GlioblastomaPhase 1NCT03493932
Cytokine Microdialysis for Real-Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade
A Phase 1 study testing Nivolumab and BMS-986016 in people with Glioblastoma, run by National Institute of Neurological Disorders and Stroke (NINDS) at 2 sites in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Glioblastoma
- What is being tested?
- Nivolumab and BMS-986016
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 2 sitesUnited States
- Study dates
- 24 Sep 2018to 27 Jun 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- To be eligible for entry into the study, a candidate must meet all the following criteria:
- Be 18 years of age or older.
- Have recurrent glioblastoma that is amenable to surgical resection.
- Agree to undergo brain surgery.
- Are eligible for 03-N-0164 "Evaluation and Treatment of Neurosurgical Disorders" protocol 5. Willing and able to appoint a durable power of attorney.
- Willing and able to appoint a durable power of attorney
- 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.
Who cannot join
- Candidates will be excluded if they:
- 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.
- 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.
- Are pregnant or breastfeeding
- Cannot have an MRI scan.
- Are claustrophobic
Show all 24Show fewer
- Are not able to lie on their back for up to 60 minutes
- Have primary CNS lymphoma.
- Has received systemic immunosuppressive treatments, aside from systemic corticosteroids (such as methotrexate, chloroquine, azathioprine, etc) within six months of registration
- 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
- Have a significant cardiac history, such as 2 or more MIs OR 2 or more coronary revascularization procedures.
- 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
- Are currently undergoing treatment with another therapeutic agent for glioblastoma
- 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).
- Have an ejection fraction less than 50% on screening echocardiogram
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) at the time of enrollment
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) at the time of enrollment.
- Have an active infection that requires systemic antibacterial, antiviral or antifungal therapy Less than 7 days prior to initiation of study drug therapy
- Have a history of transfer of autologous or allogeneic T cells
- Have a history of solid organ or tissue transplants
- Have cardiac Troponin T or I greater than 2 times the institutional upper limit of normal at screening
- 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.
- Cannot speak English or Spanish fluently
- Patients that require dexamethasone greater than 4 mg/ day or equivalent of steroids
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Emory University
Atlanta, Georgia, 30322
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: Cytokine Microdialysis For Real Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade
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.
Read more
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.
...
Read the 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.
- Conditions
- Glioblastoma
- Being tested
- Nivolumab, BMS-986016
- Keywords
- Glioblastoma, Glioma, Brain Tumor, Immune Therapy, Checkpoint Inhibition
- Medical subject headings
- Glioblastoma, Glioma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NivolumabDrug
OPDIVO is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
BMS-986016Drug
Anti-Lymphocyte Activation Gene-3 antibody undergoing clinical evaluation by Bristol-Myers Squibb
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab and BMS-986016 | Experimental | Recurrent Glioblastoma patients Receives: Drug: Nivolumab; Drug: BMS-986016 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increase of Interferon Gamma Levels
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.
Measured: Day 8
Microdialysis Catheter
The number of patients with any adverse events that are directly attributable to placement of the microdialysis catheter. Specifically, intracranial hemorrhage, intracranial infection, wound infection, or new neurological deficit attributable to location of microdialysis catheter placement were to be captured
Measured: Day 8
Drug Safety
The safety of the combination of nivolumab and BMS-986016 in recurrent glioblastoma patients
Measured: Day 8
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2018
- Study start24 Sep 2018
- Primary completion21 Apr 2023
- Study completion27 Jun 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for GlioblastomaStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Sadhana Jackson, M.D., Principal investigator, National Institute of Neurological Disorders and Stroke (NINDS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03493932
- Sponsor's protocol ID
- 180077
- Other IDs
- 18-N-0077
- Status last verified
- Sep 2023
- First submitted
- 10 Apr 2018
- Last updated
- 24 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cytokine Microdialysis For Real Time Immune Monitoring in Glioblastoma Patients Undergoing Checkpoint Blockade
- ClinicalTrials.gov ID
- NCT03493932
- Acronym / sponsor ID
- 180077
- Conditions
- Glioblastoma
- Keywords
- Glioblastoma, Glioma, Brain Tumor, Immune Therapy, Checkpoint Inhibition
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 24 Sep 2018 (actual)
- Primary completion
- 21 Apr 2023 (actual)
- Study completion
- 27 Jun 2023 (actual)
- First posted
- 11 Apr 2018 (actual)
- Results
- Posted 24 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Nivolumab and BMS-986016 | Experimental | Drug: Nivolumab, Drug: BMS-986016Recurrent Glioblastoma patients |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- To be eligible for entry into the study, a candidate must meet all the following criteria:
- Be 18 years of age or older.
- Have recurrent glioblastoma that is amenable to surgical resection.
- Agree to undergo brain surgery.
- Are eligible for 03-N-0164 "Evaluation and Treatment of Neurosurgical Disorders" protocol 5. Willing and able to appoint a durable power of attorney.
Key exclusion criteria (24 listed)
- 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.
- 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.
- Are pregnant or breastfeeding
- Cannot have an MRI scan.
- Are claustrophobic
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NivolumabOPDIVO is a human programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. | Drug | Nivolumab and BMS-986016 |
| BMS-986016Anti-Lymphocyte Activation Gene-3 antibody undergoing clinical evaluation by Bristol-Myers Squibb | Drug | Nivolumab and BMS-986016 |
Primary outcome
Increase of Interferon Gamma Levels
Time frame: Day 8
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.
Microdialysis Catheter
Time frame: Day 8
The number of patients with any adverse events that are directly attributable to placement of the microdialysis catheter. Specifically, intracranial hemorrhage, intracranial infection, wound infection, or new neurological deficit attributable to location of microdialysis catheter placement were to be captured
Drug Safety
Time frame: Day 8
The safety of the combination of nivolumab and BMS-986016 in recurrent glioblastoma patients
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sadhana Jackson, M.D. principal investigator
National Institute of Neurological Disorders and Stroke (NINDS)
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Nivolumab and BMS-986016 in people with Glioblastoma, run by National Institute of Neurological Disorders and Stroke (NINDS) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increase of Interferon Gamma Levels (time frame: Day 8). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jul 2024.