Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study

The purpose of this bridging phase I study was to characterize the toxicity pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days I and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Orgonization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (loctone and total) with the capsule formu lotion was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 mu M center dot h, suspension = 5.33 mu M center dot h; total: capsule = 393 mu M center dot h, suspension = 176 mu M center dot h) and day 12 (lactane: capsule = 22.1 mu M center dot h, suspension = 6.1 mu M center dot h; total: capsule = 1302 mu M center dot h, suspension = 309 mu M center dot h). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactane = 15.9 mu M center dot h, total = 605 mu M center dot h) relative to fasted conditions (lactone = 8.53 mu M center dot h, total = 393 mu M center dot h) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).