Short Course Radiotherapy for the Treatment of Patients With Glioblastoma, SAGA Study

Study Overview
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Brief Summary
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This phase II trial compares the effect of short course radiotherapy (RT) to standard course RT for the treatment of patients diagnosed with glioblastoma (GBM). The researchers want to learn whether the shorter course treatment is non-inferior (not worse than the standard of care), for patients with GBM. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Short course radiotherapy delivers higher doses of radiation over a shorter period of time and may kill more tumor cells and have fewer side effects.

Detailed Description
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PRIMARY OBJECTIVE: I. To demonstrate non-inferior 12-month overall survival (OS) of patients with GBM treated with dose escalated hypofractionated radiotherapy compared to standard of care. SECONDARY OBJECTIVES: I. To demonstrate the safety of short-course radiotherapy via physician-reported grade (G) 3+ toxicity. II. To explore patient-reported outcomes to demonstrate favorable quality of life with short-course radiotherapy for GBM. III. To analyze the impact of shortening the treatment duration on treatment related lymphopenia and absolutely lymphocyte counts. EXPLORATORY OBJECTIVES: I. To determine the cost-effectiveness of the 5-fraction treatment regimen compared to standard of care. II. To explore the impact on the immune system with the 5-fraction treatment regimen. Immune phenotyping will be assessed by Flow Cytometry and cytometry by flight (CyTOF). III. To analyze series of cytokine levels over time. IV. To assess patterns of failure, specifically focusing on differences in volume delineation via Fluorodopa F 18 (FDOPA) and magnetic resonance imaging (MRI) and recurrences in-field versus (vs.) out of field. V. To conduct a subgroup analysis for just patients =< 65 cc. VI. To conduct a subgroup analysis for just patients with and without tumor treating fields. VII. To analyze patient demographic data compared to historical controls to determine whether the short-course treatment regimen improves access to underserved populations. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients undergo short course RT over 1-2 weeks on study. ARM B: Patients undergo standard course RT over 3-6 weeks on study. Patients in arms A and B also receive temozolomide orally (PO) on study, undergo positron emission tomography/computed tomography (PET/CT) with 18-F-DOPA administered intravenously (IV) prior to RT on study, and undergo MRI throughout the trial.

Official Title
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Stereotactic Accelerated Radiotherapy in GlioblastomA (SAGA)

Conditions
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Glioblastoma

Intervention / Treatment
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* Radiation: Accelerated Hypofractionated Radiation Therapy
* Procedure: Computed Tomography
* Drug: Fluorodopa F 18
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Radiation: Radiation Therapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Histological and/or molecular confirmation of glioblastoma Eastern Oncology Group (ECOG) performance status (PS) =< 3 Ability to complete questionnaire(s) by themselves or with assistance Provide written informed consent Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Postoperative/post-biopsy tumor plus surgical bed size =< 6 cm in maximum diameter. This measurement includes both the enhancing region identified via T1 MRI with contrast, as well as the surgical cavity Exclusion Criteria: Unable to undergo MRI scans with contrast Unable to undergo an 18F-DOPA-PET scan Concurrent use of anti-dopaminergic medications or dopamine agonists Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Tumors with IDH mutation are excluded Patients who will not receive any radiation treatment or who will receive radiation treatment elsewhere (Note: radiotherapy can be given on the trial at Mayo Clinic facilities in Rochester, Arizona, or Florida, as well as at the Mayo Clinic Health System sites). Temozolomide, however, can be provided by another institution

Ages Eligible for Study
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Minimum Age: 18 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (short course RT)<br>Patients undergo short course RT over 1-2 weeks on study. Patients also receive temozolomide PO on study, undergo PET/CT with 18-F-DOPA administered IV prior to RT on study, and undergo MRI throughout the trial. | Radiation: Accelerated Hypofractionated Radiation Therapy<br>* Undergo short course RT<br>* Other names: AHRT;Procedure: Computed Tomography<br>* Undergo CT simulation<br>* Other names: tomography;Drug: Fluorodopa F 18<br>* Given IV<br>* Other names: L-6-(18F)Fluoro-DOPA;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Complete questionnaires<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Active Comparator: Arm B (standard course RT)<br>Patients undergo standard course RT over 3-6 weeks on study. Patients also receive temozolomide PO on study, undergo PET/CT with 18-F-DOPA administered IV prior to RT on study, and undergo MRI throughout the trial. | Procedure: Computed Tomography<br>* Undergo CT simulation<br>* Other names: tomography;Drug: Fluorodopa F 18<br>* Given IV<br>* Other names: L-6-(18F)Fluoro-DOPA;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: PT;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Complete questionnaires<br>Radiation: Radiation Therapy<br>* Undergo standard course RT<br>* Other names: Therapy, Radiation;Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients alive (overall survival [OS]) at 12 months | Comparisons between arms will be made by using a one-sided non-inferiority test of the difference in proportions with a non-inferiority limit of 10% and alpha level of .10. All patients meeting eligibility criteria who have signed a consent form, were randomized, and started treatment will be considered evaluable. | Up to 12 months after enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients whose physician reported a grade 3+ toxicity | Comparisons between arms will be made by using either the Chi-square or Fisher's Exact test for each time point. All patients meeting the eligibility criteria who signed a consent form and started treatment will be in the analysis. | Up to 30-, 90-, and 180-days post-radiotherapy (RT) | 
| Quality of life: Wilcoxon Rank-sum test | Changes over time from baseline will be compared between arms using the 2-sample t-test (or Wilcoxon Rank-Sum test for non-normal data). All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses. Changes will be measured from baseline over time of study. | From baseline up to 3 years | 
| Quality of life: EORTC QLQ-C30 (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire) | Changes over time from baseline will be compared between arms using the EORTC QLQ-C30 questionnaire. All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses. Score is caluclated from the mean of 13 of the 15 QLQ-C30 scales. | From baseline up to 3 years | 
| Quality of life: EORTC QLQ-BN20 Questionnaire | Changes over time from baseline will be compared between arms using the EORTC-BN20 questionnaire. All patients meeting the eligibility criteria who have signed a consent form, started treatment, and have non-missing data on these questionnaires will be evaluable for these analyses on a scale of 1-4, 1 being the lesser degree and 4 being the highest degree. | From baseline up to 3 years | 
| Lymphocyte count | Lymphocyte count at nadir will be compared between arms using the 2-sample t-test (or Wilcoxon Rank-Sum test for non-normal data). Additionally, the absolute change in lymphocyte count from pretreatment to end of RT will be compared between arms using an analysis of covariance (ANCOVA). | From baseline up to 3 years |