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

This study has been completed.
Sponsor:
Collaborators:
SmithKline Beecham
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier:
NCT00005793
First received: June 2, 2000
Last updated: September 24, 2012
Last verified: September 2012
  Purpose

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 Intervention Phase
Leukemia
Drug: Cytarabine
Drug: Daunorubicin
Drug: Etoposide
Drug: Topotecan
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by H. Lee Moffitt Cancer Center and Research Institute:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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.


Enrollment: 41
Study Start Date: July 1999
Study Completion Date: November 2006
Primary Completion Date: July 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: daunorubicin hydrochloride
Drug: Etoposide Drug: Topotecan
Other Name: topotecan hydrochloride

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.

  Eligibility

Ages Eligible for Study:   16 Years to 59 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00005793

Locations
United States, Florida
H. Lee Moffitt Cancer Center and Research Institute
Tampa, Florida, United States, 33612-9497
Sponsors and Collaborators
H. Lee Moffitt Cancer Center and Research Institute
SmithKline Beecham
Investigators
Study Chair: Hussain I. Saba, MD, PhD H. Lee Moffitt Cancer Center and Research Institute
  More Information

Additional Information:
No publications provided

Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
ClinicalTrials.gov Identifier: NCT00005793     History of Changes
Other Study ID Numbers: MCC-11941, CA 82533
Study First Received: June 2, 2000
Last Updated: September 24, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:
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)

Additional relevant MeSH terms:
Leukemia
Neoplasms
Neoplasms by Histologic Type
Cytarabine
Daunorubicin
Etoposide
Etoposide phosphate
Topotecan
Anti-Infective Agents
Antibiotics, Antineoplastic
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Antiviral Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Topoisomerase I Inhibitors
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on October 21, 2014