A phase I trial of topotecan and gemcitabine administered weekly for 3 consecutive weeks to patients with advanced tumors

BACKGROUND. The complementary action of gemcitabine and topotecan on DNA me tabolism suggested the potential for their use in combination chemotherapy. Gemcitabine, a synthetic cytidine analogue chain terminator, and topotecan , a topoisomerase-l inhibitor, have been reported to have broad antitumor a ctivity and are approved for clinical use. METHODS. The cytotoxicity of the combination in various models in vitro was additive. In the current study, the authors conducted a Phase I study to d etermine the recommended Phase II doses and toxicity profile of gemcitabine and topotecan when administered weekly in combination. Gemcitabine (400-10 00 mg/m(2)) was given intravenously over 30 minutes followed by a 15-minute infusion of topotecan (0.75-2.5 mg/m(2)) weekly for 3 consecutive weeks in a 4-week treatment cycle. Thircy-eight patients with advanced refractory s olid tumors and good performance status were treated. RESULTS. Myelosuppression in the form of granulocytopenia and thrombocytope nia were the major dose-limiting toxicities. Other toxic effects included a nemia, nausea, and elevated hepatic transaminases. Partial responses were o bserved in two patients tone with nonsmall cell lung carcinoma and one with pancreatic carcinoma). Disease stabilization occurred in five patients (th ree with pancreatic carcinoma, one with rectal carcinoma, and one with meta static carcinoma of an unknown primary site). Gemcitabine, 1000 mg/m(2), an d topotecan, 2.5 mg/m(2), were the maximum tolerated doses for this combina tion. CONCLUSIONS., The results of the current study showed that the combination of weekly gemcitabine and topotecan for 3 weeks in a I-week cycle schedule appeared to be well tolerated and was associated with clinical activity. Th erefore, this combination is recommended for a further Phase II evaluation. (C) 2001 American Cancer Society.