Phase I trial of capecitabine in combination with interferon alpha in patients with metastatic renal cancer: toxicity and pharmacokinetics

Abstract.

Purpose: The present study was designed to determine the toxicity and maximum tolerated doses of oral intermittent oral capecitabine and subcutaneous (s.c.) rHuIFNα2a in patients with metastatic renal cell carcinoma (RCC). The pharmacokinetics of capecitabine and its metabolites were also investigated. Methods: A total of 27 patients were treated at four dose levels of capecitabine (825 or 1000 mg/m² twice daily orally, days 1–14, 22–36) and rHuIFNα2a (1.5 or 3.0 MU/m² s.c. three times weekly). Unchanged capecitabine and its metabolites were analyzed in plasma using liquid chromatography/mass spectrometry in ten patients. Results: The toxicity of combined capecitabine and rHuIFNα2a was moderate. Patients experienced mild nausea/vomiting (70%) and diarrhea (63%). The hand-foot syndrome was seen in 67% of patients and was generally mild, as was hematologic toxicity. Dose-limiting toxicity included diarrhea, mucositis, neutropenia and the hand-foot syndrome. The dose level recommended for further trials included capecitabine 1000 mg/m² twice daily and rHuIFNα2a 3.0 MU/m² three times weekly. One patient had a partial response of a liver lesion (duration >200 days). Pharmacokinetic parameters of capecitabine and its metabolites (5′-deoxy-5-fluorouridine, 5-fluorouracil and α-fluoro-β-alanine) were similar to those reported by other authors. There was rapid conversion to 5′-deoxyuridine. The peak plasma concentrations of capecitabine occurred between 0.5 and 3.0 h. Conclusions: The combination of capecitabine and rHuIFNα2a was well tolerated. The recommended dose levels for phase II trials are: rHuIFNα2a 3.0 MU/m² s.c. three times weekly and oral capecitabine 1000 mg/m² twice daily for 2 weeks. No evidence of an effect of rHuIFNα2a on the pharmacokinetics of capecitabine or its metabolites was apparent. A phase II trial in untreated patients with metastatic RCC is planned.