05-001: Treatment of Acute Lymphoblastic Leukemia in Children

NCT00400946 | Completed Phase 3 Results DMC

• 4 other identifiers: 05-001 / CDR0000513019P01CA068484P30CA006516DFCI-05001
• Study Type: interventional
• Target: 800
• Locations: 2 countries
• Sites: 8

Brief Summary

RATIONALE: L-asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia, but is also associated with notable side-effects, including hypersensitivity, pancreatitis, and thrombosis. We have previously reported that patients with acute lymphoblastic leukemia in whom asparaginase treatment was discontinued because of intolerable side-effects had survival outcomes that were inferior to those who received all or nearly all of their intended doses. Two bacterial sources of asparaginase exist: Escherichia coli (E coli) and Erwinia chrysanthemia (Erwinia). Generally, the E coli-derived enzyme has been used as front-line therapy and the Erwinia-derived preparation has been reserved for patients who develop hypersensitivity reactions. Pegylated E coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than native E coli L-asparaginase, and has been used as the initial asparaginase preparation in some pediatric acute lymphoblastic leukemia treatment regimens. PURPOSE: Although the pharmacokinetics of each of these asparaginase preparations: intravenous PEG-asparaginase (IV-PEG) and intramuscular native E coli L-asparaginase (IM-EC) have been well characterized, their relative efficacy and toxicity have not been studied extensively.

Conditions

Leukemia; Drug/Agent Toxicity by Tissue/Organ

Keywords

drug/agent toxicity by tissue/organ; untreated childhood acute lymphoblastic leukemia; L1 childhood acute lymphoblastic leukemia; L2 childhood acute lymphoblastic leukemia; T-cell childhood acute lymphoblastic leukemia

Outcome Measures

Primary Outcomes (1)

• Asparaginase-Related Toxicity Rate

  Asparaginase-related toxicity rate is defined as the percentage of patients who experience allergy (all grades), symptomatic pancreatitis (grade 2 or worse), thrombotic or bleeding complications requiring intervention (grade 2 or worse) with treatment attribution of possibly, probably or definite based on CTCAEv3.

  30-week post-induction asparaginase treatment period

Secondary Outcomes (9)

• 5-Year Disease-Free Survival

  Disease evaluations occurred continuously on treatment. Suggested long-term follow-up was monthly for 6m, bi-monthly for 6m, every 4 months for 1y, semi-annually for 1y, then annually. Median follow-up in this study cohort is 6 yrs, up to 10y.

• Post-Induction Nadir Serum Asparaginase Activity Level

  Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

• Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate

  Samples for nadir serum asparaginase activity analyses were obtained before doses administered at weeks 5, 11, 17, 23 and 29 of post-induction asparaginase treatment.

• Induction Infection Toxicity Rate

  Assessed daily during remission induction days 4-32.

• Induction Serum Asparaginase Activity Level

  Samples for serum asparaginase activity analyses were obtained days 4, 11, 18 and 25 post one-dose of IV-PEG on day 7 of the induction phase.

Study Arms (2)

Intramuscular native E coli L-asparaginase (IM-EC)

ACTIVE COMPARATOR

Patients in this arm were randomized to intramuscular native E coli L-asparaginase 25 000 IU/m2 weekly for 30 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: methylprednisolone; Drug: prednisolone; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy

Intravenous PEG-asparaginase (IV-PEG)

EXPERIMENTAL

Patients in this arm were randomized to intravenous PEG-asparaginase 2500 IU/m2 every 2 weeks for 15 doses. Protocol therapy was comprised of 5 phases: Induction, Consolidation I, CNS, Consolidation II, Continuation and varied dependent on risk classification. Patients who achieved complete remission after induction were eligible for post-induction asparaginase randomization. Further details are provided in the study description section.

