Background: Topoisomerase I inhibitors have some activity in refractory sarcomas, such as rhabdomyosarcoma and other round cell tumors, with responses between 70-20% depending on the histologic type. mTOR inhibitors have also a modest activity against sarcomas. I and T have different mechanisms of actions. This Phase IB study evaluates the combination of I and T for refractory metastatic sarcomas. The aims were to determine (1) the maximum tolerated dose and toxicity profile, (2) the antitumor activity in an expanded cohort. Aim 1 is reported. Methods: Pts with metastatic sarcomas who failed at least one chemotherapy regimen were eligible if they had signed a consent form, and had good performance status and normal organ functions. Treatment was administered weekly x 3 every 4 weeks and clinical response evaluated every 2 courses by RECIST criteria. A 2 arm crossing design was used (Lee SJ, et al. Invest New Drugs. 2008). In arm 1, I dose was fixed at 80 mg/m²/dose and T was escalated by 5 mg starting at 15 mg/dose. In arm 2, T dose was fixed at 25 mg/dose and I was escalated by1 5 mg starting at 50 mg/m²/dose. AEs were recorded using NCI-CTCAE v3. DLTs were defined as grade 3 neutropenia on retreatment day, a grade 4 febrile neutropenia, a drug-related grade >3 non-hematologic toxicity (except fatigue, nausea, vomiting or grade 3 hypersensitivity reaction), and incapacity to retreat on a weekly basis. Results: Fourteen pts were enrolled. Arm 2: Two/3 pts had DLT and could not be retreated weekly. This arm was closed. Arm1: The first cohort was expanded to 6 pts because one pt could not be retreated weekly. Grade 2 & 3 hematologic side effects observed were neutropenia (2 & 1pts) with one neutropenic fever and thrombocytopenia (1 & 2pts). Non-hematological side effects were grade 2 nausea, vomiting and diarrhea in 1, 1, and 2 pts and mucositis in 1 pt. Two patients have received 11 (leiomyosarcoma) and 6+ courses (sarcoma NOS) each with stable disease. All other patients progressed after 2 courses. Conclusions: The recommended Phase II dose of the weekly combination of I and T is I 80 mg/m² with T 20 mg. We are now expanding this Phase II dosing to better evaluate this regimen.