A Pilot Study to Evaluate PBR PET in Brain Tumor Patients Treated With Chemoradiation or Immunotherapy

Study Overview
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Brief Summary
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This research study is studying the changes in primary and metastatic brain tumor inflammation using positron emission tomography (PET) imaging using a radioactive substance called [11C] PBR28a, which is also known as peripheral benzodiazepine receptors (PBR), or PBR-PET.

Detailed Description
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This research study is a Pilot Study, which is the first time investigators are examining this study intervention. The purpose of a pilot study is to obtain the preliminary data needed to justify performing a larger clinical trial on the effectiveness of an investigational intervention. Standard treatment for the subjects' disease includes chemoradiation and immunotherapy. In PET scans, a radioactive substance is injected into the body. The scanning machine finds the radioactive substance, which tends to go to cancer cells and areas of inflammation. For the PET scans in this study, the investigators are using a radioactive substance called [11C]PBR28. The investigators would like to see if this tracer can be used to detect changes in inflammation during tumor treatment. PBR-PET scans will be performed at screening before therapy and then several weeks/months after the start of therapy, depending on the type of therapy used. No diagnostic decisions or clinical treatment decisions will be made based on any results obtained from these PET scans, and there will be no change in care. The information from these studies may help the investigators design methods that could be used in larger studies to more completely understand the role of inflammation in the treatment of cancer.

Official Title
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A Pilot Study to Evaluate PBR PET in Brain Tumor Patients Treated With Chemoradiation or Immunotherapy

Conditions
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Intracranial Tumors, Glioblastoma, Melanoma

Intervention / Treatment
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* Other: PBR PET
* Biological: Cancer Immunotherapy
* Radiation: Radiation and chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have evidence of metastatic melanoma to the brain for Cohort A or histologically confirmed GBM for Cohorts Band C. Those with newly diagnosed GBM but suspected to have pseudoprogression after completion of chemoradiation can enroll in Cohort C. Participants must have measurable brain disease, defined as at least one lesion that is 10 mm in diameter. Age > 18 years. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) Life expectancy of greater than 3 months. Participants must have normal organ and marrow function as defined below: leukocytes ≥3,000/mcL absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal creatinine within normal institutional limits --- OR creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. For Cohort A, only patients with metastatic melanoma to the brain for whom their treating physician has planned to give immunotherapy as monotherapy are eligible for this study. This can be in the setting of a clinical trial or not. For Cohort B, only patients with GBM for whom their treating physician has planned to give immunotherapy are eligible for this study. This can be in the setting of a clinical trial or not. For Cohort C, patients with newly diagnosed GBM who have completed standard temozolomide + radiation and have suspected pseudoprogression within the first 3 months of completing chemoradiation can enroll. Patient must be able to undergo MRI and PET scans. Patient must be maintained on a stable corticosteroid regimen for 5 days prior each MR-PET scan. High or mixed affinity binders (Ala/Ala or Ala/Thr) based on genotyping result from PBR affinity test. This blood test will be performed as part of the screening process after consent has been obtained. The effects of PBR on the developing human fetus are unknown. For this reason and because radiopharmaceuticals agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Radiopharmaceutical agents are known to be teratogenic. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: History of allergic reactions attributed to compounds of similar chemical or biologic composition to PBR. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded from this study because PBR is a radiopharmaceutical agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to exposure of the mother to PBR, breastfeeding should be discontinued. These potential risks may also apply to other agents used in this study. HIV-positive participants are excluded because their immune system is compromised and may affect the interpretation of the imaging data. Patients who are not suitable to undergo MRI or PET or use gadolinium contrast due to: Claustrophobia Presence of metallic objects or implanted medical devices in body (i.e. cardiac pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel implants) The craniotomy patients will all have titanium but this is MRI compatible Sickle cell disease Renal failure Reduced renal function, as determined by creatinine clearance < 30 mL/min based on a serum creatinine level obtained within 28 days prior to registration

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metastatic Melanoma to the Brain (Cohort A)<br>Assess Inflammation (PBR PET) Immunotherapy Assess Inflammation (PBR PET) | Other: PBR PET<br> <br> * Other names: PBR28;Biological: Cancer Immunotherapy<br>* Subjects who are to be treated with immunotherapy for glioblastoma or melanoma brain metastases will be eligible for 2 of the 3 arms.<br>* Other names: Checkpoint inhibition; Vaccine;|
| Experimental: Primary Brain Tumor (Cohort B)<br>Assess Inflammation (PBR PET) Immunotherapy Assess Inflammation (PBR PET) | Other: PBR PET<br> <br> * Other names: PBR28;Biological: Cancer Immunotherapy<br>* Subjects who are to be treated with immunotherapy for glioblastoma or melanoma brain metastases will be eligible for 2 of the 3 arms.<br>* Other names: Checkpoint inhibition; Vaccine;|
| Experimental: Primary Brain Tumor (Cohort C)<br>Chemoradiation Assess inflammation (PBR PET) Follow Patients | Other: PBR PET<br> <br> * Other names: PBR28;Radiation: Radiation and chemotherapy<br>* Subjects with glioblastoma will receive or will have received treatment with chemotherapy and radiation per the standard of care.<br>* Other names: Chemoradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PBR Uptake (Changes in PBR Uptake by PET) | The change in PBR uptake in arms cohorts A and B from baseline to the start of cycle 4 for metastatic melanoma patients or cycle 3 for glioblastoma patients. The 18-kDa translocator protein (TSPO) is a protein that is expressed in mitochondria and is particularly prominently expressed by activated microglia, infiltrating macrophages, and reactive astrocytes. Thus, it is a marker of neuro-inflammation. PBR28 is a second generation PET tracer that binds to TPSO. PBR28 uptake was quantified using the standardized uptake value (SUV), which is the ratio of activity per unit volume of the region of interest (ROI) compared to cerebellum. Higher values indicate increased uptake in the ROI. | At baseline and 3 to 4 months post baseline | 
| Median PBR Uptake | The median PBR28 uptake as measured by positron emission tomography (PET) following chemo-radiation. The 18-kDa translocator protein (TSPO) is a protein that is expressed in mitochondria and is particularly prominently expressed by activated microglia, infiltrating macrophages, and reactive astrocytes. Thus, it is a marker of neuro-inflammation. PBR28 is a second generation PET tracer that binds to TPSO. PBR28 uptake was quantified using the standardized uptake value (SUV), which is the ratio of activity per unit volume of the region of interest (ROI) compared to cerebellum. Higher values indicate increased uptake in the ROI. | At the time of suspected pseudo-progression (up to 4 weeks after consent) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intracranial Tumors, Glioblastoma, Melanoma