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

Inclusion Criteria:

• Histopathologically proven diagnosis of glioblastoma, OR molecular diagnosis ofglioblastoma per Consortium to Inform Molecular and Practical Approaches to CentralNervous 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 7gain 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)

• Note: Prior temozolomide, prior tumor-treating fields, and/or Gliadel wafers (if placed at initial tumor resection) are allowed, but none of these arerequired

• Unequivocal radiographic evidence of tumor progression by contrast-enhanced magneticresonance imaging (MRI) scan within 21 days prior to registration

• Per radiation oncologist review of MRI within 21 days prior to registration, musthave 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 inlargest 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 beingtargeted for FSRT) is allowed if the above criteria are met for the tumor thatis the proposed target for FSRT

• Surgical cohort only (Phase II only):

• Must be a candidate for repeat surgery (significant debulking or gross totalresection of the contrast enhancing area) as determined by the neurosurgeon ormultidisciplinary team

• Tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT)methylation status must be available from any prior GBM tumor specimen; results ofroutinely used methods for MGMT methylation testing (e.g. mutagenically separatedpolymerase chain reaction [MSPCR] or quantitative polymerase chain reaction [PCR])are acceptable)

• The following intervals from previous treatments to registration are required to beeligible:

• If prior radiation was < 60 Gy, an interval of at least 12 weeks (84 days) musthave elapsed since the completion of radiation therapy

• If prior radiation was >= 60 Gy, an interval of least 6 months (182 days) musthave elapsed since the completion of radiation therapy, unless the targetlesion for FSRT is outside of the 80% isodose line of the original radiationplan

• 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 atleast 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-targetingagents 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 beenrolled) (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 xULN (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 priorto 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, forthe 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 thelast dose of atezolizumab. Administration of atezolizumab or tocilizumab may have anadverse effect on pregnancy and poses a risk to the human fetus, includingembryo-lethality. Should a woman become pregnant or suspect she is pregnant whileshe or her partner is participating in this study, she should inform her treatingphysician immediately

• Women of childbearing potential must have a negative serum or urine pregnancy testwithin 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 theprevention of opportunistic infections

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral 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 unlessthe viral load becomes undetectable on suppressive therapy. Patients who areimmune 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 beentreated 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 (HCVribonucleic acid [RNA]) indicating acute or chronic infection would make thepatient ineligible unless the viral load becomes undetectable on suppressivetherapy

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry

• Availability of prior radiotherapy treatment plan details in Digital Imaging andCommunications 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 trialeligibility

• Diffuse leptomeningeal disease

• Known contrast-enhancing tumor in brainstem or spinal cord. If not previouslycompleted, spinal imaging is not required to determine trial eligibility

• Patients with clinically significant mass effect or midline shift (e.g., 1-2 cm ofmidline shift)

• Prior bevacizumab therapy

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of theinvestigational regimen are excluded from this trial. Otherwise, patients with prioror concurrent malignancy are eligible

• Patients with prior allogeneic bone marrow transplantation or prior solid organtransplantation

• Prior treatment with anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapeutic antibody orpathway-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 limitedto, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumornecrosis factor [anti-TNF] agents) within 2 weeks prior to registration

• Systemic corticosteroids used to treat brain edema and/or related symptoms at a doseof > 2 mg of dexamethasone (or equivalent) daily within 5 days prior toregistration. Patients receiving systemic corticosteroids for other indications areexcluded

• Patients with increased risk for gastrointestinal perforations including history ofdiverticulitis

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinanthuman antibodies

• History of severe allergic, anaphylactic, or other hypersensitivity reactions tochimeric or humanized antibodies or fusion proteins

• Known clinically significant liver disease, including active viral, alcoholic, orother hepatitis; cirrhosis; fatty liver; and inherited liver disease

• History or risk of autoimmune disease, including, but not limited to, systemic lupuserythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory boweldisease, vascular thrombosis associated with antiphospholipid syndrome, Wegener'sgranulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiplesclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.

• Note: patients with the below conditions are eligible:

• Autoimmune hypothyroidism on a stable dose of thyroid replacement hormoneare eligible.

• Controlled type 1 diabetes mellitus on a stable insulin regimen areeligible.

• Eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologicmanifestations only are permitted provided that they meet the followingconditions:

• Patients with psoriasis must have a baseline ophthalmologic exam torule out ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potencytopical 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 12months (not requiring psoralen plus ultraviolet A radiation [PUVA],methotrexate, retinoids, biologic agents, oral calcineurininhibitors; high potency or oral steroids)

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), ororganizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizingpneumonia, etc.)

• Note: History of radiation pneumonitis in a prior radiation field (fibrosis) ispermitted

• Patients with active tuberculosis (TB) are excluded

• Severe infections within 3 weeks prior to registration including, but not limitedto, 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

• Note: Patients receiving prophylactic antibiotics (e.g., for prevention of aurinary tract infection or chronic obstructive pulmonary disease) are eligible

• Major surgical procedure within 21 days prior to registration or anticipation ofneed for a major surgical procedure during the course of study treatment

• Administration of a live, attenuated vaccine within 4 weeks before registration oranticipation that such a live, attenuated vaccine will be required during receipt ofstudy treatment and up to 5 months after the last dose of study drug

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Women who are pregnant or nursing (and unwilling to discontinue) are excluded fromthis study. Atezolizumab and tocilizumab are agents with the potential forteratogenic or abortifacient effects. Because there is an unknown but potential riskfor adverse events in nursing infants secondary to treatment of the mother withatezolizumab and tocilizumab breastfeeding should be discontinued if the mother istreated with atezolizumab and tocilizumab