Testing the Addition of the Immune Therapy Drugs Tocilizumab and Atezolizumab to Radiation Therapy for Recurrent Glioblastoma

  • STATUS
    Recruiting
  • End date
    Jun 1, 2025
  • participants needed
    12
  • sponsor
    National Cancer Institute (NCI)
Updated on 3 September 2021

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.

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).

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) 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.

GROUP I (NON-SURGICAL COHORT): Patients receive systemic treatment with tocilizumab IV over 60 minutes with or without atezolizumab IV over 30-60 minutes (dependent upon the results of the Safety Run-In) 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.

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 (dependent upon the results of the Safety Run-In) 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.

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.

After completion of study treatment, patients are followed up at 30 days, 3, 6, 9, 12, 18, and 24 months.

Details
Condition Recurrent Glioblastoma, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype, Diffuse Astrocytoma, IDH-Wildtype
Treatment conventional surgery, Tocilizumab, Atezolizumab, Fractionated Stereotactic Radiation Therapy
Clinical Study IdentifierNCT04729959
SponsorNational Cancer Institute (NCI)
Last Modified on3 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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)
Tumor that is in first recurrence following prior first-line radiation therapy (prior dose >= 40 Gy). Prior temozolomide, prior tumor-treating fields, and/or Gliadel wafers (if placed at initial tumor resection) are allowed, but none of these are required
Unequivocal radiographic evidence of tumor progression by contrast-enhanced magnetic resonance imaging (MRI) scan within 21 days prior to registration
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
Of 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
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
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)
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)
Age >= 18 years
Karnofsky performance status >= 70 within 14 days prior to registration
History/physical examination within 14 days prior to registration
Leukocytes >= 2,500/mm^3 (within 14 days prior to registration)
Absolute neutrophil count >= 1,500/mm^3 (within 14 days prior to registration)
Absolute lymphocyte count >= 800/mm^3 (within 14 days prior to registration)
Platelets >= 100,000/mm^3 (within 14 days prior to registration)
Hemoglobin >= 8 g/dL (within 14 days prior to registration)
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)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (within 14 days prior to registration)
Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (within 14 days prior to registration)
Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to registration)
Creatinine clearance >= 30 mL/min/1.73 m^2 by Cockcroft-Gault (within 14 days prior to registration)
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
Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to registration
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
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
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
The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
Availability of prior radiotherapy treatment plan details in Digital Imaging and Communications in Medicine (DICOM) format

Exclusion Criteria

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
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
Diffuse leptomeningeal disease
Known contrast-enhancing tumor in brainstem or spinal cord. If not previously completed, spinal imaging is not required to determine trial eligibility
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
Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody or pathway-targeting agents
Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-alpha or interleukin [IL]-2) within 4 weeks prior to registration
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
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
Patients with increased risk for gastrointestinal perforations including history of diverticulitis
Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
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
Note: patients with the below conditions are eligible
Autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
Controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only 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)
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), or organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.). History of radiation pneumonitis in a prior radiation field (fibrosis) is permitted
Patients with active tuberculosis (TB) are excluded
Severe infections within 3 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
Signs or symptoms of infection within 1 week prior to registration
Received oral or intravenous (IV) antibiotics within 2 weeks prior to registration. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
Major surgical procedure within 21 days prior to registration or anticipation of need for a major surgical procedure during the course of study treatment
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
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
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
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