Phase I study of rubitecan and gemcitabine in patients with advanced malignancies

Background: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. Patients and methods: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m 2 /day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m 2 administered intravenously on days I and 8 of a 21-day cycle. Results: The MTD was defined as rubitecan I mg/m 2 administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m 2 administered intravenously over 30 min days I and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. Conclusions: The recommended phase II dose is rubitecan 1 mg/m 2 given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m 2 as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.