A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies

Objective. The mTOR inhibitor, temsirolimus, has clinical activity in the treatment of gynecologic malignancies, particularly endometrial cancer. We sought to determine the tolerability of the combination of weekly topotecan with weekly temsirolimus. Methods. Women with a history of advanced or recurrent gynecologic malignancy refractory to curative therapy were enrolled. A starting dose of 1 mg/m(2) of intravenous topotecan days 1, 8 and 15 was combined with 25 mg temsirolimus days 1, 8, 15 and 22 of a 28 day cycle. Patients with and without prior pelvic radiotherapy (RT) were dose-escalated in separate cohorts. Results. Fifteen patients were treated on study. Forty-three cycles were administered, with between 1 and 7 cycles received per patient. Patient characteristics included ovarian cancer (n = 7), endometrial cancer (n = 3), uterine carcinosarcoma (n = 3), and cervical cancer (n = 2): performance status 0 (n = 10) and 1 (n = 5); prior chemotherapy regimens one (n = 8), two (n = 4), and three (n = 3). Dose-limiting toxicity included asymptomatic neutropenia and thrombocytopenia. Four patients without prior pelvic RI were successfully treated with 1 mg/m(2) topotecan with 25 mg temsirolimus, days 1, 8, and 15 of a 28 day cycle. The combination was not tolerated in patients with a history of pelvic RT. Conclusions. Dose-limiting toxicity for the combination of temsirolimus with topotecan was myelosuppression. The regimen may be safe in women who have not previously received radiation, but full doses of each agent could not be administered in combination. (C) 2010 Elsevier Inc. All rights reserved.