Using Modeling & Simulation to Develop a Dosing Regimen for a Bispecific Antibody for Pediatric Cancer

In the US, approximately 800 new cases of pediatric non-Hodgkin lymphoma (NHL) are diagnosed each year. Improved treatment options are needed for pediatric patients, particularly those with relapsed/refractory disease following chemoimmunotherapy, who often have poor outcomes. Regeneron Pharmaceuticals is seeking to evaluate the use of odronextamab in relapsed/refractory pediatric patients with B-cell NHL (B-NHL).

Conducting pediatric clinical trials requires significant methodological rigor that is often difficult to achieve in a vulnerable patient population that is historically difficult to recruit. In addition, running clinical studies on pediatric cancer patients presents multifaceted and complex ethical challenges. Thus, the Regeneron team wanted to choose the dosing regimen for odronextamab that would have the highest likelihood of technical success in clinical trials in this vulnerable population.

Population pharmacokinetic (PK) modeling and simulation is a cost-effective, powerful tool that can increase dosing accuracy, reduce adverse effects, and ultimately improve patient outcomes. To select intravenous (IV) regimens for testing in pediatric patients, Certara pharmacometricians partnered with the Regeneron team to adapt a population PK model for odronextamab developed in adults to the pediatric population. The largest translational challenges and our solutions follow:

1. Differences in PK parameters in adult and pediatric patients are mainly driven by differences in body weight.
2. Maturation effect on nonspecific drug elimination is considered in addition to weight effects for infants younger than 1 year of age.
3. Similarity of target and tumor burden in adult and pediatric patients supports similar targeted-related nonlinear drug clearance

The odronextamab adult Pop PK model indicated that weight was the only statistically significant covariate on linear clearance and volume parameters in adult patients with B‑NHL with a weight range of 42 to 165 kg. Therefore, the differences in key PK parameters that described odronextamab linear clearance and volumes of distribution in adult and pediatric patients were assumed to be mainly driven by differences in body weight. To account for weight effects, allometric scaling of clearance and volume parameters was utilized for PK extrapolation to pediatric patients. The simulated population included patients from 6 months to <18 years old to ensure that odronextamab exposures in children of different ages and body weight groups matched adult exposures with step-up, treatment, and maintenance dosing.⁴

A virtual pediatric population was created with demographics derived from the 2017–2018 National Health and Nutrition Examination Survey database. Pediatric model parameters were extrapolated from adults by applying the effects of body weight and age on factors such as drug clearance and volume of distribution.

A maturation effect was added on linear clearance to account for the age-associated difference in nonspecific elimination for infants younger than 1 year of age.

CD20, the target for odronextamab, is universally expressed in all B-NHL in pediatric and adult patients. There is currently no evidence of tumor biomarkers that may confer different sensitivities to treatment in adults with odronextamab.

Odronextamab clearance was concentration and time dependent following IV infusion over a dose range from 0.03 mg to 320 mg in patients with R/R B-NHL, which reflected target-mediated drug elimination via target cells (i.e., B cells) [Study R1979-PK-21139-SR-01V1]. Consistent with these observations, PK parameters of odronextamab describing nonlinear clearance (e.g., maximum nonlinear clearance at baseline) were not correlated with body weight or tumor size at baseline in adult patients with B-NHL (data on file). Collectively, the similarity of tumor target expression and tumor burden in adult and pediatric patients supports that the same target-mediated nonlinear clearance was used during PK extrapolation from adults to pediatrics with B-NHL.

Population PK modeling and simulation helped identify the best dosing regimens for pediatric patients that preserved the efficacy of odronextamab observed in adults without increasing the risk of acute toxicity. The proposed regimen for pediatric patients in each weight band reasonably predicted step-up doses with split dosing, treatment doses, and maintenance doses that matched the exposures in adult patients.

This approach helped identify odronextamab IV dosing regimens that are suitable for investigational use in children with B-NHL.