Nivolumab, Ipilimumab, and Short-course Radiotherapy in Adults With Newly Diagnosed, MGMT Unmethylated Glioblastoma

Inclusion Criteria

• Male or female subjects aged ≥18 years.
• Histopathological evidence of glioblastoma or gliosarcoma, WHO grade IV.
• Tumor MGMT promoter DNA not methylated (i.e., unmethylated) by central testing.
• Maximal tumor diameter (including residual tumor and resection cavity if subjects had tumor resection rather than only stereotactic biopsy) of 6.6 cm or less. Maximal tumor size allowed is derived from an estimated maximal radiotherapy planning target volume (PTV) of 150 cm3.
• Subjects must not have received any prior standard or investigational anti-tumor therapy other than surgery and must not intend to receive any standard or investigational anti-tumor therapy other than the study regimen.
• Karnofsky performance status (Appendix 2) of ≥60.
• Availability of a paraffin-embedded or frozen tumor-tissue block with a minimum of 1 cm2 of tumor surface area, or 20 unstained slides from the glioblastoma tissue specimen if a tumor block cannot be submitted.
• Subjects must start study agent within 6 weeks from the first diagnostic surgery for glioblastoma.
• An interval of at least 2 weeks for surgical resection and 1 week for stereotactic biopsy from the start of study treatment.
• A contrast-enhanced MRI must be obtained within 7 days of the first dose of study treatment.
• Adequate hematologic, hepatic, and renal function defined by
• White blood cell count ≥ 2.0 x 109/L
• Absolute neutrophil count ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin > 9 g/dL
• Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40 mL/min according to the Cockcroft-Gault formula or local institutional standard method
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
• Subjects on a standard high-dose steroid taper after craniotomy or stereotactic biopsy may have received a higher dose of corticosteroids within 14 days of registration, however must be at a dose < 10 mg daily prednisone or bioequivalent per day within 5 days prior to initiation of study drug.
• Administration of steroids through a route known to result in a minimal systemic exposure [i.e., intranasal, intraocular, inhaled, topical, or local injection (e.g., intra-articular injection) corticosteroids (<5% of body surface area)] are permitted in the absence of active autoimmune disease.
• Subjects requiring adrenal replacement with corticosteroids are eligible if the steroids are at doses ≤ 10 mg prednisone or bioequivalent per day in the absence of active autoimmune disease.
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) are allowed.
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. The following conditions are not exclusions (subjects with the following conditions are permitted):

a.Patients with diabetes type I, vitiligo, residual hypo- or hyperthyroidism due to autoimmune condition only requiring hormone replacement, or psoriasis not requiring systemic immunosuppressive treatment, or autoimmune conditions not expected to recur in the absence of an external trigger.

• Prior organ transplantation, including allogeneic stem cell transplantation.
• Known history of, or any evidence of active, non-infectious pneumonitis within the last 5 years.
• Known severe (NCI-CTCAE v4.03 Grade 3 or 4) infusion-related allergy or acute hypersensitivity reaction attributed to any monoclonal antibody, any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
• Unable tolerate an MRI, or have a contraindication to MRI.
• Active infection requiring systemic therapy.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquir