Phase I Study of Topoisomerase I Inhibitor Exatecan Mesylate (DX-8951f) Given as Weekly 24-Hour Infusions Three of Every Four Weeks

• Published in: Clinical cancer research Vol. 7; no. 12; pp. 3963 - 3970
• Main Authors: SHARMA, Sunil, KEMENY, Nancy, HOLLYWOOD, Ellen, SALTZ, Leonard B, SCHWARTZ, Gary K, KELSEN, David, O'REILLY, Eileen, ILSON, David, COYLE, John, DE JAGER, Robert L, DUCHARME, Martin P, KLEBAN, Sarah
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-12-2001
• Subjects: Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Chemotherapy; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Female; Humans; Infusions, Intravenous; Leukopenia - chemically induced; Male; Medical sciences; Metabolic Clearance Rate; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - urine; Neutropenia - chemically induced; Pharmacology. Drug treatments; Thrombocytopenia - chemically induced; Topoisomerase I Inhibitors; Antineoplastic agent; Human; Solid tumor; Intravenous administration; Exatecan; Enzyme; Maximal dose; Toxicity; Treatment efficiency; DNA topoisomerase; Enzyme inhibitor; Administration schedule; Malignant tumor; Resistance; Increasing dose; Alkaloid; Chemotherapy; Isomerases; Treatment; Analog; Phase I trial; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265

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.