The Preston Robert Tisch Brain Tumor Center at Duke

Clinical Trials for Adults | A Randomized Phase IIB Open Label Study of Nivolumab or Nivolumab in Combination with Ipilimumab versus Bevacizumab in Adult Subjects with Recurrent Glioblastoma (GBM)

This is the first study examining the use of nivolumab and ipilimumab in GBM. This study will include two cohorts: a safety lead-in with nivolumab or nivolumab in combination with
ipilimumab (Cohort 1); and an efficacy cohort comparing nivolumab or nivolumab in combination with ipilimumab versus bevacizumab randomized in a 1:1:1 fashion (Cohort 2).

Randomization in Cohort 2 will only occur after successful demonstration of tolerability in the safety lead in phase of the study.

  • Dosing is based upon prior experience with the investigational agents in the treatment of other tumor types (eg,, melanoma).
    • Subjects in the nivolumab arm will receive 3mg/kg every 2 weeks.
    • Subjects in the combination arm, will receive nivolumab1mg/kg + ipilimumab 3mg/kg every 3 weeks for four doses, then nivolumab 3mg/kg every 2 weeks thereafter.
    • Subjects in the combination arm who discontinue nivolumab + ipilimumabdue to treatment related adverse events prior to completing the fourth dose may begin nivolumab 3 mg/kg every 2 weeks with prior approval of BMS
    • Cohort 2 Bevacizumab will be dosed at 10mg/kg every 2 weeks per drug label.

Subjects will continue to receive study medication until confirmed tumor progression, and then will enter a follow-up phase to gather information on overall survival. This study will also provide data regarding progression free survival, objective response rate, biomarkers of disease progression, and health outcomes.


Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of immuno-oncology and treatment with investigational agents targeting this mechanism has
induced regressions in several types of cancer. Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) receptor are two important cellular targets that play complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. In preclinical models, combined blockade of PD-1 and CTLA-4 achieved more pronounced antitumor activity than blockade of either pathway alone.

Nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) is a fully human monoclonal immunoglobulin (Ig) G4 antibody that binds to the PD-1 cell surface membrane receptor, a
negative regulatory molecule expressed by activated T and B lymphocytes. Inhibition of the interaction between PD-1 and its ligands promote immune responses and antigen-specific T cell responses to both foreign and self antigens. PD-1 receptor blockade by nivolumab is a new approach for immunotherapy of tumors.

Results from a Phase I/II study (CA209003) indicate that nivolumab is active in multiple tumor types. Nivolumab 3 mg/kg monotherapy is currently being studied in phase 3 clinical trials in advanced melanoma, renal cell carcinoma (RCC) and non-small cell lung carcinoma (NSCLC).

Ipilimumab is a fully humanized IgG1 monoclonal antibody (mAb) binding to the anti-cytotoxic T-cell lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for metastatic
melanoma [Yervoy] Prescribing Information, 2011] and has demonstrated improved overall survival as monotherapy and in combination with dacarbazine. Ipilimumab has been studied in combination with multiple standard of care (SOC) therapies including chemotherapy for squamous and non-squamous NSCLC and radiotherapy for hormone resistant prostate cancer. Phase III studies are ongoing in NSCLC, small cell lung carcinoma (SCLC), and prostate carcinoma. In vitro combinations of nivolumab plus ipilimumab increase IFN- production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone.

Inclusion criteria:

  • Men and women, age >18 years old at the time of screening
  • Histologically confirmed diagnosis of World Health Organization Grade IV malignant glioma (glioblastoma or gliosarcoma)
  • Previous first line treatment with at least radiotherapy and temozolomide
  • Documented first recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) performed within 28 days of randomization per RANO criteria
  • 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:
    • histopathologic confirmation of recurrent tumor, or
    • new enhancement on MRI outside of the radiotherapy treatment field
  • At least one measurable GBM lesion prior to randomization that meets the following criteria:
    • contrast enhancing and clearly defined, bi-dimensionally measurable margins AND
    • at least two perpendicular diameters measuring >10mm x >10mm (Note: MRI measurements will not include surgical cavity, cyst, or necrotic area)
  • Karnofsky performance status of 70 or higher
  • An interval of >4 weeks since surgical resection prior to randomization
  • An interval of >4 weeks after the last administration of any other treatment for GBM
  • Life expectancy of >12 weeks
  • Women of childbearing potential (WOCBP) must have negative serum or urine pregnancy test within 24 hours prior to the start of the study drug and subject must agree to use two highly effective methods of contraception
  • Screening/baseline lab values must meet the following criteria (using CTCAE v4) WBC >2000/uL, Neutrophils >1500/uL, platelets >100 x103/uL, Hemoglobin >9.0 g/dL, serum creatinine <1.5x ULN, AST <3xULN, ALT <3x ULN, Bilirubin <1.5x ULN
  • Subjects must have resting baseline O2 saturation by pulse oximetry of >92% at rest

Exclusion criteria:

  • More than one recurrence of GBM
  • 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
  • Presence of extracranial metastatic or leptomeningeal disease
  • Diagnosis of secondary GBM (ie, glioblastomas that progress from low grade diffuse astrocytoma or anaplastic astrocytoma)
  • Subjects with active, known or suspected autoimmune disease. 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.
  • Previous bevacizumab or other VEGF or anti-angiogenic treatment
  • Previous radiation therapy with anything other than standard radiation therapy (ie, focally directed radiation)
  • Subjects requiring escalating or chronic supraphysiologic doses of corticosteroids (>10 mg/day prednisone equivalents) for control of their disease at randomization are excluded
  • Previous treatment with Gliadel
  • Previous treatment with a PD-1 or CTLA-4 targeted therapy
  • Evidence of > Grade 1 CNS hemorrhage on the baseline MRI scan
  • Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg) within 28 days of first study treatment
  • Prior history of hypertensive crisis, hypertensive encephalopathy, reversible posterior leukoencephalopathy syndrome (RPLS)
  • Prior history of gastrointestinal diverticulitis, perforation, or abscess
  • Clinically significant (ie, active) cardiovascular disease, for example cerebrovascular accidents <6 months prior to study enrollment, myocardial infarction <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
  • 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
  • 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 > NCI CTCAE Grade 3
  • History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (ie, in the absence of therapeutic anticoagulation);
  • Current or recent (within 10 days of study enrollment) use of aspirin (>325 mg/day), clopidogrel (>75 mg/day) or equivalent. Prophylactic use of anticoagulants is allowed
  • 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
  • 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)
  • History of intracranial abscess within 6 months prior to randomization
  • History of active gastrointestinal bleeding within 6 months prior to randomization
  • Serious, non-healing wound, active ulcer, or untreated bone fracture
  • Subjects unable (due to existent medical condition, eg, pacemaker or ICD device) or unwilling to have a head contrast enhanced MRI

Physical and Laboratory Test Findings

  • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
  • 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

Allergies and Adverse Drug Reaction

  • History of allergy to study drug components
  • History of severe hypersensitivity reaction to any monoclonal antibody


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