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Phase I Evaluation of Sequential Doxorubicin Gemcitabine Then Ifosfamide Paclitaxel Cisplatin for Patients With Unresectable or Metastatic Transitional-Cell Carcinoma of the Urothelial Tract

From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine; Department of Radiology; the Division of Epidemiology and Biostatistics; and Division of Urology, Department of Surgery, Memorial Sloan-Kettering Cancer Center; and Department of Medicine, Joan and Sanford Weill Medical College of Cornell University, New York, NY.

Address reprint requests to Dean F. Bajorin, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

PURPOSE: This phase I trial sought to evaluate the toxicity of and determine the maximum-tolerated dose (MTD) for the two-drug regimen doxorubicin and gemcitabine (AG) followed by the three-drug regimen of ifosfamide, paclitaxel, and cisplatin (ITP) in patients with unresectable or metastatic transitional-cell carcinoma.

PATIENTS AND METHODS: Patients received AG every other week for six cycles followed by ITP every 3 weeks for four cycles. Five AG dose levels were investigated, up to doxorubicin 50 mg/m² and gemcitabine 2,000 mg/m², to determine the MTD of the regimen. The dose and schedule of ITP were constant: ifosfamide 1,500 mg/m² (days 1 to 3); paclitaxel 200 mg/m² (day 1); and cisplatin 70 mg/m² (day 1). Granulocyte colony-stimulating factor was given between all cycles of therapy.

RESULTS: Fifteen patients enrolled onto this phase I trial. AG was well tolerated at all dose levels, with no grade 3 or 4 myelosuppression. Toxicity experienced with ITP included grade 3 and 4 granulocytopenia in four patients and grade 3 nausea/vomiting in three patients. No grade 3 and 4 neurotoxicity was observed. Eight of 14 assessable patients experienced a major response to AG, including five of six patients treated at the two highest AG dose levels. After completion of AG-ITP, nine of 14 assessable patients had a major response (three complete responses and six partial responses).

CONCLUSION: AG is a well-tolerated and active regimen. Sequential chemotherapy with AG-ITP is also well tolerated, and phase II investigation at the highest dose level is ongoing.

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