Selection of Odronextamab Pediatric Dosing Regimens for Aggressive Non-Hodgkin Lymphoma Via a Modeling and Simulation Approach

Background Odronextamab is a hinge-stabilized, human CD20×CD3 IgG4-based bispecific antibody that binds CD20-expressing cells and CD3 on T cells, targeting CD20+ cells via T-cell-mediated cytotoxicity, independent of T-cell receptor-mediated recognition. Clinical studies of odronextamab in adult patients with relapsed/refractory CD20+ B-cell malignancies are ongoing. Encouraging efficacy has been reported in patients participating in the Phase I study ELM-1 (NCT02290951; Bannerji R, et al. Lancet Haematol. 2022;9:e327-39). 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 have poor outcomes. A study of odronextamab in relapsed/refractory pediatric patients with B-cell NHL (B-NHL) is being planned. The objective of this analysis was to determine intravenous (IV) regimens for testing in pediatric patients that can achieve similar exposures to those achieved in adults.

Methods The analysis was conducted in 6 steps: 1) A population pharmacokinetic (PK) model was developed with data from adults receiving IV odronextamab and assessed effects of body weight (WT) on drug clearance (CL) and volume of distribution (V); 2) A virtual pediatric population was created with demographics derived from the 2017-2018 National Health and Nutrition Examination Survey database; 3) Pediatric model parameters were extrapolated from those of adults by applying effects of WT and age on CL and V as appropriate; 4) Odronextamab PK profiles were simulated in virtual pediatric patients aged 6 months to 18 years in 4 weight bands (≥40 kg, 20-39 kg, 10-19 kg, 6-9 kg) using the extrapolated pediatric population model parameters; 5) Odronextamab drug amounts were adjusted in each weight band for each weekly (QW) dosing period, and every 2 weeks (Q2W) dosing period with the aim of matching adult patient exposures; and 6) Pediatric regimens were selected for testing based on 2 criteria. Firstly, for safety, median maximal concentration (C_max) during Cycle 1 step-up dosing within 80-125% of the adult value. Secondly, for efficacy, median minimal concentration (C_min) at steady state during Cycle 2 onwards not less than the adult value.

Results Step-up dosing is used in Weeks 1-3 of treatment of adult patients with odronextamab to mitigate the risk of cytokine release syndrome, a common adverse event with T-cell engaging therapies. Applying a simulation approach, dosing regimens tiered by WT bands were proposed for pediatric patients (Table). Children with WT ≥40 kg could receive the adult's regimen; those weighing <40 kg could receive reduced doses according to their WT bands. The regimens and model assumptions will be tested in a pediatric study with patients weighing ≥20 kg enrolled first.

The proposed regimens were predicted to achieve odronextamab exposures similar to those with the adult regimen. No significant difference in C_max was predicted with the step-up doses; the ratios of median C_max for the pediatric WT groups relative to adults fell within 0.831-1.24. The median C_min values at steady state were not below those observed in adults.

Additional exploratory simulations were performed to assess uniform weight-based dosing (mg/kg) for the overall pediatric population. This approach was inferior to the regimens tiered by WT bands due to above-target concentrations among individuals weighing ≥20 kg and below-target concentrations in those weighing 6-9 kg.

Conclusion The modeling and simulation approach allowed the identification of dosing regimens that might be suitable for investigational use in children with B-NHL. Based on predicted PK profiles, pediatric dosing regimens tiered by WT bands may preserve the efficacy of odronextamab observed in adults, without increasing the risk of acute toxicity.

Zhu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Dodds:Certara: Current Employment; Regeneron Pharmaceuticals, Inc.: Consultancy. Ambati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Mohamed:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chittenden:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Merck: Ended employment in the past 24 months. Yan:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Chaudhry:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Davis:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company.