Testing the Addition of the Immune Therapy Drugs, Tocilizumab and Atezolizumab, to Radiation Therapy for Recurrent Glioblastoma
- Conditions
- Recurrent GlioblastomaDiffuse Astrocytoma, IDH-Wildtype
- Interventions
- Procedure: Biospecimen CollectionRadiation: Fractionated Stereotactic Radiation TherapyProcedure: Conventional SurgeryProcedure: Magnetic Resonance Imaging
- Registration Number
- NCT04729959
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
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 21-24 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 53
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Histopathologically proven diagnosis of glioblastoma, OR molecular diagnosis of glioblastoma per Consortium to Inform Molecular and Practical Approaches to Central Nervous System Tumor Taxonomy (c-IMPACT-NOW) criteria ("diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, World Health Organization [WHO] grade IV"; this requires presence of amplification of EGFR, whole chromosome 7 gain AND whole chromosome 10 loss, or TERT promoter mutation)
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Tumor that is in first recurrence following prior first-line radiation therapy (prior dose >= 40 Gy)
- Note: Prior temozolomide, prior tumor-treating fields, and/or Gliadel wafers (if placed at initial tumor resection) are allowed, but none of these are required
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Unequivocal radiographic evidence of tumor progression by contrast-enhanced magnetic resonance imaging (MRI) scan within 21 days prior to registration
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Per radiation oncologist review of MRI within 21 days prior to registration, must have focus of progressive, contrast-enhancing tumor that is amenable to FSRT, defined as the following:
- At least 1 cm x 1 cm contrast-enhancing tumor that is no greater than 4 cm in largest dimension
- FSRT target is at least 0.5 cm from the optic chiasm and brainstem
- Note, multifocal disease (i.e., other sites of tumor beyond the tumor being targeted for FSRT) is allowed if the above criteria are met for the tumor that is the proposed target for FSRT
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Surgical cohort only (Phase II only):
- Must be a candidate for repeat surgery (significant debulking or gross total resection of the contrast enhancing area) as determined by the neurosurgeon or multidisciplinary team
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Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) methylation status must be available from any prior GBM tumor specimen; results of routinely used methods for MGMT methylation testing (e.g. mutagenically separated polymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR]) are acceptable)
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The following intervals from previous treatments to registration are required to be eligible:
- If prior radiation was < 60 Gy, an interval of at least 12 weeks (84 days) must have elapsed since the completion of radiation therapy
- If prior radiation was >= 60 Gy, an interval of least 6 months (182 days) must have elapsed since the completion of radiation therapy, unless the target lesion for FSRT is outside of the 80% isodose line of the original radiation plan
- At least 21 days from temozolomide
- At least 28 days from any investigational (not Food and Drug Administration [FDA]-approved for glioblastoma) agents, or within a time interval less than at least 5 half-lives of the investigational agent whichever is shorter (Note: anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or pathway-targeting agents are not allowed)
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Age >= 18 years
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Karnofsky performance status >= 70 within 14 days prior to registration
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History/physical examination within 14 days prior to registration
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Leukocytes >= 2,500/mm^3 (within 14 days prior to registration)
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Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to registration)
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Absolute lymphocyte count >= 800/mm^3 (within 14 days prior to registration)
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Platelets >= 100,000/mm^3 (within 14 days prior to registration)
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Hemoglobin >= 8 g/dL (within 14 days prior to registration)
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Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (however, patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled) (within 14 days prior to registration)
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Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (within 14 days prior to registration)
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Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (within 14 days prior to registration)
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Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to registration)
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Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault (within 14 days prior to registration)
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Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of receipt of study treatment, and for 60 days (males) or 90 days (females) from the last dose of tocilizumab and for 5 months (150 days) after the last dose of atezolizumab. Administration of atezolizumab or tocilizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
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Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to registration
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Patients positive for human immunodeficiency virus (HIV) are allowed on study (note: HIV testing is not required), but HIV-positive patients must have:
- An undetectable viral load within 6 months of registration
- A stable regimen of highly active anti-retroviral therapy (HAART)
- No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
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For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
- Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-Hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B
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For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
- Note: Known positive test for hepatitis C virus ribonucleic acid (HCV ribonucleic acid [RNA]) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
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Availability of prior radiotherapy treatment plan details in Digital Imaging and Communications in Medicine (DICOM) format
