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

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