Background: Preclinical studies suggest that temsirolimus (T), an inhibitor of mammalian target of rapamycin (mTOR) combined with cetuximab (C), an anti-EGFR monoclonal antibody, may have synergistic antitumor effects. Methods: A dose escalation study was conducted to define the MTD and to characterize the pharmacokinetics and safety profile of T (30 min infusion) given 1 hour later after C (1 hour infusion) on a weekly schedule of a 28-day cycle. Five dose-levels were evaluated with dose range of T from 15 to 25 mg weekly and C from 150 to 250 mg/m²weekly. Sequential biopsies were mandatory during the expansion cohort. Results: 39 patients (15M/24F), median age 57 years (range 38-76), previous number of lines 3 (range: 2-15) received the combination of T + C. The most common tumor types were colorectal (N = 6), breast (N = 5), uterine cervix SCC (N = 4) and NSCLC (N = 4). Three patients experienced dose limiting toxicities: grade 3 pulmonary embolism (at C 200 + T 20 level), grade 3 stomatitis (at C 250 + T 20 level) and grade 3 acneiform rash (at C 250 + T 25 level). The C 250 mg/m²and T 25mg/week dose level was selected as the recommended dose. The most common treatment-related adverse events were (All grade/grade 3-4): rash acneiform (97%/15%), mucositis oral (82%/23%), fatigue (59%/13%), nausea (41%/0%) diarrhea (36%/0%), hypomagnesaemia (79%/5%), , and hyperglycemia (66%/10%). The median progression-free survival and overall survival were respectively 2.0 months 95%CI [1.8-3.5] and 7.5 months 95%CI [5.5-11.9]. Among all patients partial responses (PR) and stable diseases were observed in 2 (5.1%) and 18 pts (46.2%). Fifteen pts (38.5%) were treated because of a molecular aberration involving the EGFR and/or PIK3 pathways. Among molecularly selected patients (N = 16), 2 PR (12.5%) were observed (cervix scc with an EGFR amplification and head and neck cancer with a PIK3CA amplification) and 7 pts (44%) had a PFS upper 5.5 months. Conclusions: Tolerance of T + C was acceptable. Clinical activity was modest among all patients. Molecular selection increased the objective response rate. Pre and post-exposure biopsies are available in 20 patients and are currently been analyzed for pathway modulation and DNA structural changes. Clinical trial information: NCT02215720