DX‐8951f: Summary of Phase I Clinical Trials

A bstract : 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 ×5, 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.