Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks Journal Article
| Authors: | Sharma, S.; Kemeny, N.; Schwartz, G. K.; Kelsen, D.; O'reilly, E.; Ilson, D.; Coyle, J.; De Jager, R. L.; Ducharme, M. P.; Kleban, S.; Hollywood, E.; Saltz, L. B. |
| Article Title: | Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks |
| Abstract: | 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/m2 was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m2, was tolerated without any severe toxicities. Nonhematological toxicifies 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/m2 in minimally pretreated patients and 0.53 mg/m2 in patients who are heavily pretreated. |
| Keywords: | adult; cancer chemotherapy; clinical article; controlled study; aged; middle aged; clinical trial; constipation; drug tolerability; neutropenia; diarrhea; dose response; neoplasms; colorectal cancer; controlled clinical trial; leukopenia; nausea; thrombocytopenia; antineoplastic agents, phytogenic; camptothecin; dose-response relationship, drug; asthenia; liver carcinoma; pancreas carcinoma; enzyme inhibitors; drug infusion; metabolic clearance rate; phase 1 clinical trial; drug half life; dna topoisomerase inhibitor; infusions, intravenous; stomach carcinoma; dose calculation; exatecan; esophagus carcinoma; dna topoisomerases, type i; drug elimination; compartment model; humans; human; male; female; priority journal; article |
| Journal Title: | Clinical Cancer Research |
| Volume: | 7 |
| Issue: | 12 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2001-12-01 |
| Start Page: | 3963 |
| End Page: | 3970 |
| Language: | English |
| PUBMED: | 11751488 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
