Testing the Addition of the Immune Therapy Drugs, Tocilizumab and Atezolizumab, to Radiation Therapy for Recurrent Glioblastoma
Testing the Addition of the Immune Therapy Drugs, Tocilizumab and Atezolizumab, to Radiation Therapy for Recurrent Glioblastoma
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), atezolizumab (anti-PD-L1), and FSRT. (Phase
 II Non-Surgical Cohort).

 II. 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
 Non-Surgical 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.

 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.
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.

 -  Must have confirmation of tumor progression via a biopsy

 -  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

 -  21 days from temozolomide

 -  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])/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)

 -  Administration of atezolizumab or tocilizumab may have an adverse effect on pregnancy
 and poses a risk to the human fetus, including embryo-lethality. 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 up to 5 months (150 days) after the last dose of
 study agent. 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:

 -  A stable regimen of highly active anti-retroviral therapy (HAART)

 -  No requirement for concurrent antibiotics or antifungal agents for the prevention
 of opportunistic infections

 -  A CD4 count above 250 cells/mm^3 and an undetectable HIV viral load on standard
 PCR-based tests

 -  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.

 -  Patients receiving dexamethasone or other systemic corticosteroids to treat brain
 edema and/or brain edema-related symptoms may be enrolled if the dexamethasone
 dose is =< 2 mg of dexamethasone (or equivalent) daily for a minimum of 5 days
 prior to registration. Patients receiving systemic corticosteroids for other
 indications are excluded.

 -  The use of topical corticosteroids, inhaled corticosteroids and
 mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic
 hypotension or adrenocortical insufficiency is allowed

 -  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.

 -  Patients with past or resolved hepatitis B infection (defined as having a
 negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
 [antibody to hepatitis B core antigen] antibody test) are eligible.

 -  Patients positive for hepatitis C virus (HCV) antibody are eligible only if
 polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)

 -  History or risk of autoimmune disease, including, but not limited to, systemic lupus
 erythematosus, rheumatoid 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.

 -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
 replacement hormone are eligible.

 -  Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are
 eligible.

 -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
 dermatologic manifestations only (e.g., patients with psoriatic arthritis would
 be excluded) 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)

 -  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

 -  Influenza vaccination should be given during influenza season only (approximately
 October to March). Patients must not receive live, attenuated influenza vaccine
 within 4 weeks prior to cycle 1, day 1 or at any time during study treatment

 -  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 because 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