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