A Randomized Phase IIB Open Label Study of Nivolumab or Nivolumab in Combination with Ipilimumab versus Bevacizumab in Adult Subjects with Recurrent Glioblastoma (GBM)
Inclusion Criteria: a) Histologically confirmed diagnosis of World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma), b) Previous first line treatment with at least radiotherapy and temozolomide, c) Documented first recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) performed within 28 days of randomization per RANO criteria, d) If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after the end of prior radiation therapy is required unless there is either: i) histopathologic confirmation of recurrent tumor, or ii) new enhancement on MRI outside of the radiotherapy treatment field, e) At least one measurable GBM lesion prior to randomization that meets the following criteria: i) Contrast enhancing and clearly defined, bi-dimensionally measurable margins AND ii) At least two perpendicular diameters measuring greater than and equal to 10mm x greater than and equal to 10mm (Note: MRI measurements will not include surgical cavity, cyst, or necrotic area), f) An interval of greater than or equal to 4 weeks since surgical resection prior to randomization, g) An interval of greater than or equal to 4 weeks after the last administration of any other treatment for GBM, h) Karnofsky performance status of 70 or higher (Appendix 1), i) Life expectancy of greater than or equal to 12 weeks, j) Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been randomized/has not been treated). If re-enrolled, the subject must be re-consented, k) Men and women, age greater than or equal to 18 years old at the time of screening. Exclusion Criteria: 1. Target Disease Exceptions a) More than one recurrence of GBM, b) Presence of extracranial metastatic or leptomeningeal disease, and c) Diagnosis of secondary GBM (ie, glioblastomas that progress from low grade diffuse astrocytoma or anaplastic astrocytoma), 2. Medical History and concurrent Diseases a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. b) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition. c) Previous radiation therapy with anything other than standard radiation therapy (ie, focally directed radiation). d) Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids ( greater than 10mg/day prednisone equivalents) for control of their disease at randomization are excluded e) Previous treatment with Gliadel f) Previous bevacizumab or other VEGF or anti-angiogenic treatment g) Previous treatment with a PD-1 or CTLA-4 targeted therapy h) Evidence of greater than Grade 1 CNS hemorrhage on the baseline MRI scan; i) Inadequately controlled hypertension (defined as systolic blood pressure ï¿½ 150 mmHg and/or diastolic blood pressure ï¿½ 100 mmHg) within 28 days of first study treatment; j) Prior history of hypertensive crisis, hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome (RPLS); k) Prior history of gastrointestinal diverticulitis, perforation, or abscess; l) Clinically significant (ie, active) cardiovascular disease, for example cerebrovascular accidents ï¿½ 6 months prior to study enrollment, myocardial infarction ï¿½ 6 months prior to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with protocol treatment; m) History or evidence upon physical/neurological examination of central nervous system disease (eg, seizures) unrelated to cancer unless adequately controlled by medication or potentially interfering with protocol treatment; n) Significant vascular disease (eg, aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to start of study treatment. Any previous venous thromboembolism greater than NCI CTCAE Grade 3; o) History of pulmonary hemorrhage/hemoptysis ï¿½ grade 2 (defined as ï¿½ 2.5 mL bright red blood per episode) within 1 month prior to randomization; p) History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (ie, in the absence of therapeutic anticoagulation); q) Current or recent (within 10 days of study enrollment) use of aspirin ( greater than 325 mg/day), clopidogrel ( greater than 75 mg/day) or equivalent. Prophylactic use of anticoagulants is allowed; r) Surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to first study treatment, or anticipation of need for major surgical procedure during the course of the study; s) Minor surgical procedure (eg, stereotactic biopsy within 7 days of first study treatment; placement of a vascular access device within 2 days of first study treatment); t) History of intracranial abscess within 6 months prior to randomization; u) History oumabf active gastrointestinal bleeding within 6 months prior to randomization; v) Serious, non-healing wound, active ulcer, or untreated bone fracture; w) Subjects unable (due to existent medical condition, eg, pacemaker or ICD device) or unwilling to have a head contrast enhanced MRI 3. Physical and Laboratory Test Findings a) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection b) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated by local requirements. 4. Allergies and Adverse Drug Reaction a) History of allergy to study drug components. b) History of severe hypersensitivity reaction to any monoclonal antibody. 5. Sex and Reproductive Status 6. Other Exclusion Criteria a) Prisoners or subjects who are involuntarily incarcerated b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
The study is divided into two cohorts (groups). The purpose of Cohort 1 is to test the safety and tolerability of an investigational drug called nivolumab (also known as BMS-936558), either alone or in combination with a drug called ipilimumab (also known as Yervoy) in patients diagnosed with glioblastoma (a type of brain tumor). Both nivolumab and ipilimumab are antibodies (a type of human protein) that are being tested to see if it will allow the body's immune system to work against tumor cells. Ipilimumab (Yervoy) is approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA) and other health authorities for the treatment of metastatic melanoma. An investigational drug is one that is not approved by the FDA or any other agency and is being studied and developed. The purpose of the second group, Cohort 2, is to test the effectiveness (how well the drug works), safety, and tolerability of nivolumab and of nivolumab in combination with ipilimumab will be compared with bevacizumab (Avastin). Bevacizumab is an anti-angiogenic (tumor starving/anti-cancer) therapy. Bevacizumab blocks a protein called vascular endothelial growth factor (VEGF). Blocking VEGF may prevent the growth of new blood vessels that feed tumors. Bevacizumab is approved in the United States by the FDA for the treatment of patients diagnosed with glioblastoma that has recurred following prior therapy. In Cohort 2 the effectiveness of the study medications will be determined by comparing the survival time of patients who receive nivolumab, or nivolumab and ipilimumab versus those who receive bevacizumab.
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