Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade

Summary

Objectives

Objective

This protocol is being performed to 1) characterize the clinical and 2) immunological
response of patients with recurrent glioblastoma to treatment with Nivolumab, together
with an anti-Lag-3 antibody, BMS-986016, and to evaluate the safety of brain tumor
microdialysis in this patient population.

Study Population

10 patients (total, after replacement for any dropout), 18 years old and older with
recurrence of glioblastoma after standard treatment of surgery, chemotherapy, and
radiation.

Study Design

Patients will be screened by study neurosurgeons or neuro-oncologists to verify their
confirmed or likely diagnosis of a recurrent glioblastoma. Patients will be offered
standard of care therapy, including repeat surgery and/or recommendations for
chemotherapeutic agents and other trials. If the patients are deemed to be surgical
candidates for their potential recurrence, they will be enrolled in the trial. Enrolled
patients will then undergo a stereotactic brain biopsy. If a frozen section confirms a
diagnosis of recurrent glioblastoma, two microdialysis catheters will be placed in the
brain after the biopsy, and a lumbar drain will also be placed. These microdialysis
catheters will sample interstitial fluid in and around the brain tumor every 6 hours. We
will collect blood and cerebral spinal fluid samples daily for comparison. After two days
(Day 3), the patients will be given one dose of Nivolumab, 240mg IV. We will continue to
collect samples every six hours from the microdialysis catheters and daily from blood and
cerebral spinal fluid for 5 additional days, after which patients will undergo surgical
resection of their tumors and removal of the microdialysis catheters and lumbar drain.
Nivolumab, at a dose of 240mg IV over 30 minutes every 2 weeks, will be administered
after surgery (starting on Day 17(+/- 2 days), two weeks after the first dose on Day 3)
followed by BMS 986016, an anti-Lag-3 antibody at a dose of 80mg IV over 60 minutes,
until the study neuroradiologist notes tumor progression on MRI or the patient
experiences treatment toxicity. While on therapy with Nivolumab and BMS-986016, patients
will be seen and examined every 2 weeks +/- two days for signs of toxicity. Patients will
be followed for at least three months after the surgical procedure.

Outcome Measures

The primary outcome measures are the proportion of patients who have a measurable
increase of interferon gamma levels in the brain tumor tissue after their first dose of
Nivolumab as compared to the pre-treatment baseline, the safety of using brain tumor
microdialysis to monitor response to immune modulators in patients with recurrent
glioblastoma and the safety of the combination of Nivolumab and BMS-986016. Exploratory
outcome measures include: 1) To determine the change in interferon gamma production
within the tumor microenvironment and in the rest of the body from before and after
therapy with the immune checkpoint inhibitor, nivolumab; 2) To evaluate the pathological
response of the immune microenvironment of brain tumor tissue to the first dose of
Nivolumab; 3) To evaluate the clinical response (progression free survival, overall
survival) of recurrent glioblastoma patients to this treatment combination; 4) To
describe the difference in survival between responders and non-responders on this
treatment combination; 5) To examine the differences in the immune cells and secreted
factors of the tumor environment as compared to the immune cells and secreted factors of
the cerebral spinal fluid, blood and, potentially, bone marrow in response to this
treatment.