Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia

August 23, 2013 updated by: Children's Oncology Group

Treatment of Patients With Acute Lymphoblastic Leukemia With Unfavorable Features: A Phase III Group-wide Study

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 the drugs in different combinations may kill more cancer cells.

PURPOSE: Randomized phase III trial to compare the effectiveness of standard combination chemotherapy treatment with more intensive combination chemotherapy in treating children with acute lymphocytic leukemia.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

OBJECTIVES: I. Compare the outcomes in children with higher risk acute lymphocytic leukemia (ALL) treated with postinduction chemotherapy based on marrow response on day 7 of induction therapy: for patients with rapid early response (M1/M2), standard vs intensified consolidation chemotherapy and standard vs prolonged duration of intensification chemotherapy; for patients with slow early response, addition of doxorubicin vs idarubicin and cyclophosphamide to intensification chemotherapy. II. Decrease the incidence of avascular necrosis by alternating dexamethasone dosing in patients undergoing 2 courses of delayed intensification. III. Assess the impact of day 7 marrow status on outcome in these patients. IV. Determine prognosis more precisely by supplementing presenting clinical features, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios, pattern of tyrosine kinase activation, leukemic burden following induction and intensification therapy, and development of high antibody titer to E. coli asparaginase. V. Correlate the traditional prognostic factors of day 7 marrow response, immunophenotype, ploidy, cytogenetics, and early marrow response with BAX/BCL-2 ratios.

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified by center. Patients receive one course of the VPLD regimen comprised of vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0 and 7, oral prednisone daily on days 0-7, intrathecal cytarabine on day 0, and asparaginase or pegaspargase intramuscularly on days 3, 5, and 7. Patients are assigned to 1 of 2 two postinduction chemotherapy groups based on bone marrow response on day 7 of induction. Patients with M1/M2 marrow on day 7 are considered rapid early responders. Patients with M3 marrow on day 7 are considered slow early responders. Group 1: Rapid early responders Patients receive 2 additional courses of VPLD induction chemotherapy. Patients are then randomized to 1 of 4 treatment arms: Arm I: Beginning on day 35 of induction therapy, patients receive standard Berlin-Frankfurt-Munster (BFM) regimen with standard delayed intensification. Standard BFM for patients in arm I consists of the following: consolidation over 5 weeks with cyclophosphamide, cytarabine, and mercaptopurine; interim maintenance over 8 weeks with oral methotrexate and mercaptopurine (MTX/MP); and delayed intensification over 7 weeks consisting of reinduction with vincristine, doxorubicin, oral dexamethasone, and asparaginase or pegaspargase followed by reconsolidation with cyclophosphamide, thioguanine, and cytarabine. Arm II: Patients receive standard BFM regimen with double delayed intensification. Patients receive therapy similar to those in arm I, but dexamethasone is interrupted for 1 week during delayed intensification and the intensification regimen is repeated, separated by an 8 week interim maintenance course of oral MTX/MP. Arm III: Patients receive augmented BFM regimen with standard delayed intensification. Patients receive 9 weeks of consolidation therapy with 2 courses of vincristine and pegaspargase alternating with the arm I consolidation therapy. Vincristine, intravenous methotrexate, and pegaspargase (the Capizzi I regimen) are substituted for oral MTX/MP in the interim maintenance regimen. Pegaspargase is substituted for asparaginase and two additional doses of vincristine are administered during delayed intensification. Arm IV: Patients receive augmented BFM regimen with double delayed intensification. Patients receive intensified chemotherapy throughout, combining the additional therapy given to patients in arms II and III. Patients receiving augmented BFM regimen receive pegaspargase instead of asparaginase. Patients with CNS disease at diagnosis are treated only on arm IV. Patients who are Philadelphia chromosome positive and do not have a bone marrow donor are nonrandomly assigned to the treatment group for slow early responders. All RER patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal methotrexate is administered periodically throughout protocol treatment. Group 2: Slow early responders Patients receive augmented BFM consolidation therapy and Capizzi I interim maintenance identical to that received by rapid early responders in arm IV. Patients are then randomized to receive double delayed intensification with either idarubicin or doxorubicin and concurrent cyclophosphamide. All patients receive the same maintenance therapy with vincristine/prednisone and oral MTX/MP. Intrathecal MTX is administered periodically throughout protocol treatment. Patients with CNS disease at entry receive craniospinal irradiation daily for 5 consecutive days beginning on day 0 of consolidation therapy. All slow early responders at diagnosis receive cranial irradiation daily for 5 consecutive days during consolidation therapy. Patients with testicular leukemia at diagnosis receive bilateral testicular irradiation daily for 5 consecutive days during consolidation chemotherapy. Groups 1 and 2: Maintenance therapy continues for 2 years for girls or 3 years for boys beyond completion of consolidation therapy. Patients are followed every 4-6 weeks for 1 year, every 3 months for 1 year, every 6 months for 2 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 1,520 patients will be accrued for this study over 4 years.

