A Phase I/II Study of Induction Chemotherapy With Daunorubicin, Cytarabine, Topotecan and Etoposide
Condition: Leukemia
MeSH terms: Leukemia
Study type: Interventional
Phase: Phase 1/Phase 2

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.

      PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy in treating
      patients who have previously untreated acute myeloid leukemia.
    

Detailed description: 
      OBJECTIVES:

        -  Determine the maximum tolerated dose (MTD) of topotecan when combined with daunorubicin,
           cytarabine, and etoposide in patients with de novo acute myeloid leukemia.

        -  Determine the efficacy of this regimen at the MTD of topotecan by measuring the complete
           response rate in this patient population.

        -  Determine the days of hospitalization and number of infections associated with this
           regimen in these patients.

        -  Correlate serum levels of topotecan and etoposide with the expression of topoisomerase I
           and II in tumor cells and in peripheral blood mononuclear cells (PBMN), as well as with
           toxicity and response rate in these patients.

        -  Correlate tumor cell and PBMN expression and activity of topoisomerase I and II with
           hematological toxicity and clinical response in these patients.

        -  Correlate levels of activation of STAT signaling proteins with expression of bcl-2
           family proteins and response to chemotherapy in these patients.

      OUTLINE: This is a dose-escalation study of topotecan (phase I) followed by a response
      rate-determination (phase II) study.

      Patients receive induction chemotherapy with daunorubicin IV over 10-15 minutes on days 1-3,
      cytarabine IV continuously on days 1-5, topotecan IV continuously on days 6-8, and etoposide
      IV over 60 minutes on days 9 and 10. Within 4 weeks of hematologic recovery, patients
      achieving remission after induction receive consolidation chemotherapy with cytarabine IV
      over 1 hour every 12 hours on days 1, 3, and 5. Subsequent courses of consolidation
      chemotherapy begin within 2 weeks of documentation of hematologic recovery from the prior
      consolidation course. Consolidation chemotherapy continues for 4 courses in the absence of
      unacceptable toxicity or disease progression.

      Cohorts of 3-6 patients receive escalating doses of topotecan until the maximum tolerated
      dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
      of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional
      patients are accrued to receive induction chemotherapy at the recommended phase II dose.

      Patients are followed at 1 month, every 2 months for 1 year, every 3 months for 2 years,
      every 6 months for 2 years, and then annually thereafter.

      PROJECTED ACCRUAL: A total of 3-36 patients (phase I) and then an additional 24-27 patients
      (phase II) will be accrued for this study within 4 years.
    

Intervention name(s): Cytarabine; Daunorubicin; Etoposide; Topotecan
Intervention type(s): Drug; Drug; Drug; Drug
Other intervention name(s): daunorubicin hydrochloride; topotecan hydrochloride
Intervention MeSH terms: Cytarabine; Etoposide; Daunorubicin; Topotecan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: untreated adult acute myeloid leukemia; adult acute erythroid leukemia (M6); adult acute myeloblastic leukemia without maturation (M1); adult acute myeloblastic leukemia with maturation (M2); adult acute myelomonocytic leukemia (M4); adult acute monoblastic leukemia (M5a); adult acute megakaryoblastic leukemia (M7); adult acute monocytic leukemia (M5b); adult acute minimally differentiated myeloid leukemia (M0); 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)