Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks.
Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m(2) was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m(2), was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.
Sharma
S
S
Division of Gastrointestinal Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. sharma1@mskcc.org
Kemeny
N
N
Schwartz
G K
GK
Kelsen
D
D
O'Reilly
E
E
Ilson
D
D
Coyle
J
J
De Jager
R L
RL
Ducharme
M P
MP
Kleban
S
S
Hollywood
E
E
Saltz
L B
LB
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C095887:exatecan; D002166:Camptothecin