A Safety Run-in and Phase II Study Evaluating the Efficacy, Safety, and Impact on the Tumor Microenvironment of the Combination of Tocilizumab, Atezolizumab, and Fractionated Stereotactic Radiotherapy in Recurrent Glioblastoma (NRG-BN010)

May 11 2022

Patients diagnosed with glioblastoma (GBM) are typically faced with a life expectancy of less than two years. Additionally, there’s a significant lack of treatment options due to many challenges, such as marked tumor heterogeneity and limited brain penetration by most chemotherapies and targeted therapies. Immunotherapy can potentially overcome such challenges, as tumor-specific T cells can target different subclones and cross the blood-brain barrier. Therefore, the NRG Oncology clinical trial NRG-BN010 strives to answer the question of whether GBM can shrink or be stabilized by the addition of immunotherapy to stereotactic radiation therapy.

NRG Oncology’s clinical trial NRG-BN010 is currently still in progress and recruiting patients.

This study consists of 3 components: an initial safety run-in phase to confirm safety/tolerability of the treatment regimen, a single-arm nonsurgical cohort to assess efficacy of the treatment regimen, and a randomized window-of-opportunity surgical cohort for patients with a clinical indication for surgical resection of the tumor. The safety run-in phase will enroll patients at 3 sequential dose levels, each administered with FSRT (8 Gy x 3 fx): (1) single-agent tocilizumab 4mg/kg, (2) single-agent tocilizumab 8mg/kg, and (3) tocilizumab 8mg/kg + atezolizumab 1680mg. The primary objective the safety run-in is to determine the maximum-tolerated dose (MTD) among these three sequential dose levels. The MTD will be used in the Phase II testing.

After the safety run-in phase is completed, patients will be placed in either the primary nonsurgical cohort or the randomized surgical cohort. Patients in the primary nonsurgical cohort of the study will receive the safe dose determined from the safety run-in, and then FSRT (8 Gy x 3 fx) 3 to 7 days later. Following FSRT, systemic therapy will be resumed at the same dose regimen and administered every 4 weeks for 2 years or until disease progression or unacceptable toxicity.Patients in the phase II surgical cohort will be randomized 1:1 to FSRT + atezolizumab or FSRT+ tocilizumab at the dose level determined safe in the safety run-in to determine the impact of tocilizumab on the tumor immune microenvironment.Patients in the surgical arm will receive cycle 1 of the systemic agent(s), then FSRT 3-7 days later, then surgical resection 7-14 days after FSRT. After surgery, systemic therapy will be administered every 4 weeks for 2 years or until disease progression or unacceptable toxicity. The primary objective of Phase II is to determine the efficacy of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent GBM, as measured by the objective radiographic response rate (ORR).

“Strong preclinical data has determined that IL-6 has a critical role in GBM immune invasion, that targeting IL-6 in combination with anti-PD-L1 therapy may result in synergistic anti-tumor effects, and that FSRT is capable of inciting multiple immunostimulatory effects in the tumor microenvironment. Therefore, the primary hypothesis of this study is that the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT will lead to a robust anti-tumor immune response in GBM,” as stated by the study’s Principal Investigator, Stephen J. Bagley, MD, MSCE, Hospital of the University of Pennsylvania.

For more information about the NRG-BN010 study, click here: NCT04729959

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