Study of Ch14.18 in Young Patients With High-Risk Neuroblastoma

• PK parameters of Ch14.18 in children with high‐risk neuroblastoma during and after 4 daily 10‐hour infusions, including the peak concentration, trough concentration, AUC, clearance, volume of distribution, half-life, and mean residence time [ Time Frame: Before and after infusion on days 3-5; before, after, and 4-6 hours after infusion on day 6; 12-14 hours after infusion on day 7; on the morning of days 10, 14, 17, and 24; and before infusion on day 31 ] [ Designated as safety issue: No ]
  PK parameters will be derived from the plasma concentration-time data. A one-compartment model fit to the concentration-time data will estimated the volume of distribution and the first order elimination rate constant, which will in turn be used to calculate clearance, half-life, AUC0-infinity, AUC0-last, and the mean residence time. An error function and the dependency for each fitted parameter will be reported.
  
  
• Coefficient of variation of Ch14.18 clearance [ Time Frame: Up to 158 days ] [ Designated as safety issue: No ]
  The coefficient of variation of Ch14.18 clearance is used to quantify the degree of inter-patient and intra-patient variability of Ch14.18 pharmacokinetics. The relationship between patient characteristics, HACA, tumor burden, and plasma GD2 levels will be assessed graphically in an exploratory fashion with regression models.
  
  

• Severity of neuropathic pain, quantified using an observational pain scale based on the FLACC and the total dose of morphine administered to control pain [ Time Frame: Up to 158 days ] [ Designated as safety issue: No ]
  The severity of neuropathic pain will be correlated with plasma concentrations of Ch14.18. A Ch14.18 concentration-effect curve will be generated for each patient of the course of the 4 day treatment. The overall drug exposure during the infusion will be correlated with the total morphine dose administered over the 4 days of treatment.
  
  
• AUC of Ch14.18 [ Time Frame: Up to 158 days ] [ Designated as safety issue: No ]
  A limited sampling strategy that will accurately quantify the AUC of Ch14.18 will be developed.
  
  

PRIMARY OBJECTIVES:

I. Describe the pharmacokinetics (PKs) of monoclonal antibody Ch14.18 (Ch14.18) in children with high-risk neuroblastoma.

II. Quantify the degree of inter-patient and intra-patient variability in the clearance of Ch14.18, and correlate Ch14.18 clearance with patient characteristics, the presence of human anti-chimeric antibody (HACA), tumor burden (assessed on scans), and plasma G_D2 levels to identify sources of variability in the clearance.

III. (Exploratory) Develop a PK model to describe the PK profile of Ch14.18 and derive PK parameters.

SECONDARY OBJECTIVES:

I. Correlate plasma concentrations of Ch14.18 with the severity of neuropathic pain, which is being quantified using an observational pain scale, and the total dose of morphine administered to control pain.

II. Develop a limited-sampling strategy that will accurately quantify the area under the curve (AUC) of Ch14.18.

III. Simulate alternative dosing strategies with the PK model in order to reduce variability and simplify drug administration.

OUTLINE:

Patients undergo blood sample collection at baseline and during and after course 1, 3, or 5 of monoclonal antibody Ch14.18 (Ch14.18) and sargramostim for pharmacokinetic, human anti-chimeric antibody, and concentration of ganglioside G_D2 studies. The Ch14.18A level is measured via ELISA. A pharmacokinetic model is then developed using the Modeling Laboratory (MLAB) software.

Parents, guardians, or caretakers are asked to assess patients' pain three times a day, prior to, during, and at the end of Ch14.18 treatment.