S0106 Cytarabine and Daunorubicin w/ or w/o Gemtuzumab Followed By HD Cytarabine and Either Gemtuzumab or Nothing in de Novo AML
Condition: Leukemia
MeSH terms: Leukemia
Study type: Interventional
Phase: Phase 3

Summary: 
      RATIONALE: Drugs used in chemotherapy, such as cytarabine and daunorubicin, work in different
      ways to stop cancer cells from dividing so they stop growing and die. Monoclonal antibodies,
      such as gemtuzumab ozogamicin, can locate cancer cells and either kill them or deliver
      cancer-killing substances to them without harming normal cells. Combining chemotherapy with
      gemtuzumab ozogamicin may kill more cancer cells. It is not yet known whether induction
      therapy using cytarabine and daunorubicin is more effective with or without gemtuzumab
      ozogamicin or whether postconsolidation therapy using gemtuzumab ozogamicin is more effective
      than no additional therapy in treating de novo (first occurrence) acute myeloid leukemia.

      PURPOSE: This randomized phase III trial is comparing two different regimens of chemotherapy
      and monoclonal antibody therapy to see how well they work in treating patients with
      previously untreated de novo acute myeloid leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Compare disease-free survival of patients with previously untreated de novo acute
           myeloid leukemia treated with induction therapy comprising cytarabine and daunorubicin
           with vs without gemtuzumab ozogamicin followed by consolidation therapy comprising
           high-dose cytarabine and post-consolidation therapy comprising gemtuzumab ozogamicin vs
           no additional therapy.

        -  Compare the complete remission rate in patients treated with these regimens.

        -  Compare the frequency and severity of the toxic effects of these regimens in these
           patients.

      Other objectives (if funding allows):

        -  Determine the prognostic significance of CD33 expression on the response rate in
           patients receiving gemtuzumab ozogamicin.

        -  Determine the prognostic significance of FLT3 mutations in these patients before
           treatment with these regimens.

        -  Determine the prognostic significance of minimal residual disease in remission specimens
           from these patients treated with these regimens.

        -  Determine the prognostic significance of the flow cytometric detection of minimal
           residual disease in specimens collected from these patients treated with these regimens.

      OUTLINE: This is a randomized, multicenter study. Patients are stratified during induction
      therapy according to age (< 35 years vs ≥ 35 years) and during post-consolidation therapy
      according to preinduction cytogenetic risk group.

        -  Induction therapy: Patients are randomized to 1 of 2 treatment arms.

             -  Arm I: Patients receive daunorubicin IV on days 1-3, cytarabine IV continuously on
                days 1-7, and gemtuzumab ozogamicin IV over 2 hours on day 4. Patients receive
                filgrastim (G-CSF) or sargramostim (GM-CSF) IV or subcutaneously once daily
                beginning on day 15 and continuing until blood counts recover.

             -  Arm II: Patients receive daunorubicin, cytarabine, and G-CSF or GM-CSF as in arm I.

      Patients in both arms undergo bone marrow aspiration and biopsy on day 14 (and on day 19, if
      applicable) and then proceed to reinduction therapy.

        -  Reinduction therapy: Patients receive daunorubicin IV on days 1-3 and cytarabine IV
           continuously on days 1-7. Patients also receive G-CSF or GM-CSF as in induction therapy.

      Patients who achieve A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease
      status proceed to consolidation therapy.

        -  Consolidation therapy: Patients receive high-dose cytarabine IV over 3 hours twice daily
           on days 1, 3, and 5. Treatment repeats every 28 days for 3 courses in the absence of
           disease progression or unacceptable toxicity.

      Patients who maintain A1 bone marrow, B1 peripheral blood, and C1 extramedullary disease
      status after consolidation therapy proceed to post-consolidation therapy.

        -  Post-consolidation therapy: Patients are randomized to 1 of 2 treatment arms.

             -  Arm I: Patients receive gemtuzumab ozogamicin IV over 2 hours on day 1. Treatment
                repeats every 28 days for 3 courses in the absence of disease progression or
                unacceptable toxicity.

             -  Arm II: Patients receive no additional therapy. Patients are observed at days 30
                and 60 after randomization.

      Patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually
      for 3 years.

      PROJECTED ACCRUAL: A total of 684 patients (342 per treatment arm) will be accrued for this
      study within 4.5-5 years.
    

Intervention name(s): gemtuzumab ozogamicin; observation; Cytosine arabinoside; Daunomycin
Intervention type(s): Drug; Other; Drug; Drug
Intervention description(s): Given IV, induction Arm1 6mg/m2 D4; post-consolidation 5mg/m2 3 doses >/= 28 days apart; No treatment given; IV; induction Arms1/2 and reinduction 100 mg/m2/d days 1-7; consolidation 3gm/m2 q3hrs D1, 3, 5; IV; induction Arm1 45mg/m2 D1-3; Arm2 and reinduction 60 mg/m2 D1-3;
Other intervention name(s): mylotarg; Ara-C; daunorubicin
Intervention MeSH terms: Cytarabine; Daunorubicin; Gemtuzumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated adult acute myeloid leukemia; adult acute eosinophilic leukemia; adult acute basophilic leukemia; adult acute monocytic leukemia (M5b); adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute myeloid leukemia with 11q23 (MLL) abnormalities; adult acute myeloid leukemia with inv(16)(p13;q22); adult acute myeloid leukemia with t(16;16)(p13;q22); adult acute myeloid leukemia with t(8;21)(q22;q22)