Clinical trial NCT00005793: A Phase I/II Study of Induction Chemotherapy With Daunorubicin, Cytarabine, Topotecan and Etoposide
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Leukemia
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)
Lead sponsor: H. Lee Moffitt Cancer Center and Research Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: SmithKline Beecham
First posted: 2003-05-07
Enrollment: 41
Sex: ALL
Minimum age (years): 16
Maximum age (years): 59
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Maximum Tolerated Dose (MTD)
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
Study officials:
affiliation: H. Lee Moffitt Cancer Center and Research Institute
name: Hussain I. Saba, MD, PhD
role: STUDY_CHAIR
References: