A Phase I Clinical Trial of Rituximab for Pediatric Opsoclonus-Myoclonus Syndrome
Opsoclonus-myoclonus syndrome (OMS) is a rare but pervasive, paraneoplastic neurological
disorder, purported to be autoantibody-mediated. We demonstrated expansion of B-cells in
cerebrospinal fluid (CSF) despite tumor resection, chemotherapy, or conventional
immunotherapy. Whether B-cells can be purged from the CSF compartment with benefit to the
patient is unknown. Targeting of CSF B lymphocytes represents a novel and valuable paradigm
shift in the therapy of centrally-mediated paraneoplastic disorders. The objective of this
preliminary study is to determine if rituximab, a monoclonal antibody against CD20+ B-cells,
reduces or eliminates CSF B-cells in OMS and whether the reduction results in clinical
improvement. B lymphocyte subsets and relevant T-cell subsets will be immunophenotyped in
the CSF and peripheral blood of children with OMS by four-color dual-laser flow cytometry.
Sixteen children with an increased percentage of CSF B-cells will be treated with rituximab
375 mg/m2 IV once weekly for four consecutive weeks and CSF testing will be repeated at six
months with more frequent clinical evaluations and blood testing out to 12 months. Clinical
outcome will be rated blindly from videotapes by an experienced observer using a validated
12-item motor evaluation scale and quantifiable parameters of sleep, behavior and motor
function. Immunological outcome variables will include percentages of B-cell subsets and
quantitative immunoglobulins. Post-treatment results will be compared to pre-treatment
values statistically. If rituximab proves to be an efficacious and safe method of treating
CSF B-cell expansion and the neurological syndrome, this study will lead to a phase II trial
with the eventual aim of gaining FDA approval of rituximab for this indication.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Determine the effectiveness & selectivity of rituximab at depleting CSF B-cells in OMS with intrathecal B-cell expansion. This requires CSF & blood lympocyte immunophenotyping prior to the first infusion & intervals for 1 year after the final infusion.
Michael R Pranzatelli, M.D.
National Pediatric Myoclonus Center
United States: Food and Drug Administration
|National Pediatric Myoclonus Center, Department of Neurology, SIU School of Medicine, 751 N Rutledge St||Springfield, Illinois 62794|