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2492 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)

Acute Lymphoblastic Leukemia: Clinical Studies
Program: Oral and Poster Abstracts
Session: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Xavier Thomas, MD, PhD1, Yves Bertrand, MD, PhD2*, Andre Baruchel, MD, PhD3, Nicolas Blin, MD4*, Emmanuelle Tavernier, MD5*, Stephane Ducassou, MD6*, Norbert Vey7, Virginie Gandemer, MD, PhD8, Victoria Cacheux, MD9*, Francoise Mazingue, MD10, Emmanuel Raffoux11*, Genevieve Plat, MD12*, Jose Fernandes, MD13*, Maryline Poiree, MD14*, Luc Fornecker, MD15*, Jean-Louis Stephan, MD16*, Mathilde Hunault, MD, PhD17*, Anne Auvrignon, MD18*, Thibault Leguay, MD19*, Stephane Lepretre, MD20*, Alina Ferster, MD, PhD21, Isabelle Pellier, MD22*, Emmanuel Plouvier, MD23*, Claudine Schmitt24*, Cecile Bonin, Pharm D25*, Yann Godfrin, PhD25 and Iman El Hariry, MD, PhD25*

1Hematology Department, Hopital Edouard Herriot, Lyon, France
2Pediatric hematology, CHU Lyon, Lyon, France
3Pediatric Hematology, Hopital Saint Louis, Paris, France
4Department of Hematology, Nantes University Hospital, Nantes, France
5hematology, Institut de cancerologie de la Loire, Saint Priez en jarez, 42271, France
6Pediatric Hematology, CHU de Bordeaux,Hopital des Enfants-Hôpital Pellegrin, Bordeaux, France
7Hematology, Institut Paoli-Calmettes, Marseille, France
8Pediatric Hematology, Centre Hospitalier Universitaire de Rennes, Rennes, France
9Hematology Clermont Ferrand,, CHU Clermont Ferrand, Clermont Ferrand, France
10hematology, CHRU Lille, Lille, France
11Hematology Department, Saint Louis Hospital, Paris, France
12pediatric hematology, CHU Toulouse, Toulouse, France
13Centre Hospitalier Valenciennes Hematology, Valenciennes, France
14CHU Lenval Pediatric Hematology, Nice, France
15Oncology and Hematology, Hopital de Hautepierre, Strasbourg, France
16Hopital Nord - CHU Saint Etienne, Saint Priez en jarez, 42271, France
17Hematology Department, CHU, Angers, France
18Pediatric Hematology, AP-HP,GH-HUEP Trousseau Hospital, PARIS, France
19Department of Hematology, CHU, Bordeaux, Bordeaux,, France
20Hematology, CLCC H Becquerel, Rouen, France
21Dept. of Hémato-oncologie pédiatrique, Children's University Hospital Reine Fabiola, Brussels, Belgium
22CHU Angers, Angers Cedex, France
23pediatric hematology, CHRU Besançon, Besançon, France
24Pediatric Hematology, CHU de nancy, Nancy, France
25ERYTECH Pharma, Lyon, France

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.

Disclosures: Thomas: ERYTECH Pharma: Consultancy . Bertrand: ERYTECH Pharma: Consultancy , Membership on an entity’s Board of Directors or advisory committees . Vey: Celgene: Honoraria ; Roche: Honoraria ; Janssen: Honoraria . Bonin: ERYTECH Pharma: Employment . Godfrin: ERYTECH Pharma: Employment . El Hariry: ERYTECH Pharma: Employment .

*signifies non-member of ASH