Abstract
Background: Neuroblastoma is the primary cause of death from paediatric cancer for children between 1 and 5 years of age and accounts for 13% of all paediatric cancer mortality. In these patients, MYCN amplification in tumour cells is associated with relapse and poor prognosis. Available experimental data on a new molecule (BGA002) aimed at the inhibition of the MYCN gene show treatment efficacy on cell viability and mRNA transcription and in tumour growth models in mice.
Here we assess the pharmacokinetic-pharmacodynamic (PKPD) relationships of BGA002 as the basis for the selection of the doses to be evaluated in naïve and relapsed paediatric patients along with an optimised Phase I/IIa trial design to assess the safety, tolerability and pharmacological effects associated with the inhibition of MYCN-amplified tumours.
Methods: First, in vitro cell viability and mRNA inhibition levels were analysed. Next, in vivo data including doses from 2.5 to 50 mg/kg were pooled to describe the pharmacokinetics of BGA002 in plasma. Tumour concentration measurements were linked to plasma pharmacokinetics. An integrated PKPD model was then developed to describe the drug effect on tumour growth in mice following 2-week treatment with ascending doses of BGA002. Allometric concepts were applied to scale PK parameters from animals to humans. Finally, clinical trial simulations were performed to explore the feasibility of optimising the protocol design for an integrated Phase I/IIa study in paediatric patients.
Results: Direct inhibition and turnover models were found to adequately describe the available experimental data. Parameter estimates suggest that MYCN inhibition ≥ 80% is required to affect cell viability and tumour growth. The results from the different simulation scenarios show that systemic exposure to BGA002 in a first-time-in-children/proof-of-concept protocol should range from 50 h*ng/ml to 1400 h*ng/ml.
Conclusion: In contrast to the use of toxicity parameters as criteria for dose selection and escalation in Phase I studies, a model-based approach allows effective integration of pre-clinical data, providing a robust basis for the dose rationale. Moreover, in conjunction with adaptive procedures, the use of clinical trial simulations allows for the identification of informative protocol designs in early paediatric oncology trials.
