8060 Background: The mammalian target of rapamycin (mTOR) pathway is a key cell-signaling cascade that is aberrantly activated in non-small cell lung cancer (NSCLC). Everolimus (E), an mTOR inhibitor, is active as monotherapy for advanced NSCLC. Based on preclinical synergy between everolimus and docetaxel (D), we conducted a phase I and feasibility study with the combination. Methods: Patients with stage IIIB/IV NSCLC, progression following prior platinum-based chemotherapy and ECOG performance status (PS) of 0–2 were eligible. Sequential cohorts of patients were treated with increasing doses of D (day 1) and E (PO QD, days 1–19). Treatment cycles (C) were repeated every 3 weeks. A standard ‘up and down’ dose escalation scheme was utilized. The primary endpoint was determination of optimal dose of the two agents that can be administered in combination. Results: Twenty three patients were enrolled. Median age - 62 yrs; Females- 11; ECOG PS: 0–6; 1 -16; # of prior regimens: 1–12, 2–6, ≥3 -5. At dose level 1 (D- 60 mg/m², E- 5mg), none of 6 patients had DLT. Four out of 12 patients at dose level 2 (D-75 mg/m², E-5 mg) had fever with gr 3/4 neutropenia during cycle 1. At dose level 3 (D- 75 mg/m², E- 7.5 mg), 2 of 3 pts had DLT (fever with neutropenia and grade 3 mucositis). Pharmacokinetic (PK) sampling was performed on days 1 (n=14), 8 (n=9), and 15 (n=10) of cycle 1. Mean E half-life (hr) on days 1, 8, and 15 were 9.66 (2–14), 12.6 (2.2–21.1), and 14.8 (2–21.2), respectively. E accumulation occurred and was greater than expected. In contrast to the mean predicted accumulation factor (R) based on AUC of 1.22 (1–1.44), actual R on day 8 and 15 were 1.78 (0.72–3.17) and 1.88 (0.37–3.3) respectively. Among 20 pts. evaluable for response, 1 had a partial response and 10 had disease stabilization. Six patients completed 6 cycles of combination therapy and continued on E as maintenance. Conclusions: The recommended doses of docetaxel and everolimus that can be administered as a combination are 60 mg/m² and 5 mg PO QD respectively. The PK characteristics of everolimus appear unaffected by co-administration with docetaxel. Promising anti-cancer activity was noted with clinical benefit in 55% of the pts. A phase II study has been initiated with the combination in refractory NSCLC. Supported by NCI 5 P01 CA116676. [Table: see text]