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

Rao S, Starling N, Cunningham D, Benson M, Wotherspoon A, Lüpfert C, Kurek R, Oates J, Baselga J, Hill A - Br. J. Cancer (2008)

Bottom Line: Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Royal Marsden Hospital, Surrey, UK.

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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Related in: MedlinePlus

Pharmacodynamics of matuzumab on EGFR downstream signalling events.
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fig2: Pharmacodynamics of matuzumab on EGFR downstream signalling events.

Mentions: Pharmacodynamic results were available from 18 subjects in total. Skin biopsy data were consistent between patients at each DL (Figure 2). Following the administration of matuzumab, the total EGFR expression remained in the range of 80–100%. In contrast, EGFR phosphorylation was inhibited and there was a similar reduction in pMAPK for all investigated DLs. Increased levels of p27 and p-STAT3 were detected. Baseline Ki67 decreased following matuzumab treatment in all but one patient. Cytokeratin 1 levels in skin biopsies generally increased during treatment although there were decreased levels in two patients. The changes in these marker proteins described were not dose dependent.


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

Rao S, Starling N, Cunningham D, Benson M, Wotherspoon A, Lüpfert C, Kurek R, Oates J, Baselga J, Hill A - Br. J. Cancer (2008)

Pharmacodynamics of matuzumab on EGFR downstream signalling events.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2538760&req=5

fig2: Pharmacodynamics of matuzumab on EGFR downstream signalling events.
Mentions: Pharmacodynamic results were available from 18 subjects in total. Skin biopsy data were consistent between patients at each DL (Figure 2). Following the administration of matuzumab, the total EGFR expression remained in the range of 80–100%. In contrast, EGFR phosphorylation was inhibited and there was a similar reduction in pMAPK for all investigated DLs. Increased levels of p27 and p-STAT3 were detected. Baseline Ki67 decreased following matuzumab treatment in all but one patient. Cytokeratin 1 levels in skin biopsies generally increased during treatment although there were decreased levels in two patients. The changes in these marker proteins described were not dose dependent.

Bottom Line: Pharmacokinetic evaluation demonstrated that the coadministration of ECX did not alter the exposure of matuzumab.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Royal Marsden Hospital, Surrey, UK.

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.

Show MeSH
Related in: MedlinePlus