In this study, the investigators propose to combine retifanlimab with radiation therapy (RT) and bevacizumab with or without epacadostat in the treatment of recurrent glioblastoma (GBM). The investigators hypothesize that this combination provides a powerful synergy between RT and immune modulators to produce more robust anti-tumor immune response, induce tumor regression and improve overall survival.

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 condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Has a severe acute or chronic medical condition including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
• Has had an allogeneic tissue/solid organ transplant.
• Has an active infection requiring intravenous antibiotic therapy. Has a known history of active tuberculosis (TB; bacillus tuberculosis).
• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or IDO inhibitor.
• If a patient is enrolled to regimen B, they are prohibited from receiving monoamine oxidase inhibitors (MAOIs) or drug which has significant MAOI activity (meperidine, linezolid, methylene blue) within the 21 days before screening.
• If a patient is enrolled to regimen B, the use of any UGT1A9 inhibitor from screening through follow-up period, including acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, phenytoin, probenecid, propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, valproic acid, and verapamil is prohibited.
• If a patient is enrolled to regimen B, the use of probiotics from screening through end of treatment is prohibited.
• If a patient is enrolled to regimen B, the use of warfarin is prohibited. If anti-coagulation is needed during the conduct of the study and non-warfarin regimens are not feasible, the participant must discontinue study therapy.
• Chronic use of systemic antibiotics (> 14 days) unless medical monitor review and approval.
• Any history of serotonin syndrome (SS) after receiving serotonergic drugs.
• Has uncontrolled HIV (HIV 1/2 antibodies). Well-controlled HIV is defined as CD4+ count > 300 cells, undetectable viral load, and receiving HAART/ART. Study specific HIV testing is not required for patients who do not have any prior history of HIV.
• Has uncontrolled active hepatitis B (e.g., HBsAg reactive or HBV DNA detected by quant RT PCR) or hepatitis C (e.g. HCsAg reactive or HCV RNA [qualitative or quantitative] is detected).
• Uncontrolled intercurrent illness including, but not limited to, clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 60 months prior to enrollment), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication.
• History or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening QTc interval > 480 msec will require investigator's evaluation on patient's eligibility. Subjects with left bundle branch block are excluded.
• Presence of a gastrointestinal condition that may affect drug absorption.
• Receipt of live attenuated vaccine within 30 days before the first dose of study treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test prior to the start of study treatment.