GRASPA (Erythrocytes Encapsulating L-asparaginase) in Patients With Relapse of Acute Lymphoblastic Leukemia

Condition(s) targeted: Acute Lymphoblastic Leukemia, in Relapse

Intervention: GRASPA (Drug); L-asparaginase (Drug)

Phase: Phase 2/Phase 3

Status: Active, not recruiting

Sponsored by: ERYtech Pharma

Official(s) and/or principal investigator(s):
Yves Bertand, MD, Principal Investigator

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 (A-Abs), which can also neutralize asparaginase without any clinical signs of hypersensitivity (silent inactivation). GRASPA improves pharmacokinetics, tolerability and maintain circulating asparaginase activity due to the protective barrier of the erythrocyte membrane. This study is run to confirm the benefit/risk profile of GRASPA at 150 IU/kg in combination with the COOPRALL regimen in adults and children patients with relapsed ALL, with or without known hypersensitivity to L-asparaginase.

Official title: Phase 2/3 Study Evaluating Efficacy and Safety of Erythrocytes Encapsulating L-asparaginase (GRASPA)Versus Reference L-asparaginase Treatment in Combination With Standard Polychemotherapy in Patient With First Recurrence of Philadelphia Negative Acute Lymphoblastic Leukemia

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: efficacy and toxicity combined

Secondary outcome:

Molecular response rate

Plasma concentration of asparagine, aspartate, glutamine, glutamate and asparaginase

Specific anti L-asparaginase antibodies

Event free survival

Relapse free survival

Overall survival

Percentage of patient with complete remission

Detailed description: This open, randomized international Phase 2/3 study will enrol patients with relapsed ALL. The co-primary endpoints were the duration of asparagine depletion < 2µmol/L and the incidence of asparaginase hypersensitivity during induction. Key secondary endpoints are complete remission (CR), minimal residual disease (MRD), event free survival (EFS) and overall survival (OS).The study was powered to detect 3-fold difference in the incidence of allergic reactions between treatments. patients will be randomized to GRASPA or to Reference L-asparaginase. Patients with history of hypersensitivity to previous L-asparaginase treatment will be treated with GRASPA (exploratory arm)

Minimum age: 1 Year. Maximum age: 55 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Patient from 1 to 55 years old (Children and adolescents from 1 to 17 years/ Adults

from 18 to 55 years)

- Patients with 1st ALL relapse, which could be either isolated bone marrow relapse, or

combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma) OR Failure to ALL first line treatment (no complete remission obtained)

- Patient previously treated with free E. Coli L-asparaginase form or pegylated one

- Performance Status ≤ 2 (WHO score)

- Patient informed and consent provided (the 2 parents need to consent when children

are below 18) Exclusion Criteria:

- ALL t(9;22) and/or BCR-ABL positive (Philadelphia chromosome positive)

- Patient with 2nd relapse and over

- Women of childbearing potential without effective contraception as well as pregnant

or breast feeding women

- Patient unable to receive treatments used in global chemotherapy protocols, due to

general or visceral conditions such as: Severe cardiac impairment (NYHA grade 3 or 4 cardiomyopathy)/Serum creatinine 2 x ULN unless related to ALL /ALT or AST 5 x ULN unless related to ALL /Pancreatitis history /Other malignancy that ALL / Severe Infection, HIV positive, active hepatitis related to B or C virus infection / Trisomy 21 / Other serious conditions according to investigator's opinion

- Known grade 4 allergic reaction to E. Coli L-asparaginase (according NCI-CTCAE,

Version 3. 0)

- History of grade 3 transfusional incident

- Presence of specific anti-erythrocyte antibodies preventing from getting a compatible

erythrocyte concentrate for the patient

- Patient under concomitant treatment likely to cause hemolysis

- Patient undergoing yellow fever vaccination

- Patient under phenytoin treatment

- Patient included in previous clinical study less than 6 weeks ago

Hopital Des Enfants Reine Fabiola, Bruxelles, Belgium

Chr de La Citadelle, Liege, Belgium

Chu D'Angers, Angers, France

Hopital Saint Jacques, Besancon, France

Hopital Pellegrin Enfants, Bordeaux, France

Chu Estaing, Clermont Ferrand, France

Hopital Henri Mondor, Creteil, France

Chu Grenoble, Grenoble, France

Chru Lille - Hop Jeanne de Flandres, Lille, France

Institut Hematologie Oncologie Pediatrique, Lyon, France

Institut Paoli Calmettes, Marseille, France

Hopital Mere Enfant, Nantes, France

Hotel Dieu, Nantes, France

Hopital de L'Archet 2, Nice, France

Hopital Armand Trousseau, Paris, France

Hopital Robert Debre, Paris, France

Hopital Saint Louis, Paris, France

Hopital Haut-Leveque, Pessac, France

Hopital Lyon Sud, Pierre Benite, France

Chru Hopital Sud, Rennes, France

Centre Henri Becquerel, Rouen, France

Chu Hopital Nord, Saint Etienne, France

Institut Cancerologie de La Loire, Saint Priest En Jarez, France

Hopital de Hautepierre, Strasbourg, France

Chu de Toulouse Enfants, Toulouse, France

Hotel Dieu, Valenciennes, France

Hopital Brabois Enfants, Vandoeuvre Les Nancy, France

Hopital de Brabois, Vandoeuvre Les Nancy, France

Starting date: December 2009
Last updated: March 4, 2015