A phase I and pharmacodynamic study of sequential topotecan and etoposide in patients with relapsed or refractory acute myelogenous and lymphoblastic leukemia.
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.
Cooper
Brenda W
BW
Department of Medicine, University Hospitals of Cleveland, Cleveland, OH 44106, USA. bxc12@po.cwru.edu
Donaher
Erin
E
Lazarus
Hillard M
HM
Green
Sylvan B
SB
Gosky
David M
DM
Rosenthal
Nancy S
NS
Berger
Sosamma J
SJ
Li
Xiaolin
X
Ingalls
Stephen T
ST
Hoppel
Charles L
CL
Gerson
Stanton L
SL
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology; D001853:Bone Marrow / Q000201:enzymology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016609:Neoplasms, Second Primary / Q000188:drug therapy / Q000201:enzymology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology; D012008:Recurrence; D012074:Remission Induction; D016879:Salvage Therapy; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; D005047:Etoposide; D019772:Topotecan; D004250:DNA Topoisomerases, Type II