Background: Asparaginase is a critical therapeutic agent in the treatment of childhood ALL, and pegaspargase (Oncospar, ONC) is now the preferred product in COG frontline ALL trials. EZN-2285 replaces the succinimidyl succinate linker in ONC with a succinimidyl carbamate linker creating a more stable molecule. AALL07P4 was designed to determine the PK comparability of EZN-2285 to ONC when given intravenously in newly diagnosed patients with NCI high-risk (HR) B-precursor ALL. Methods: 162 eligible patients were randomized to receive EZN-2285 at 2100 (LD, n=66) or 2500 (HD, n=42) IU/m² vs. 2500 IU/m² of ONC (n=51) in a 2:1 manner based on the prednisone/Capizzi methotrexate arm of COG AALL0232. All groups were similar demographically with the exception of number of patients over the age of 16 years were 6, 5, and 19 in the ONC, HD and LD, respectively. Results: PK, PD and targeted AEs (Gr 3-5) after the first doses of study drug are presented in the table below. Adverse events in induction were not significantly different between arms with the exception of a higher incidence of hyperglycemia (p=0.042). Conclusions: Based on C_{max ,} AUC_{0-25d ,} and asparaginase activity 25 days post drug, EZN-2285 2500 IU/m² appears to have an improved PK/PD profile compared to pegaspargase 2500 IU/m² and a comparable toxicity profile in children with HR ALL.

PK/PD (mean±SD) and AEs post induction dose.

	Pegaspargase 2500 IU/m2 (n=43)	EZN-2285 2500 IU/m2 (n=40)	EZN-2285 2100 IU/m2 (n=62)
Cmax (mIU/mL)	1,647±474	1,655±366	1,291±379
t½ (hrs)	127±51	322±118	305±98
AUC0-25d (mIU*hr/mL)	359,781±80,309	470,742±123,584	369,998±122,013
AUC0-inf (mIU*hr/mL)	387,015±85,753	574,091±158,574	454,394±144,348
Asparaginase activity (mIU/mL) 25 D post drug	72.8±47.9	339.6±126.8	271.6±118.2
Asparaginase activity ≥100/≥400 mIU/mL 25 D post drug (%)	67/0	98/28	94/14
Plasma asparagine depletion 25/42 D post drug (%)	88/8	92/72.4	93/75
Safety population	(n=54)	(n=42)	(n=69)
Allergy (%)	7	2	1
Coagulopathy (%)	0	7	3
Hyperbilirubinemia (%)	7	12	9
Hyperglycemia (%)	15	26	35
Hyperlipidemia (%)	6	5	1
Pancreatitis (%)	4	5	6
Thrombosis (%)	0	0	6
CNS (%)	0	0	1