Drug: cyclophosphamide; Drug: cytarabine; Drug: dexamethasone; Drug: dexrazoxane hydrochloride; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: methylprednisolone; Drug: pegaspargase; Drug: prednisolone; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate; Radiation: radiation therapy

Interventions

asparaginase DRUG

Intramuscular native E coli L-asparaginase (IM-EC)

cyclophosphamide DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

cytarabine DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

dexamethasone DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

dexrazoxane hydrochloride DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

doxorubicin hydrochloride DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

etoposide DRUG

Given IV

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

leucovorin calcium DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

mercaptopurine DRUG

Given orally

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

methotrexate DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

methylprednisolone DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

pegaspargase DRUG

Given IV

Intravenous PEG-asparaginase (IV-PEG)

prednisolone DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

therapeutic hydrocortisone DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

vincristine sulfate DRUG

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

radiation therapy RADIATION

Intramuscular native E coli L-asparaginase (IM-EC); Intravenous PEG-asparaginase (IV-PEG)

Eligibility Criteria

• Age: 1 Year - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

DISEASE CHARACTERISTICS: * Diagnosis of acute lymphoblastic leukemia (ALL) * No known mature B-cell ALL, defined by the presence of any of the following: * Surface immunoglobulin * L3 morphology * t(8;14)(q24;q32) * t(8;22) * t(2;8) * T-cell surface markers and t(8;14)(q24;q11) allowed * No secondary ALL PATIENT CHARACTERISTICS: * No known HIV positivity * Not pregnant or nursing * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: * No prior therapy except steroids of ≤ 1 week in duration and/or emergent radiation therapy to the mediastinum * Patients treated with steroids within the past 7 days will not receive steroid prophase during study treatment

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• National Cancer Institute (NCI): collaborator

Study Sites (8)

Dana Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, 10032, United States

Location

James P. Wilmot Cancer Center at University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Albert Einstein Cancer Center at Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

Hasbro Children's Hospital

Providence, Rhode Island, 02903, United States

Location

McMaster Children's Hospital at Hamilton Health Sciences

Hamilton, Ontario, L8N 3Z5, Canada

Location

Hopital Sainte Justine

Montreal, Quebec, H3T 1C5, Canada

Location

Centre de Recherche du Centre Hospitalier de l'Universite Laval

Sainte-Foy, Quebec, GIV 4G2, Canada

Location

Related Publications (4)

• Silverman LB, Supko JG, Stevenson KE, Woodward C, Vrooman LM, Neuberg DS, Asselin BL, Athale UH, Clavell L, Cole PD, Kelly KM, Laverdiere C, Michon B, Schorin M, Schwartz CL, O'Brien JE, Cohen HJ, Sallan SE. Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood. 2010 Feb 18;115(7):1351-3. doi: 10.1182/blood-2009-09-245951. Epub 2009 Dec 10.

  PMID: 20007809 RESULT

• Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. doi: 10.1016/S1470-2045(15)00363-0. Epub 2015 Nov 6.

  PMID: 26549586 RESULT

• Vrooman LM, Blonquist TM, Harris MH, Stevenson KE, Place AE, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001. Blood Adv. 2018 Jun 26;2(12):1449-1458. doi: 10.1182/bloodadvances.2018016584.

  PMID: 29941458 DERIVED

• Kahn JM, Cole PD, Blonquist TM, Stevenson K, Jin Z, Barrera S, Davila R, Roberts E, Neuberg DS, Athale UH, Clavell LA, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJG, Sallan SE, Silverman LB, Kelly KM. An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001. Pediatr Blood Cancer. 2018 Mar;65(3):10.1002/pbc.26871. doi: 10.1002/pbc.26871. Epub 2017 Nov 1.

  PMID: 29090520 DERIVED

MeSH Terms

Conditions

Drug-Related Side Effects and Adverse Reactions; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Interventions

Asparaginase; Cyclophosphamide; Cytarabine; Dexamethasone; Dexrazoxane; Doxorubicin; Etoposide; Leucovorin; Mercaptopurine; Methotrexate; Methylprednisolone; pegaspargase; Prednisolone; Hydrocortisone; Vincristine; Radiotherapy

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Amidohydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Razoxane; Diketopiperazines; Piperazines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Aminoglycosides; Glycosides; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Sulfhydryl Compounds; Sulfur Compounds; Purines; Aminopterin; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Indolizidines; Indolizines; Therapeutics

Results Point of Contact

• Title: Lynda Vrooman, MD
• Organization: Dana-Farber Cancer Institute

Lynda_Vrooman@dfci.harvard.edu

6176322659

Study Officials

• Lynda Vrooman, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Lynda Vroom, MD

Study Record Dates

• First Submitted: November 16, 2006
• First Posted: November 17, 2006
• Study Start: April 1, 2005
• Primary Completion: August 1, 2014
• Study Completion: June 1, 2019
• Last Updated: February 13, 2026
• Results First Posted: June 14, 2017

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); US (5)