title: DX-8951f: summary of phase I clinical trials.
abstract: Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.
authors.affiliation: Daiichi Pharmaceutical Corporation, USA.
authors.forename: R
authors.initials: R
authors.lastname: De Jager
authors.forename: P
authors.initials: P
authors.lastname: Cheverton
authors.forename: K
authors.initials: K
authors.lastname: Tamanoi
authors.forename: J
authors.initials: J
authors.lastname: Coyle
authors.forename: M
authors.initials: M
authors.lastname: Ducharme
authors.forename: N
authors.initials: N
authors.lastname: Sakamoto
authors.forename: M
authors.initials: M
authors.lastname: Satomi
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C095887:exatecan; D002166:Camptothecin