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

September 24, 2012 updated by: H. Lee Moffitt Cancer Center and Research Institute

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

41

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Tampa, Florida, United States, 33612-9497
        • H. Lee Moffitt Cancer Center and Research Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 59 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Endocrine therapy:

  • Not specified

Radiotherapy:

  • Not specified

Surgery:

  • Not specified

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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: Topotecan
Other Names:
  • topotecan hydrochloride
Drug: Cytarabine
Drug: Etoposide
Drug: Daunorubicin
Other Names:
  • daunorubicin hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD)
Time Frame: 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.
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

H. Lee Moffitt Cancer Center and Research Institute

Collaborators

National Cancer Institute (NCI)
SmithKline Beecham

Investigators

  • Study Chair: Hussain I. Saba, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 1999

Primary Completion (Actual)

July 1, 2006

Study Completion (Actual)

November 1, 2006

Study Registration Dates

First Submitted

June 2, 2000

First Submitted That Met QC Criteria

May 6, 2003

First Posted (Estimate)

May 7, 2003

Study Record Updates

Last Update Posted (Estimate)

September 25, 2012

Last Update Submitted That Met QC Criteria

September 24, 2012

Last Verified

September 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MCC-11941
  • CA 82533 (Other Identifier: NCI)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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