A French Protocol for the Treatment of Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents (CAALL-F01)

A still major question in the field of acute lymphoblastic leukemia (ALL) in children - an extremely heterogeneous disease though curable in 80-90% of children and 70-80% of the adolescents - is the optimal use of L-asparaginase (ASNase). It is known that administering ASNase results in the depletion of asparagine circulating in the blood, which starves the leukemic cells and results in their death. But indeed the use of ASNase varies between protocols considering the different brands, the dose and the administration modalities. Oncaspar (PEGylated E. coli asparaginase, pegaspargase) was thus developed with the goal of reducing the immunogenicity of the native ASNase.

This is a French prospective multicentric cohort study of children and adolescents with ALL, stratified on (i) the type of ALL ( B vs T) and (ii) the anticipated risk (stratified in 3 groups for childhood B-cell precursor (BCP)-ALL and 2 groups for T-cell ALL).

It aims to answer to two different issues:

1. Randomized question: what is the best way to administer pegaspargase? A cohort of children and adolescents with standard or medium risk ALL will be randomized to receive during induction either one infusion of ONCASPAR® 2500 IU/m2 at D12 or two infusions of ONCASPAR® at 1250 IU/m2 each at D12 and D26. Patients will then receive 2500 IU/m2 or 1250 IU/m2 per dose during consolidation and delayed intensification according to the initial arm of randomization.
2. Non randomized question: In the High/Very High Risk groups, a non randomized intensification of the scheme of asparaginase administration is proposed during induction therapy: 2 infusions of 2500 IU/m2/day (D12 and D26) will be administered. All patients will receive 2500 IU/m2 per dose during consolidation and delayed intensifications.

Study Overview

• Status: Recruiting
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: pegaspargase 2500 IU/m2 x 1; Drug: pegaspargase 1250 IU/m2 x 2

• Study Type: Interventional
• Enrollment (Anticipated): 1578
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: André Baruchel, MD; Phone Number: +33 1 40 03 53 88; Email: andre.baruchel@aphp.fr
• Study Contact Backup: Name: Yves Bertrand, MD; Phone Number: +33 4 69 16 65 70; Email: yves.bertrand@ihope.fr

Study Locations

• France
  • Amiens, France, 80054
    • Recruiting
    • CHU
    • Contact: Catherine Devoldere, MD
  • Angers, France, 49033
    • Recruiting
    • CHU
  • Besançon, France, 25030
    • Recruiting
    • CHRU
    • Contact: Pauline Simon, MD
  • Bordeaux, France, 33076
    • Recruiting
    • CHU
    • Contact: Yves Perel, MD
  • Brest, France, 29609
    • Recruiting
    • CHU
    • Contact: Liana Carausu, MD
  • Caen, France, 14033
    • Recruiting
    • CHU
    • Contact: Odile Minckes, MD
  • Clermont-Ferrand, France, 63003
    • Recruiting
    • CHU
    • Contact: Justyna Kanold, MD
  • Dijon, France, 21079
    • Recruiting
    • CHU
    • Contact: Elodie Colomb, MD
  • Grenoble, France, 38043
    • Recruiting
    • CHU
  • Lille, France, 59037
    • Recruiting
    • CHU
    • Contact: Françoise Mazingue, MD
  • Limoges, France, 87042
    • Recruiting
    • CHU
  • Lyon, France, 69373
    • Recruiting
    • Chu-Ihope
    • Contact: Yves Bertrand, MD; Email: yves.bertrand@ihope.fr
  • Marseille, France, 13385
    • Recruiting
    • CHU
    • Contact: Gérard Michel, MD
  • Montpellier, France, 34295
    • Recruiting
    • CHU
    • Contact: Nicolas Sirvent, MD
  • Nancy, France, 54511
    • Recruiting
    • CHU
    • Contact: Claudine Schmitt, MD
  • Nantes, France, 44093
    • Recruiting
    • CHU
    • Contact: Caroline Thomas, MD
  • Nice, France, 06200
    • Recruiting
    • CHU
    • Contact: Pierre-Simon Rohrlich, MD
  • Paris, France, 75019
    • Recruiting
    • CHU Robert Debré
    • Contact: André Baruchel, MD; Email: andre.baruchel@aphp.fr
  • Paris, France, 75010
    • Recruiting
    • CHU Saint Louis
    • Contact: Nicolas Boissel, MD
  • Paris, France, 75012
    • Recruiting
    • CHU Armand Trousseau
    • Contact: Arnaud Petit, MD
  • Poitiers, France, 86000
    • Recruiting
    • CHU
    • Contact: Frédéric Millot, MD
  • Reims, France, 51100
    • Recruiting
    • CHU
    • Contact: Stéphanie Gordes-Grosjean, MD
  • Rennes, France, 35203
    • Recruiting
    • CHU
    • Contact: Virginie Gandemer, MD
  • Rouen, France, 76031
    • Recruiting
    • CHU
    • Contact: Pascale Schneider, MD
  • Saint Etienne, France, 42270
    • Recruiting
    • CHU
    • Contact: Sandrine Thouvenin-Doulet, MD
  • Strasbourg, France, 67098
    • Recruiting
    • CHU
    • Contact: Patrick Lutz, MD
  • Toulouse, France, 31059
    • Recruiting
    • CHU
    • Contact: Geneviève Plat, MD
  • Tours, France, 37044
    • Recruiting
    • CHU
    • Contact: Pascale Blouin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• ALL L1 or L2
• B-lineage or T- lineage ALL

