Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours

Abstract

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).

Keywords: glycoengineered monoclonal antibody; her2; phase I; solid tumours; trasgex.

Conflict of interest statement

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.

Figures

Figure 1

Scatterplot of (A) terminal half-life (t1/2) and (B) clearance (CL) by dose cohort calculated for the first TrasGEX infusion.

Figure 2

Waterfall plots of the best per cent change from baseline in sum of longest diameters (SLD) for target lesions. Baseline is defined as the last non-missing value before the first dose of TrasGEX. Twenty-eight patients in the total population (n= 37) had valid baseline and postbaseline values. Tumour assessment was not performed in nine patients because of absence of target lesions (n= 2), or early withdrawal due to clinical deterioration (n= 3), adverse event (n=3) or withdrawal of informed consent (n= 1). The red dotted lines indicate the cut off for partial response (−30%) and progressive disease (+20%). Bars marked with an asterisk denote nine patients with stable target lesions but progressive disease because of progression of non-target lesions or appearance of new lesions. BC, breast cancer; bladder CA, urinary bladder cancer; CRC, colorectal cancer; EGCA, esophagogastric junction cancer; GCA, gastric cancer; NSCLC, non-small cell lung cancer; OVCA, ovarian cancer; PanC, pancreatic cancer; parotid CA, parotid gland cancer.