Background Changes in glycosylation of the constant domain (Fc) of monoclonal antibodies (mAbs) enhance antibody-dependent cell-mediated cytotoxicity independently of downstream effects following receptor blockade by the antibody, thus extending their indication. We investigated the safety, pharmacokinetics, pharmacodynamics and antitumour activity of tomuzotuximab, an IgG1 glycoengineered mAb against the epidermal growth factor receptor with enhanced tumour cytotoxicity in a phase I dose-escalation study (NTC01222637).
Patients and methods Forty-one patients with advanced solid tumours refractory to standard therapies received tomuzotuximab weekly (12–1370 mg) or two-weekly (990 mg) on a three-plus-three dose escalation design.
Results A maximum tolerated dose was not reached. The most frequent treatment-related adverse events were infusion-related reactions in 31 (76%) patients (grade 3, 12%), mainly confined to the first dose, and skin toxicities (grade 1 or 2) in 30 (73%) patients. Hypomagnesaemia was observed in 9 out of 23 evaluable patients (39%). Similar to cetuximab, tomuzotuximab concentrations increased proportionally to dose from doses≥480 mg with a median terminal half life (t½) of 82 hours, range 55–113 hours. Antitumour activity included one complete response ongoing since more than 4.5 years in a patient with non-small-cell lung cancer and one partial response lasting 353 days in a patient with colorectal cancer. Twelve patients achieved stable disease (median, 166 days, range, 71–414 days) and two patients had prolonged control (>1 year) of their non-measurable disease.
Conclusion Tomuzotuximab was safe and showed promising antitumour activity in heavily pretreated patients with advanced metastatic disease. A phase IIb trial of chemotherapy and weekly tomuzotuximab or cetuximab followed with maintenance therapy with the corresponding mAb in patients with recurrent or metastatic head and neck squamous cell carcinoma is ongoing.
- phase I
- monoclonal antibody
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Contributors Conception and design: WF, HB, BD, SG, AD, CS, LG. Provision of study materials or patients: WF, SC, HS-B, JW, SDD, AT, HB, BD, AD, CS, LG. Collection and assembly of data: WF, SC, HS-B, JW, SDD, AT, HB, CS, LG. Data analysis and interpretation: WF, HB, BD, AD, SG, AZ, CS, LG. Reading and approval of the final manuscript: all authors.
Funding This work was supported by Glycotope GmbH, which provided the drug and financial support for the conduct of the trial. 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.
Competing interests Employment or leadership position: HB, BD, SG, AZ, AD. Stock ownership: HB, SG, AD. MS was employee of Pharma Brains AG, which received funding for the study from Glycotope GmbH. Other remuneration: WF, Meeting participation to present the data at the American Society of Clinical Oncology 2013 Annual Meeting.
Patient consent Obtained.
Ethics approval Ethik-Kommission der Ärztekammer Hamburg and the Ethics Committees of each Center.
Provenance and peer review Not commissioned; externally peer reviewed.
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