Exclusion Criteria:

• L3 (Burkitt's leukemia)
• Mixed Phenotype Acute Leukemia (WHO criteria).
• Infant ALL (age ≤ 365 days)
• Philadelphia (Ph)+/Breakpoint Cluster region (BCR)-Abelson (ABL) ALL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1; pegaspargase 2500 IU/m2 x 1: infusion of a conventional dose of pegaspargase during induction therapy: 2500 IU/m2x1	Drug: pegaspargase 2500 IU/m2 x 1; only for ALL of standard risk and medium risk; Other Names: ONCASPAR 2500 IU/m2 x 1
Experimental: Arm 2; pegaspargase 1250 IU/m2 x 2: fractionation of the 2500 IU/m2 pegaspargase dose in two infusions of 1250 IU/m2 each	Drug: pegaspargase 1250 IU/m2 x 2; only for ALL of standard risk and medium risk; Other Names: ONCASPAR 1250 IU/m2 x 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 33 of induction therapy	asparaginase activity > 100 IU/L	Day 33
Incidence of directly asparaginase-related severe toxicities (Grade ≥ 3 as assessed by CTCAE v4.0) observed during induction therapy	Incidence of severe toxicities (Grade ≥ 3) directly asparaginase-related (CNS thrombosis, pancreatitis, anaphylaxis, and hyperbilirubinemia) between Day 12 and Day 49 of treatment and anyway before Day 8 of consolidation	Between Day 12 of induction and Day 8 of consolidation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L		Day 33 of induction
Incidence of adequate (> 100 IU/L) asparaginase activity measured in the plasma at day 40 of induction therapy		Day 40 of induction
Incidence of asparagine depletion measured in plasma by a concentration below the Limit of Quantification (LOQ) of 0.4 micromol/L		Day 40 of induction
Incidence of antibodies against asparaginase, measured in serum		Day 4 of delayed intensification
Incidence of silent inactivation	Silent inactivation or subclinical hypersensitivity is defined as a plasma PEGasparaginase activity level <100 IU/L at day 7+/- 1 or <20 IU/L at day 14 +/- 11 after administration in a patient without clinical symptoms of allergy	First 6-9 months
Percentage of patients without switch to Erwinia asparaginase		First 6-9 months
Percentage of patients receiving more than 95% of the intended dose of asparaginase		First 6-9 months
Morphological Complete Remission (CR) rates	Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).	Day 35-Day 42
Minimal Residual Disease (MRD)	MRD will be assessed by Ig/T cell receptor (TCR)-based real-time quantitative (RQ)-polymerase chain reaction (PCR), assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL). Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).	Day 35-Day 42, Day 65-Day 105
Cumulative Incidence of relapses	Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).	5 years
Cumulative Incidence of relapse according to site of relapse	Bone-Marrow (BM) relapses, central nervous system (CNS) relapses, gonadal relapses, combined relapses. Assessed on the whole population or on subgroups (B-Lineage ALL, T-cell ALL).	5 years
All other adverse events related to asparaginase	Drug-induced hyperglycemia or diabetes, coagulopathy, allergy Non CNS thrombosis Grade 1-2 Adverse Events (AE): pancreatitis, hyperbilirubinemia	within the first 7 weeks (Day 49) of treatment and anyway before Day 8 of consolidation
Late adverse events related to asparaginase		after Day 49 of induction or anyway at Day 8 of consolidation or after

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Shire

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Anticipated): April 1, 2026
• Study Completion (Anticipated): April 1, 2026

Study Registration Dates

• First Submitted: February 15, 2016
• First Submitted That Met QC Criteria: March 17, 2016
• First Posted (Estimate): March 23, 2016

Study Record Updates

• Last Update Posted (Actual): February 19, 2019
• Last Update Submitted That Met QC Criteria: February 18, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Antineoplastic Agents; Asparaginase; Pegaspargase
• Other Study ID Numbers: AOM10205

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided