Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study

The objective of this study was to characterize the maximum tolerated dose dose-limiting toxicities (DLT), pharmacokinetics,. and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLt and MTD. Twenty-five patients received 73 courses of therapy Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenio and grade 4 diarrhea. TWO complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.