The purpose of this study is to test the effectiveness (how well the drug works), safety and
tolerability of an investigational drug called nivolumab (also known as BMS-936558) in
glioblastoma (a malignant tumor, or GBM), when added to bevacizumab.
Nivolumab is an antibody (a kind of human protein) that is being tested to see if it will
allow the body's immune system to work against glioblastoma tumors. Opdivo (Nivolumab) is
currently FDA approved in the United States for melanoma (a type of skin cancer), non-small
cell lung cancer, renal cell cancer (a type of kidney cancer), Hodgkin's lymphoma but is not
approved in glioblastoma. Nivolumab may help your immune system detect and attack cancer
Bevacizumab is a drug which works on the blood vessel that supply the tumor and potentially
can starve the tumor by cutting off the blood supply to these tumors. Bevacizumab is
commercially available and FDA approved for patients with recurrent glioblastoma.
This study has two study groups. Arm 1 will receive the study drug Nivolumab 240mg and
bevacizumab 10 mg (standard dose) every 2 weeks and Arm 2 will receive the study drug
Nivolumab 240 mg and bevacizumab 3 mg (reduced dose) every 2 weeks. A process will be used to
assign patients, by chance, to one of the study groups. Neither patients nor doctors can
choose which group patients are in. This is done by chance because no one knows if one study
group is better or worse than the other. 90 total patients are expected to participate in
this study (45 patients in each arm).
Your total participation in this study from the time you have signed the informed consent to
your last visit, including follow-up visits, may be more than three years (depending on what
effect the treatment has on your cancer, and how well you tolerate the treatment).
Primary Endpoint(s) To evaluate the efficacy of nivolumab when administered with standard and
reduced bevacizumab dosing among recurrent glioblastoma patients as measured by the rate of
overall survival at twelve months.
Secondary Endpoint(s) To evaluate the safety and tolerability of nivolumab in combination
with bevacizumab administered according to standard and reduced dosage schedules for
recurrent glioblastoma patients.
To compare progression free survival (PFS) at 6 months of nivolumab when administered with
standard and reduced bevacizumab dosing for recurrent glioblastoma patients.
To compare the overall survival rate of nivolumab when administered with standard and reduced
bevacizumab dosing for recurrent glioblastoma patients.
To compare progression free survival (PFS) of when administered with standard and reduced
bevacizumab dosing for recurrent glioblastoma patients.
To compare the objective response rate (ORR) of nivolumab and bevacizumab administered
according to standard and reduced dosage schedules for recurrent glioblastoma patients
Exploratory Endpoints (s) To evaluate whether baseline values or subsequent changes in
circulating immunologic parameters (including but not limited to the number of T-cells,
B-cells and natural killer (NK) cells; the number of T cell subsets; soluble circulating
cytokines) are associated with outcome.
To assess neurologic functioning in the treatment arms using the Neurologic Assessment in
To assess the perfusion and diffusion base imaging to correlate with changes and response to
nivolumab when administered with standard and reduced bevacizumab dosing.
To assess response using the immunotherapy response assessment in neuro-oncology criteria
relative to survival.
Study design and duration This is a randomized, open-label, phase 2 safety study of nivolumab
and bevacizumab administered according to standard and reduced dosage schedules in adult (≥
18 years) subjects with a first recurrence or second recurrence of glioblastoma (GBM).
Subjects must have received previous treatment with radiotherapy and may have up to 2
recurrences. Patients will undergo 1:1 randomization to receive treatment with either
nivolumab (240 mg flat dosing IV every 2 weeks) and bevacizumab administered according to
standard (10 mg/kg IV every 2 weeks; Arm A) and reduced (3 mg/kg IV every 2 weeks; Arm B)
dosage schedules for recurrent glioblastoma patients. The study will allow patients that
require decadron up to 4 mg/ day to participate in the study.
