1. ¹Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands
2. ²Oncopharmacology Unit, Centre Antoine Lacassagne, Nice, France
3. ³Department of Medical Oncology, Institut Curie, Paris, France
4. ⁴Eisai Ltd., London, UK
5. ⁵Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, The Netherlands
6. ⁶Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

Correspondence: Dr AS Zandvliet, E-mail: anthe.zandvliet@slz.nl

⁷These authors contributed equally to this work

Received 9 July 2007; Revised 4 February 2008; Accepted 11 February 2008.

Abstract

This dose escalation study was designed to determine the recommended dose of the multi-targeted cell cycle inhibitor indisulam in combination with capecitabine in patients with solid tumours and to evaluate the pharmacokinetics of the combination. Thirty-five patients were treated with indisulam on day 1 of each 21-day cycle. Capecitabine was administered two times daily (BID) on days 1–14. Plasma concentrations of indisulam, capecitabine and its three metabolites were determined for pharmacokinetic analysis. The main dose-limiting toxicity was myelosuppression. Hand/foot syndrome and stomatitis were the major non-haematological toxicities. The recommended dose was initially established at indisulam 700 mg m^-2 and capecitabine 1250 mg m^-2 BID. However, during cycle 2 the recommended dose was poorly tolerated in three patients. A dose of indisulam 500 mg m^-2 and capecitabine 1250 mg m^-2 BID proved to be safe at cycle 1 and 2 in nine additional patients. Indisulam pharmacokinetics during cycle 1 were consistent with pharmacokinetic data from phase I mono-therapy studies. However, exposure to indisulam was remarkably increased at cycle 2 due to a drug–drug interaction between capecitabine and indisulam. Partial response was confirmed in two patients, one with colon carcinoma and the other with pancreatic carcinoma. Seventeen patients had stable disease. Indisulam (700 mg m^-2) in combination with capecitabine (1250 mg m^-2 BID) was well tolerated during the first cycle. A dose of indisulam 500 mg m^-2 and capecitabine 1250 mg m^-2 BID was considered safe in multiple treatment cycles. The higher incidence of toxicities observed during cycle 2 can be explained by a time-dependent pharmacokinetic drug–drug interaction.