Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in GBM

Inclusion Criteria:

* Written informed consent and HIPAA authorization 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 by MRI.
* Histologically confirmed diagnosis of supratentorial glioblastoma
* Previous first line treatment with at least radiotherapy
* Documented first recurrence of GBM by diagnostic biopsy or contrast enhanced magnetic resonance imaging (MRI) performed within 21 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
* An interval of \> 28 days and full recovery (i.e., no ongoing safety issues) from surgical resection prior to randomization.
* Karnofsky performance status (KPS) of 70 or higher (Appendix 1)
* Life expectancy \> 12 weeks
* Up to ten unstained slides of 5 microns thickness or a block of tissue will be required to be sent if tissue is available. If the tissue is not available then Principal investigator permissions is required prior to enrollment
* Women of childbearing potential (WOCBP,) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 1 day 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 6 months post treatment completion for a treatment arm A (nivolumab + standard dose bevacizumab)and treatment arm B (nivolumab + low dose bevacizumab).
* Men who are sexually active with WOCBP must use contraceptive method such as male condom with spermicide. 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.
* 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.
* At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below:
* HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

  * Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by WOCBP subjects or male subject's WOCBP partner.
  * Nonhormonal IUDs, such as ParaGard
  * Tubal ligation
  * Vasectomy.
  * Complete Abstinence\* ---\*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.
* LESS EFFECTIVE METHODS OF CONTRACEPTION

  * Diaphragm with spermicide
  * Cervical cap with spermicide
  * Vaginal sponge
  * Male Condom without spermicide\*
  * Progestin only pills by WOCBP subjects or male subject's WOCBP partner
  * Female Condom\* ---\*A male and female condom must not be used together
* Women of Child Bearing Potential (WOCBP)

  --A women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes. In addition, women under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level \> 40mIU/mL to confirm menopause.\*

  ---\*Women treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH level. The duration of the washout period is a function of the type of HRT used. The duration of the washout period below are suggested guidelines and the investigators should use their judgment in checking serum FSH levels. If the serum FSH level is \> 40 mIU/ml at any time during the washout period, the woman can be considered postmenopausal:
  * 1 week minimum for vaginal hormonal products (rings, creams, gels)
  * 4 week minimum for transdermal products
  * 8 week minimum for oral products
* Other parenteral products may require washout periods as long as 6 months Each of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study. Use the checklist to confirm a patient's eligibility. The checklist must be completed for each patient and must be signed and dated by the treating physician.
* 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
  * nitrosureas
  * (≥) 14 days elapsed from administration of any non-cytotoxic agent (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid)
* Screening/Baseline laboratory values must meet the following criteria (using CTCAE v5.0):

  * WBC ≥ 2000/uL
  * Neutrophils ≥ 1500/uL
  * Platelets ≥ 100x103/uL
  * Hemoglobin ≥ 9.0 g/dL
  * Serum creatinine \< 1.5 x 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
  * AST ≤ 3x ULN
  * ALT≤ 3x ULN
  * Pregnancy test (serum)
  * Bilirubin ≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have
  * Total bilirubin \< 3.0 mg/dL)

Exclusion Criteria:

* 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 VEGF or anti-angiogenic treatment
* Previous treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy
* Evidence of \> Grade 1 CNS hemorrhage on the baseline MRI scan
* Inadequately controlled hypertension (defined as systolic blood pressure ≥160 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 treatment;
* 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 within 3 months prior to start of study treatment;
* 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 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, e.g., pacemaker or ICD device) or unwilling to have a head contrast enhanced MRI
* 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