Phase I Trial of Weekly Topotecan and Gemcitabine in Patients With Solid Tumors

Abstract

Objective This phase I trial was designed to determine the maximal tolerated dose (MTD) of the combination of topotecan and gemcitabine given in a weekly schedule. Materials and Methods In this single-arm, open label, dose-escalation study, we administered topotecan (0.75–1.5 mg/m2) and gemcitabine (1000 mg/m2) on days 1, 8, and 15 every 4 weeks to 25 patients with advanced solid tumors. Results The topotecan MTD, when combined with gemcitabine, was 1.25 mg/m2/wk. Dose-limiting toxicities consisted of febrile granulocytopenia in 2 patients at the highest dose level. At the MTD, no episodes of granulocytopenia were observed, whereas 2/9 patients exhibited grade 3 thrombocytopenia. Other common grades 3–4 adverse events across all cohorts included non-neutropenic infections, fatigue, skin reactions, vomiting, and fever. One partial response and 2 stable diseases were observed in patients with nasopharyngeal carcinoma. Disease stabilization was also observed in patients with squamous cell carcinoma of the head and neck (3), nonsmall cell lung cancer (1), and thymoma (1). Conclusions Topotecan and gemcitabine combined in a weekly schedule exhibit a favorable toxicity profile. Efficacy results support the further evaluation of this regimen in patients with head and neck cancer (particularly nasopharyngeal carcinoma).

A novel oral camptothecin analog, gimatecan, exhibits superior antitumor efficacy than irinotecan toward esophageal squamous cell carcinoma in vitro and in vivo

“…However, this causes the formation of irreversible double-stranded DNA breaks when a DNA replication fork collides with the cleavable complex 5 , 6 , Camptothecins can show preferential or selective toxicity to proliferating cells, particularly tumor cells, which are highly proliferative. As a result, the camptothecin analogs topotecan and irinotecan have already been widely used to treat several solid tumors, including colorectal carcinoma 7 , 8 and lung cancer 9 – 12 . Recently, irinotecan has also shown promising results for the treatment of advanced ESCC 13 – 15 .…”

A phase I study of topotecan and gemcitabine in advanced solid tumors

“…Other studies utilizing different doses and schedules of gemcitabine and topotecan have shown variable activity in numerous solid tumors [25][26][27][28]. Particular activity has been suggested in non-small cell lung [25,26] and head and neck carcinomas [28].…”