Purpose TrasGEX is a second-generation monoclonal antibody of trastuzumab, glyco-optimised to enhance antibody-dependent cellular cytotoxicity while fully retaining trastuzumab’s antigen-binding properties to human epidermal growth factor receptor 2 (HER2). A phase I dose-escalation study was conducted to establish the optimal TrasGEX dose and regimen for phase II studies and to define the safety, pharmacokinetics (PK) and preliminary antitumour activity of TrasGEX.
Patients and methods A total of 37 patients with advanced HER2-positive carcinomas and progressive disease received TrasGEX intravenously every 3 weeks until disease progression in doses of 12–720 mg in a three-plus-three dose escalation design, including an expansion cohort at the highest dose.
Results No dose limiting toxicity was observed, and no maximum tolerated dose was reached. Drug-related adverse events were mainly infusion-related reactions occurring during the first infusion in 51% of patients; all but two were mild-to-moderate. Compared with trastuzumab, the PK parameters were dose dependent, with a mean terminal half-life (t1/2) of 263±99 hours for the 720 mg dose. Clinical benefit in 15 out of 30 (50%) evaluable patients included one ongoing complete response, two partial remissions lasting 16 and 77 weeks and disease stabilisation (SD) in 12 patients lasting a median (range) of 17 (7–26) weeks; three of them had SD of 24, 25 and 26 weeks, respectively.
Conclusion TrasGEX was safe, well-tolerated and showed antitumour activity in 50% of evaluable patients, all with progressive disease at study entry. Infusions at an interval of 2–3 weeks should achieve clinically relevant trough levels for future studies (NCT01409343).
- phase I
- glycoengineered monoclonal antibody
- solid tumours
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Contributors Conception and design: WF, HB, BD, MS and SG. Development of methodology: HB and AD. Acquisition of data (provided preclinical in vitro studies, acquired and managed patients and provided facilities): AD, WF, HS, AP, GG, JW and SDD. Analysis and interpretation of data (statistical analysis, biostatistics and computational analysis): WF, HB, BD and SG. Writing, review and/or revision of the manuscript: the authors were fully responsible for all content and editorial decisions, were involved in all stages of manuscript preparation and have approved the final version. Administrative, technical or material support (reporting or organising data and constructing databases): HB, AD and BD. Study supervision: BD and MS.
Funding The trial was sponsored by Glycotope GmbH, Berlin, Germany, which provided the drug and financial support for the conduct of the trial. The funding source was involved in the study design; in the analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. We confirm the independence of researchers from funders. All authors, external and internal, had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.
Competing interests All authors have completed the ICMJE uniform disclosure form and have sent them to the corresponding author. BD, HB, AD and SG are/were employees of Glycotope GmbH. Employment or leadership position: BD, H, AD and SG. Patent holders: HB, SG and AD. Stock ownership: HB, SG and AD. MS was employee of Medpace Ltd, which received funding for the study from Glycotope GmbH. Other remunerations: WF, meeting participation to present the data at the American Society of Clinical Oncology 2013 Annual Meeting. All remaining authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Patient consent Not required.
Ethics approval The study was approved by the corresponding local ethics committee of the institutions involved in the study, and patients written informed consent was obtained. The study was performed according to the declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
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