Low-dose Bevacizumab With HSRT vs BVZ Alone for GBM at First Recurrence

A Randomized Phase II Trial of Concurrent Low-dose Bevacizumab and HSRT Versus Bevacizumab Alone for Glioblastoma at First Recurrence: HSCK-005

This randomized phase II trial studies how well lose dose bevacizumab with Hypofractionated Stereotactic Radiotherapy (HSRT) works versus bevacizumab alone in treating patients with glioblastoma at first recurrence. The primary endpoint is 6-month progress-free survivaloverall survival after the treatment. Secondary endpoints included overall survival, objective response rate, cognitive function, quality of life and toxicity.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioma; Recurrent Glioma
• Intervention / Treatment: Radiation: Hypofractionated Stereotactic Radiotherapy; Drug: Bevacizumab

Detailed Description

To establish an improvement in 6-month pfs in recurrent glioblastoma patients receiving low-dose bevacizumab and re-irradiation compared with patients receiving bevacizumab alone.

• Study Type: Interventional
• Enrollment (Anticipated): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • CyberKnife Center, Department of Neurosurgery, Huashan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 18-70 years of age;
• Karnofsky performance status (KPS) ≥ 60;
• Original histopathologically proven diagnosis World Health Organization (WHO) Grade 3/4 glioma;
• Underwent surgery, chemoradiotherapy and adjuvant chemotherapy (Stupp Protocol) after initial diagnosis, recurrent based on the Response Assessment in Neuro-Oncology (RANO) criteria and/or histopathologically proven;
• Measurable disease;
• Estimated survival of at least 3 months, maximal diameter on T1+C MRI ≤ 3.5 cm;
• Hgb > 9 gm; absolute neutrophil count (ANC) > 1500/μl; platelets > 100,000; Creatinine < 1.5 times the upper limit of laboratory normal value; Bilirubin < 2 times the upper limit of laboratory normal value; serum glutamate pyruvate transaminase (SGPT) or serum glutamate oxaloacetate transaminase (SGOT) < 3 times the upper limit of laboratory normal value;
• Signed informed consent form;
• Agreed to participate the follow-up.

Exclusion Criteria:

• Prior invasive malignancy unless disease free;
• Received re-irradiation;
• More than 3 relapses or evidence of subtentorial recurrent disease or tumor greater than 6 cm in maximum diameter;
• Prior therapy with an inhibitor of vascular endothelial growth factor (VEGF) or VEGFR;
• Pregnancy or or nursing mothers;
• Participated in other trials after diagnosis of recurrent;
• Influence factors toward oral medications;
• Patients with CTCAE5.0 grade 3+ bleeding;
• Suffering from severe cardiovascular disease: myocardial ischemia or myocardial infarction above grade II, poorly controlled arrhythmias (including men with QTc interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV Insufficient function, or cardiac color Doppler ultrasound examination indicates left ventricular ejection fraction (LVEF) <50%;
• Long-term unhealed wounds or fractures;
• History of organ transplantation;
• Serious diseases that endanger patients' safety or affect patients' completion of research,according to the researchers' judgment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bevacizumab; Bevacizumab every 2 weeks	Drug: Bevacizumab; Staring within 2 weeks of randomization, IV 5mg/kg (experimental group) or 10mg/kg (comparison group) every two weeks until disease progression.; Other Names: Avastin; anti-VEGF monoclonal antibody; rhuMAb VEGF
Experimental: HSRT+Low-dose Bevacizumab; HSRT with low-dose bevacizumab every 2 weeks	Radiation: Hypofractionated Stereotactic Radiotherapy; Starting with low-dose bevacizumab, 25Gy in 5 fractions of 5 Gy each delivered on consecutive treatment days.; Other Names: Image-Guided Radiation Treatment (IGRT); Hypofractionated Stereotactic Radiosurgery; Stereotactic Radiosurgery (SRS); Drug: Bevacizumab; Staring within 2 weeks of randomization, IV 5mg/kg (experimental group) or 10mg/kg (comparison group) every two weeks until disease progression.; Other Names: Avastin; anti-VEGF monoclonal antibody; rhuMAb VEGF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival rate at 6 Months	Prgression was defined using Response Assessment in Neuro-Oncology (RANO) Criteria. Progression-free at 6 months means patient alive without progression at 6 months. Survival rates are estimated by the Kaplan-Meier method.	From randomization to six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method.	From randomization to last follow-up, up to approximately 24 months
Progression-free Survival	Prgression was defined using Response Assessment in Neuro-Oncology (RANO) Criteria. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method.	From randomization to last follow-up, up to approximately 24 months
Objective response rate	ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Assessment in Neuro-Oncology (RANO) prior to progression or any further therapy.	Bimonthly up to intolerance the toxicity or progressive disease (PD), up to approximately 24 months
Number of Participants With Grade 3+ Toxicity rate	Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Grade refers to the severity of the AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months
Quality of Life score (QoL)	EORTC QLQ-C30 (version 3.0) questionnaire to evaluate the quality of life. All scales range in score from 0 to 100. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months
Cognitive function	Mini-Mental State Exam (MMSE, score range 0 to 30) to evaluate the cognitive function. Any score of 24 or more (out of 30) indicates a normal cognition. Below this, scores can indicate severe (≤9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.	Bimonthly up to intolerance the toxicity or PD, up to approximately 24 months

Collaborators and Investigators

• Sponsor: Huashan Hospital

Publications and helpful links

General Publications

• Guan Y, Li J, Gong X, Zhu H, Li C, Mei G, Liu X, Pan L, Dai J, Wang Y, Wang E, Liu Y, Wang X. Safety and Efficacy of Hypofractionated Stereotactic Radiotherapy with Anlotinib Targeted Therapy for Glioblastoma at the First Recurrence: A Preliminary Report. Brain Sci. 2022 Apr 2;12(4):471. doi: 10.3390/brainsci12040471.
• Guan Y, Xiong J, Pan M, Shi W, Li J, Zhu H, Gong X, Li C, Mei G, Liu X, Pan L, Dai J, Wang Y, Wang E, Wang X. Safety and efficacy of Hypofractionated stereotactic radiosurgery for high-grade Gliomas at first recurrence: a single-center experience. BMC Cancer. 2021 Feb 5;21(1):123. doi: 10.1186/s12885-021-07856-y.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: October 28, 2022
• First Submitted That Met QC Criteria: November 3, 2022
• First Posted (Actual): November 10, 2022

Study Record Updates

• Last Update Posted (Actual): November 10, 2022
• Last Update Submitted That Met QC Criteria: November 3, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Recurrence; Glioma; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab
• Other Study ID Numbers: KY2022-798

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: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes