Background: Sym004 is a recombinant antibody 1:1 mixture of two chimeric anti-EGFR mAbs, which elicits superior cancer cell growth inhibition in preclinical models. Uniquely, Sym004 mediates cell surface receptor removal by triggering EGFR internalization and degradation. Results from a first-in-human multicenter trial evaluating safety and tolerability of multiple doses of Sym004 are reported. Methods: The trial comprises a dose-escalating part A (0.4 mg/kg-12 mg/kg) with classical 3+3 design after the first 2 cohorts and an extension part B at maximum tolerated dose (MTD). Patients (pts) received weekly IV infusions of Sym004 until disease progression or unacceptable toxicity. Pharmacokinetics and safety is evaluated weekly, with dose-limiting toxicities (DLT) assessed in the first 4 weeks, and tumor response every 8 weeks. Results: In part A, 17 pts (median age 60 years) were treated with doses up to 9 mg/kg without reaching the MTD: 0.4 mg/kg (1 had 6 doses), 0.75 mg/kg (1 had 35* doses), 1.5 mg/kg (3 pts had 6, 6 and 21 doses), 3 mg/kg (3 pts had 3, 5 and 6 doses), 6 mg/kg (3 pts had 3, 12* and 13 doses) and 9 mg/kg (6 had 1, 4*, 4*, 5*, 6* and 9* doses [*ongoing]). Most common tumor types were colorectal (11 pts) and pancreatic carcinomas (3 pts). 90% of adverse events (AEs) were CTCAE grade 1 or 2. The most frequent events were skin toxicities, diarrhea, nausea, infusion related reaction and electrolyte disturbances, similar to marketed anti-EGFR mAbs. 5 pts had non-serious, grade 1 mucositis. 4 pts had serious AEs related to Sym004: grade 2 rash and grade 1 allergic reaction (6 mg/kg), grade 3 acneiform rash (6 mg/kg), grade 3 hypomagnesemia (9 mg/kg) and grade 3 infusion related reaction (9 mg/kg). The latter event led to the introduction of an intensified pre-medication scheme with steroids, antihistamines and paracetamol before the first 4 infusions and lowered infusion rate. No further infusion reactions were observed thereafter. Of the 11 pts treated with doses up to 6 mg/kg, 4 remained in the trial for more than 8 weeks. AUC and Cmax for both mAbs constituting Sym004 were similar and increased with dose. Conclusions: Sym004 is well tolerated with no unexpected toxicities and shows preliminary signs of clinical activity.