Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia

February 7, 2017 updated by: Children's Oncology Group

Randomized Comparisons of Oral Mercaptopurine vs Oral Thioguanine and IT Methotrexate vs ITT for Standard Risk Acute Lymphoblastic Leukemia

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug and giving them in different ways may kill more cancer cells. It is not yet known which regimen of combination chemotherapy is more effective for acute lymphoblastic leukemia

PURPOSE: Randomized phase III trial to compare different regimens of combination chemotherapy in treating children who have newly diagnosed acute lymphoblastic leukemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES: I. Identify response related factors predictive of relapse among children with previously untreated standard risk acute lymphoblastic leukemia (ALL). II. Determine the prognostic significance of residual leukemic blasts at specific times during induction therapy: M3 marrow status (greater than 25% blasts) at day 7; M2 status (5%-25% blasts) at day 14; and residual circulating leukemic blasts at days 7 and 14. III. Determine the prognostic significance of residual leukemic burden, as measured by fluorescence activated cell sorting/leukemic progenitor cell assay, on marrow aspirates acquired at the end of induction therapy, at the beginning of maintenance therapy, and at the completion of all therapy in patients with B precursor ALL. IV. Determine the prognostic significance of residual t(1;19) detected in marrow aspirates by PCR-based analyses of the fusion transcript E2A-PBX1 at the end of induction therapy, at the beginning of maintenance therapy, and at the completion of all therapy. V. Examine the interrelationships among these response-related prognostic factors and their correlation with ploidy, karyotype, and immunophenotype. VI. Determine, in a randomized study, whether substitution of oral thioguanine (TG) for oral mercaptopurine (MP) during consolidation, interim maintenance, and maintenance therapy improves event-free survival for patients with standard-risk ALL. VII. Study and compare the cellular pharmacokinetics of oral MP and oral TG during interim maintenance and maintenance therapy in selected patients. VIII. Compare the concentrations of MP and TG red blood cell metabolites (i.e., nucleotides, nucleosides, free bases, and methylated metabolites) during interim maintenance and maintenance therapy, and determine whether low levels of metabolites predict relapse in selected patients. IX. Determine the activities of thiopurine methyltransferase and hypoxanthine guanine phosphoribosyl transferase several times during interim maintenance and maintenance treatment, and compare the activities between the two thiopurine treatment groups in selected patients. X. Compare the incidence of central nervous system (CNS) relapse and event-free survival in patients receiving intrathecal methotrexate (MTX) vs. triple intrathecal chemotherapy (MTX/cytarabine/hydrocortisone) for presymptomatic CNS treatment. XI. Determine whether cerebrospinal fluid (CSF) terminal deoxynucleotidyl transferase (TdT) positivity predicts for CNS or marrow relapse by measuring TdT activity on CSF cytospins in cases with low white blood cell count (less than 5 cells per cubic millimeter) and suspected or questionable "blasts" during maintenance therapy. XII. Determine event-free survival in patients with standard-risk ALL and M3 marrow at day 14 when treated with intensive therapy designed for higher-risk ALL.