- Written informed consent and HIPAA authorization (applies to covered entities in the
USA only) obtained from the subject/legal representative prior to performing any
protocol-related procedures, including screening evaluations
- Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory testing, and other requirements of the study, including disease assessment
- Histologically confirmed diagnosis of supratentorial glioblastoma
- Previous first line treatment with at least radiotherapy
- Documented first or second recurrence of GBM by diagnostic biopsy or contrast enhanced
magnetic resonance imaging (MRI) performed within 21 days of randomization per RANO
- 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
- An interval of > 28 days and full recovery (i.e., no ongoing safety issues) from
surgical resection prior to randomization.
- An interval of > 4 weeks after the last administration of any other treatment for GBM.
- Karnofsky performance status of 70 or higher
- Life expectancy > 12 weeks
- Women of childbearing potential (WOCBP, as defined in Section 5.4) must have a
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
units of HCG) within 1 days prior to the start of study drug
- Women must not be breastfeeding
- WOCBP must use appropriate method(s) of contraception from the time of enrollment for
the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus
30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment
completion for subjects enrolled to treatment arm A (nivolumab). Subjects enrolled to
treatment arm B (nivolumab + bevacizumab) must use appropriate method(s) of
contraception for 6 months post treatment completion.
- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
active with WOCBP will be instructed to adhere to contraception for the duration of
treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days
(duration of sperm turnover) for a total of 31 weeks post-treatment completion.
- Women who are not of childbearing potential (i.e., who are postmenopausal or
surgically sterile as well as azoospermic men) do not require contraception.
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However WOCBP subjects must still undergo pregnancy
testing as described in these sections.
- Recovery from the toxic effects of prior therapy, with a minimum time of:
- ≥ 28 days elapsed from the administration of any investigational agent
- ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except
- ≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from
- ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g.,
interferon, tamoxifen, thalidomide, cis-retinoic acid)
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on
the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on
the use of highly effective methods of contraception. Highly effective methods of
contraception have a failure rate of < 1% per year when used consistently and correctly.
- Screening/Baseline laboratory values must meet the following criteria:
- White Blood Cells ≥ 2000/uL
- Neutrophils ≥ 1500/uL
- Platelets ≥ 100x103/uL
- Hemoglobin ≥ 9.0 g/dL
- Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >
40 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
- aspartate transaminase (AST) ≤ 3x ULN
- alanine transaminase (ALT) ≤ 3x ULN
- Bilirubin ≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL)
- More than two recurrences of GBM
- Presence of extracranial metastatic, significant leptomeningeal disease or tumors
primarily localized to the brainstem or spinal cord.
- 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.
- 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 chronic and systemic
immunosuppressive treatment, or conditions not expected to recur in the absence of an
external trigger are permitted to enroll. Subjects have any other condition requiring
systemic treatment with corticosteroids or other immunosuppressive agents within 14
days. Inhaled or topical steroids and adrenal replacement doses >10mg daily prednisone
equivalent are permitted in absence of active autoimmune disease.
- Previous radiation therapy with anything other than standard radiation therapy (i.e.,
focally directed radiation) administered as first line therapy.
- Previous treatment with carmustine wafer except when administered as first line
treatment and at least 6 months prior to randomization
- Previous bevacizumab or other vascular endothelial growth factor (VEGF) or
- Previous treatment with a programmed cell death protein 1 (PD-1), programmed death
ligand 1 (PD-L1) or CTLA-4 targeted therapy
- Evidence of > Grade 1 central nervous system (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 7 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 (i.e., 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
- Significant vascular disease (e.g., 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 of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright red
blood per episode) within 1 month prior to randomization;
- History or evidence of inherited bleeding diathesis or significant coagulopathy at
risk of bleeding (i.e., in the absence of therapeutic anticoagulation);
- Current or recent (within 10 days of study enrollment) use of anticoagulants that, in
the opinion of the investigator, would place the subject at significant risk for
bleeding. 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 (e.g., stereotactic biopsy within 7 days of first study
treatment; placement of a vascular access device within 2 days of first study
- 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, e.g., pacemaker or vascular
endothelial growth factor (ICD) device) or unwilling to have a head contrast enhanced
- Positive test for hepatitis B virus surface antigen (HBV sAg) or detectable hepatitis
C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection
- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS)
- History of severe hypersensitivity reaction to any monoclonal antibody
- Patients that require decadron > 4 mg/ day or equivalent of steroids