Bridging Study Using ch14.18/CHO Antibody in Children With Refractory Neuroblastoma
Anti-ganglioside GD2 antibody ch14.18 is a monoclonal antibody specifically recognizing the
target antigen GD2, which is expressed on virtually all neuroblastoma tumours. This antibody
is a chimeric protein and consists to 30% of mouse variable light and heavy chain and to 70%
of human constant heavy and light chain. Ch 14.18 has already been tested in stage 4
neuroblastoma patients in phase I/II clinical trials with encouraging response rates.
Therefore, the European SIOP neuroblastoma group designed a Phase III protocol to test the
efficacy of ch14.18 immunotherapy in a randomised trial.
However, the ch14.18 antibody for this Phase III trial was recloned and produced in Chinese
hamster ovary (CHO) cells in contrast to ch14.18 antibody used for previous clinical trials,
which was produced in murine, non-secreting myeloma cells (SP2/0). Although the
antibody-gene transfer into CHO and SP2/0 was done with exactly the same plasmid assuring an
identical protein sequence, changes in the glycosylation of the final protein product may
occur since the glycosylation pattern varies between different production cell lines.
Glycosylation is important for the immunological effector function of the antibody and the
pharmacokinetics in patients. Therefore, this change is considered to be a major change in
production requiring the reassessment of the new product in a Phase I clinical trial.
The primary objective of this trial is the re-evaluation of toxicity of the new ch14.18/CHO
antibody. This is ultimately followed by the secondary objectives including the
determination of pharmacokinetics and immunostimulation in patients receiving ch14.18/CHO
therapy. This involves particularly the determination of activation of immune effector cells
and complement during and after application of ch14.18/CHO. Subsequently, we will evaluate
the clinical effect of this treatment on the course of the disease.
The nature of this phase I trial is a bridging study for a medicinal product subjected to a
major change in production according to the guidelines provided by the "Committee for
Proprietary Medicinal Products" (CPMP) of the "European Agency for the Evaluation of
Medicinal Products (EMEA) (Document Number CPMP/BWP/3207/00).
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Adverse events as a measure of safety/tolerability
Reassess the toxicity profile of one treatment cycle with ch14.18 recloned in CHO cells (ch14.18/CHO), when administered as daily eight-hour infusions and accompanied by supportive care measures in particular to prevent pain, fever and allergic reactions according to previously established standards.
4 weeks (end of cycle 1)
Holger Lode, MD
Charite Children's Hospital
Austria: Federal Ministry for Health and Women