Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas
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Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas. / Fiedler, Walter; Cresta, Sara; Schulze-Bergkamen, Henning; De Dosso, Sara; Weidmann, Jens; Tessari, Anna; Baumeister, Hans; Danielczyk, Antje; Dietrich, Bruno; Goletz, Steffen; Zurlo, Alfredo; Salzberg, Marc; Sessa, Cristiana; Gianni, Luca.
In: ESMO OPEN, Vol. 3, No. 2, 2018, p. e000303.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Phase I study of tomuzotuximab, a glycoengineered therapeutic antibody against the epidermal growth factor receptor, in patients with advanced carcinomas
AU - Fiedler, Walter
AU - Cresta, Sara
AU - Schulze-Bergkamen, Henning
AU - De Dosso, Sara
AU - Weidmann, Jens
AU - Tessari, Anna
AU - Baumeister, Hans
AU - Danielczyk, Antje
AU - Dietrich, Bruno
AU - Goletz, Steffen
AU - Zurlo, Alfredo
AU - Salzberg, Marc
AU - Sessa, Cristiana
AU - Gianni, Luca
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1136/esmoopen-2017-000303
DO - 10.1136/esmoopen-2017-000303
M3 - SCORING: Journal article
C2 - 29464112
VL - 3
SP - e000303
JO - ESMO OPEN
JF - ESMO OPEN
SN - 2059-7029
IS - 2
ER -