The main purpose of this study is to evaluate the safety and tolerability of nivolumab,
given in combination with hypofractionated stereotactic re-irradiation of recurrent high
- Histologically confirmed diagnosis of World Health Organization (WHO) Grade III or IV
- Documented recurrence by diagnostic biopsy or contrast enhanced magnetic resonance
imaging (MRI) performed within 28 days of entry in to the trial as per Response
Assessment in Neuro-Oncology (RANO) criteria.
- Maximum diameter of enhancing tumor (target lesion) should be ≤ 4 cm.
- An interval of at least 6 months after the end of prior radiation therapy is required
unless there is a new recurrence outside of the previous radiotherapy treatment
- Previous first line treatment with at least standard dose of radiotherapy (total dose
≥ 54 Gy) and temozolomide
- An interval of ≥ 4 weeks since surgical resection prior to study treatment.
- An interval of ≥ 4 weeks after the last administration of any investigational agent,
bevacizumab, or prior cytotoxic therapy.
- ≥18 years of age on day of signing informed consent.
- Karnofsky performance status of 70 or higher.
- Demonstrate adequate organ function. All screening labs should be performed within 14
days of treatment initiation.
- Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest.
- Must have recovered from the toxic effects of prior therapies (≤ Grade 1).
- Willing and able to provide written informed consent for the trial.
- Life expectancy ≥ 12 weeks
- Women of childbearing potential (WOCBP) should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required. WOCBP should be willing to use 2 methods of birth control or be
surgically sterile, or abstain from heterosexual activity for the course of the study
through 120 days after the last dose of study medication.
- Males should agree to use an adequate method of contraception starting with the first
dose of study therapy through 120 days after the last dose of study therapy.
- Has more than three recurrences of high grade glioma. Previous recurrences of low
grade glioma is not considered.
- Has received re-radiation to recurrent disease (other than standard frontline
adjuvant radiation therapy).
- Recurrent tumors near the brainstem and optic chiasm must not have received prior
- Has infratentorial, or leptomeningeal evidence of recurrent disease.
- Has recurrent or persistent tumor (enhancing area) greater than 4 cm in maximum
- Has prior treatment with Gliadel unless it was administered as first line treatment
and at least 3 months prior to study treatment.
- Is unable (due to existent medical condition) or unwilling to have a contrast
enhanced MRI of brain.
- Is currently participating in or has participated in a study of an investigational
agent or using an investigational device within 4 weeks of the first dose of
- Has a diagnosis of immunodeficiency or is receiving systemic immunosuppressive
therapy within 7 days prior to the first dose of trial treatment. Physiologic doses
of steroid therapy (≤ 10 mg/day prednisone equivalents) is allowed.
- Has had a prior chemotherapy, targeted small molecule therapy, or monoclonal antibody
within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
baseline) from adverse events due to agents administered more than 4 weeks earlier.
- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.
- Has an active autoimmune disease requiring systemic treatment within the past 3
months or a documented history of clinically severe autoimmune disease, or a syndrome
that requires systemic steroids or immunosuppressive agents. Potential participants
with vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Potential participants that require intermittent use of bronchodilators or local
steroid injections would not be excluded from the study. Potential participants with
hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be
excluded from the study.
- Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- Had major surgical procedure, open biopsy, or significant traumatic injury within 28
days prior to day 1 of treatment on study.
- Requires escalating or chronic supraphysiologic doses of corticosteroids (> 10 mg/day
- Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with
participation for the full duration of the trial, or is not in the best interest of
the participant, in the opinion of the treating investigator.
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation
or checkpoint pathways).
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C Virus (HCV) (e.g.,
HCV RNA [qualitative] is detected).
- Has received a live vaccine within 30 days prior to the first dose of trial