Clinical Trials /

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

NCT03493932

Description:

Background: Glioblastoma (GBM) brain tumors almost always return after treatment. When that happens the tumor can never completely be removed by surgery, so most people also receive drugs. Researchers want to see if combining the drugs nivolumab and BMS-986016 may help. Objectives: To study how nivolumab affects the brain s immune system in people who have had glioblastoma brain tumors return. To study how nivolumab and BMS-986016 affect brain tumors. Eligibility: Adults age 18 and older who have had a return of GBM Design: Participants will be screened with: Medical history Physical exam Cheek swab Heart, blood and urine tests Chest x-ray Magnetic resonance imaging (MRI) brain scan. Participants will lie on a table that slides in and out of a cylinder in a strong magnetic field. A contrast agent will be injected in an arm vein. Participants will stay in the hospital. They will: Have surgery. A tube will be inserted into the back. Brain tumor and bone marrow samples will be taken. Tubes will be inserted into the brain. Have a computed tomography brain scan. Stay in Intensive Care (ICU) 7 days. Fluid from the brain and back will be collected every few hours. In the ICU, participants will get nivolumab by IV for 30 minutes. Have surgery to remove the tubes. Have standard surgery to remove as much of the GBM as possible. Bone marrow will be removed. After leaving the hospital, participants will have visits every 2 weeks to get the study drugs by IV and have physical exams and blood tests. Participants will have a brain MRI once a month. ...

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade
  • Official Title: Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade

Clinical Trial IDs

  • ORG STUDY ID: 180077
  • SECONDARY ID: 18-N-0077
  • NCT ID: NCT03493932

Conditions

  • Glioblastoma

Interventions

DrugSynonymsArms
Nivolumab1
BMS-9860161

Purpose

Background: Glioblastoma (GBM) brain tumors almost always return after treatment. When that happens the tumor can never completely be removed by surgery, so most people also receive drugs. Researchers want to see if combining the drugs nivolumab and BMS-986016 may help. Objectives: To study how nivolumab affects the brain s immune system in people who have had glioblastoma brain tumors return. To study how nivolumab and BMS-986016 affect brain tumors. Eligibility: Adults age 18 and older who have had a return of GBM Design: Participants will be screened with: Medical history Physical exam Cheek swab Heart, blood and urine tests Chest x-ray Magnetic resonance imaging (MRI) brain scan. Participants will lie on a table that slides in and out of a cylinder in a strong magnetic field. A contrast agent will be injected in an arm vein. Participants will stay in the hospital. They will: Have surgery. A tube will be inserted into the back. Brain tumor and bone marrow samples will be taken. Tubes will be inserted into the brain. Have a computed tomography brain scan. Stay in Intensive Care (ICU) 7 days. Fluid from the brain and back will be collected every few hours. In the ICU, participants will get nivolumab by IV for 30 minutes. Have surgery to remove the tubes. Have standard surgery to remove as much of the GBM as possible. Bone marrow will be removed. After leaving the hospital, participants will have visits every 2 weeks to get the study drugs by IV and have physical exams and blood tests. Participants will have a brain MRI once a month. ...

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalRecurrent Glioblastoma patients
  • Nivolumab
  • BMS-986016

Eligibility Criteria

        -  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 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.

          5. Willing and able to appoint a durable power of attorney

          6. Are willing to use an effective method of contraception during the clinical study as
             defined on the consent and for 24 weeks (for women) or 33 weeks (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.

          2. Has a known additional malignancy that is progressing or requires active treatment
             within 3 years of registration. 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.

          3. Are pregnant or breastfeeding

          4. Cannot have an MRI scan.

          5. Are claustrophobic

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

          7. Have an absolute lymphocyte count less than 500

          8. Have primary CNS lymphoma.

          9. Has received systemic immunosuppressive treatments, aside from systemic
             corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six
             months of registration

         10. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

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

         12. 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

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

         14. 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).

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

         16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) at the
             time of enrollment

         17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected) at the time of enrollment.

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

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

         20. Have a history of solid organ or tissue transplants

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

         22. 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.

         23. Cannot speak English or Spanish fluently

         24. Patients that require dexamethasone greater than 4 mg/ day or equivalent of steroids
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Increase of interferon gamma levels
Time Frame:End of study
Safety Issue:
Description:The proportion of patients that have a rise in interferon gamma levels within the tumor microenvironment of 4 pg/ml or higher before the first dose of Nivolumab as compared to the 5th day after treatment with Nivolumab.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Institute of Neurological Disorders and Stroke (NINDS)

Trial Keywords

  • Glioblastoma
  • Glioma
  • Brain Tumor
  • Immune Therapy
  • Checkpoint Inhibition

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