A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients.

PURPOSE: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance protein-mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. EXPERIMENTAL DESIGN: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m(2) i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1 of cycles 1 and 2 of part II. RESULTS: Complete apparent oral bioavailability of topotecan (102 +/- 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. CONCLUSION: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days.

Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan in patients with advanced solid tumors.

PURPOSE: The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study. EXPERIMENTAL DESIGN: Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m(2) once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m(2)/d. RESULTS: The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m(2)/d for irinotecan single agent and 30/1,600 mg/m(2)/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively. CONCLUSIONS: In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m(2)/d administered daily for 14 days every 3 weeks.

Current state of the art of new tubulin inhibitors in the clinic.

For years the microtubule stabilizing agents docetaxel and paclitaxel belong to the most successful clinical chemotherapeutic agents. Several attempts have been made over the years to equal and better these drugs. Both taxanes are associated with the notorious side effect neurotoxicity and are often accompanied with increased drug resistance and cross resistance with other chemotherapeutic agents. In addition their high lipophilicity demands use of co-solvents, which are associated with less favorable side effects such as hypersensitivity. To prevent these disadvantages and improve the clinical application of the taxanes several new agents have entered clinical testing. The agents that are discussed are the drug class of the discodermolides; XAA296A and the epothilones; BMS-247550, BMS-310705, epo906, kos-862 and the agents ABT-751 and D-24851. Here we present an overview of recently performed clinical studies to determine the current state of the art of the tubulin inhibitors which are intended to enlarge and improve the clinical use of the taxanes docetaxel and paclitaxel.

Modulation of oral drug bioavailability: from preclinical mechanism to therapeutic application.

Currently, more than one fourth of all anticancer drugs are developed as oral formulations, and it is expected that this number will increase substantially in the near future. To enable oral drug therapy, adequate oral bioavailability must be achieved. Factors that have proved to be important in limiting the oral bioavailability are the presence of ATP-binding cassette drug transporters (ABC transporters) and the cytochrome P450 enzymes. We discuss the tissues distribution and physiological function of the ABC transporters in the human body, their expression in tumors, currently known polymorphisms and drugs that are able to inhibit their function as transporter. Furthermore, the role of the ABC transporters and drug-metabolizing enzymes as mechanisms to modulate the pharmacokinetics of anticancer agents, will be reviewed. Finally, some clinical examples of oral drug modulation are discussed. Among these examples are the coadministration of paclitaxel with CsA, a CYP3A4 substrate with P-glycoprotein (P-gp) modulating activity, and topotecan combined with the BCRP/P-gp transport inhibitor elacridar. Both are good examples of improvement of oral drug bioavailability by temporary inhibition of drug transporters in the gut epithelium.

Topoisomerase I inhibitors in the treatment of gastrointestinal cancer: from intravenous to oral administration.

This article reviews the current status of the topoisomerase I (top I) inhibitors in the treatment of gastrointestinal (GI) malignancies. We focus on oral drug administration, the mode of administration that is generally preferred by patients with cancer. However, the great majority of the studies have been performed with intravenous (I.V.) administration. The most extensively investigated GI malignancy in phase I/II studies is colorectal cancer (CRC), for which I.V. irinotecan is currently approved in the United States and Europe. We discuss the activity and efficacy of irinotecan as a single agent in CRC and in combination regimens. Also, results obtained with monotherapy and in combination treatment in other GI malignancies such as esophageal, gastric, and pancreatic cancer are discussed. Few phase I studies have been performed with oral irinotecan and its clinical activity has not yet been fully determined. Several top I inhibitors are discussed, including topotecan, 9-aminocamptothecin, rubitecan, exatecan, and lurtotecan. None of these agents, given orally or intravenously, have shown activity in CRC similar to that of I.V. irinotecan. However, several agents show promising results in other GI malignancies, eg, rubitecan and exatecan in pancreatic cancer. A complicating factor in the oral administration of the top I inhibitors is the often encountered low and variable oral bioavailability. This can partly be explained by the high affinity for the drug efflux pumps BCRP (ABCG2) and P-glycoprotein, which are highly expressed in the epithelial apical membrane of the GI tract. A novel approach to improve the oral bioavailability of the top I inhibitors by temporary blockade of the drug transporter BCRP is described.