Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma
Phase 2 Study of Durvalumab (MEDI4736) in Patients With Glioblastoma
This is an ongoing Phase 2, open-label, multicenter, non-randomized study of MEDI4736
 (durvalumab) in subjects with glioblastoma (GBM) enrolled into 5 non-comparative cohorts.
 Primary study objectives, which vary by cohort due to differences in subject populations,
 include evaluation of the clinical efficacy as measured by the overall survival (OS) rate at
 12 months (Cohort A), progression-free survival (PFS) at 6 months (Cohorts B, B2, and B3),
 and OS at 6 months (Cohort C). For all cohorts, secondary objectives include evaluation of
 the safety/tolerability and clinical efficacy of study treatment, and exploratory objectives
 include evaluation of the neurologic function and correlative biomarkers.
Eligible subjects are enrolled in parallel into one of the following 5 cohorts as described
 below. In each cohort, the first study drug administration for the first subject and the
 second subject are separated by at least 1 week.

 -  Cohort A: Subjects with newly diagnosed unmethylated O^6-methylguanine-deoxyribonucleic
 acid methyltransferase (MGMT) GBM receive durvalumab (10 mg/kg every 2 weeks [Q2W]) +
 standard radiotherapy. The first 6 subjects are evaluated for dose-limiting toxicity
 (DLT) for 10 weeks to determine whether the durvalumab dose should be lowered to 3 or 1
 mg/kg.

 -  Cohort B: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg
 Q2W) as monotherapy.

 -  Cohort B2: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg
 Q2W) + bevacizumab (10 mg/kg Q2W).

 -  Cohort B3: Bevacizumab-naïve subjects with recurrent GBM receive durvalumab (10 mg/kg
 Q2W) + bevacizumab (3 mg/kg Q2W).

 -  Cohort C: Bevacizumab-refractory subjects with recurrent GBM receive durvalumab (10
 mg/kg Q2W) + continued bevacizumab (10 mg/kg Q2W). The first 6 subjects are evaluated
 for DLTs for 6 weeks to determine whether the durvalumab dose should be lowered to 3 or
 1 mg/kg.

 The Core Study lasts for up to 12 months; optional extension treatment may be offered to
 subjects who complete 51 weeks of treatment on the Core Study with stable disease or better
 and upon agreement between the subject, Investigator, and Sponsor.

 Subjects are followed on study for 90 days after the last drug administration and off study
 every 6 months for 3 years from the date of the first dose of study treatment.

 The primary study endpoints have been met, although some subjects remain in treatment and/or
 follow-up and data collection is ongoing.
Inclusion Criteria [criteria apply to all cohorts unless otherwise specified]:

 1. Cohort A: Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are
 eligible for standard radiation therapy.

 2. 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.

 3. 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).

 4. Cohorts B, B2, B3: No prior vascular endothelial growth factor (VEGF)/VEGF receptor
 targeted therapy; Cohort C: No more than one prior bevacizumab regimen.

 5. 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.

 6. Subjects with measurable or non-measurable disease.

 7. Histopathologic confirmation of glioblastoma.

 8. 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.

 9. 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.

 10. Eastern Cooperative Oncology Group (ECOG) ≤ 1 or Karnofsky performance status of ≥ 70.

 11. 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 < 1000 mg in a
 24-hour urine sample.

 12. Age must be greater than or equal to 18 years at date of consent.

 13. Written informed consent and any locally required authorization (e.g., Health
 Insurance Portability and Accountability Act [HIPAA] in the United States) obtained
 from the subject/legal representative prior to performing any protocol-related
 procedures, including screening evaluations.

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

 1. Primary tumors localized to the brain stem or spinal cord.

 2. Locally directed therapies including but not limited to stereotactic radiosurgery,
 re-irradiation, Gliadel®, and therapeutics administered by direct injection or
 convection-enhanced delivery within 6 months of start of study treatment.

 3. Prior exposure to durvalumab or other programmed cell death-1 (PD-1), programmed cell
 death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
 antibodies.

 4. Presence of diffuse leptomeningeal disease or extracranial disease.

 5. Active, suspected or prior documented autoimmune disease (including inflammatory bowel
 disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and
 Hashimoto's thyroiditis). Subjects with vitiligo, 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 are permitted to enroll.

 6. Known primary immunodeficiency or active human immunodeficiency virus.

 7. Known active or chronic viral hepatitis or history of any type of hepatitis within the
 last 6 months indicated by positive test for hepatitis B virus surface antigen or
 hepatitis C virus ribonucleic acid (hepatitis C virus antibody).

 8. History of organ transplant requiring use of immunosuppressive medication.

 9. History of active tuberculosis.

 10. Significant active systemic illness including infections requiring intravenous
 antibiotics.

 11. Current pneumonitis or interstitial lung disease.

 12. Other invasive malignancy within 2 years prior to entry into the study, except for
 those treated with surgical therapy only.

 13. History of severe allergic reactions to any unknown allergens or any components of the
 study drugs.

 14. Any prior grade ≥ 3 immune-related adverse event (irAE) or any prior
 corticosteroid-refractory irAE.

 15. Mental impairment that may compromise the ability to give informed consent and comply
 with the requirements of the study.

 16. Lack of availability for follow-up assessments.

 17. Lack of availability for Post Study Follow-up contacts to determine relapse and
 survival.

 18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test
 (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin).

 19. Women of childbearing potential not using a medically acceptable means of
 contraception for the duration of the study and unsterilized males not willing to
 abide by protocol-specified requirements for contraception.

 20. If a subject previously received another investigational treatment, the last dose of
 investigational treatment was administered within 4 weeks of Day 1 of the study.

 21. Any condition that, in the clinical judgment of the treating physician, is likely to
 prevent the subject from complying with any aspect of the protocol or that may put the
 subject at unacceptable risk.

 22. Cohorts B2, B3, and C:

 -  Evidence of hemorrhage on the baseline MRI or computed tomography (CT) scan other
 than those that are ≤ grade 1 and either post-operative or stable on at least two
 consecutive scans;

 -  Current use of warfarin sodium or any other Coumadin®-derivative anticoagulant.
 Participant must be off Coumadin-derivative anticoagulants for at least 7 days
 prior to starting study drug. Low molecular weight heparin and Factor Xa
 antagonists are allowed;

 -  History of clinically significant bleeding within 6 months of enrollment;

 -  History of arterial thromboembolism within 12 months prior to enrollment;

 -  Inadequately controlled hypertension (defined as systolic blood pressure > 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.

 23. Subjects must not donate blood while on study and for at least 90 days following the
 last durvalumab treatment.