OUTLINE: This is a randomized study. Patients are stratified according to participating institution. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase (E. coli), NSC-109229 CTX Cyclophosphamide, NSC-26271 DM Dexamethasone, NSC-34521 DNR Daunorubicin, NSC-82151 DOX Doxorubicin, NSC-123127 HC Hydrocortisone, NSC-10483 MP Mercaptopurine, NSC-755 MTX Methotrexate, NSC-740 PEG-ASP Pegaspargase, NSC-624239 PRED Prednisone, NSC-10023 TG Thioguanine, NSC-752 TIT Triple Intrathecal Therapy (IT MTX/IT ARA-C/IT HC) VCR Vincristine, NSC-67574 Induction: All patients receive oral PRED on days 0-27, VCR IV on days 0, 7, 14, and 21, and ASP IM 3 times a week for 3 weeks beginning on day 2-4. ARA-C IT is administered on day 0, and MTX IT is administered on days 7 and 28 (days 7, 14, 21, and 28 if CNS disease at diagnosis). Following Induction, patients who achieve remission are randomly assigned to 1 of 4 treatment arms. Arm I: Consolidation (begins day 28 of Induction): PRED is tapered from Induction over 10 days. Patients receive VCR IV on day 0, oral MP on days 1-27, and MTX IT on days 7, 14, and 21 (only day 7 if CNS disease at diagnosis). Interim Maintenance 1 (begins day 28 of Consolidation): Patients receive oral PRED on days 0-4 and 28-32, VCR IV days 0 and 28, oral MTX on days 0, 7, 14, 21, 28, 35, 42, and 49, and oral MP on days 0-49. Delayed Intensification 1 (begins day 56 of Interim Maintenance 1): Patients receive oral DM on days 0-6 and 14-20, VCR IV on days 0, 7, and 14, DOX IV over 15-120 min on days 0, 7, and 14, ASP IM twice a week for 2 weeks beginning day 2-4, CTX IV over 20-30 min on day 28, oral TG on days 28-41, ARA-C IV or SC on days 29-32 and 36-39, and MTX IT on days 0, 28, and 35. Interim Maintenance 2 (begins day 56 of Delayed Intensification 1): Patients receive PRED/VCR/MTX/MP as in Interim Maintenance 1. Delayed Intensification 2 (begins day 56 of Interim Maintenance 2): Patients receive DM/VCR/DOX/ASP, CTX/TG/ARA-C, and MTX IT as in Delayed Intensification 1. Maintenance (begins day 56 of Delayed Intensification 2): Patients receive oral PRED on days 0-4, 28-32, and 56-60, VCR IV on days 0, 28, and 56, oral MP on days 0-83, oral MTX on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77 (omitted during wk of IT therapy), and MTX IT on day 0. Treatment continues every 84 days for 2 years (girls) or 3 years (boys) from the beginning of Interim Maintenance 1. Arm II: Patients receive treatment as in arm I, except TIT is TIT substituted for MTX IT. Arm III: Patients receive treatment as in arm I with oral TG substituted for oral MTX in Consolidation, Interim Maintenance 1 and 2, and Maintenance. If secondary veno-occlusive disease occurs, MP is substituted for TG during Maintenance. Arm IV: Patients receive treatment as in arm III with TIT substituted for MTX IT. If secondary veno-occlusive disease