Enhanced Local Intensified Radiation Therapy in Elderly Glioblastoma: A Phase 2 Hybrid Randomized Trial

Enhanced Local Intensified Radiation Therapy in Elderly Glioblastoma (ELITE-GBM): A Phase 2 Hybrid Randomized Trial Leveraging External Data

Glioblastoma (GBM) is an aggressive malignancy of the central nervous system. Older adults with GBM have a unique constellation of medical, psychosocial, and supportive care needs. To address these challenges, prior work has evaluated the feasibility of hypofractionation, a treatment approach delivering fewer, larger radiation dosages over a shorter time period. Common hypofractionated regimens deliver a lower biologically equivalent radiation dose than the conventional regimens used for younger adults. Whether dose escalated hypofractionation can further improve outcomes in older adults remains unclear.

This will be a hybrid randomized control trial comparing the efficacy and safety of dose-escalated and standard hypofractionated radiotherapy among older adults with newly-diagnosed glioblastoma compared to standard three-week course. This research study involves the administration of radiation therapy. Radiation will either be delivered at the standard daily dose or at an increased daily dose over a three weeks course of radiation treatment.

Research study procedures will include a screening evaluation to assess eligibility, as well as clinical visits for radiation delivery and to assess symptoms during treatment and at scheduled follow-up times.

Participants will be randomly assigned to one of the two arms of the trial:

1. Standard hypofractionated radiation over 3 weeks
2. Dose-escalated hypofractionated radiation over 3 weeks

Inclusion Criteria:

• Histological confirmation of WHO grade 4 glioblastoma (IDH wild-type by immunohistochemistry or sequencing). Histopathology must be confirmed by central review.
• Newly diagnosed disease, with time elapsed from diagnostic surgery/resection <8 weeks.
• Age ≥ 65 years old at time of glioblastoma diagnosis
• Adequate functional status as measured by a ECOG Performance Status 0, 1 or 2, at time of enrollment.
• Adequate hematological, renal and hepatic functions as defined by the following required laboratory values obtained within 45 days prior to randomization:

Platelet count ≥ 100 x 10^9/L (100,000 cells/mm^3) Serum creatinine ≤ 1.5 times the upper limit of normal Total serum bilirubin ≤ 1.5 times the upper limit of normal ALT (SGPT) < 2.5 times the upper limit of normal and/or AST (SGOT) < 2.5 times the upper limit of normal

-Patient may have received corticosteroids, but must be on a stable or decreasing dose for at least 14 days prior to randomization.

Exclusion Criteria:

• Participants with recurrent glioma.
• Participants with evidence of spinal, leptomeningeal, or more distant disease.
• Participants with another active central nervous system malignancies requiring treatment.
• Participants with a second invasive malignancy that is A) incompletely treated or requiring ongoing treatment, or B) reasonably anticipated to be associated with a median overall survival of less than 1 year based on population-level data for the specified disease site and stage.
• Participants with any other major medical illnesses or psychiatric treatments that in the treating physician's opinion will prevent administration or completion of protocol therapy.
• Participants with inadequate mental capacity to provide informed consent
• Participants who cannot receive gadolinium
• Participants who have undergone prior head and neck or cranial radiation or radiation to any other site previously that would be reasonably anticipated to result in a significant overlap in radiation fields.
• Participants who have received systemic or radiosensitizing therapy for a prior head and neck or central nervous system malignancy or any investigational cancer drug for glioblastoma prior to randomization.
• Participants who have received or plan to receive any other form of non-surgical local or field treatment overlapping with the anticipated radiation field.
• Patients with a serious active infection (such as a wound infection requiring parenteral antibiotics) or other acute medical conditions at the time of randomization that would impair the ability of the patient to receive protocol treatment.