Novel infusion strategy to reduce major side effects caused by anti-GD2 monoclonal antibody naxitamab without affecting its pharmacokinetics.
Authors: Mora Jaume , Varo Amalia , Castañeda Alicia , Chamorro Saray , Muñoz Juan Pablo , Gorostegui Maite , Celma Monica Sanchez , Lopez Sandra , Simao Margarida , Perez-Jaume Sara , Cheung Irene Y. , Cheung Nai-Kong V. 
Published: June 2022

e14502 Background: Intravenous administration of anti-ganglioside GD2 monoclonal antibodies (mAbs) is commonly associated with adverse events (AEs) such as pain and hypertension. Naxitamab is an anti-GD2 mAb intended for outpatient use with a short (30-60 minutes) administration time with 60%-70% of patients in clinical studies experiencing grade 3-4 pain or hypotension. To reduce this risk we assessed a novel administration protocol (StU) that modulates the pharmacodynamics (PD) of naxitamab and mitigates infusion-related reactions. Methods: High-Risk Neuroblastoma (HR-NB) patients in complete remission (CR) received naxitamab as consolidation. Naxitamab cycles comprised priming doses of sc GM-CSF for 5 days at 250 μg/m2/day followed by naxitamab + sc GM-CSF for 5 days at 500 μg/m2/day (days 1-5). Standard naxitamab protocol infusion is provided over 60 minutes at 3 mg/kg/day on day 1 and over 30 minutes on days 3 and 5. Infusions in the StU protocol day 1 were initiated at 1 ml/h with doubling of infusion rate every 15 minutes over 75 minutes (16% of the total dose) and completing the infusion to a final cumulative dose of 3 mg/kg over the remaining 45 minutes; total infusion time of 2h (Table). A faster program (30% of the dose administered in 60 minutes and completed with further 30 minutes) was used for days 3 and 5 infusions. Treatment cycles were repeated every 4 weeks for a goal of 5 cycles. Pharmacokinetics was studied by quantifying serum naxitamab concentrations by ELISA. Infusion related adverse events (AEs) were graded according to the CTCAE v 4.0. Results: 42 HR-NB patients were treated during 2021, 19 with the standard, 15 using the StU, and 8 with both, for a total of 159 cycles (77 StU including 20 cycle one), 477 (231 StU) infusions. All pts presented non-serious CTCAE G1-2 AEs and 7 (37%) CTCAE G3/4 AEs (hypertension x1, hypotension x4, pain x3, airway constriction x5) on the standard protocol. Among the 15 pts on the StU protocol, 1 (6.7%) had CTCAE G3 hypertension. Of the 8 pts who received both types of cycles, 5 (62.5%) had CTCAE G3/4 toxicities (laryngospasm x3; pain x2), 3 with the standard regimen and 2 with the StU protocol. When protocols were compared, the standard regimen cycles (22 cycle one) generated 14.6% (12 of 82) G3/4 AEs whereas the StU 3.9% (3 of 77). Using mixed effects logistic regression analysis, an odds ratio of 0.23 with 95% CI=(0.05, 0.96) and p=0.045 is obtained with the StU cycles reducing the chances to develop G3/4 AEs in 77% compared to the standard regimen. The median serum naxitamab levels pre-StU infusion is 11.46 ug/mL and post infusion 100.95 ug/mL, within the same range as the standard protocol. Conclusions: A pharmacodynamics guided protocol of infusion significantly decreased the severe AEs permitting more tolerable infusions of naxitamab.[Table: see text]