occurs, MP is substituted for TG during Maintenance. Patients with M3 marrow after 2 weeks or M2 marrow after 4 weeks of Induction, or with Philadelphia chromosome (t[9;22][q34;q11]), t(4;11)(q21;q23), or hypodiploidy, proceed to the following more intensive treatment regimen for further therapy: Induction (begins day 14 to day 19 of initial Induction): Patients receive oral PRED on days 14-27, VCR IV on days 14 and 21 (day 14 dose omitted if day 14 dose from original Induction already given), DNR IV continuously on days 14-16 (48 hours total), ASP IM three times a week for 9 total doses (including those received on original Induction), MTX IT on days 28 and 35 (days 21, 28, and 35 if CNS disease at diagnosis). Patients with M1/M2 bone marrow after day 35 proceed to Consolidation. Consolidation (begins day 28 or 35 of Induction in this regimen, depending on timing of entry on this regimen): PRED is tapered from Induction over 10 days. Patients receive CTX IV 20-30 minutes on days 0 and 28, oral MP on days 0-13 and 28-41, ARA-C IV or SC on days 1-4, 8-11, 29-32, and 36-39, VCR IV on days 14, 21, 42, and 49, PEG-ASP IM on days 14 and 42, and MTX IT on days 7, 14, and 21 (only day 7 if CNS disease at diagnosis). Patients with M1 or M2 marrow and no extramedullary leukemia after day 63 proceed to Interim Maintenance 1. Interim Maintenance 1 (begins day 63 of Consolidation): Patients receive VCR IV on days 0, 10, 20, 30, and 40, MTX IV on days 0, 10, 20, 30, and 40, and PEG-ASP IM on days 1 and 21. Patients with M1 bone marrow after day 56 proceed to Delayed Intensification I. Delayed Intensification 1 (begins day 56 of Interim Maintenance 1): Patients receive oral DM on days 0-6 and 14-20, VCR IV on days 0, 7, 14, 42, and 49, DOX IV over 15-120 minutes on days 0, 7, and 14, PEG-ASP IM on days 3 and 42, CTX IV over 20-30 minutes on day 28, oral TG on days 28-41, ARA-C IV or SC on days 29-32 and 36-39, and MTX IT on days 28 and 35. Interim Maintenance 2 (begins day 56 of Delayed Intensification 1): Patients receive VCR/MTX/PEG-ASP as in Interim Maintenance 1, and MTX IT on days 0, 20, and 40. Delayed Intensification 2 (begins day 56 of Interim Maintenance 2): Patients receive DM/VCR/DOX/PEG-ASP, CTX/TG/ARA-C, and MTX IT as in Delayed Intensification 1. Maintenance (begins day 56 of Delayed Intensification 2): Patients receive PRED/VCR/MP/MTX, and MTX IT as in arm I Maintenance. Patients with CNS or testicular involvement at diagnosis receive appropriate radiotherapy concurrent with Consolidation. Radiotherapy begins within 4 days of initiation of Consolidation. Craniospinal irradiation is given 5 days a week. Testicular irradiation is given to both testes 5 days a week over 2-3 weeks. Patients are followed every 6-8 weeks during year 1, every 3 months during year 2, every 6 months during year 3, and then annually thereafter.