Study Type

Interventional

Enrollment (Actual)

2078

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 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, 92868
        • Children's Hospital of Orange County
      • San Francisco, California, United States, 94143-0128
        • 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, 60637-1470
        • University of Chicago Cancer Research Center
    • Indiana
      • Indianapolis, Indiana, United States, 46202-5289
        • Indiana University Cancer Center
    • Iowa
      • Iowa City, Iowa, United States, 52242-1009
        • Holden Comprehensive Cancer Center at the University of Iowa
    • 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
    • Nebraska
      • Omaha, Nebraska, United States, 68198-3330
        • University of Nebraska Medical Center
    • New Jersey
      • New Brunswick, New Jersey, United States, 08901-1780
        • Saint Peter's University Hospital
    • New York
      • New York, New York, United States, 10021
        • Memorial Sloan-Kettering Cancer Center
      • New York, New York, United States, 10016
        • NYU School of Medicine's Kaplan Comprehensive Cancer Center
      • New York, New York, United States, 10029
        • Mount Sinai School of Medicine
      • 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-Ingram Cancer Center
    • Texas
      • Houston, Texas, United States, 77030-4009
        • University of Texas - MD Anderson Cancer Center
    • Washington
      • Seattle, Washington, United States, 98105
        • Children's Hospital and Regional Medical Center - Seattle
      • Seattle, Washington, United States, 98109-1024
        • Fred Hutchinson Cancer Research Center
    • Wisconsin
      • Madison, Wisconsin, United States, 53792-6164
        • 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 21 years (ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

DISEASE CHARACTERISTICS: Acute lymphocytic leukemia (ALL) with M3 bone marrow No FAB L3 morphology CNS or overt testicular leukemia at diagnosis allowed High risk status 10-21 years old with any white blood count (WBC) 1-9 years old with WBC of 50,000/mm3 or greater

PATIENT CHARACTERISTICS: Age: 1 to 21 Performance status: Not specified Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified

