Trial Information

A Phase I/II Study of Induction Chemotherapy With Daunorubicin, Cytarabine, Topotecan and Etoposide (DATE) for De Novo AML: In the Treatment of Young Patients Ages 16-59

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.