Retifanlimab and Epacadostat in Combination With Radiation and Bevacizumab in Patients With Recurrent Gliomas

Inclusion Criteria

• Recurrent WHO grade 4 glioblastoma or gliosarcoma, including molecular features of glioblastoma and WHO grade 4 astrocytoma or WHO grade high grade glioma.
• Other GBM variants and "secondary GBM" are allowed. All grade 4 gliomas that have relapsed more than once may be included, as the prognosis of multiply recurrent grade 4 glioma patients may not differ based on IDH mutation status.
• Disease must have recurred, and patient must be a candidate for re-irradiation and bevacizumab. Any number of recurrences are allowed.
• Patients must have measurable disease per RANO criteria. Lesions will be considered measurable when they are bi-dimensional with clearly defined margins of ≥5 mm in two perpendicular diameters.
• Prior transient use of bevacizumab for cerebral edema or radiation necrosis is allowed without a washout period. Prior bevacizumab use is permitted if used for treatment of disease if administered more than 4 months prior to registration.
• At least 18 years of age.
• Karnofsky performance status ≥ 60%
• Normal bone marrow and organ function as defined below:
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 75,000/mcL
• Hemoglobin ≥ 9.0 g/dL or > 5.6 mmol/L (transfusion is acceptable to meet this criterion)
• Serum creatinine ≤ ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 by Cockcroft-Gault for patients
• Serum total bilirubin ≤ 1.5 ULN
• AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN
• INR or PT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• aPTT ≤ 1.5 x IULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
• At least 28 days from any major surgery such as craniotomy and surgical wound is fully healed, and at least 14 days from LITT or biopsy. Prior to surgery, there must be imaging evidence of measurable progressive disease (PD) per RANO criteria as noted above.
• Women of childbearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
• Prior use of the Optune device is allowed, without a washout period. However, concurrent Optune use is not permitted while on treatment for this trial.

Exclusion Criteria

• Currently receiving any other investigational agents.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to epacadostat, retifanlimab, bevacizumab, or other agents used in the study.
• Dexamethasone dose > 4 mg daily at the time of registration (higher dose of steroid for symptom control is allowed during the study).
• History of intracranial abscess within 6 months prior to start of study therapy.
• Has active autoimmune disease or syndrome (i.e. moderate or severe rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, active inflammatory bowel disease) that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) or who are receiving systemic therapy for an autoimmune or inflammatory disease (i.e. with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Subjects are permitted to enroll if they have vitiligo, resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to autoimmune condit