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

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.

- INCLUSION CRITERIA:

To be eligible for entry into the study, a candidate must meet all the following criteria:

1. Be 18 years of age or older.

2. Have solitary recurrent glioblastoma that is amenable to surgical resection.

3. Agree to undergo brain surgery.

4. Are eligible for 03-N-0164 "Evaluation and Treatment of Neurosurgical Disorders"
protocol 5. Willing and able to appoint a durable power of attorney.

6. Are not on steroids, or are on a stable (without an increase for the preceding 2 weeks)
or decreasing dose of steroids

7. Are willing to use an effective method of contraception during the clinical study as
defined on the consent and for 5 months (for women) or 7 months (for men) after the last
dose of the study drug.

EXCLUSION CRITERIA:

Candidates will be excluded if they:

1. Have a bleeding disorder that cannot be corrected before invasive testing or surgery,
or other medical conditions that would make surgery unsafe, such as lung or cardiac
disease that would render them unable to tolerate the risk of general anesthesia, or
severe immunodeficiency or systemic cancer not related to a brain lesion.

2. Are pregnant or breastfeeding

3. Cannot have an MRI scan.

4. Are claustrophobic

5. Are not able to lie on their back for up to 60 minutes

6. Have an absolute lymphocyte count less than 500

7. Have multiple brain tumors, evidence of carcinomatous meningitis, gliomatosis cerebri,
or primary CNS lymphoma.

8. Have an unrelated autoimmune disease

9. Have a significant cardiac history, such as 2 or more MIs OR 2 or more coronary
revascularization procedures.

10. Have abnormal findings on ECG such as prolonged QT interval, T-wave abnormalities or
arrhythmia. Abnormal findings on ECG will prompt an evaluation by a cardiologist prior
to enrollment in the study

11. Are currently undergoing treatment with another therapeutic agent for glioblastoma

12. Have a history of having been treated with immune therapy

13. Have an ejection fraction less than 50% on screening echocardiogram

14. Have positive serology for HIV, HBV and HCV

15. Have an active infection that requires systemic antibacterial, antiviral or antifungal
therapy Less than 7 days prior to initiation of study drug therapy

16. Have a history of transfer of autologous or allogeneic T cells

17. Have a history of solid organ or tissue transplants

18. Have cardiac Troponin T or I greater than 2 times the institutional upper limit of
normal at screening

19. At the time of enrollment, lack of consent capacity due to cognitive impairment that
would make them incapable of understanding the explanation of the procedures in this
study. Cognitive capacity to consent will be determined at the time of enrollment.
Patients with mental disorders or those patients who are cognitively impaired yet
still retain consent capacity will not be excluded.

20. Cannot speak English or Spanish fluently