Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study.

Abstract

PURPOSE:

This study aimed to assess the safety, pharmacokinetic and activity profiles of the human-mouse chimeric monoclonal anti-disialoganglioside GD2 antibody ch14.18 produced in Chinese hamster ovary (CHO) cells (ch14.18/CHO).

METHODS:

Sixteen children with recurrent/refractory neuroblastoma (median age 7.6 y) were enrolled in this Phase 1 dose-finding study. Patients received ch14.18/CHO courses of 10, 20 or 30 mg/m (2)/day as an eight-hour infusion over five consecutive days. Three courses at the same dose level were allowed unless disease progressed. Clearance and biodistribution of radiolabelled ch14.18/CHO in Balb/c and A/J mice were analyzed.

RESULTS:

A total of 41 ch14.18/CHO courses were given (10 × 3 courses, 5 × 2 courses, 1 × 1 course). Side effects were similar in expectedness, frequency and magnitude to those reported for ch14.18/SP2/0. The dose level of 20 mg/m(2)/day was confirmed. Toxicity was reversible and no treatment-related deaths occurred. In children, the peak plasma concentration was 16.51 µg/ml ± 5.9 µg/ml and the half-life was 76.91 h ± 52.5 h. A partial response following ch14.18/CHO was observed in 2/7 patients with residual disease. In mice, the half-lives were 22.7 h ± 1.9h for ch14.18/CHO and 25.0 h ± 1.9 h for ch14.18/SP2/0. The biodistribution of (125)I-ch14.18/CHO in mice with neuroblastoma was identical to (125)I-ch14.18/SP2/0, indicating GD 2 targeting activity in vivo. Ch14.18 produced in CHO cells showed an unchanged toxicity profile and pharmacokinetics in neuroblastoma patients compared with ch14.18 produced in SP2/0 cells, and evidence of clinical activity was observed. In mice, analysis of pharmacokinetics and biodistribution showed comparable results between ch14.18/CHO and ch14.18/SP2/0. Based on these results, ch14.18/CHO was accepted for prospective clinical evaluation.

• Authors: Ruth Ladenstein, Silke Weixler, Bianca Baykan, Matthias Bleeke, Renate Kunert, Dietmar Katinger, Ingrid Pribill, Petra Glander, Steffen Bauer, Vito Pistoia, Jean Michon, Alberto Garaventa, Holger N Lode
• Journal: mAbs (MAbs) 2013 Sep-Oct Vol. 5 Issue 5 Pg. 801-9 ISSN: 1942-0870 [Electronic] United States
• PMID: 23924804 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• dinutuximab

Topics

• Adolescent
• Anemia (chemically induced)
• Animals
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Area Under Curve
• CHO Cells
• Child
• Child, Preschool
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm
• Female
• Fever (chemically induced)
• Humans
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Inbred BALB C
• Mice, Inbred Strains
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Neuroblastoma (drug therapy, metabolism, pathology)
• Tissue Distribution
• Treatment Outcome