PRIOR CONCURRENT THERAPY: No prior therapy for ALL except: Emergency therapy for blast crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration Biologic therapy: Not specified Chemotherapy: Intrathecal cytarabine or methotrexate allowed at diagnostic lumbar puncture Induction therapy must begin within 72 hours after intrathecal injection Endocrine therapy: At least 1-2 months since prior prednisone, for less than 48 hours, for reactive airway disease Inhalational steroids allowed Radiotherapy: Not specified 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
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Arm A - Standard BFM of Standard Duration (RER)
Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow. Consolidation (Phase II) (5 weeks) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy.
Radiation: radiation therapy
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC-26271
Drug: cytarabine
Given IV
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • NSC-63878
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC-123127
Drug: vincristine sulfate
Given IV
Other Names:
  • Oncovin
  • NSC-67574
Drug: prednisone
Given PO
Other Names:
  • NSC-10023
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Daunomycin Hydrochloride
  • Cerrubidine
  • NSC-82151
Drug: dexamethasone
Given IV
Other Names:
  • Decadron
  • NSC-34521
Drug: asparaginase
Given IV
Other Names:
  • E. coli
  • Elspar
  • NSC-109229
Drug: thioguanine
Given IV
Other Names:
  • 6-TG
  • NSC-752
Drug: idarubicin
Given IV
Other Names:
  • Idamycin
  • Idarubicin Hydrochloride
  • NSC-256439
Drug: pegaspargase
Given IV
Other Names:
  • Oncaspar
  • Asparaginase
Drug: mercaptopurine
Given IV
Other Names:
  • 6-MP
  • Purinethol
  • NSC-755
Drug: methotrexate
Given PO
Other Names:
  • NSC-740
EXPERIMENTAL: Arm B - Standard BFM with Double Delayed Intensification (RER)
Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (5 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy.
Radiation: radiation therapy
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC-26271
Drug: cytarabine
Given IV
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • NSC-63878
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC-123127
Drug: vincristine sulfate
Given IV
Other Names:
  • Oncovin
  • NSC-67574
Drug: prednisone
Given PO
Other Names:
  • NSC-10023
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Daunomycin Hydrochloride
  • Cerrubidine
  • NSC-82151
Drug: dexamethasone
Given IV
Other Names:
  • Decadron
  • NSC-34521
Drug: asparaginase
Given IV
Other Names:
  • E. coli
  • Elspar
  • NSC-109229
Drug: thioguanine
Given IV
Other Names:
  • 6-TG
  • NSC-752
Drug: idarubicin
Given IV
Other Names:
  • Idamycin
  • Idarubicin Hydrochloride
  • NSC-256439
Drug: pegaspargase
Given IV
Other Names:
  • Oncaspar
  • Asparaginase
Drug: mercaptopurine
Given IV
Other Names:
  • 6-MP
  • Purinethol
  • NSC-755
Drug: methotrexate
Given PO
Other Names:
  • NSC-740
EXPERIMENTAL: Arm C - Augumented BFM of Standard Duration (RER)
Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy.
Radiation: radiation therapy
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC-26271
Drug: cytarabine
Given IV
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • NSC-63878
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC-123127
Drug: vincristine sulfate
Given IV
Other Names:
  • Oncovin
  • NSC-67574
Drug: prednisone
Given PO
Other Names:
  • NSC-10023
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Daunomycin Hydrochloride
  • Cerrubidine
  • NSC-82151
Drug: dexamethasone
Given IV
Other Names:
  • Decadron
  • NSC-34521
Drug: asparaginase
Given IV
Other Names:
  • E. coli
  • Elspar
  • NSC-109229
Drug: thioguanine
Given IV
Other Names:
  • 6-TG
  • NSC-752
Drug: idarubicin
Given IV
Other Names:
  • Idamycin
  • Idarubicin Hydrochloride
  • NSC-256439
Drug: pegaspargase
Given IV
Other Names:
  • Oncaspar
  • Asparaginase
Drug: mercaptopurine
Given IV
Other Names:
  • 6-MP
  • Purinethol
  • NSC-755
Drug: methotrexate
Given PO
Other Names:
  • NSC-740
EXPERIMENTAL: Arm D - Augmented BFM with Dbl Delayed Intensification (RER)
Induction chemotherapy Days 0 - 7. Prednisone 60 mg/m² PO 4 x day. Vincristine sulfate 1.5 mg/m² IV push weekly x 2 Days 0 and 7. Daunomycin (daunorubicin hydrochloride) 25 mg/m² IV push (over 15 min.) weekly x 2 Days 0 and 7. IT Cytosine Arabinoside (cytarabine, Ara-C) Day 0. Asparaginase 6000 IU/m² IM x 3 Days 3, 5, and 7. Day 7 Bone Marrow Consolidation (9 weeks) (Phase II) Prednisone Taper, cyclophosphamide, cytosine arabinoside (Ara-C), mercaptopurine, vincristine sulfate, pegaspargase, IT Methotrexate and radiation therapy.
Radiation: radiation therapy
Drug: cyclophosphamide
Given IV
Other Names:
  • Cytoxan
  • NSC-26271
Drug: cytarabine
Given IV
Other Names:
  • Ara-C
  • Cytosar-U
  • Cytosine Arabinoside
  • NSC-63878
Drug: doxorubicin hydrochloride
Given IV
Other Names:
  • Adriamycin
  • NSC-123127
Drug: vincristine sulfate
Given IV
Other Names:
  • Oncovin
  • NSC-67574
Drug: prednisone
Given PO
Other Names:
  • NSC-10023
Drug: daunorubicin hydrochloride
Given IV
Other Names:
  • Daunomycin Hydrochloride
  • Cerrubidine
  • NSC-82151
Drug: dexamethasone
Given IV
Other Names:
  • Decadron
  • NSC-34521
Drug: asparaginase
Given IV
Other Names:
  • E. coli
  • Elspar
  • NSC-109229
Drug: thioguanine
Given IV
Other Names:
  • 6-TG
  • NSC-752
Drug: idarubicin
Given IV
Other Names:
  • Idamycin
  • Idarubicin Hydrochloride
  • NSC-256439
Drug: pegaspargase
Given IV
Other Names:
  • Oncaspar
  • Asparaginase
Drug: mercaptopurine
Given IV
Other Names:
  • 6-MP
  • Purinethol
  • NSC-755
Drug: methotrexate
Given PO
Other Names:
  • NSC-740

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event Free Survival
Time Frame: from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.
The primary outcome index used in examining most of the randomized treatment groups will be event-free survival (EFS).
from the time of randomization where the life table events will consist of the first occurrence of the following events: failure to achieve remission, leukemic relapse at any site, death, or occurrence of a second malignancy.

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: Nita L. Seibel, MD, Children's National Research Institute

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

September 1, 1996

Primary Completion (ACTUAL)

March 1, 2006

Study Registration Dates

First Submitted

November 1, 1999

First Submitted That Met QC Criteria

November 21, 2003

First Posted (ESTIMATE)

November 24, 2003

Study Record Updates

Last Update Posted (ESTIMATE)

August 26, 2013

Last Update Submitted That Met QC Criteria

August 23, 2013

Last Verified

August 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1961
  • CCG-1961 (OTHER: Children's Cancer Group)
  • CDR0000064953 (OTHER: 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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