Trial of Combination TTF(Optune), Nivolumab Plus/Minus Ipilimumab for Bevacizumab-naïve, Recurrent Glioblastoma

Phase II trial in which participants with bevacizumab-naïve, recurrent glioblastoma will
receive a combination of tumor treating fields(portable device), nivolumab with or without
ipilimumab.

The NovoTTF200A (OptuneTM) device is worn continuously for a goal of 75% or more of the time,
ranging from at least 18 hours daily uninterrupted or 22 hours daily with 2-3 days off
monthly. Therapy is planned for approximately 24 months.

Infusions with nivolumab will start within 1 week of study start. Ipilimumab will either
start with the second nivolumab infusion or at after tumor progression. Nivolumab is infused
intravenously at 240 mg once every 2 weeks with or without ipilimumab for a maximum of 24
months. Ipilimumab is dosed at 1 mg/kg once every 6 weeks for a maximum of 4 doses (24
weeks). Infusions will continue until maximum doses are completed or there is confirmed tumor
progression, intolerable adverse effects or withdrawal of consent.

Inclusion Criteria:

- Histologically confirmed World Health Organization Grade IV glioblastoma with
supratentorial distribution.

- Unequivocal evidence of progressive disease on contrast-enhanced brain CT or MRI as
defined by RANO criteria, or documented recurrent glioblastoma on biopsy.

- Prior therapies including radiation and temozolomide.

- Only 1-2 prior treatments for recurrences are allowed. Resection of recurrent
glioblastoma is not considered a prior treatment.

- Must be at least 12 weeks from radiotherapy or progression outside of the high-dose
radiation target volume or unequivocal evidence of progressive tumor on biopsy.

- All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy,
and/or surgery) must be resolved, except for alopecia.

- Karnofsky Performance Status (KPS) ≥ 60

- Adequate organ and marrow function as defined below, all screening labs should be
performed within 14 days of treatment initiation:

- absolute neutrophil count ≥ 1,000/mcL

- platelets ≥ 100,000/mcL

- hemoglobin > 8.0 mg/dL

- total bilirubin ≤ 2.0 x upper limit of normal

- AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal

- creatinine or creatinine clearance ≥60 mL/min/1.73 m2 for creatinine >ULN

- Corticosteroid dose must be stable or decreasing for at least 5 days prior to
enrollment.

- Ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

- Infratentorial disease.

- Prior use of bevacizumab, ipilimumab or other CTLA-4 inhibitor, or TTFields.

- Tumors with known IDH1 or IDH2 mutations.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab or ipilimumab or their excipients.

- Current or planned participation in a study of an investigational agent or using an
investigational device.

- Uncontrolled intercurrent illness that would limit compliance with study requirements.

- Active or life-threatening infection requiring intravenous or >2 weeks of systemic
therapy.

- Prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy
requires a biopsy to confirm radiographic progression is consistent with progressive
tumor and not treatment-related necrosis unless the recurrent lesion is outside of any
prior high-dose radiation target volume or distant from the prior CED or brachytherapy
site.

- breastfeeding must be discontinued by enrollment on study.

- Uncontrolled HIV or AIDS is not allowed. Patients with known history of HIV but with
undetectable viral load on antiretroviral therapy are allowed.

- CHF, or MI or hemorrhagic/ischemic stroke in the last 3 months.

- Active illicit drug use or diagnosis of alcoholism

- Known additional malignancy that is progressing or requires active treatment within 3
years of start of study drug.

- Any surgery (not including minor diagnostic procedures such as lymph node biopsy)
within 2 weeks of start of treatment.

- Any significant autoimmune disorders expected to impact multiple or internal organs,
excluding mild eczema or autoimmune thyroiditis treated with thyroidectomy and
requiring systemic immunosuppressive or immunomodulatory therapy.

- Any implanted programmable cranial device, including reprogrammable
ventriculoperitoneal shunt (VPS) or cochlear implants, that precludes use of TTFields
(Optune) therapy.