Pharmacokinetic and Pharmacodynamic Characterization of Graspa Versus Native L-Asparaginase in Combination with Cooprall Chemotherapy in a Phase 3 Randomized Trial for the Treatment of Patients with Relapsed Acute Lymphoblastic Leukemia (NCT01518517)

Background

Asparaginase is a cornerstone in the treatment of ALL, but its utility is limited by toxicities including hypersensitivity. Clinical allergy is associated with inactivation of asparaginase by antibodies, which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA (eryaspase - proposed INN) is an L-asparaginase encapsulated into the red blood cells. In a recent Phase III trial, it has shown to prolong the asparaginase activity and significantly reduce the incidence of allergic reactions in pts with relapsed ALL.

 Methods

This open, randomized international Phase 3 study enrolled pts with relapsed ALL. The co-primary endpoints were the mean duration of asparaginase (ASPA) activity > 100 IU/L and incidence of hypersensitivity reactions during induction phase. Key secondary endpoints were safety, tolerability, complete remission and minimal residual disease rate, pharmacokinetic (PK), pharmacodynamics (PD) and anti-ASPA antibodies at baseline. Pts (n=80), aged 1-55 years without prior hypersensitivity were randomized to GRASPA (150 IU/kg, n=26, Arm A) or native L-asparaginase (L-ASP, 10,000 IU/m², n= 28, Arm B). Additionally, 26 pts with prior hypersensitivity were treated with GRASPA in a single stratum (Arm C, GRASPA-s). All pts received COOPRALL protocol as a backbone chemotherapy. Here we report the report the PK of asparaginase activity, and PD effects.

Results

A total of 80 pts enrolled into the trial. A total 100% and 96% of patients had at least one day with asparaginase level >100 IU/L during induction, with GRASPA and L-ASP, respectively. Only one patient in L-Asp group did not reach this threshold. All patients in Arm C have also achieved total blood asparaginase level > 100 IU/L during induction. Prolonged ASPA activity was maintained across several key subpopulations as follows:

 

	GRASPA	L-ASP	GRASPA	L-ASP
Age group	Children		Adults
N	21	21	5	7
Mean (SD)	20.8  (5.3)	11.4 (7.3)	19.3 (5.5)	3.2 (2.8)
Median	22.0	8.3	22.1	2.3
Risk Score	S1/S2		S3/S4
N	16	15	10	13
Mean (SD)	20.2 (6.0)	12.0 (8.6)	20.9  (3.9)	6.3 (4.4)
Median	22.4	9.0	22.0	6.2
F1-F2/VANDA	F1-F2		VANDA
N	16	15	10	13
Mean (SD)	19.5 ± 6.5	11.5 (9.0)	22.0 (0.2)	6.9 (4.2)
Median	22.9	8.8	22.0	6.9

The total ASPA activity >100 IU/L until the loss of that activity demonstrated that the activity was retained in the majority of pts in the GRASPA arm (89%) compared to only 26% in the L-ASP arm. The median times from first assessment of activity > 100 IU/L to loss of activity was not reached in the GRASPA arm by Day 28, but was 15 days in the L-ASP arm. The difference was statistically significant (table below). Similar trend was also observed with GRASPA-s.

 

Time from first assessment showing ASPA activity > 100 IU/L until loss of ASPA activity > 100 IU/L	Number (%) of events	Median [95% CI]	Hazard ratio	95% CI	Logrank test: p-value for superiority
L-ASP N= 28	27 (96.4)	15 [11; 21]	0.14	0.07, 0.28	<0.001
GRASPA N= 26	26 (100)	NR*

                                                                        NR: not reached

Additional information correlating ASPA with asparagine depletion and other amino acid changes (aspartate, glutamic acid, and glutamate) will be provided at the meeting.

 Conclusion

GRASPA consistently demonstrated activity compared to L-ASP for the treatment of pts with relapsed ALL, and is therefore a suitable option for patients with relapsed ALL.