A Phase I/II Study of Induction Chemotherapy With Daunorubicin, Cytarabine, Topotecan and Etoposide

Sponsor

H. Lee Moffitt Cancer Center and Research Institute (Other)

Overall Status

Completed

CT.gov ID

NCT00005793

Collaborator

National Cancer Institute (NCI) (NIH), SmithKline Beecham (Industry)

Enrollment

Location

Arm

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Cytarabine Drug: Daunorubicin Drug: Etoposide Drug: Topotecan	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 1999

Actual Primary Completion Date :

Jul 1, 2006

Actual Study Completion Date :

Nov 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Combination Chemotherapy 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.	Drug: Cytarabine Drug: Daunorubicin Other Names: daunorubicin hydrochloride Drug: Etoposide Drug: Topotecan Other Names: topotecan hydrochloride

Arm

Intervention/Treatment

Experimental: Combination Chemotherapy

Drug: Cytarabine

Drug: Daunorubicin

Other Names:

daunorubicin hydrochloride

Drug: Etoposide

Drug: Topotecan

Other Names:

topotecan hydrochloride

Outcome Measures

Primary Outcome Measures

Maximum Tolerated Dose (MTD) [2 years]
Determine the maximum tolerated dose (MTD) of topotecan when combined with daunorubicin, cytarabine, and etoposide in patients with de novo acute myeloid leukemia. 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 59 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed newly diagnosed, previously untreated acute myeloid leukemia (AML)
All FAB types, M0-M7, excluding M3
No AML after myelodysplastic syndrome

PATIENT CHARACTERISTICS:

Age:

16 to 59

Performance status:

Eastern Cooperative Oncology Group (ECOG) 0-2

Life expectancy:

Not specified

Hematopoietic:

Not specified

Hepatic:

Bilirubin less than 2 mg/dL
SGOT/SGPT normal unless due to leukemic disease
Alkaline phosphatase normal unless due to leukemic disease

Renal:

Creatinine no greater than 2.0 mg/dL OR
Creatinine clearance greater than 60 mL/min

Cardiovascular:

Ejection fraction at least 50% by MUGA
No myocardial infarction or serious ventricular arrhythmia within the past 6 months

Other:

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No other prior malignancy within the past 5 years except resected skin cancer
HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Not specified

Chemotherapy:

No prior topotecan or any other DNA topoisomerase I inhibitor (e.g., irinotecan, aminocamptothecin, or nitrocamptothecin) or etoposide for any prior malignancy