PROJECTED ACCRUAL: A total of 1970 patients will be accrued for this study within 3.5 years.

Study Type

Interventional

Enrollment (Actual)

1970

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • Western Australia
      • Perth, Western Australia, Australia, 6001
        • Princess Margaret Hospital for Children
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3V4
        • British Columbia Children's Hospital
    • Nova Scotia
      • Halifax, Nova Scotia, Canada, B3J 3G9
        • IWK Grace Health Centre
  • United States
    • California
      • Long Beach, California, United States, 90806
        • Long Beach Memorial Medical Center
      • Los Angeles, California, United States, 90095-1781
        • Jonsson Comprehensive Cancer Center, UCLA
      • Los Angeles, California, United States, 90027-0700
        • Children's Hospital Los Angeles
      • Orange, California, United States, 92668
        • Children's Hospital of Orange County
      • San Francisco, California, United States, 94115-0128
        • UCSF Cancer Center and Cancer Research Institute
    • Colorado
      • Denver, Colorado, United States, 80218
        • Children's Hospital of Denver
    • District of Columbia
      • Washington, District of Columbia, United States, 20010-2970
        • Children's National Medical Center
    • Illinois
      • Chicago, Illinois, United States, 60637
        • University of Chicago Cancer Research Center
    • Indiana
      • Indianapolis, Indiana, United States, 46202-5265
        • Indiana University Cancer Center
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa Hospitals and Clinics
    • Michigan
      • Ann Arbor, Michigan, United States, 48109-0752
        • University of Michigan Comprehensive Cancer Center
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota Cancer Center
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic Cancer Center
    • Missouri
      • Kansas City, Missouri, United States, 64108
        • Children's Mercy Hospital - Kansas City
    • Nebraska
      • Omaha, Nebraska, United States, 68198-3330
        • University Of Nebraska Medical Center
    • New York
      • New York, New York, United States, 10021
        • Memorial Sloan-Kettering Cancer Center
      • New York, New York, United States, 10016
        • Kaplan Cancer Center
      • New York, New York, United States, 10032
        • Herbert Irving Comprehensive Cancer Center
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599-7295
        • Lineberger Comprehensive Cancer Center, UNC
    • Ohio
      • Cincinnati, Ohio, United States, 45229-3039
        • Children's Hospital Medical Center - Cincinnati
      • Cleveland, Ohio, United States, 44106-5065
        • Ireland Cancer Center
      • Columbus, Ohio, United States, 43205-2696
        • Children's Hospital of Columbus
    • Oregon
      • Portland, Oregon, United States, 97201-3098
        • Doernbecher Children's Hospital
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Children's Hospital of Philadelphia
      • Pittsburgh, Pennsylvania, United States, 15213
        • Children's Hospital of Pittsburgh
    • Tennessee
      • Nashville, Tennessee, United States, 37232-6838
        • Vanderbilt Cancer Center
    • Texas
      • Houston, Texas, United States, 77030
        • University of Texas - MD Anderson Cancer Center
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • Huntsman Cancer Institute
    • Washington
      • Seattle, Washington, United States, 98109
        • Fred Hutchinson Cancer Research Center
      • Seattle, Washington, United States, 98105
        • Children's Hospital and Medical Center - Seattle
    • Wisconsin
      • Madison, Wisconsin, United States, 53792
        • University of Wisconsin Comprehensive Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 9 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS: Newly diagnosed acute lymphoblastic leukemia (ALL) obtained by bone marrow aspirate or bone marrow biopsy No greater than 25% L3 blasts Initial white blood cell count less than 50,000/mm3 (performed at CCG institution) Massive lymphadenopathy, massive splenomegaly, and/or large mediastinal mass allowed CNS or testicular leukemia allowed Allogeneic bone marrow transplant should be considered (if donor available) for patients with Philadelphia chromosome (t[9;22][q34;q11]) or translocation (4;11)(q21;q23)

