Trial of Combination Tumor Treating Fields (TTF; Optune), Nivolumab Plus/Minus Ipilimumab for Recurrent Glioblastoma
Condition: Recurrent Glioblastoma
MeSH terms: Glioblastoma; Recurrence
Intervention: Nivolumab 240 mg IV; Nivolumab 3 mg/kg; Ipilimumab 1 mg/kg; NovoTTF200A (Optune)
Intervention description: Nivolumab IV 240mg IV every 2 weeks for maximum of 24 months.; Nivolumab IV 3mg/kg every 2 weeks for maximum of 24 months.; Ipilimumab IV 1 mg/kg every 6 weeks for maximum of 4 doses.; A device to be worn continuously for a goal of 75% of the time, ranging from 18 hours daily nonstop or 22 hours daily with 2-3 days off monthly.
Intervention MeSH terms: Nivolumab; Ipilimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: This is an open-label, phase II trial with two parallel arms, two-stage design and appropriate stopping rules for poor efficacy. Arm A will enroll participants without prior PD1/PDL1 checkpoint inhibitor, while Arm B will enroll participants with prior PD1/PDL1 checkpoint inhibitor. The investigator expect to enroll at least 30 (15 in each Arm) and a maximum of 60 (30 in each Arm) evaluable subjects. All subjects will receive tumor treating field (TTF) therapy plus nivolumab infusions for a maximum of 24 months, plus/minus concurrent ipilimumab for a maximum of 4 doses.
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: recurrent glioblastoma

Summary:

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

Eligibility criteria:

        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 Response Assessment in Neuro-Oncology (RANO) criteria, or documented
             recurrent glioblastoma on biopsy.

          -  Measurable disease based on RANO criteria.

          -  Prior therapies including radiation and temozolomide.

          -  Any number of recurrences are allowed. Resection of recurrent glioblastoma is not
             considered a prior treatment.

          -  From the projected start date of study treatment, the following periods must have
             elapsed: 4 weeks from any investigational agent, 4 weeks from cytotoxic therapy
             (except 23 days for temozolomide and 6 weeks from nitrosoureas), or 4 weeks from any
             other antibodies or any other antineoplastic therapies.

          -  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.

          -  Nivolumab and ipilimumab are potentially teratogenic or abortifacient. Women of
             childbearing potential and men must agree to use adequate contraception (hormonal or
             barrier method of birth control; abstinence) prior to entry and for the duration of
             study. Should a woman become pregnant or suspect she is pregnant while she or her
             partner is participating in this study, she should inform her treating physician
             immediately. Male subjects should agree to use adequate method of contraception
             starting with the first dose through 7 months after the last dose of therapy.

          -  Brain CT or MRI within 14 days prior to start of study drug.

          -  Archival tissue for evaluation of correlative objectives (if available).

          -  Ability to understand and the willingness to provide written informed consent.

        Exclusion Criteria:

          -  Infratentorial disease.

          -  Bevacizumab within 2 months of enrollment. Prior use of ipilimumab or other CTLA-4
             inhibitor or prior TTFields.

          -  Tumors with known IDH1 (isocitrate dehydrogenase 1) or IDH2 mutations as determined by
             immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant
             gliomas have a prolonged overall survival rate compared to IDH1/2-wildtype gliomas,
             indicating distinct natural history.

          -  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 including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations 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.

          -  There is an unknown but potential risk for adverse events in nursing infants secondary
             to treatment of the mother with these agents, so 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.

          -  Congestive heart failure, myocardial infarction, 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. Exceptions include basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, in situ cervical cancer or other in situ
             malignancy that has undergone potentially curative therapy and/or with >90%
             probability of survival beyond 5 years.

          -  Any surgery (not including minor diagnostic procedures such as lymph node biopsy)
             within 2 weeks of start of treatment. Incomplete recovery from any side effects of
             previous procedures is also exclusionary.

          -  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.