A phase I trial of temsirolimus and erlotinib in patients with refractory solid tumors.

Purpose Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). 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 Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib. Results Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease. Conclusion The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).