Inclusion Criteria:
1. Age ≥ 18 years old. 2. Pathologically confirmed GBM, IDHwt. 3. Clinical or radiologic evidence of first or second recurrence following radiation
and TMZ. Note: A diagnostic biopsy is required prior to the commencement of the
study drug if there is uncertainty about the MRI findings being true progression
versus pseudoprogression.
4. Tissue available from initial diagnosis of primary GBM. 5. Adequate organ function:
1. Hemoglobin ≥ 9 g/dl. 2. Platelet count ≥ 75,000/µl. 3. Neutrophil count ≥ 1000 cells/mm3. 4. Creatinine ≤ 1.5 x ULN (calculated using the Cockcroft-Gault formula)
5. Total bilirubin ≤ 1.5 x ULN (Exception: Participant has known or suspected
Gilbert's Syndrome for which additional lab testing of direct and/or indirect
bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤
3.0 x ULN is acceptable.)
6. Alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN)
7. AST and ALT ≤ 2.5 x ULN. 8. Serum albumin ≥ 25 g/L (2.5 g/dL)
9. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x ULN. 6. Karnofsky Performance Status (KPS) ≥ 70%
7. Patient or partner(s) meets one of the following criteria:
1. Non-childbearing potential (i.e., not sexually active, physiologically
incapable of becoming pregnant, including any female who is post-menopausal or
surgically sterile, or any male who has had a vasectomy). Surgically sterile
females are defined as those with a documented hysterectomy and/or bilateral
oophorectomy or tubal ligation. Postmenopausal for purposes of this study is
defined as 1 year without menses.; or. 2. Childbearing potential and agrees to use one of the following methods of birth
control: approved hormonal contraceptives (e.g., birth control pills, patches,
implants, or infusions), an intrauterine device, or a barrier method of
contraception (e.g., a condom or diaphragm) used with spermicide.
8. A signed informed consent form approved by the Institutional Review Board (IRB) will
be required for patient enrollment into the study. Patients must be able to read and
understand the informed consent document and must sign the informed consent
indicating that they are aware of the investigational nature of this study.
9. Negative HIV test at screening, with the following exception: patients with a
positive HIV test at screening are eligible provided they are stable on
anti-retroviral therapy, have a CD4 count > 200/µL, and have an undetectable viral
load. 10. Negative hepatitis B surface antigen (HBsAg) test at screening. Negative total
hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test
followed by a negative hepatitis B virus (HBV) DNA test at screening Note: The HBV
DNA test will be performed only for patients who have a negative HBsAg test and a
positive total HBcAb test.
11. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV
antibody test followed by a negative HCV RNA test at screening Note: The HCV RNA
test must be performed for patients who have a positive HCV antibody test.
Exclusion Criteria:
1. Pregnancy or breastfeeding or intention of becoming pregnant during study treatment
or within 5 months of final dose of atezolizumab therapy. a) For women of childbearing potential: Agree to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods as defined below: i) Women
must remain abstinent or use contraceptive methods with a failure rate of < 1% per
year during the treatment period and for 5 months after the final dose of
atezolizumab. Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine
devices. The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation
methods) and withdrawal are not adequate methods of contraception. If required per
local guidelines or regulations, locally recognized adequate methods of
contraception and information about the reliability of abstinence will be described
in the local Informed Consent Form.
ii) A woman is of childbearing potential if she is post-menarchal, has not reached a
postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause
other than menopause), and has not undergone surgical sterilization (removal of
ovaries, fallopian tubes and/or uterus) or another cause as determined by the
investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal
ligation is of childbearing potential. The definition of childbearing potential may
be adapted for alignment with local guidelines or requirements.
b) For men with pregnant female partners and/or with female partners of childbearing
potential: Agree to remain abstinent (refrain from heterosexual intercourse) or use
a condom and refrain from donating sperm.
i) With a female partner of childbearing potential or pregnant female partner, men
must remain abstinent or use a condom during the treatment period for 5 months after
the final dose of atezolizumab to avoid exposing the embryo. Men must refrain from
donating sperm during this same period. The reliability of sexual abstinence should
be evaluated in relation to the duration of the clinical trial and the preferred and
usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, or postovulation methods) and withdrawal are not adequate methods of
preventing drug exposure. If required per local guidelines or regulations,
information about the reliability of abstinence will be described in the local
Informed Consent Form.
2. Prior treatment with immunotherapy. 3. Prior treatment with bevacizumab within 4 weeks before biopsy. Note: Bevacizumab
will be permitted if necessary to control inflammatory side effects 5-7mg/kg Q 3/52
for up to 3 cycles. 4. Treatment with systemic immunosuppressive medication (including, but not limited to,
more than 2 mg of dexamethasone or equivalent corticosteroids, cyclophosphamide,
azathioprine, methotrexate, thalidomide, and anti-TNF-a agents) within 2 weeks prior
to initiation of study treatment, or anticipation of need for systemic
immunosuppressive medication during study treatment, with the following exceptions:
1. Patients who received acute, low-dose systemic immunosuppressant medication or
a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours
of corticosteroids for a contrast allergy) are eligible for the study.
2. Patients who received mineralocorticoids (e.g., fludrocortisone),
corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or
low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
are eligible for the study.
5. History of severe allergic anaphylactic reactions to chimeric or humanized
antibodies or fusion proteins. 6. Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation. 7. Active autoimmune disease or immune deficiency, including, but not limited to,
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody
syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or
multiple sclerosis (see Appendix E in Section 16.5 for a more comprehensive list of
autoimmune diseases and immune deficiencies), with the following exceptions:
1. Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of following conditions are
met:
i) Rash must cover < 10% of body surface area ii) Disease is well controlled at
baseline and requires only low-potency topical corticosteroids iii) There has been
no occurrence of acute exacerbations of the underlying condition requiring psoralen
plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral
calcineurin inhibitors, or high-potency or oral corticosteroids within the previous
12 months.
8. < 12 weeks from radiation therapy, unless progressive disease outside of previous
radiation field or 2 progressive MRIs, 4 weeks apart; (to avoid enrolling patients
with pseudoprogression)
9. Contraindication to surgery. 10. Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within
3 months prior to initiation of study treatment, unstable arrhythmia, or unstable
angina. 11. Major surgical procedure, other than for diagnosis, within 4 weeks prior to
initiation of study treatment, or anticipation of need for a major surgical
procedure during the study. 12. History of malignancy within 12 months prior to screening, with the exception of
malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >
90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin
carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage 1 uterine
cancer.
13. Severe infection within 4 weeks prior to initiation of study treatment, including,
but not limited to, hospitalization for complications of infection, bacteremia, or
severe pneumonia, or any active infection that could impact patient safety. 14. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of
study treatment, or anticipation of need for such a vaccine during atezolizumab
treatment or within 5 months after the final dose of atezolizumab. 15. Treatment with investigational therapy within 28 days prior to initiation of study
treatment. 16. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies. 17. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX) are allowed.
18. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium >
12 mg/dL or corrected serum calcium > ULN)
19. Active tuberculosis. 20. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis. History of radiation pneumonitis in the radiation field
(fibrosis) is permitted.
21. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
22. Prior allogeneic stem cell or solid organ transplantation
