3096 Background: NECs are a varied group of endocrine neoplasms characterized by neurosecretory granules and cell surface markers. Except for islet cell carcinomas, NECs are resistant to conventional cytotoxics. Hormonal therapy such as somatostatin analogs or local therapies such as hepatic resection or arterial embolization are generally delivered to palliate symptoms. Temsirolimus is a novel mTOR inhibitor that downregulates cascades activated by loss of the tumor suppressor protein PTEN, a defect reported in moderately differentiated NECs. Due to the lack of effective systemic therapy for NECs, loss of PTEN detected in some cases, and a report of a partial response in this tumor type from phase I trials, a multi-centre 2-stage phase II trial in NECs was conducted. Methods: Patients were eligible if they demonstrated 25% increase in tumor volume, clinical deterioration or new tumor focus in the last 6 months. Temsirolimus 25 mg was administered intravenously over 30 minutes on a weekly basis. Results: To date, 23 patients (pts) with progressive NECs have been enrolled with the following demographics from 18 pts with baseline data: median age=55, range=36–68, M:F=9:9, ECOG 0:1:2= 8:9:1, and 11 pts had prior chemotherapy. Toxicity information is available from 15 pts in 50 four weekly cycles. The most frequently encountered grade 3–4 toxicities expressed as % of treatment cycles are: hypophosphatemia (14%), hyperglycemia (10%), cough (10%), hypokalemia (8%), hypercholesterolemia (8%), and hypertension (8%). The most frequent toxicities considering all grades are: fatigue (86%), anemia (76%) and lymphopenia (70%). Among 15 pts evaluable for response thus far, 10 have achieved prolonged stable disease (range: 3–11 cycles), including 1 pt with a 24% tumor shrinkage by RECIST criteria after 4 cycles, and 2 pts who have experienced significant clinical benefit and are on cycles 9 and 11, respectively. Levels of p70S6kinase in peripheral blood mononuclear cells at 24 hours post treatment have not shown correlation with clinical outcome in the majority of pts. Markers of cell cycle inhibition and apoptosis in paired tumor biopsies will be reported. Conclusions: Temsirolimus appears to have antitumor activity in NECs, study accrual is ongoing. No significant financial relationships to disclose.