Radioactive Tracer for Multiple Sclerosis
Recruiting in Palo Alto (17 mi)
DS
Overseen byDaniel S Reich, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS)
Disqualifiers: Pregnant, Lactating, Severe claustrophobia, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
Background: Multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML) are disorders that affect the central nervous system (CNS). The CNS includes the brain, spinal cord, and optic nerves. Both diseases can cause muscle weakness and impair vision, speech, and coordination. Researchers are working to better understand how MS and PML affect the CNS. Objective: To test whether an experimental radioactive tracer (minibody) can help positron emission tomography (PET) scans detect certain immune cells in the CNS of people with MS and PML. Eligibility: People aged 18 years and older with MS or PML. Design: Participants will come to the clinic for at least 3 visits over 4 to 6 weeks. Participants will undergo testing. They will have a physical and neurological exam. They will have blood tests and tests of their heart function. They will have a magnetic resonance imaging (MRI) scan of the brain. They may have a spinal tap: Their lower back will be numbed, and a needle will be inserted between the bones of the spine to withdraw fluid from around the spinal cord. Minibody is given through a tube with a needle placed in a vein in the arm. This takes 5 to 10 minutes. Participants will have heart function tests before and after receiving the minibody. Participants will return the next day for the PET scan. They will lie on a table that moves through a doughnut-shaped machine. This scan will take about 1 hour. Participants with PML may opt to repeat the minibody infusion and the PET scan within 6 months.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.
What data supports the effectiveness of the drug 89Zr-Df-crefmirlimab for treating multiple sclerosis?
Research shows that zirconium-89 labeled antibodies, like those used in 89Zr-Df-crefmirlimab, can effectively target specific cells in the body, as seen in studies with mice that have a condition similar to multiple sclerosis. This suggests that the drug might help in visualizing and targeting areas of inflammation in multiple sclerosis.12345
How does the radioactive tracer treatment for multiple sclerosis differ from other treatments?
Research Team
DS
Daniel S Reich, M.D.
Principal Investigator
National Institute of Neurological Disorders and Stroke (NINDS)
Eligibility Criteria
Adults aged 18+ with Multiple Sclerosis or Progressive Multifocal Leukoencephalopathy can join. They must be part of existing NINDS studies, understand and agree to the study's consent form, follow all procedures, and women must use effective contraception. Excluded are pregnant or breastfeeding individuals, those who can't have MRI contrast or fit in scanners, and anyone with conditions that could affect their participation.Inclusion Criteria
I have been diagnosed with PML or PML-IRIS based on clinical and lab tests.
PML Inclusion Criteria: Able to understand and willing to sign a written, informed consent document
Multiple Sclerosis Inclusion Criteria: Able to understand, and willing to sign, a written, informed consent document
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Exclusion Criteria
Weighs > 350 lb (158 kg; weight limit for the scanner table) or is unable to fit within the MRI or PET imaging gantry
Pregnant or lactating
Contraindications for MRI gadolinium contrast administration or 3T MRI
See 2 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Baseline and Initial Testing
Participants undergo baseline testing including physical and neurological exams, blood tests, heart function tests, and MRI scans.
1 week
1 visit (in-person)
Treatment and Imaging
Participants receive the minibody infusion followed by a PET/CT scan to detect CD8+ T cells in the CNS.
1 week
2 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, with optional repeat imaging for PML cohort.
up to 6 months
Variable visits (in-person)
Treatment Details
Interventions
- 89 Zr-Df-crefmirlimab (Monoclonal Antibodies)
Trial OverviewThe trial is testing a radioactive tracer called minibody (89 Zr-Df-crefmirlimab) used during PET scans to detect immune cells in the CNS of MS and PML patients. Participants will receive an infusion of minibody followed by PET scans over several visits spanning 4-6 weeks.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Progressive Multifocal LeukoencephalopathyExperimental Treatment1 Intervention
PML cohort- Up to five study visits. (1) Baseline; (2) Day 0: MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer"); (3) Day 1: PET/CT scan; (4) Study visit 4 (optional; time-period between study visit 3 and 4 is variable): MRI brain (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka "PET/CT tracer") following clinical, radiological and/or laboratory-defined immune reconstitution (spontaneous or facilitated); (5) Study visit 5: PET/ CT scan
Group II: Multiple SclerosisExperimental Treatment1 Intervention
MS cohort- Three study visits. (1) Baseline; (2) Day 0: MRI brain/spinal cord (with gadolinium) followed by an intravenous injection of anti-CD8 minibody (aka"PET/CT tracer"); (3) Day 1: PET/CT scan
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Institute of Neurological Disorders and Stroke (NINDS)
Lead Sponsor
Trials
1403
Patients Recruited
655,000+
References
Immuno-Positron Emission Tomography with Zirconium-89-Labeled Monoclonal Antibodies in Oncology: What Can We Learn from Initial Clinical Trials? [2022]Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.
89Zr-Immuno-PET with Immune Checkpoint Inhibitors: Measuring Target Engagement in Healthy Organs. [2023]Label="INTRODUCTION" NlmCategory="BACKGROUND"> 89Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([89Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [89Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses.
Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. [2022]To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).
Efficient Distribution of a Novel Zirconium-89 Labeled Anti-cd20 Antibody Following Subcutaneous and Intravenous Administration in Control and Experimental Autoimmune Encephalomyelitis-Variant Mice. [2020]Objective: To investigate the imaging and biodistribution of a novel zirconium-89 (89Zr)-labeled mouse anti-cd20 monoclonal antibody (mAb) in control and experimental autoimmune encephalomyelitis (EAE) mice following subcutaneous (s. c.) and intravenous (i.v.) administration. Background: Anti-cd20-mediated B-cell depletion using mAbs is a promising therapy for multiple sclerosis. Recombinant human myelin oligodendrocyte glycoprotein (rhMOG)-induced EAE involves B-cell-mediated inflammation and demyelination in mice. Design/Methods: C57BL/6J mice (n = 39) were EAE-induced using rhMOG. On Day 14 post EAE induction, 89Zr-labeled-anti-cd20 mAb was injected in control and EAE mice in the right lower flank (s.c.) or tail vein (i.v.). Positron emission tomography/computed tomography (PET/CT) imaging and gamma counting (ex vivo) were performed on Days 1, 3, and 7 to quantify tracer accumulation in the major organs, lymphatics, and central nervous system (CNS). A preliminary study was conducted in healthy mice to elucidate full and early kinetics of the tracer that were subsequently applied in the EAE and control mice study. Results:89Zr-labeled anti-cd20 mAb was effectively absorbed from s.c. and i.v. injection sites and distributed to all major organs in the EAE and control mice. There was a good correlation between in vivo PET/CT data and ex vivo quantification of biodistribution of the tracer. From gamma counting studies, initial tracer uptake within the lymphatic system was found to be higher in the draining lymph nodes (inguinal or subiliac and sciatic) following s.c. vs. i.v. administration; within the CNS a significantly higher tracer uptake was observed at 24 h in the cerebellum, cerebrum, and thoracic spinal cord (p < 0.05 for all) following s.c. vs. i.v. administration. Conclusions: The preclinical data suggest that initial tracer uptake was significantly higher in the draining lymph nodes (subiliac and sciatic) and parts of CNS (the cerebellum and cerebrum) when administered s.c. compared with i.v in EAE mice.
89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. [2022]Label="BACKGROUND">Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.
Pharmacokinetic drug evaluation of daclizumab for the treatment of relapsing-remitting multiple sclerosis. [2018]Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Despite the availability of several disease-modifying therapies for relapsing MS, there is a need for highly efficacious targeted therapy with a favorable benefit-risk profile and a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Areas covered: Daclizumab blocks the activation and expansion of autoreactive T cells that plays a role in the immune pathogenesis of MS. As its modulatory effects on the immune system, daclizumab's potential for use in MS was tested extensively showing a high efficacy in reducing relapse rate, disability progression and the number and volume of gadolinium-enhancing lesions on brain magnetic resonance imaging. Moreover, phase II and III trials showed a favorable pharmacokinetic (PK) profile with slow clearance, linear pharmacokinetics at doses above 100 mg and high subcutaneous bioavailability, not influenced by age, sex or other clinical parameters. Expert opinion: Among the new emerging drugs for MS, daclizumab also, thanks to a favorable PK profile, may represent an interesting and promising therapeutic option in the wide MS therapies armamentarium.
A double-blind, placebo-controlled, single ascending-dose study of remyelinating antibody rHIgM22 in people with multiple sclerosis. [2022]The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22).
Pharmacokinetics and Bioavailability of Monomethyl Fumarate Following a Single Oral Dose of Bafiertam™ (Monomethyl Fumarate) or Tecfidera® (Dimethyl Fumarate). [2022]Label="BACKGROUND">Tecfidera® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy.
Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies. [2023]Dimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population.
Daclizumab: A Review in Relapsing Multiple Sclerosis. [2022]Daclizumab (Zinbryta®; previously known as daclizumab high-yield process) is a therapeutic monoclonal antibody that has recently been approved for the treatment of relapsing forms of multiple sclerosis (MS) in adults. Daclizumab is a humanized IgG1 monoclonal antibody directed against CD25, the alpha subunit of the high-affinity interleukin-2 receptor. As demonstrated in the phase III DECIDE trial, once-monthly subcutaneous daclizumab was superior to once-weekly intramuscular interferon (IFN) β-1a in reducing the clinical relapse rate and radiological measures of disease in patients with relapsing-remitting MS. In addition, daclizumab has demonstrated efficacy in reducing disability progression and in improving health-related quality of life in patients with relapsing MS. Ongoing open-label clinical trials indicate that daclizumab's efficacy is maintained in the longer term (3 years or more). Daclizumab appears to be generally well tolerated, with adverse events of interest (including hepatic, infectious and cutaneous events) generally manageable with regular monitoring and/or standard therapies. The place of daclizumab in MS treatment remains to be fully determined. However, based on available evidence, daclizumab provides a useful alternative option to other currently available disease-modifying therapies in the treatment of relapsing MS.