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Clinical Trial
. 2008 Sep 16;99(6):868-74.
doi: 10.1038/sj.bjc.6604622.

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

S Rao  1 , N Starling, D Cunningham, M Benson, A Wotherspoon, C Lüpfert, R Kurek, J Oates, J Baselga, A Hill
Affiliations
Clinical Trial

Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer

S Rao et al. Br J Cancer. .

Abstract

To evaluate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of the humanised antiepidermal growth factor receptor monoclonal antibody matuzumab combined with epirubicin, cisplatin and capecitabine (ECX) in patients as first-line treatment for advanced oesophagogastric cancer that express epidermal growth factor receptor (EGFR). This was a phase I dose escalation study of matuzumab at 400 and 800 mg weekly and 1200 mg every 3 weeks combined with ECX (epirubicin 50 mg m(-2), cisplatin 60 mg m(-2) on day 1 and capecitabine 1000 mg m(-2) daily). Patients were treated until disease progression, unacceptable toxicity or for a maximum of eight cycles. Twenty-one patients were treated with matuzumab at three different dose levels (DLs) combined with ECX. The main dose-limiting toxicity (DLT) was grade 3 lethargy at 1200 mg matuzumab every 3 weeks and thus 800 mg matuzumab weekly was the maximum-tolerated dose (MTD). Other common toxicities included rash, nausea, stomatitis and diarrhoea. Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab. Pharmacodynamic studies on skin biopsies demonstrated inhibition of the EGFR pathway. Objective response rates of 65% (95% confidence interval (CI): 43-82), disease stabilisation of 25% (95% CI: 11-47) and a disease control rate (CR + PR + SD) of 90% were achieved overall. The MTD of matuzumab in combination with ECX was 800 mg weekly, and at this DL it was well-tolerated and showed encouraging antitumour activity. At the doses evaluated in serial skin biopsies, matuzumab decreased phosphorylation of EGFR and MAPK, and increased phosphorylation of STAT-3.

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Figures

Figure 1
Figure 1
Concentration–time courses of matuzumab in the dose groups 400 mg weekly (dashed line and circles), 800 mg weekly (continuous line and triangles) and 1200 mg every 3 weeks (bold line and squares). The mean concentrations (symbols) are fitted with a two-compartment model per dose group.
Figure 2
Figure 2
Pharmacodynamics of matuzumab on EGFR downstream signalling events.
See this image and copyright information in PMC

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