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.
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