A Phase II Study of Pulse Reduced Dose Rate Radiation Therapy With Bevacizumab

Study Overview
=================
Brief Summary
-----------------
To determine the efficacy of Pulse Reduced Dose Rate (PRDR) radiation when given in 27 fraction over 5.5 weeks with concurrent bevacizumab followed by adjuvant bevacizumab until time of progression in patients with recurrent high grade gliomas (grade III and grade IV). Patients will be placed in 1 of 4 groups based on their histologic diagnosis and prior exposure to bevacizumab.

Official Title
-----------------
A Phase II Study of Pulse Reduced Dose Rate Radiation Therapy With Bevacizumab

Conditions
-----------------
Glioma

Intervention / Treatment
-----------------
* Drug: Bevacizumab
* Radiation: PRDR


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically or molecularly confirmed Grade 3 or 4 glioma, IDH mutant or wildtype, as defined by the 2021 WHO guidelines Recurrent disease based on combination of clinical, imaging or histologic confirmation Must have previously received radiation and temozolomide to treat their glioma Bevacizumab naive patients must be > 5 months post completion of initial radiation therapy Bevacizumab exposed patients must be > 3 months post completion of initial radiation therapy Age must be >18years, KPS must be greater than 60 Hematology, chemistry and a urinalysis must meet protocol specified criteria Exclusion Criteria: Pregnant or breastfeeding Uncontrolled hypertension (>160/90mmHg) Prior malignancy unless treated >1 year prior to study and have been without treatment and disease free for 1 yr active second malignancy unless non-melanoma skin cancer or cervical cancer in situ

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bevacizumab-naïve with recurrent IDH wildtype high grade glioma<br>27fractions over 5.5weeks of PRDR radiation with bevacizumab followed by adjuvant bevacizumab until time of progression | Drug: Bevacizumab<br>* 10mg/kg every 2weeks.<br>Radiation: PRDR<br>* Daily dose of 2.0gy delivered in .2gy pulses for a total of 54gy over 5.5 weeks and 27 fractions. In the rare instance of the presence of extensive disease requiring essentially whole brain radiation, a total daily dose of 1.8 Gy delivered in .2 Gy pulses for 23 fractions to a total dose of 41.4 Gy will be utilized.<br>* Other names: re-irradiation;|
| Active Comparator: Bevacizumab-exposed with refractory recurrent IDH wildtype high grade glioma<br>27fractions over 5.5weeks of PRDR radiation with bevacizumab followed by adjuvant bevacizumab until time of progression | Drug: Bevacizumab<br>* 10mg/kg every 2weeks.<br>Radiation: PRDR<br>* Daily dose of 2.0gy delivered in .2gy pulses for a total of 54gy over 5.5 weeks and 27 fractions. In the rare instance of the presence of extensive disease requiring essentially whole brain radiation, a total daily dose of 1.8 Gy delivered in .2 Gy pulses for 23 fractions to a total dose of 41.4 Gy will be utilized.<br>* Other names: re-irradiation;|
| Active Comparator: Bevacizumab-naïve with recurrent IDH mutant glioma<br>27fractions over 5.5weeks of PRDR radiation with bevacizumab followed by adjuvant bevacizumab until time of progression | Drug: Bevacizumab<br>* 10mg/kg every 2weeks.<br>Radiation: PRDR<br>* Daily dose of 2.0gy delivered in .2gy pulses for a total of 54gy over 5.5 weeks and 27 fractions. In the rare instance of the presence of extensive disease requiring essentially whole brain radiation, a total daily dose of 1.8 Gy delivered in .2 Gy pulses for 23 fractions to a total dose of 41.4 Gy will be utilized.<br>* Other names: re-irradiation;|
| Active Comparator: Bevacizumab-exposed with recurrent IDH mutant glioma<br>27fractions over 5.5weeks of PRDR radiation with bevacizumab followed by adjuvant bevacizumab until time of progression | Drug: Bevacizumab<br>* 10mg/kg every 2weeks.<br>Radiation: PRDR<br>* Daily dose of 2.0gy delivered in .2gy pulses for a total of 54gy over 5.5 weeks and 27 fractions. In the rare instance of the presence of extensive disease requiring essentially whole brain radiation, a total daily dose of 1.8 Gy delivered in .2 Gy pulses for 23 fractions to a total dose of 41.4 Gy will be utilized.<br>* Other names: re-irradiation;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | time of first dose of PDRD+ Bevacizumab until time of death | end of study, which will be an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events | time of first dose of PDRD+ Bevacizumab until time of death. All changes from baseline assessment will be recorded until 30 days post last dose of bevacizumab, assessed using the NCI CTCAE version 4.0 criteria. | up to 30 days post last dose of bevacizumab | 
| Incidence of Late Toxicities | Late toxicity that is likely attributable to re-irradiation or bevacizumab will be recorded. | from 90 days post radiotherapy until time of death | 
| progression free survival | Progression free survival (PFS) will be defined as the time from the first study treatment to the first occurrence of disease progression or death. | at 3 months for bevacizumab exposed patients, at 6 and 12 months for all patients | 
| Change in Mini Mental State Exam (MMSE) Score | The MMSE survey is a clinician facilitated instrument scored on a scale of 0-30 where scores of 0-17 indicate severe cognitive impairment, 18-23 indicate mild cognitive impairment, and 24-30 indicate no cognitive impairment. | baseline and then approximately every 8 weeks for 18 months | 
| Change in Participant Reported FACT-BR Score | The Functional Assessment of Cancer Therapy - Brain (FACT-BR) instrument is a 50-item survey with each item scored on a 5 point likert scale where 0 is 'not at all' and 4 is 'very much'. The total possible range of scores is 0-200 where higher scores indicate higher quality of life. | baseline and then approximately every 8 weeks for 18 months | 
| Change in Participant Reported FACIT-F Score | The Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) instrument is a 13-item survey with each item scored on a 5 point likert scale where 0 is 'not at all' and 4 is 'very much'. The total possible range of scores is from 0-52 where higher scores indicate better quality of life. A score of less than 30 indicates severe fatigue. | baseline and then approximately every 8 weeks for 18 months | 
| Change in Karnofsky Performance Status | The Karnofsky Performance Status measures a cancer patient's ability to perform ordinary tasks. It is score from 0-100 where 0 means a person has died, less than 40 is various degrees of unable to care for oneself, 50-70 is unable to work but can care for personal needs with variable assistance, and 80-100 is able to carry on normal activity with variable symptoms of disease. | baseline and then approximately every 8 weeks for 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Glioblastoma, anaplastic glioma