Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT00002812
First received: November 1, 1999
Last updated: August 23, 2013
Last verified: August 2013

November 1, 1999
August 23, 2013
September 1996
March 2006   (final data collection date for primary outcome measure)
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. ] [ Designated as safety issue: No ]
The primary outcome index used in examining most of the randomized treatment groups will be event-free survival (EFS).
Not Provided
Complete list of historical versions of study NCT00002812 on ClinicalTrials.gov Archive Site
Not Provided
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Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia
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.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Leukemia
  • Drug: asparaginase
    Given IV
    Other Names:
    • E. coli
    • Elspar
    • NSC-109229
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • Cytoxan
    • NSC-26271
  • Drug: cytarabine
    Given IV
    Other Names:
    • Cytosine Arabinoside
    • Ara-C
    • Cytosar-U
    • NSC-63878
  • Drug: daunorubicin hydrochloride
    Given IV
    Other Names:
    • Daunomycin Hydrochloride
    • Cerrubidine
    • NSC-82151
  • Drug: dexamethasone
    Given IV
    Other Names:
    • Decadron
    • NSC-34521
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • Adriamycin
    • NSC-123127
  • Drug: idarubicin
    Given IV
    Other Names:
    • Idarubicin Hydrochloride
    • Idamycin
    • NSC-256439
  • Drug: mercaptopurine
    Given IV
    Other Names:
    • 6-MP
    • Purinethol
    • NSC-755
  • Drug: methotrexate
    Given PO
    Other Name: NSC-740
  • Drug: pegaspargase
    Given IV
    Other Names:
    • Asparaginase
    • Oncaspar
  • Drug: prednisone
    Given PO
    Other Name: NSC-10023
  • Drug: thioguanine
    Given IV
    Other Names:
    • 6-TG
    • NSC-752
  • Drug: vincristine sulfate
    Given IV
    Other Names:
    • Oncovin
    • NSC-67574
  • Radiation: radiation therapy
  • 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.
    Interventions:
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: idarubicin
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: pegaspargase
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: radiation therapy
  • 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.
    Interventions:
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: idarubicin
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: pegaspargase
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: radiation therapy
  • 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.
    Interventions:
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: idarubicin
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: pegaspargase
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: radiation therapy
  • 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.
    Interventions:
    • Drug: asparaginase
    • Drug: cyclophosphamide
    • Drug: cytarabine
    • Drug: daunorubicin hydrochloride
    • Drug: dexamethasone
    • Drug: doxorubicin hydrochloride
    • Drug: idarubicin
    • Drug: mercaptopurine
    • Drug: methotrexate
    • Drug: pegaspargase
    • Drug: prednisone
    • Drug: thioguanine
    • Drug: vincristine sulfate
    • Radiation: radiation therapy

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
2078
Not Provided
March 2006   (final data collection date for primary outcome measure)

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

Both
1 Year to 21 Years
No
Contact information is only displayed when the study is recruiting subjects
Canada,   United States,   Australia
 
NCT00002812
1961, CCG-1961, CDR0000064953
Yes
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Study Chair: Nita L. Seibel, MD Children's Research Institute
Children's Oncology Group
August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP