This phase II trial studies the best dose and effect of tocilizumab in combination with atezolizumab and stereotactic radiation therapy in treating glioblastoma patients whose tumor has come back after initial treatment (recurrent). Tocilizumab is a monoclonal antibody that binds to receptors for a protein called interleukin-6 (IL-6), which is made by white blood cells and other cells in the body as well as certain types of cancer. This may help lower the body's immune response and reduce inflammation. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Fractionated stereotactic radiation therapy uses special equipment to precisely deliver multiple, smaller doses of radiation spread over several treatment sessions to the tumor. The goal of this study is to change a tumor that is unresponsive to cancer therapy into a more responsive one. Therapy with fractionated stereotactic radiotherapy in combination with tocilizumab may suppress the inhibitory effect of immune cells surrounding the tumor and consequently allow an immunotherapy treatment by atezolizumab to activate the immune response against the tumor. Combination therapy with tocilizumab, atezolizumab and fractionated stereotactic radiation therapy may shrink or stabilize the cancer better than radiation therapy alone in patients with recurrent glioblastoma.
PRIMARY OBJECTIVES: I. To determine the maximum-tolerated dose (MTD) among three sequential dose levels: single-agent tocilizumab 4 mg/kg, single-agent tocilizumab 8 mg/kg, and tocilizumab 8 mg/kg + atezolizumab 1680 mg (each administered with fractionated stereotactic radiation therapy \[FSRT\]), to be used for subsequent phase II testing. (Safety Run-In) II. To determine the efficacy of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent glioblastoma (GBM), as measured by the objective radiographic response rate (ORR). (Phase II \[Non-Surgical Cohort\]) SECONDARY OBJECTIVES: I. To estimate the progression-free survival (PFS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R) and FSRT (and atezolizumab \[anti-PD-L1\], if dose level 3 is MTD). (Phase II Non-Surgical Cohort and Safety Run-in Cohort) II. To estimate the overall survival (OS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R) and FSRT (and atezolizumab \[anti-PD-L1\], if dose level 3 is MTD)), atezolizumab (anti-PD-L1), and FSRT. (Phase II Non-Surgical Cohort and Safety Run-in Cohort) III. To estimate the progression-free survival (PFS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT. (Phase II Surgical Cohort) IV. To estimate the overall survival (OS) in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT. (Phase II Surgical Cohort) V. To determine the rate and severity of adverse events (AEs) of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT in recurrent glioblastoma according to Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. (Separately in the Nonsurgical and Surgical Cohorts) EXPLORATORY OBJECTIVES: I. To determine the effect of the combination of atezolizumab (anti-PD-L1) and FSRT, with versus (vs.) without tocilizumab (anti-IL6R), on the GBM immune microenvironment. (Phase II Surgical Cohort) II. To evaluate the pharmacodynamic impact of the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT on peripheral blood immune cell populations. (Phase II Surgical Cohort) III. To detect tumor and/or blood biomarkers associated with the outcomes of OS, PFS, and/or ORR in patients with recurrent GBM treated with the combination of tocilizumab (anti-IL6R), atezolizumab (anti-PD-L1), and FSRT. (Phase II Non-Surgical Cohort) OUTLINE: SAFETY RUN-IN: Patients receive systemic treatment with either tocilizumab intravenously (IV) over 60 minutes with or without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days, patients undergo FSRT for 3 fractions over 3-5 days. Starting 4 weeks from the first dose of systemic treatment, patients resume treatment with tocilizumab with or without atezolizumab. Treatment repeats every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) throughout the trial. (CLOSED TO ACCRUAL 08-AUG-2023) GROUP I (NON-SURGICAL COHORT): Patients receive systemic treatment with tocilizumab IV over 60 minutes with or without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days, patients undergo FSRT for 3 fractions over 3-5 days in the absence of disease progression or unacceptable toxicity. Starting 4 weeks from the first dose of systemic treatment, patients resume treatment with tocilizumab with or without atezolizumab. Treatment repeats every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial. GROUP II (SURGICAL COHORT): Patients are randomized to 1 of 2 arms. ARM I: Patients receive systemic treatment with tocilizumab IV over 60 minutes with or without atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days, patients undergo FSRT for 3 fractions over 3-5 days. Within 7-14 days after FSRT, patients undergo surgery. Within 21-24 days from the first dose of systemic treatment, patients resume treatment with tocilizumab with or without atezolizumab. Treatment repeats every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. ARM II: Patients receive systemic treatment with atezolizumab IV over 30-60 minutes on day 1. Within 3-7 days, patients undergo FSRT for 3-5 fractions over 3-5 days. Within 7-14 days after FSRT, patients undergo surgery. Within 21-42 days from the first dose of systemic treatment, patients resume treatment with tocilizumab IV over 60 minutes with or without atezolizumab. Treatment repeats every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, 12, 18, and 24 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
59
Given IV
Undergo blood sample and tumor tissue collection
Undergo surgery
Undergo FSRT
Undergo MRI
Given IV
Kaiser Permanente-Anaheim
Anaheim, California, United States
Kaiser Permanente-Bellflower
Bellflower, California, United States
Kaiser Permanente Los Angeles Medical Center
Los Angeles, California, United States
Los Angeles General Medical Center
Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Dose-limiting toxicities (Safety Run-In)
Will be assessed by Common Terminology Criteria for Adverse Events version 5.0.
Time frame: Up to 1 post-fractionated stereotactic radiation therapy (FRST) cycle of systemic therapy for which dose-limiting toxicity is reached (1 cycle = 4 weeks)
Maximum-tolerated dose (Safety Run-In)
Time frame: Up to 1 post-FRST cycle of systemic therapy for which dose-limiting toxicity is reached (1 cycle = 4 weeks)
Objective radiographic response rate (Phase II, Non-Surgical Cohort)
Will be determined using modified Response Assessment in Neuro-oncology with the pretreatment magnetic resonance imaging as baseline. Frequencies and percent of responses will be provided for patients with measurable disease.
Time frame: Up to 6 months from enrollment
Progression-free survival (PFS) (Phase II, Non-Surgical Cohort)
PFS curves will be assessed via the Kaplan-Meier method.
Time frame: Time from study enrollment to disease progression or death from any cause, assessed up to 2 years
Overall survival (Phase II, Non-Surgical Cohort)
Will be assessed via the Kaplan-Meier method.
Time frame: From study enrollment to death from any cause, assessed up to 2 years
Progression-free survival (Phase II, Non-Surgical Cohort)
Kaplan-Meier method will be used to estimate the PFS within each randomized arm separately as well as combined.
Time frame: From randomization to disease progression or death from any cause, assessed up to 2 years
Overall survival (Phase II, Surgical Cohort)
Will be assessed via the Kaplan-Meier method.
Time frame: From study enrollment to death from any cause, assessed up to 2 years
Incidence of adverse events (Surgical Cohort and Non-Surgical Cohort)
Will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all adverse events by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) adverse event per patient will be presented overall and by adverse event type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher adverse event will be compared between treatment arm. Similarly, frequencies for specific potentially treatment related adverse events where grade 3 or higher events are noted may be compared. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level 0.05.
Time frame: Up to 2 years
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Kaiser Permanente-Ontario
Ontario, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer Center
Orange, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
Roseville, California, United States
Sutter Roseville Medical Center
Roseville, California, United States
Sutter Medical Center Sacramento
Sacramento, California, United States
...and 100 more locations