Gemcitabine modulation of alkylator therapy: A phase I trial of escalating gemcitabine added to fixed doses of ifosfamide and doxorubicin

BACKGROUND. The authors investigated the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) associated with the addition of a biomodulating dose of gemcitabine to an established regimen of ifosfamide and doxorubicin as part of a program to explore the potential of low-dose gemcitabine to modulate the activity of alkylating agents. METHODS. A Phase I trial was carried out in a population of patients with bladder or pelvic carcinoma for whom no standard therapy was available, Doses of ifosfamide and doxorubicin were held fixed at 2 g/m² for 4 days and 20 mg/m² for 3 days, respectively. Gemcitabine was given on Day 2 and Day 4 at doses of 90 mg/m², 150 mg/m², and 200 mg/m² per dose. RESULTS. A total of 18 patients received 53 courses of therapy. Myelosuppression was dose limiting. Nonhematologic toxicity also was significant, with 10 of 18 patients experiencing toxicity of Grade 3 or greater. For previously untreated patients with an intact performance status, the MTD for gemcitabine in this context was at least 150 mg/m² per dose. According to an intent-to-treat analysis, 11 of 18 patients demonstrated a clinically significant response to this regimen. CONCLUSIONS. The regimen of ifosfamide and doxorubicin with the addition of gemcitabine was significantly toxic but has promising activity. Based on the observed activity and the generally reversible nature of the toxicity, the authors have initiated a Phase II trial of this regimen in patients with untreated, metastatic urothelial carcinoma.