Preoperative Radiosurgery for the Treatment of High Grade Glioma, The NeoGlioma Study

Study Overview
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Brief Summary
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This phase I/IIA trial finds out the possible benefits and/or side effects of radiosurgery before surgery (preoperative) in treating patients with high grade glioma. Radiosurgery uses special equipment to position the patient and precisely give a single large dose of radiation to the tumor. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving pre-operative radiosurgery may improve the odds of brain tumor control and reduce treatment-related side effects.

Detailed Description
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PRIMARY OBJECTIVE: I. To evaluate the safety of preoperative radiosurgery in the treatment of patients with biopsy-proven high grade glioma prior to conventional therapy. SECONDARY OBJECTIVES: I. Acute clinical toxicity profile using Common Terminology Criteria for Adverse Events (CTCAE) version 5 (defined as within 4 weeks of completion of postoperative radiotherapy. II. Radiographic tumor control at 12 months following surgery (per Response Assessment in Neuro-Oncology [RANO] criteria). III. Rate of pseudoprogression at first post radiation scan (RANO criteria). IV. Overall survival at 12 months following surgery. CORRELATIVE RESEARCH OBJECTIVE: I. Evaluation of the tumor repair pathways triggered by radiation, tumor vascular changes, tumor microenvironment immune profiling, cell cultures, and the creation of orthotopic xenograft models for future study. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT A: Patients undergo magnetic resonance imaging (MRI)-guided stereotactic biopsy. Patients then undergo radiosurgery over 1 fraction. Within 14 days, patients undergo surgery. Within 4-6 weeks, patients then receive standard of care radiation therapy over 30 fraction and temozolomide daily with or without tumor treating fields (TTF) at the discretion of the treating neuro-oncologist. COHORT B: Patients undergo surgery. Within 4-6 weeks, patients then receive standard of care radiation therapy over 30 fraction and temozolomide daily with or without TTF at the discretion of the treating neuro-oncologist. After completion of study treatment, patients are followed up every 2-3 months for up to 5 years.

Official Title
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Preoperative Radiosurgery in High Grade Glioma: A Phase I/IIA Clinical Trial: The NeoGlioma Study

Conditions
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Malignant Glioma

Intervention / Treatment
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* Radiation: Radiation Therapy
* Radiation: Radiosurgery
* Procedure: Stereotactic Biopsy
* Drug: Temozolomide
* Procedure: Therapeutic Conventional Surgery
* Procedure: Tumor Treating Fields Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Clear clinical and radiographic evidence of primary high grade glioma (HGG) as judged by the Mayo multidisciplinary neuro-oncology team (World Health Organization [WHO] grade III-IV, including glioblastoma) regardless of IDH and MGMT status Planned neurosurgical resection of tumor Judged to not be at risk of significant clinical risk (i.e. herniation) with radiation-induced edema prior to resection No prior history of cranial radiotherapy Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 Negative pregnancy test done =< 14 days prior to registration, for women of childbearing potential only Ability to complete questionnaire(s) by themselves or with assistance Provide written informed consent Planning to receive adjuvant radiotherapy at enrolling institution Willing to provide tissue and/or blood samples for correlative research purposes Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days prior to registration) Platelet count >= 80,000/mm^3 (80 x 10^9/L) (obtained =< 14 days prior to registration) Hemoglobin (Hgb) >= 9 g/dL (=< 14 days prior to registration) Exclusion Criteria: Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Unwillingness to participate in study Investigator discretion that enrollment on the study would pose undo harm or risk to the patient Non-MRI compatible implanted medical device Use of systemic anti-cancer therapy within the previous 3 months Medical contraindication to craniotomy and tumor resection Pathologic confirmation of grade I-II glioma, brain metastasis, or other brain tumor Note: Patients with a history of grade I-II glioma are eligible if they have only received surgery as treatment and now there is concern for transformation to grade III-IV tumor Primary spinal cord glioma or primary brainstem glioma Residual tumor of excessive volume or eloquent location per investigator discretion Patients who are unwilling or unable to comply with study procedures

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A (stereotactic biopsy, radiosurgery, surgery)<br>Patients undergo MRI-guided stereotactic biopsy. Patients then undergo radiosurgery over 1 fraction. Within 14 days, patients undergo surgery. Within 4-6 weeks, patients then receive standard of care radiation therapy over 30 fraction and temozolomide daily with or without TTF at the discretion of the treating neuro-oncologist. | Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Radiation: Radiosurgery<br>* Undergo radiosurgery<br>* Other names: Radiation Surgery;Procedure: Stereotactic Biopsy<br>* Undergo MRI-guided stereotactic biopsy<br>Drug: Temozolomide<br>* Drug<br>* Other names: TMZ;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Procedure: Tumor Treating Fields Therapy<br>* Undergo TTF<br>* Other names: TTFields;|
| Active Comparator: Cohort B (surgery, radiation therapy, chemotherapy)<br>Patients undergo surgery. Within 4-6 weeks, patients then receive standard of care radiation therapy over 30 fraction and temozolomide daily with or without TTF at the discretion of the treating neuro-oncologist. | Radiation: Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Therapy, Radiation;Drug: Temozolomide<br>* Drug<br>* Other names: TMZ;Procedure: Therapeutic Conventional Surgery<br>* Undergo surgery<br>Procedure: Tumor Treating Fields Therapy<br>* Undergo TTF<br>* Other names: TTFields;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients experiencing any acute grade 3 or greater unplanned adverse event | Assessed per Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. The toxicity rate will be estimated using a binomial estimator and a one-sided 95% confidence interval (CI) of the rate will be computed with normal approximation. | Up to 4 weeks postoperative radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute clinical toxicity | Assessed per CTCAE v5.0. The maximum grade for each type of acute adverse events will be recorded for each patient. Data will be summarized as frequencies and relative frequencies by treatment arm. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Rates will be compared between arms using chi-squared tests. | Up to 4 weeks postoperative radiotherapy | 
| Radiographic tumor control | Assessed per Response Assessment in Neuro-Oncology (RANO) criteria. The cumulative incidence of radiographic tumor recurrence will be estimated using a competing risks method (Gooley et al.) by treatment arm. The competing risks will be death. Comparison between arms will employ Fine-Gray regression. | At 12 months post-surgery | 
| Rate of pseudoprogression | Assessed per RANO criteria. Data will be summarized as frequencies and relative frequencies by treatment arm. Additionally, the relationship of the pseudoprogression(s) to the study treatment will be taken into consideration. Rates will be compared between arms using chi-squared tests. | At first post radiation scan | 
| Overall survival | Will be estimated with a Kaplan-Meier estimator and curve by treatment arm. Estimates will be given for specific time points along with 95% CIs. Comparison between arms will employ a log-rank test. | At 12 months post-surgery |