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

Abstract

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 1 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 Organization 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 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) 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).

Interspecies scaling of a camptothecin analogue: Human predictions for intravenous topotecan using animal data

“…Although it was a retrospective analysis of preclinical TPT data, we believe an opportunity exists for a prospective allometric scaling of camptothecin analogues especially some newer ones that are in discovery and development (Chatterjee et al 2005;Rose et al 2006;Yount et al 2007;Samori et al 2008). Since TPT is predominantly renally eliminated, other CPTs that have renal excretion as a major route of elimination may render itself better suited for simple allometric scaling such as the one employed in the present work.…”

“…Because topoisomerase I is found in both proliferating and non-proliferating cells, selective inhibition of the enzyme appears to be prudent for a unique therapeutic approach to the treatment of slow-growing tumour types. The unique mechanism of action that enabled the formation of TopoI cleavage complex, the impressive preclinical efficacy data, and the clinical success of irinotecan and topotecan has stimulated intensive efforts to identify novel analogues of CPTs (Garcia-Carbonero and Supko 2002;Chatterjee et al 2005;Clark 2006; Beretta and Zunino 2007;Yount et al 2007;Samori et al 2008).…”

Other Anticancer Drugs Targeting DNA and DNA-Associated Enzymes

“…87,88 Examples of A ring-substituted compounds include rubitecan 89 and its active metabolite 9-aminocamptothecin. 90 Among B ring-substituted compounds are lurtotecan, 91 exatecan (DX-8951f), 92,93 DRF1042, 94 and belotecan (CKD-602, Camtobell ® ). The latter compound gained approval in some countries for the treatment of ovarian and small cell lung cancer.…”

Natural products as lead compounds in drug discovery

“…Elomotecan 16, an inhibitor of topoisomerase I and II, is in Phase I trials against colon, breast and prostate cancer [27]. Clinical phase I trials have been conducted on DRF 1042 17 for the treatment of solid tumours [28]. …”