine clearance ≥ 50 mL/min, 24-hour urine creatinine clearance ≥ 50 mL/min; 9. subjects should agree to use adequate contraception from the first dose until 3 months after the last dose.

Exclusion Criteria:

• 1. Pregnant or lactating women. 2. Active infection requiring intravenous antibiotics requiring therapeutic anticoagulation with warfarin.

  3. History of allergy to monoclonal antibodies; 4. Use of non-tumor vaccines containing live viruses to prevent infectious diseases within 12 weeks before the study drug; 5. Subjects with serious medical, neurological or psychiatric disorders and judged to be unable to fully comply with study treatment or assessments; 6. Active infectious diseases within 7 days before starting the study drug; 7. Severe liver dysfunction (persistent grade 3 or greater liver adverse events) or known active chronic hepatitis, human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) test positive; 8. Patients with active autoimmune diseases requiring systemic treatment (i.e., the use of corticosteroids or immunosuppressive agents), except replacement therapy (e.g., thyroxine, insulin or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency), allowing inhalation or local steroids and adrenal replacement dose > 10 mg daily prednisone equivalent, requiring long-term systemic corticosteroid therapy (> 10 mg prednisone or equivalent per day) or any other immunosuppressive therapy (including anti-TNF-a therapy); 9. Investigate the allergic history of drug ingredients; 10. Inadequate control of hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg (using antihypertensive drugs); 11. Any past history of hypertensive crisis or hypertensive encephalopathy; 12. New York Heart Association (NYHA) Class II or greater congestive heart failure; 13. History of myocardial infarction or unstable angina within 6 months prior to enrollment; 14. History of stroke or transient ischemic attack within 6 months prior to enrollment; 15. Severe vascular diseases (such as aortic aneurysm, aortic dissection); 16. Symptomatic peripheral vascular disease. 17. Evidence of bleeding diathesis or coagulopathy. 18. Major surgery, open biopsy or severe traumatic injury within 28 days prior to study enrollment, or major surgery is expected to be required during the course of the study.

  19. Core biopsy or other minor surgical procedures, excluding placement of vascular access devices, within 7 days prior to study enrollment.

  20. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to study entry; 21. Severe, non-healing wounds, ulcers or fractures. 22. Urine protein to creatinine ratio ≥ 1.0 or urine protein ≥ 2 +. 23. Subjects with high intracranial pressure who are not suitable for lumbar puncture, and the researchers believe that they are not suitable for inclusion in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bevacizumab arterial infusion combined with Tislelizumab intrathecal injection; This is a prospective, interventional, multicenter Phase 2 trial for the treatment of patients with recurrent GBM who will receive Bevacizumab arterial infusion combined with Tislelizumab intrathecal injection. The study consists of two parts: the "arterial infusion part" in part 1, where each subject will receive 15 mg/Kg of Bevacizumab by cerebral arterial infusion over 15 minutes at a fixed time (d0, d30, d60); the infusion of 20% mannitol 12.5 ml over 120 seconds prior to the infusion of Bevacizumab; and the "intrathecal injection part" in part 2, where the subject will receive a fixed dose of intrathecal PD1 therapy (Tislelizumab 20 mg, d1, Q3W) intrathecal injection every 3 weeks for 6 cycles.

Drug: Tislelizumab and Bevacizumab; Tislelizumab is a drug material authorized for marketing in China. Tislelizumab will be administered off-label in this study. Subjects with recurrent GBM will receive intrathecal tislelizumab every 3 weeks for six times. Intrathecal administration of Bevacizumab will be performed via Ommaya reservoir or intraventricular catheter.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival	PFS was defined as the time from random assignment until objective tumor progression (independent image committee assessment) or death (any cause)	Up to 10 approximately months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	ORR is defined as the percentage of patients with a best overall response of CR or PR relative to the appropriate analysis set.	Up to 10 approximately months
Overall Survival	OS was defined as the time from random assignment until death (any cause) or censored at the last date of known survival.	Up to 10 approximately months
Duration of Response	Time from the patient 's first assessment of clinical response to the first assessment of disease progression or death from any cause.	Up to 10 approximately months
Safety and Tolerability	The safety endpoints will be assessed by a review of adverse events and serious adverse events according to CTCAE up to 10 approximately months after last dose	Up to 10 approximately months

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Nanchang University
• Collaborators: Zhejiang University
• Investigators: Principal Investigator: Xingen Zhu, Dr., Second Affiliated Hospital of Nanchang University

Study record dates

Study Major Dates

• Study Start (Anticipated): April 15, 2023
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 30, 2025

Study Registration Dates

• First Submitted: March 21, 2023
• First Submitted That Met QC Criteria: April 12, 2023
• First Posted (Actual): April 13, 2023

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 12, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: IIT-I-2023-016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No