Combination Chemotherapy in Treating Children With Newly Diagnosed Acute Lymphoblastic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      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 may kill more cancer cells. It is
      not yet known which regimen of chemotherapy is more effective for acute lymphoblastic
      leukemia.

      PURPOSE: This randomized phase III trial is comparing four regimens of combination
      chemotherapy to see how well they work in treating children with newly diagnosed acute
      lymphoblastic leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Determine if multidrug delayed-intensification therapy improves outcome in children with
           newly diagnosed standard-risk acute lymphocytic leukemia.

        -  Compare the efficacy and toxicity of methotrexate administered over 4 hours vs
           methotrexate administered over 24 hours in this patient population.

        -  Determine the correlation between event-free survival, minimal residual disease, and
           early response in this patient population treated with this multiple drug regimen.

      OUTLINE: This is a randomized, multicenter study.

        -  Induction (weeks 1-4): Patients receive induction therapy on POG 9900.

        -  Consolidation (weeks 5-32): Patients are randomized to one of four treatment arms.
           Patients with t(1;19) are randomized to either arm III or arm IV.

             -  Arm I (weeks 5-24): Patients receive IT methotrexate (MTX) on day 1 followed by MTX
                IV over 20 minutes followed by MTX continuously over 23.6 hours on weeks 7, 10, 13,
                16,19, and 22. At 42 hours after the beginning of the MTX infusion, patients
                receive oral leucovorin calcium every 6 hours for a total of 3 doses. Patients also
                receive oral mercaptopurine daily beginning on week 5 and continuing until the
                completion of consolidation therapy; oral dexamethasone twice daily on days 1-7 of
                weeks 8 and 17; and vincristine IV on day 1 of weeks 8, 9, 17, and 18.

             -  Arm II (weeks 5-24): Patients receive MTX IV over 4 hours on weeks 7, 10, 13, 16,
                19, and 22. At 42 hours after the beginning of the MTX infusion, patients receive
                oral leucovorin calcium as in arm I. Patients also receive mercaptopurine,
                dexamethasone, vincristine, and IT MTX as in arm I.

             -  Arm III (weeks 5-32): Patients receive MTX IV as in arm I on weeks 7, 10, 13, 24,
                27, and 30; leucovorin calcium as in arm I; pegaspargase IM on day 2, 3, OR 4 of
                week 16; and oral mercaptopurine daily on weeks 5-13, and from week 24 until the
                completion of consolidation therapy. Patients also receive IT MTX as in arm I on
                weeks 7, 10, 13, 16, 20, 21, and 30; oral dexamethasone twice daily on weeks 8,
                16-18, and 28 for a total of 35 days; vincristine IV on day 1 of weeks 8, 9, 16,
                17, 18, 28, and 29; daunorubicin IV on day 1 of weeks 16-18; cyclophosphamide IV
                over 30 minutes on day 1 of week 20; cytarabine IV or subcutaneously daily on days
                2-5 of weeks 20 and 21; and oral thioguanine daily on weeks 20-21.

             -  Arm IV (weeks 5-32): Patients receive MTX IV as in arm II on weeks 7, 10, 13, 24,
                27, and 30; leucovorin calcium as in arm I; and pegaspargase, mercaptopurine, IT
                MTX, dexamethasone, vincristine, daunorubicin, cyclophosphamide, cytarabine, and
                thioguanine as in arm III.

        -  Intensive continuation (weeks 25-80): At weeks 25-72 for arms I and II, and at weeks
           33-80 for arms III and IV, patients receive oral MTX every 6 hours for 4 doses on weeks
           1, 3, 5, 7, 9, and 11; oral mercaptopurine daily; oral leucovorin calcium every 12 hours
           for 2 doses beginning 48 hours after the start of MTX; IT MTX and vincristine IV on day
           1 of week 12; and oral dexamethasone twice daily on days 1-7, beginning with the
           administration of vincristine. Treatment repeats every 12 weeks for 4 courses.

        -  Additional continuation (weeks 73-130): At weeks 73-130 for arms I and II, and at weeks
           81-130 for arms III and IV, patients receive oral MTX weekly; oral mercaptopurine daily;
           vincristine IV on day 1 every 12 weeks; oral dexamethasone as during intensive
           continuation therapy; and IT MTX on day 1 every 12 weeks, beginning with the last week
           of the first course (in place of oral MTX).

      Patients are followed monthly for 1 year, every 2 months for 1 year, every 3 months for 1
      year, every 6 months for 1 year, and then every 6-12 months for 1 year.

      PROJECTED ACCRUAL: A total of 1,014 patients will be accrued for this study within 3.22
      years.
    

Intervention name(s): cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; leucovorin calcium; mercaptopurine; methotrexate; pegaspargase; thioguanine; vincristine sulfate
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): 30 mg/m2 IV Day 1 of weeks 16, 17, and 18. Give Week 16 dose if ANC ≥ 500/μL and platelets ≥ 75,000/μL. Continue to give during Weeks 17 and 18, even in the face of uncomplicated myelosuppression; 6 mg/m2/day divided BID for 7 days during weeks 8 and 17.; 5 mg/m2/dose of leucovorin will be given PO q12h x 2 doses beginning 48 hours after the start of the MTX.; 50 mg/m2 dose po qhs Weeks 5 through 13 (total 9 wks) and from Week 24 until the end of consolidation. Only hold for uncomplicated myelosuppression, only if IV MTX course is delayed, until ANC > 500/μL and platelets > 75,000/uL; IV: 1 gm/m2 given as a 200 mg/m2 bolus over 20 min followed by 800 mg/m2 over 23.6 hours given during Weeks 7, 10, 13, 16, 19, and 22.
IT: Doses by age, Weeks 7, 10, 13, 16, 19 and 22.; 2,500 IU/m2 will be given IM x 1 on Days 2,3,or 4 of Week 16; > or = 1 day after the IT MTX; 60 mg/m2 po qhs during Weeks 20 and 21 (total 14 days). Start week 20 when ANC > or = 500/ul and platelets > or = 75,000/uL. Continue to give all 14 doses despite uncomplicated myelosuppression.; 1.5 mg/m2 IV on Day 1 of Weeks 8, 9, 17 and 18 (max 2 mg)
Other intervention name(s): daunomycin; DEX; 6-MP; MTX; PEG; 6-TG; VCR
Intervention MeSH terms: Leucovorin; Cytarabine; Dexamethasone; Cyclophosphamide; Methotrexate; Vincristine; Daunorubicin; Mercaptopurine; Pegaspargase; Thioguanine; Levoleucovorin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated childhood acute lymphoblastic leukemia