Preoperative Radiosurgery for the Treatment of High Grade Glioma, NeoGlioma Trial

Phase 1

Recruiting

Conditions: Malignant Glioma

Interventions: Radiation: Radiation Therapy
Radiation: Radiosurgery
Procedure: Stereotactic Biopsy
Drug: Temozolomide
Procedure: Tumor Treating Fields Therapy
Procedure: Magnetic Resonance Imaging
Procedure: Biospecimen Collection
Procedure: Biopsy
Procedure: Therapeutic Conventional Surgery

Registration Number: NCT05030298

Lead Sponsor: Mayo Clinic

Brief Summary: This phase I 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: PRIMARY OBJECTIVE:

I. To evaluate the feasibility, safety and maximum tolerated dose (MTD) 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: This is a dose-escalation study.

Patients undergo magnetic resonance imaging (MRI)-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.

After completion of study treatment, patients are followed up every 2-3 months for 12 months and then every 3 months for up to 3 years after registration.

Recruitment & Eligibility

Status: RECRUITING

Sex: All

Target Recruitment: 25

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
Patients who underwent a previous biopsy confirming high grade glioma are eligible for enrollment
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
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. Patients over 50 years of age who decline pregnancy testing are still eligible without a pregnancy test.
Ability to complete questionnaire(s) by themselves or with assistance
Provide written informed consent
Willing to receive adjuvant radiotherapy at enrolling institution
Willing to provide tissue and/or blood samples for correlative research purposes

Exclusion Criteria

Any of the following:
- Pregnant women
- Nursing women who are unwilling to cease during therapy
- Men or women of childbearing potential who are unwilling to employ adequate contraception
Prior history of cranial radiotherapy
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

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Treatment (stereotactic biopsy, radiosurgery, surgery)	Radiation Therapy	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Radiosurgery	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Stereotactic Biopsy	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Temozolomide	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Tumor Treating Fields Therapy	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Magnetic Resonance Imaging	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Biospecimen Collection	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Biopsy	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.
Treatment (stereotactic biopsy, radiosurgery, surgery)	Therapeutic Conventional Surgery	Patients undergo MRI-guided stereotactic biopsy. Within 14 days of registration, patients undergo either standard of care surgery or radiosurgery in 1 fraction. Within 14 days, patients who underwent radiosurgery then undergo surgery. Within 4-6 weeks, all 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. Additionally, patients undergo MRI and blood sample collection and optional biopsy throughout the study.

Primary Outcome Measures

Name	Time	Method
Proportion of patients experiencing any acute grade 3 or greater unplanned adverse event	Up to 4 weeks postoperative radiotherapy	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.
Acute clinical toxicity	Up to 4 weeks postoperative radiotherapy	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.
Maximum tolerated dose (MTD) of preoperative radiosurgery	Up to 4 weeks postoperative radiotherapy	After the trial is completed, the MTD will be based on isotonic regression. The dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate will be selected as the MTD. If there are ties, the higher dose level will be selected when the isotonic estimate is lower than the target toxicity rate; and the lower dose level will be selected when the isotonic estimate is greater than or equal to the target toxicity rate.

Secondary Outcome Measures

Name	Time	Method
Radiographic tumor control	At 12 months post-surgery	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.). The competing risks will be death.
Rate of pseudoprogression	At first post radiation scan	Assessed per RANO criteria. Data will be summarized as frequencies and relative frequencies overall and by treatment dose. Additionally, the relationship of the pseudoprogression(s) to the study treatment will be taken into consideration.
Overall survival	At 12 months post-surgery	Overall survival (OS) is defined as the time from study enrollment to death by any cause. Will be estimated with a Kaplan-Meier estimator and curve for patients treated with preoperative radiosurgery. Estimates will be given for specific time points along with 95% CIs.

Trial Locations

Locations (1): Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States

Preoperative Radiosurgery for the Treatment of High Grade Glioma, NeoGlioma Trial

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