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Known somatic tumor mutation in IDH1 or IDH2 gene. If not previously completed, sequencing of the IDH1 and IDH2 genes is not required to determine trial eligibility
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Known germline DNA repair defect (mismatch repair deficiency, POLE mutation, e.g.). If not previously completed, germline sequencing is not required to determine trial eligibility
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Diffuse leptomeningeal disease
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Known contrast-enhancing tumor in brainstem or spinal cord. If not previously completed, spinal imaging is not required to determine trial eligibility
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Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm of midline shift)
-
Prior bevacizumab therapy
-
Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are excluded from this trial. Otherwise, patients with prior or concurrent malignancy are eligible
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Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
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Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or pathway-targeting agents
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Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 4 weeks prior to registration
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Treatment with systemic immunosuppressive medications (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to registration
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Systemic corticosteroids used to treat brain edema and/or related symptoms at a dose of > 2 mg of dexamethasone (or equivalent) daily within 5 days prior to registration. Patients receiving systemic corticosteroids for other indications are excluded
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Patients with increased risk for gastrointestinal perforations including history of diverticulitis
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Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
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History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
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Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
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History or risk of autoimmune disease, including, but not limited to, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.
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Note: patients with the below conditions are eligible:
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Autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible.
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Controlled type 1 diabetes mellitus on a stable insulin regimen are eligible.
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Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only are permitted provided that they meet the following conditions:
- Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
-
-
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History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), or organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.)
- Note: History of radiation pneumonitis in a prior radiation field (fibrosis) is permitted
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Patients with active tuberculosis (TB) are excluded
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Severe infections within 3 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
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Signs or symptoms of infection within 1 week prior to registration
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Received oral or intravenous (IV) antibiotics within 2 weeks prior to registration
- Note: Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
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Major surgical procedure within 21 days prior to registration or anticipation of need for a major surgical procedure during the course of study treatment
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Administration of a live, attenuated vaccine within 4 weeks before registration or anticipation that such a live, attenuated vaccine will be required during receipt of study treatment and up to 5 months after the last dose of study drug
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
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Women who are pregnant or nursing (and unwilling to discontinue) are excluded from this study. Atezolizumab and tocilizumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab and tocilizumab breastfeeding should be discontinued if the mother is treated with atezolizumab and tocilizumab
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Biospecimen Collection 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Conventional Surgery 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. Group I (tocilizumab, atezolizumab, FSRT) Magnetic Resonance Imaging 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 I (tocilizumab, atezolizumab, FSRT) Fractionated Stereotactic Radiation Therapy 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, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Conventional Surgery 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. Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Magnetic Resonance Imaging 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. Group II, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Fractionated Stereotactic Radiation Therapy 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. Group II, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Magnetic Resonance Imaging 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. Group II, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Biospecimen Collection 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. Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Fractionated Stereotactic Radiation Therapy 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. Group I (tocilizumab, atezolizumab, FSRT) Tocilizumab 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 I (tocilizumab, atezolizumab, FSRT) Atezolizumab 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, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Atezolizumab 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. Group II, Arm I (tocilizumab, atezolizumab, FSRT, surgery) Tocilizumab 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. Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Atezolizumab 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study. Group II, Arm II (tocilizumab, atezolizumab, FSRT, surgery) Tocilizumab 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 21-24 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 and tumor tissue collection on study. Patients undergo MRI throughout the trial, as well as blood sample and tumor tissue collection on study.
