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 trial to study the effectiveness of topotecan and etoposide in treating
patients who have recurrent or refractory leukemia.
OBJECTIVES: I. Determine the maximum tolerated dose of topotecan when combined with
etoposide in patients with relapsed or refractory acute myelogenous leukemia, acute
lymphoblastic leukemia, or blastic phase chronic myelogenous leukemia. II. Determine the
toxicity of this regimen in these patients. III. Measure serum levels of topotecan at steady
state and correlate them with any change in topoisomerase II content in leukemic blasts. IV.
Assess whether it is feasible to correlate any upregulation of topoisomerase II expression
with tumor response to etoposide in subsequent Phase II studies. V. Assess whether levels of
pretreatment expression of topoisomerases I and II in leukemic cells are predictive of
clinical response. VI. Assess whether it is feasible to develop a pharmacodynamic assay
based on posttreatment apoptotic changes in leukemic blasts and whether this could be
correlated with tumor response in subsequent phase II trials. VII. Determine the response in
patients treated with this regimen.
OUTLINE: Induction: 2-Drug Combination Chemotherapy. Topotecan, TOPO, NSC-609699; Etoposide,
VP-16, NSC-141540. Consolidation: 2-Drug Combination Chemotherapy. TOPO; VP-16.
PROJECTED ACCRUAL: 15-23 patients will be accrued in approximately 18 months.
DISEASE CHARACTERISTICS: Acute myelogenous leukemia (M0-M7) and acute lymphoblastic
leukemia (L1-L2) Refractory or in first or subsequent relapse Circulating blasts present
OR Greater than 5% blasts in bone marrow Acute myelogenous leukemia secondary to
myelodysplastic syndrome or cytotoxic therapy Untreated OR Maximum of 2 intensive
induction regimens Chronic myelogenous leukemia in blastic or lymphoid crisis Untreated OR
Maximum of 2 intensive induction regimens No CNS leukemia
PATIENT CHARACTERISTICS: Age: Over 18 Performance status: ECOG 0-3 Life expectancy: At
least 4 weeks Hematopoietic: Not specified Hepatic: Bilirubin no greater than 2.0 mg/dL
AST and ALT less than 3 times normal Alkaline phosphatase less than 3 times normal Renal:
Creatinine no greater than 1.5 mg/dL OR Creatinine clearance greater than 60 mL/min
Cardiovascular: No myocardial infarction within 6 months No active ischemic cardiac
disease No poorly controlled congestive heart failure No other symptomatic cardiac disease
Left ventricular ejection fraction at least 40% Pulmonary: No symptomatic restrictive or
obstructive lung disease Other: No severe neurologic disease No active infection unless
stable on antimicrobial therapy or fever is tumor related HIV negative Not pregnant or
nursing Fertile patients must use effective contraception
PRIOR CONCURRENT THERAPY: At least 2 weeks since prior cytotoxic therapy (except
hydroxyurea and steroids) Biologic therapy: No prior bone marrow transplantation At least
3 days since prior hematopoietic growth factors Chemotherapy: No prior topotecan or
camptothecin analogues Prior etoposide allowed Endocrine therapy: Not specified
Radiotherapy: Not specified Surgery: Not specified
Brenda W. Cooper, MD
Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center