Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors.

摘要: PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with camptothecins, oral administration has pharmacological and clinical advantages. This Phase study was performed to assess the feasibility of diflomotecan, to determine maximum-tolerated, dose its bioavailability, explore pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered bioavailability diflomotecan. Fourteen days later, diflomotecan p.o. once daily 5 days adult patients solid malignant tumors repeated every 3 weeks. BN80915 open form BN80942 were measured. RESULTS: Twenty-two entered received total 57 cycles oral at flat levels 0.10, 0.20, 0.27, 0.35 mg. The main toxicity hematological, but some experienced alopecia, mild gastrointestinal toxicity, fatigue. At 0.35-mg level, 2 4 dose-limiting comprising grade 3 thrombocytopenia epistaxis febrile neutropenia 1 patient and uncomplicated lasting >7 another. Toxicity acceptable 0.27-mg level which toxicities observed 12 (grade > 7 days, complicated by fever without signs infection). After two 6 had disease stabilization, maintained 2 9 months >1 year, respectively. pharmacokinetics linear over range studied. Systemic exposure correlated fall WBC counts. The mean (+/-SD) 72.24 +/- 59.2% across all levels. Urinary excretion BN80915 very low. CONCLUSIONS: recommended II studies 0.27 mg/day x regimen convenient generally well tolerated a favorable pharmacokinetic profile high variable bioavailability.