Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium.

OBJECTIVES: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P+G in patients with metastatic TCC. METHODS: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800-1,000 mg/m2 on days 1 and 15; P 400-500 mg/m2 on day 15; and C 50-70 mg/m2 on day 1. All patients received folic acid, vitamin B12, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. RESULTS: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53-82); 11/15 had KPS>or=90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed<1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3-4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). CONCLUSION: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.

Case report of an acquired factor XIII inhibitor: diagnosis and management.

A 57-year-old man presented with a spontaneous upper-extremity hematoma and compartment syndrome. The patient experienced excessive bleeding following evacuation of the hematoma, and the results of routine coagulation studies were normal. Factor XIII activity was undetectable using a photometric assay, and the presence of an inhibitor was detected with mixing studies. Bleeding was controlled with infusions of fresh frozen plasma and cryoprecipitate. Cyclophosphamide was started on the 16th hospital day, and four weekly doses of the monoclonal anti-CD20 antibody, rituximab, were begun 3 weeks later. One week after the initial dose of rituximab, the inhibitor was no longer detectable and the factor XIII level increased to 28%. After completion of the rituximab therapy, the factor XIII activity was 58% with no inhibitor present. This case illustrates the need to check for unusual defects such as factor XIII deficiency if a bleeding tendency is evident-even if routine studies are unrevealing.