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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Glioma, Recurrent Glioma

Intervention / Treatment
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* Radiation: Hypofractionated Stereotactic Radiotherapy
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |