Background: TrasGEX is a glyco-optimized anti-HER2 antibody. It is designed to fully retain the antigen-binding properties of trastuzumab. It is manifold improved by fully human glycosylation and optimized for its antibody dependent cellular cytotoxicity (ADCC)-mediated anti-tumor efficacy for all FcɣRIIIa genotypes as well as for lower HER2 expressing tumors. In vitro studies showed an approximate 10 to 140 fold improvement of ADCC-mediated anti-tumor activity for TrasGEX depending on the level of HER2 expression and of the FcɣRIIIa receptor status. Methods: This is a phase I, dose-escalation trial of TrasGEX 12 to 720 mg IV flat-dose q3w in patients progressive with advanced or metastatic cancer for whom no effective standard treatment is available and ErbB2 (HER2) positivity (at least 1+). The primary objective of this first-in-human study was to determine the optimal dose and regimen of TrasGEX in the study population. Results: A total of 37 patients were treated with up to 720 mg TrasGEX IV flat-dose q3w in 5 cohorts of 3 to 6 patients each and an extension group of 16 patients who received 720 mg. No DLT was observed, the MTD was not reached. Infusion-related reactions (IRR) were the most frequently observed drug-related AEs (51.4%) all but two of grade 1 or 2. Premedication with paracetamol and steroids reduced the frequency and intensity of IRRs. The pharmacokinetic properties were dose-dependent with a maximal half-life of 263 h ± 99 h at 720 mg. One patient with HER2+++ salivary duct tumor developed a CR, two HER2+++ patients reached strong PR (breast: 240 mg, FcɣRIIIa allotype: FF, prior trastuzumab non-responder; colon: 480 mg, FV allotype) and 12 (32.4%) showed SD (HER2+ = 4; HER2++ = 3; HER2+++ = 5), of which 40% had been exposed to trastuzumab at earlier therapies. Conclusions: TrasGEX at doses of up to 720mg IV q3w was well tolerated. No DLT was observed. The pharmacokinetic properties support a q3w infusion scheme. Evidence of activity was seen in 40.6% of patients, including one CR and 2 PRs in patients with progressive disease at study entry. Clinical trial information: NCT01409343.