Abstract
We designed a pharmacokinetic and pharmacodynamic phase I study of sequential topotecan (2.55-6.3mg/m2) by 72h infusion followed by five daily doses of etoposide for patients with refractory acute leukemia based upon synergistic anti-tumor activity of topoisomerase I and II inhibitors in vitro. Eight of the 29 patients achieved bone marrow aplasia and two patients achieved clinical remission. Common grade 3-4 toxicities included hepatic and gastrointestinal dysfunction, and correlated with increased steady-state plasma topotecan concentration. The predicted up-regulation of topoisomerase II activity by topoisomerase I inhibition was not observed at this dose and schedule and may provide insight into the modest anti-leukemia activity of the regimen.
Publication types
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Clinical Trial
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Clinical Trial, Phase I
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acute Disease
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Adult
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Aged
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage
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Antineoplastic Combined Chemotherapy Protocols / adverse effects
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Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Blast Crisis / drug therapy
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Blast Crisis / enzymology
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Bone Marrow / enzymology
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Chemical and Drug Induced Liver Injury / etiology
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DNA Topoisomerases, Type II / biosynthesis
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Drug Administration Schedule
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Drug Resistance, Neoplasm
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Enzyme Induction / drug effects
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / adverse effects
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Enzyme Inhibitors / pharmacokinetics
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Etoposide / administration & dosage
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Etoposide / adverse effects
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Etoposide / pharmacokinetics
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Female
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Gastrointestinal Diseases / chemically induced
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Leukemia, Myeloid / drug therapy*
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Leukemia, Myeloid / enzymology
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Male
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Middle Aged
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasms, Second Primary / drug therapy
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Neoplasms, Second Primary / enzymology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Recurrence
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Remission Induction
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Salvage Therapy*
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Topoisomerase I Inhibitors
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Topotecan / administration & dosage
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Topotecan / adverse effects
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Topotecan / pharmacokinetics
Substances
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Enzyme Inhibitors
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Neoplasm Proteins
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Topoisomerase I Inhibitors
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Etoposide
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Topotecan
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DNA Topoisomerases, Type II