Background: Resistance to treatment with inhibitors of mammalian Target of Rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). Based on pre-clinical evidence of synergy, we conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors. Methods: A classic 3+3 design was used for the dose escalation portion of the study. An expansion cohort at RP2D included only those with mutations that may contribute to PI3K or EGFR pathway activationor squamous histology. A cycle was defined as 28 days. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was administered weekly. Starting dose levels were 15 mg temsirolimus and 100 mg erlotinib. Results: Forty-six patients were enrolled in this study (29 in dose escalation and 17 in the expansion cohort). Two patients experienced (DLTs) (grade 3 dehydration and grade 4 renal failure). The most common drug-related adverse events of all grades were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. The RP2D is temsirolimus at a 25 mg weekly dose and 100 mg of daily erlotinib. No complete or partial responses were observed in the study. The median duration on this study was 77 days (range 15-770 days). Among 12 evaluable patients in the expansion cohort, 9 (75%) had stable disease and 3(25%) had progressive disease. The median duration on the study was 98 days (range 25- 243 days) for the expansion cohort. Clinical benefits were seen in patients with squamous cell histology; for example, a patient with refractory squamous cell cancer of the head and neck had durable disease control lasting 770 days. Stable disease was also observed in patients with specific genetic alternations; for example, a patient with refractory sarcoma with PTEN loss achieved stable disease of 194 days. Conclusions: The combination of temsirolimus and erlotinib at the RP2D is well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients. Clinical trial information: NCT00770263