- Primary Outcome Measures
Name Time Method Dose-limiting toxicities (Safety Run-In) Up to 1 post-fractionated stereotactic radiation therapy (FRST) cycle of systemic therapy for which dose-limiting toxicity is reached (1 cycle = 4 weeks) Will be assessed by Common Terminology Criteria for Adverse Events version 5.0.
Maximum-tolerated dose (Safety Run-In) 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) Up to 6 months from enrollment 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.
- Secondary Outcome Measures
Name Time Method Progression-free survival (Phase II, Non-Surgical Cohort) From randomization to disease progression or death from any cause, assessed up to 2 years Kaplan-Meier method will be used to estimate the PFS within each randomized arm separately as well as combined.
Progression-free survival (PFS) (Phase II, Non-Surgical Cohort) Time from study enrollment to disease progression or death from any cause, assessed up to 2 years PFS curves will be assessed via the Kaplan-Meier method.
Incidence of adverse events (Surgical Cohort and Non-Surgical Cohort) Up to 2 years 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.
Overall survival (Phase II, Non-Surgical Cohort) From study enrollment to death from any cause, assessed up to 2 years Will be assessed via the Kaplan-Meier method.
Overall survival (Phase II, Surgical Cohort) From study enrollment to death from any cause, assessed up to 2 years Will be assessed via the Kaplan-Meier method.
Trial Locations
- Locations (111)
Overlook Hospital
🇺🇸Summit, New Jersey, United States
Kaiser Permanente-Anaheim
🇺🇸Anaheim, California, United States
Kaiser Permanente-Bellflower
🇺🇸Bellflower, California, United States
Memorial Hospital North
🇺🇸Colorado Springs, Colorado, United States
Poudre Valley Hospital
🇺🇸Fort Collins, Colorado, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
Illinois CancerCare - Washington
🇺🇸Washington, Illinois, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
Illinois CancerCare-Kewanee Clinic
🇺🇸Kewanee, Illinois, United States
Illinois CancerCare-Princeton
🇺🇸Princeton, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Illinois CancerCare-Macomb
🇺🇸Macomb, Illinois, United States
Research Medical Center
🇺🇸Kansas City, Missouri, United States
Carle Physician Group-Mattoon/Charleston
🇺🇸Mattoon, Illinois, United States
Cancer Care Center of O'Fallon
🇺🇸O'Fallon, Illinois, United States
Illinois CancerCare-Ottawa Clinic
🇺🇸Ottawa, Illinois, United States
Illinois CancerCare-Pekin
🇺🇸Pekin, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸Peoria, Illinois, United States
OSF Saint Francis Medical Center
🇺🇸Peoria, Illinois, United States
Illinois CancerCare-Peru
🇺🇸Peru, Illinois, 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
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
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
Kaiser Permanente-San Diego Zion
🇺🇸San Diego, California, United States
California Pacific Medical Center-Pacific Campus
🇺🇸San Francisco, California, United States
UCHealth University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Miami Cancer Institute
🇺🇸Miami, Florida, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Illinois CancerCare-Bloomington
🇺🇸Bloomington, Illinois, United States
Illinois CancerCare-Canton
🇺🇸Canton, Illinois, United States
Illinois CancerCare-Carthage
🇺🇸Carthage, Illinois, United States
Centralia Oncology Clinic
🇺🇸Centralia, Illinois, United States
Carle at The Riverfront
🇺🇸Danville, Illinois, United States
UCHealth Memorial Hospital Central
🇺🇸Colorado Springs, Colorado, United States
UCHealth Greeley Hospital
🇺🇸Greeley, Colorado, United States
Cancer Care and Hematology-Fort Collins
🇺🇸Fort Collins, Colorado, United States
Boca Raton Regional Hospital
🇺🇸Boca Raton, Florida, United States
Medical Center of the Rockies
🇺🇸Loveland, Colorado, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
