Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma

Inclusion Criteria [criteria apply to all cohorts unless otherwise specified]:

• Cohort A: Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for standard radiation therapy.
• Cohorts B, B2, B3 and C: First or second recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) per modified Response Assessment in Neuro-oncology (RANO) criteria, with last baseline MRI confirmation within 14 days prior to Study Day 1. Note: Recurrence is defined as progression following therapy (i.e., chemotherapy; radiation). If the subject had a surgical resection for relapsed disease and no anti-tumor therapy was administered for up to 12 weeks, and the subject has further evidence of tumor growth or undergoes another resection, this will be considered as one episode of recurrence.
• Cohorts B, B2, B3 and C: On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease outside of the radiation field or histopathologic confirmation of unequivocal tumor).
• Cohorts B, B2, B3: No prior vascular endothelial growth factor (VEGF)/VEGF receptor targeted therapy; Cohort C: No more than one prior bevacizumab regimen.
• Cohorts B, B2, B3 and C: Recovery from any prior treatment clinically significant, related adverse events to grade ≤ 1 or pretreatment baseline with the exception of alopecia and laboratory values listed per inclusion criteria.
• Subjects with measurable or non-measurable disease.
• Histopathologic confirmation of glioblastoma.
• At the time of Study Day 1, subjects must be at least 4 weeks since major surgical procedure, open biopsy, or significant traumatic injury; there should be no anticipation of need for major surgical procedure during the course of the study. There should be no core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to Study Day 1.
• Subjects who have previously been treated with the Optune™ device are eligible for the study as long as toxicity related to the treatment has resolved to ≤ grade 1 or baseline.
• Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky performance status of ≥ 70.
• Adequate hematologic, renal and hepatic function, as defined below:
• Absolute neutrophil count ≥ 1000/mm^3;
• Platelet count ≥ 100,000/mm^3;
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN); or if subject has Gilbert syndrome, then total bilirubin ≤ 3 x ULN;
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.0 x ULN;
• Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula):
• Female CrCl = (140 - age in years) x weight in kg x 0.85/72 x serum creatinine in mg/dL;
• Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in mg/dL;
• Cohorts B2, B3 and C: Urinary protein quantitative value of ≤ 30 mg/dL in urinalysis or ≤1+ on dipstick, unless quantitative protein is 150 and/or diastolic blood pressure > 90 mmHg on antihypertensive medications);
• Any prior history of hypertensive crisis or hypertensive encephalopathy;
• Clinically significant cardiovascular disease within 12 months prior to enrollment (or randomization), including myocardial infarction, unstable angina, grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication, percutaneous transluminal coronary angioplasty/stent;
• Evidence of bleeding diathesis or coagulopathy;
• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment;
• Serious, non-healing wound, ulcer, or bone fracture.
• Subjects must not donate blood while on study and for at least 90 days following the last durvalumab treatment.