A Multicenter Trial to Identify Optimal Atezolizumab Biomarkers in the Setting of Recurrent Glioblastoma. The MOAB Trial

Inclusion Criteria:

1. Age ≥ 18 years old

2. Pathologically confirmed GBM, IDHwt

3. Clinical or radiologic evidence of first or second recurrence following radiationand TMZ. Note: A diagnostic biopsy is required prior to the commencement of thestudy drug if there is uncertainty about the MRI findings being true progressionversus pseudoprogression.

4. Tissue available from initial diagnosis of primary GBM

5. Adequate organ function:

6. Hemoglobin ≥ 9 g/dl

7. Platelet count ≥ 75,000/µl

8. Neutrophil count ≥ 1000 cells/mm3

9. Creatinine ≤ 1.5 x ULN (calculated using the Cockcroft-Gault formula)

10. Total bilirubin ≤ 1.5 x ULN (Exception: Participant has known or suspectedGilbert's Syndrome for which additional lab testing of direct and/or indirectbilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)

11. Alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN)

12. AST and ALT ≤ 2.5 x ULN

13. Serum albumin ≥ 25 g/L (2.5 g/dL)

14. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x ULN

15. Karnofsky Performance Status (KPS) ≥ 70%

16. Patient or partner(s) meets one of the following criteria:

17. Non-childbearing potential (i.e., not sexually active, physiologicallyincapable of becoming pregnant, including any female who is post-menopausal orsurgically sterile, or any male who has had a vasectomy). Surgically sterilefemales are defined as those with a documented hysterectomy and/or bilateraloophorectomy or tubal ligation. Postmenopausal for purposes of this study isdefined as 1 year without menses.; or

18. Childbearing potential and agrees to use one of the following methods of birthcontrol: approved hormonal contraceptives (e.g., birth control pills, patches,implants, or infusions), an intrauterine device, or a barrier method ofcontraception (e.g., a condom or diaphragm) used with spermicide.

19. A signed informed consent form approved by the Institutional Review Board (IRB) willbe required for patient enrollment into the study. Patients must be able to read andunderstand the informed consent document and must sign the informed consentindicating that they are aware of the investigational nature of this study.

20. Negative HIV test at screening, with the following exception: patients with apositive HIV test at screening are eligible provided they are stable onanti-retroviral therapy, have a CD4 count > 200/µL, and have an undetectable viralload

21. Negative hepatitis B surface antigen (HBsAg) test at screening. Negative totalhepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb testfollowed by a negative hepatitis B virus (HBV) DNA test at screening Note: The HBVDNA test will be performed only for patients who have a negative HBsAg test and apositive total HBcAb test.

22. Negative hepatitis C virus (HCV) antibody test at screening, or positive HCVantibody test followed by a negative HCV RNA test at screening Note: The HCV RNAtest 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 treatmentor within 5 months of final dose of atezolizumab therapy a) For women of childbearing potential: Agree to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods as defined below: i) Womenmust remain abstinent or use contraceptive methods with a failure rate of < 1% peryear during the treatment period and for 5 months after the final dose ofatezolizumab. Examples of contraceptive methods with a failure rate of < 1% per yearinclude bilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterinedevices. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of the patient.Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulationmethods) and withdrawal are not adequate methods of contraception. If required perlocal guidelines or regulations, locally recognized adequate methods ofcontraception and information about the reliability of abstinence will be describedin the local Informed Consent Form. ii) A woman is of childbearing potential if she is post-menarchal, has not reached apostmenopausal state (≥ 12 continuous months of amenorrhea with no identified causeother than menopause), and has not undergone surgical sterilization (removal ofovaries, fallopian tubes and/or uterus) or another cause as determined by theinvestigator (e.g., Müllerian agenesis). Per this definition, a woman with a tuballigation is of childbearing potential. The definition of childbearing potential maybe adapted for alignment with local guidelines or requirements. b) For men with pregnant female partners and/or with female partners of childbearingpotential: Agree to remain abstinent (refrain from heterosexual intercourse) or usea condom and refrain from donating sperm. i) With a female partner of childbearing potential or pregnant female partner, menmust remain abstinent or use a condom during the treatment period for 5 months afterthe final dose of atezolizumab to avoid exposing the embryo. Men must refrain fromdonating sperm during this same period. The reliability of sexual abstinence shouldbe evaluated in relation to the duration of the clinical trial and the preferred andusual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or postovulation methods) and withdrawal are not adequate methods ofpreventing drug exposure. If required per local guidelines or regulations,information about the reliability of abstinence will be described in the localInformed Consent Form.

2. Prior treatment with immunotherapy

3. Prior treatment with bevacizumab within 4 weeks before biopsy. Note: Bevacizumabwill be permitted if necessary to control inflammatory side effects 5-7mg/kg Q 3/52for 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 priorto initiation of study treatment, or anticipation of need for systemicimmunosuppressive medication during study treatment, with the following exceptions:

5. Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study.

6. Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

7. History of severe allergic anaphylactic reactions to chimeric or humanizedantibodies or fusion proteins

8. Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

9. 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 antibodysyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, ormultiple sclerosis (see Appendix E in Section 16.5 for a more comprehensive list ofautoimmune diseases and immune deficiencies), with the following exceptions:

10. Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.

11. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

12. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet: i) Rash must cover < 10% of body surface area ii) Disease is well controlled atbaseline and requires only low-potency topical corticosteroids iii) There has beenno occurrence of acute exacerbations of the underlying condition requiring psoralenplus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oralcalcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

13. < 12 weeks from radiation therapy, unless progressive disease outside of previousradiation field or 2 progressive MRIs, 4 weeks apart; (to avoid enrolling patientswith pseudoprogression)

14. Contraindication to surgery

15. Significant cardiovascular disease (such as New York Heart Association Class II orgreater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstableangina

16. Major surgical procedure, other than for diagnosis, within 4 weeks prior toinitiation of study treatment, or anticipation of need for a major surgicalprocedure during the study

17. History of malignancy within 12 months prior to screening, with the exception ofmalignancies 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 skincarcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage 1 uterinecancer.

18. Severe infection within 4 weeks prior to initiation of study treatment, including,but not limited to, hospitalization for complications of infection, bacteremia, orsevere pneumonia, or any active infection that could impact patient safety

19. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation ofstudy treatment, or anticipation of need for such a vaccine during atezolizumabtreatment or within 5 months after the final dose of atezolizumab

20. Treatment with investigational therapy within 28 days prior to initiation of studytreatment

21. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies

22. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently). Patients with indwellingcatheters (e.g., PleurX) are allowed.

23. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)

24. Active tuberculosis

25. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

26. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiationof study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent aurinary tract infection or chronic obstructive pulmonary disease exacerbation) areeligible for the study.

27. Prior allogeneic stem cell or solid organ transplantation