Cancer Care Specialists of Illinois - Decatur
🇺🇸Decatur, Illinois, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Carle Physician Group-Effingham
🇺🇸Effingham, Illinois, United States
Crossroads Cancer Center
🇺🇸Effingham, Illinois, United States
Illinois CancerCare-Eureka
🇺🇸Eureka, Illinois, United States
NorthShore University HealthSystem-Evanston Hospital
🇺🇸Evanston, Illinois, United States
Illinois CancerCare-Galesburg
🇺🇸Galesburg, Illinois, United States
University of Kansas Cancer Center-Overland Park
🇺🇸Overland Park, Kansas, United States
University of Kansas Hospital-Indian Creek Campus
🇺🇸Overland Park, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸Westwood, Kansas, United States
Ascension Via Christi Hospitals Wichita
🇺🇸Wichita, Kansas, United States
MaineHealth Maine Medical Center - Portland
🇺🇸Portland, Maine, United States
MaineHealth Cancer Care Center of York County
🇺🇸Sanford, Maine, United States
MaineHealth Maine Medical Center- Scarborough
🇺🇸Scarborough, Maine, United States
MaineHealth Cancer Care and IV Therapy - South Portland
🇺🇸South Portland, Maine, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
University of Kansas Cancer Center - North
🇺🇸Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit
🇺🇸Lee's Summit, Missouri, United States
University of Kansas Cancer Center at North Kansas City Hospital
🇺🇸North Kansas City, Missouri, United States
Benefis Sletten Cancer Institute
🇺🇸Great Falls, Montana, United States
Logan Health Medical Center
🇺🇸Kalispell, Montana, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Jersey Shore Medical Center
🇺🇸Neptune, New Jersey, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
🇺🇸New York, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
University of Cincinnati Cancer Center-UC Medical Center
🇺🇸Cincinnati, Ohio, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Riverside Methodist Hospital
🇺🇸Columbus, Ohio, United States
University of Cincinnati Cancer Center-West Chester
🇺🇸West Chester, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Legacy Mount Hood Medical Center
🇺🇸Gresham, Oregon, United States
Legacy Good Samaritan Hospital and Medical Center
🇺🇸Portland, Oregon, United States
Legacy Meridian Park Hospital
🇺🇸Tualatin, Oregon, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Geisinger Medical Oncology-Lewisburg
🇺🇸Lewisburg, Pennsylvania, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
UPMC-Presbyterian Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸Pittsburgh, Pennsylvania, United States
UPMC-Shadyside Hospital
🇺🇸Pittsburgh, Pennsylvania, United States
Geisinger Cancer Services-Pottsville
🇺🇸Pottsville, Pennsylvania, United States
Reading Hospital
🇺🇸West Reading, Pennsylvania, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸Wilkes-Barre, Pennsylvania, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Sanford Cancer Center Oncology Clinic
🇺🇸Sioux Falls, South Dakota, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Vanderbilt University/Ingram Cancer Center
🇺🇸Nashville, Tennessee, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
Inova Schar Cancer Institute
🇺🇸Fairfax, Virginia, United States
Bon Secours Saint Francis Medical Center
🇺🇸Midlothian, Virginia, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
Valley Medical Center
🇺🇸Renton, Washington, United States
Legacy Cancer Institute Medical Oncology and Day Treatment
🇺🇸Vancouver, Washington, United States
Legacy Salmon Creek Hospital
🇺🇸Vancouver, Washington, United States
Langlade Hospital and Cancer Center
🇺🇸Antigo, Wisconsin, United States
Aspirus Cancer Care - James Beck Cancer Center
🇺🇸Rhinelander, Wisconsin, United States
Aspirus Cancer Care - Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
UW Cancer Center at ProHealth Care
🇺🇸Waukesha, Wisconsin, United States
Aspirus Regional Cancer Center
🇺🇸Wausau, Wisconsin, United States
Aspirus Cancer Care - Wisconsin Rapids
🇺🇸Wisconsin Rapids, Wisconsin, United States