PATIENT CHARACTERISTICS: Age: 1 through 9 Performance status: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified

PRIOR CONCURRENT THERAPY: No prior treatment for ALL Biologic therapy: Not specified Chemotherapy: Intrathecal cytarabine (IT ARA-C) may begin prior to registration provided systemic chemotherapy initiated within 72 hours after IT ARA-C Endocrine therapy: See Radiotherapy At least 1 month since prior systemic steroids Steroids given for less than 48 hours allowed Inhaled corticosteroids allowed at any time Radiotherapy: Radiotherapy or dexamethasone for mediastinal mass causing superior mediastinal syndrome allowed prior to registration, if indicated Surgery: Not specified

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm I
Therapy defined in description.
Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • NSC-26271.
Drug: prednisone
Other Names:
  • NSC-10023
Drug: asparaginase
Other Names:
  • L-Asparaginase - Erwinia
  • NSC-106977
Drug: cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
Drug: daunorubicin hydrochloride
Other Names:
  • NSC-82151
Drug: dexamethasone
Other Names:
  • Decadron
  • NSC-34521
Drug: methotrexate
Other Names:
  • NSC-740
Drug: therapeutic hydrocortisone
Drug: vincristine sulfate
Other Names:
  • Oncovin
  • NSC-67574
Drug: mercaptopurine
Other Names:
  • 6-MP
  • Purinethol
Drug: thioguanine
Other Names:
  • 6-TG
  • NSC-752
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC-123127
Radiation: low-LET photon therapy
Radiation: low-LET cobalt-60 gamma ray therapy
Drug: pegaspargase
Other Names:
  • Oncaspar®
  • PEG Asparaginase
Experimental: Arm 2
Therapy defined in description.
Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • NSC-26271.
Drug: prednisone
Other Names:
  • NSC-10023
Drug: asparaginase
Other Names:
  • L-Asparaginase - Erwinia
  • NSC-106977
Drug: cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
Drug: daunorubicin hydrochloride
Other Names:
  • NSC-82151
Drug: dexamethasone
Other Names:
  • Decadron
  • NSC-34521
Drug: methotrexate
Other Names:
  • NSC-740
Drug: therapeutic hydrocortisone
Drug: vincristine sulfate
Other Names:
  • Oncovin
  • NSC-67574
Drug: mercaptopurine
Other Names:
  • 6-MP
  • Purinethol
Drug: thioguanine
Other Names:
  • 6-TG
  • NSC-752
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC-123127
Radiation: low-LET photon therapy
Radiation: low-LET cobalt-60 gamma ray therapy
Drug: pegaspargase
Other Names:
  • Oncaspar®
  • PEG Asparaginase
Experimental: Arm 3
Therapy defined in description.
Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • NSC-26271.
Drug: prednisone
Other Names:
  • NSC-10023
Drug: asparaginase
Other Names:
  • L-Asparaginase - Erwinia
  • NSC-106977
Drug: cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
Drug: daunorubicin hydrochloride
Other Names:
  • NSC-82151
Drug: dexamethasone
Other Names:
  • Decadron
  • NSC-34521
Drug: methotrexate
Other Names:
  • NSC-740
Drug: therapeutic hydrocortisone
Drug: vincristine sulfate
Other Names:
  • Oncovin
  • NSC-67574
Drug: mercaptopurine
Other Names:
  • 6-MP
  • Purinethol
Drug: thioguanine
Other Names:
  • 6-TG
  • NSC-752
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC-123127
Radiation: low-LET photon therapy
Radiation: low-LET cobalt-60 gamma ray therapy
Drug: pegaspargase
Other Names:
  • Oncaspar®
  • PEG Asparaginase
Experimental: Arm 4
Therapy defined in description.
Drug: cyclophosphamide
Other Names:
  • Cytoxan
  • NSC-26271.
Drug: prednisone
Other Names:
  • NSC-10023
Drug: asparaginase
Other Names:
  • L-Asparaginase - Erwinia
  • NSC-106977
Drug: cytarabine
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
Drug: daunorubicin hydrochloride
Other Names:
  • NSC-82151
Drug: dexamethasone
Other Names:
  • Decadron
  • NSC-34521
Drug: methotrexate
Other Names:
  • NSC-740
Drug: therapeutic hydrocortisone
Drug: vincristine sulfate
Other Names:
  • Oncovin
  • NSC-67574
Drug: mercaptopurine
Other Names:
  • 6-MP
  • Purinethol
Drug: thioguanine
Other Names:
  • 6-TG
  • NSC-752
Drug: doxorubicin hydrochloride
Other Names:
  • Adriamycin
  • NSC-123127
Radiation: low-LET photon therapy
Radiation: low-LET cobalt-60 gamma ray therapy
Drug: pegaspargase
Other Names:
  • Oncaspar®
  • PEG Asparaginase

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Event Free Survival
Primary outcome index used in examining the randomized treatment groups will be event-free survival (EFS) from the time of randomization (i.e., end of Induction), where the life table events will consist of the first occurrence of leukemic relapse at any site, death, or occurrence of a second malignancy.

Secondary Outcome Measures

Outcome Measure
Measure Description
Comparisons of CNS relapse incidence rates
Comparisons of CNS relapse incidence rates for the IT MTX versus ITT groups is also planned as an important endpoint.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Oncology Group

Collaborators

National Cancer Institute (NCI)

Investigators

  • Study Chair: Linda C. Stork, MD, Doernbecher Children's Hospital at Oregon Health and Science University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 1996

Primary Completion (Actual)

March 1, 2007

Study Completion (Actual)

March 1, 2007

Study Registration Dates

First Submitted

November 1, 1999

First Submitted That Met QC Criteria

August 31, 2004

First Posted (Estimate)

September 1, 2004

Study Record Updates

Last Update Posted (Estimate)

February 9, 2017

Last Update Submitted That Met QC Criteria

February 7, 2017

Last Verified

July 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1952
  • CCG-1952
  • CDR0000064665 (Other Identifier: Clinical Trials.gov)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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