Clinical trial NCT05849467: Central Nervous System Uptake of Anti-CD8+ T Cell Minibodies in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy
Official title: Central Nervous System Uptake of Anti-CD8+ T Cell Minibodies in Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy: A Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Multiple Sclerosis
Progressive Multifocal Leukoencephalopathy
Keywords: 89 Zr-Df-crefmirlimab
PET Imaging
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2023-05-09
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Study Description:

This study will obtain pilot data for noninvasive positron emission tomography (PET) imaging of CD8+ T lymphocytes in two inflammatory central nervous system (CNS) demyelinating diseases, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy (PML), by characterizing CNS uptake of anti-CD8+ T cell antibody fragment (aka minibody ) (89Zr-Dfcrefmirlimab), an investigational, intravenous PET tracer.

Objectives:

Primary Objective: To detect and localize infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT (computed tomography) scans using a minibody with high affinity for CD8+ T cells.

Secondary Objectives: (1) To characterize safety and tolerability of 89Zr-Df-crefmirlimab in the participant population. (2) For the PML cohort with longitudinal evaluation, to determine the effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake.

Endpoints:

Primary Endpoints: Standardized uptake values (SUV) in different tissue types (lesions, white matter, gray matter, meninges, choroid plexus, as determined from coregistered MRI) in each cohort (MS or PML) by region-of-interest (ROI) analysis.

Secondary Endpoints: (1) Frequency and nature of adverse events; (2) For the PML cohort with longitudinal evaluation, changes in SUV over time.

Eligibility criteria: * INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Multiple Sclerosis Inclusion Criteria

* Enrolled in the NINDS Natural History Study for MS (protocol 89-N-0045)
* Able to understand, and willing to sign, a written, informed consent document.
* Willing to comply with all study procedures and available for the duration of the study.
* Male or female, aged \>=18.
* Diagnosis of MS according to the 2017 revision of the McDonald diagnostic criteria48 (in the presence or absence of a clinical relapse).
* For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.
* Creatinine clearance \>= 60 mL/min as estimated by the Cockcroft-Gault equation.
* Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.

PML Inclusion Criteria

* Enrolled in the NINDS Natural History Study for PML (protocol 13-N-0017)
* Able to understand and willing to sign a written, informed consent document
* Willing to comply with all study procedures and available for the duration of the study.
* Male or female, aged \>=18.
* Diagnosis of definite PML according to 2013 AAN Consensus Criteria49 or PML-IRIS based on clinical, radiological and laboratory evidence.
* For females of reproductive potential: agrees to use highly effective contraception for at least one month prior to screening and during study participation.
* Creatinine clearance \>= 60 mL/min as estimated by the Cockcroft-Gault equation.
* Has aspartate transaminase (AST) or alanine transaminase (ALT) levels less than 1.5x ULN.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

* Pregnant or lactating.
* Contraindications for MRI gadolinium contrast administration or 3T MRI.
* History of, or current diagnosis with, concomitant medical or clinical conditions that would adversely affect participation in this study.
* Weighs \> 350 lb (158 kg; weight limit for the scanner table) or is unable to fit within the MRI or PET imaging gantry.
* Severe claustrophobia unresponsive to oral anxiolytics.
* Has an alkaline phosphatase level greater than 2x ULN unless known to have non-liver related disorder, and AST and ALT remain stable.
* Has a total bilirubin \>1.5X ULN, unless known to have elevated bilirubin due to nonliver related disorder or Gilbert s.

Primary outcomes:
measure: Infiltration of CD8+ T cells in the CNS of adults with MS and PML via PET-CT scans using a minibody with high affinity for CD8+ T cells.
timeFrame: Day 1 Study Visit
Secondary outcomes:
measure: Safety of 89Zr-Dfcrefmirlimab in the participants with CNS disease.
timeFrame: At each study visit
measure: For the PML cohort with longitudinal evaluation, effects of immune reconstitution, either spontaneous or facilitated, on 89Zr-Dfcrefmirlimab uptake.
timeFrame: up to 6 months after first PET/CT scan
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Neurological Disorders and Stroke (NINDS)
name: Daniel S Reich, M.D.
role: PRINCIPAL_INVESTIGATOR
References: