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Treatment of Acute Lymphoblastic Leukemia in Children

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Lewis B. Silverman, M.D., Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT00400946
First received: November 16, 2006
Last updated: May 19, 2017
Last verified: May 2017
  Purpose

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.


Condition Intervention Phase
Drug/Agent Toxicity by Tissue/Organ Leukemia 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: pegaspargase Drug: prednisolone Drug: therapeutic hydrocortisone Drug: vincristine sulfate Radiation: radiation therapy Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Treatment of Acute Lymphoblastic Leukemia in Children

Resource links provided by NLM:


Further study details as provided by Lewis B. Silverman, M.D., Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Asparaginase-Related Toxicity Rate [ Time Frame: 30-week post-induction asparaginase treatment period ]
    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.


Secondary Outcome Measures:
  • 5-Year Disease-Free Survival [ Time Frame: 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. ]
    Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

  • Post-Induction Nadir Serum Asparaginase Activity Level [ Time Frame: 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. ]
    Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods.

  • Post-Induction Therapeutic Nadir Serum Asparaginase Activity Rate [ Time Frame: 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. ]
    Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Post-Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL ever during post-induction therapy.

  • Induction Infection Toxicity Rate [ Time Frame: Assessed daily during remission induction days 4-32. ]
    Infection toxicity rate is defined as the percentage of patients who experience bacterial or fungal infection of grade 3 or higher with treatment attribution of possibly, probably or definite based on CTCAEv3 during remission induction phase of combination chemotherapy.

  • Induction Serum Asparaginase Activity Level [ Time Frame: 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. ]
    Serum asparaginase activity (NSAA) levels were estimated based on established methods.

  • Induction Therapeutic Nadir Serum Asparaginase Activity Rate [ Time Frame: 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. ]
    Nadir serum asparaginase activity (NSAA) levels were estimated based on established methods. Induction therapeutic NSAA rate is defined as the percentage of patients achieving a NSAA level above 0.1 IU/mL at a given timepoint.

  • 5-Year Disease-Free Survival by MRD Day 32 Status [ Time Frame: 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. ]
    Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

  • 5-Year Disease-Free Survival by Bone Marrow Day 18 Status [ Time Frame: 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. ]
    Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.

  • 5-year Disease-Free Survival by CNS Directed Treatment Group [ Time Frame: 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. ]
    Disease-free survival (DFS) in a landmark analysis is defined as the duration of time from asparaginase randomization (which occurred after patients achieved complete remission and were assigned to a final risk group) to documented relapse, death during remission or second malignant neoplasm. DFS is estimated based on the Kaplan-Meier method and 5-year DFS is the probability of patients remaining alive, relapse-free and without occurrence of second malignant neoplasm 5 years from asparaginase randomization. Disease relapse is defined as >25% lymphoblasts identified morphologically in bone marrow aspirate/biopsy, or identification of lymphoblasts in marrow (any percentage) identified to be leukemic by flow cytometry, cytogenetics, FISH, immunohistochemistry, or other tests. Appearance of leukemic cells at any extramedullary site (a single, unequivocal lymphoblast in the CSF may qualify as CNS leukemia) also qualifies if confirmed by the PI.


Enrollment: 800
Study Start Date: April 2005
Estimated Study Completion Date: June 2018
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Intramuscular native E coli L-asparaginase (IM-EC)
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
Given IV
Drug: leucovorin calcium Drug: mercaptopurine
Given orally
Drug: methotrexate Drug: methylprednisolone Drug: prednisolone Drug: therapeutic hydrocortisone Drug: vincristine sulfate Radiation: radiation therapy
Experimental: Intravenous PEG-asparaginase (IV-PEG)
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
Given IV
Drug: leucovorin calcium Drug: mercaptopurine
Given orally
Drug: methotrexate Drug: methylprednisolone Drug: pegaspargase
Given IV
Drug: prednisolone Drug: therapeutic hydrocortisone Drug: vincristine sulfate Radiation: radiation therapy

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00400946

Locations
United States, Massachusetts
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States, 10032
James P. Wilmot Cancer Center at University of Rochester Medical Center
Rochester, New York, United States, 14642
Albert Einstein Cancer Center at Albert Einstein College of Medicine
The Bronx, New York, United States, 10461
United States, Rhode Island
Hasbro Children's Hospital
Providence, Rhode Island, United States, 02903
United States, Virginia
INOVA Fairfax Hospital
Fairfax, Virginia, United States, 22031
Canada, Ontario
McMaster Children's Hospital at Hamilton Health Sciences
Hamilton, Ontario, Canada, L8N 3Z5
Canada, Quebec
Hopital Sainte Justine
Montreal, Quebec, Canada, H3T 1C5
Centre de Recherche du Centre Hospitalier de l'Universite Laval
Sainte Foy, Quebec, Canada, GIV 4G2
Puerto Rico
San Jorge Children's Hospital
Santurce, Puerto Rico, 00912
Sponsors and Collaborators
Dana-Farber Cancer Institute
National Cancer Institute (NCI)
Investigators
Principal Investigator: Lewis B. Silverman, MD Dana-Farber Cancer Institute
  More Information

Publications:
Responsible Party: Lewis B. Silverman, M.D., Silverman, Lewis MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT00400946     History of Changes
Obsolete Identifiers: NCT00165165
Other Study ID Numbers: 05-001 / CDR0000513019
P01CA068484 ( U.S. NIH Grant/Contract )
P30CA006516 ( U.S. NIH Grant/Contract )
DFCI-05001 ( Other Identifier: DFCI IRB Protocol Number )
Study First Received: November 16, 2006
Results First Received: January 17, 2017
Last Updated: May 19, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Lewis B. Silverman, M.D., Dana-Farber Cancer Institute:
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

Additional relevant MeSH terms:
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Prednisolone acetate
Methylprednisolone acetate
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Hydrocortisone acetate
Dexamethasone
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Hydrocortisone
Prednisolone hemisuccinate
Prednisolone phosphate
Liposomal doxorubicin
Pegaspargase
Cyclophosphamide
Methotrexate
Doxorubicin
Etoposide
Cytarabine
Vincristine
Asparaginase

ClinicalTrials.gov processed this record on July 25, 2017