Rao S, Starling N, Cunningham D, Benson M, Wotherspoon A, Lupfert C et al.. Phase I study of epirubicin, cisplatin and capecitabine plus matuzumab in previously untreated patients with advanced oesophagogastric cancer. Br J Cancer 99: 868-874

Department of Medicine, Royal Marsden Hospital, Surrey, UK.
British Journal of Cancer (Impact Factor: 4.84). 10/2008; 99(6):868-74. DOI: 10.1038/sj.bjc.6604622
Source: PubMed


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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    • "Matuzumab (EMD 72000, Merck) is a humanized monoclonal antibody targeting the EGFR. It has been evaluated in a Phase I study in combination with epirubicin, cisplatin, and capecitabine (ECX) as a first-line therapy for patients with EGFR-positive EGC.67 The response to different doses of matuzumab was 57% (four partial responses and two stable disease) with 400 mg and 43% (three partial responses and two stable disease) with 800 mg. "
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    ABSTRACT: The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR) are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers.
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    • "Another phase I evaluation combined matuzumab with the ECX regimen (epirubicin/cisplatin/capecitabine) as a first-line therapy for patients with EGFR-positive gastric and GE junction adenocarcinoma [133]. Of 45 patients screened, 21 (47%) were found to have EGFR-positive tumors. "
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    ABSTRACT: Gastric cancer (GC) is the fourth most common cancer and the second most frequent cause of cancer-related deaths, accounting for 10.4% of cancer deaths worldwide. Despite the improvements, estimated cure rates for patients with advanced stages remain poor, and in the metastatic setting, chemotherapy is the mainstay of palliative therapy and results in objective response rates (ORRs) of only 20-40% and median overall survivals (OS) of 8-10 months. Therefore, many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors to investigate new therapeutic strategies to combat GC, such as specific immunotherapy. In this paper, we analyze the different approaches used for immune-based (especially dendritic and T cells) therapies to gastric cancer treatment and discuss the results obtained in preclinical models as in clinical trials.
    Full-text · Article · Dec 2011 · BioMed Research International
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    • "A preliminary report of a Phase II study showed that in combination with capecitabine, a partial response and stable disease were seen in 24% and 34%, respectively.50 The EOX regimen with or without panitumumab (REAL-3 study) is ongoing,51 with Phase I trials of the combination showing a response rate of 65%.52 "
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    ABSTRACT: Advanced or metastatic gastric cancer constitutes the majority of patients in clinical practice. In North America, about 70% of cases are advanced or metastatic when diagnosed, which is higher than the 50% reported in Japan. This difference in presentation is reflected in 5-year overall survival, which is about 20% in North America and 40%-60% in Japan. Despite numerous efforts of randomized studies on advanced gastric cancer, no globally accepted standard regimen has yet been established. Systemic chemotherapy provides palliation and prolongs survival, but the prognosis remains poor. Several monotherapies and combined regimens are currently available and vary around the world. Additionally, several molecular targeting agents are under evaluation in international randomized studies. Human epidermal growth factor receptor-2 (HER-2) is overexpressed or amplified in approximately 22% of patients with gastric cancer. Trastuzumab, a recombinant humanized anti-HER-2 monoclonal antibody, is the first biological therapy that has showed a survival improvement by nearly three months (reduced risk of death by 26%). Therefore, trastuzumab in combination with cisplatin is a reasonable treatment option for patients with advanced gastric cancer who are HER-2 positive. This paper will focus on trastuzumab, its chemical and pharmacological characteristics, and the relevant efficacy, safety, and tolerability studies.
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