Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor

Vanhoefer, U.; Tewes, Mitra; Rojo, Federico; Dirsch, Olaf; Schleucher, N.; Rosen, Oliver; Tillner, J.; Kovar, Andreas; Braun, Ada; Trarbach, Tanja; Seeber, S.; Harstrick, A.; Baselga, José

doi:10.1200/jco.2004.05.114

Cited by 243 publications

(111 citation statements)

References 31 publications

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“…Cutaneous toxicities, commonly defined as rash, acne, pruritus and dry skin, have been reported as one of the predominant side effects in cancer patients treated with small-molecule tyrosine kinase inhibitors (TKI) of EGFR (gefitinib, erlotinib), dual EGFR/HER2 (lapatinib) inhibitors, pan-HER (CI-1033) inhibitors and anti-EGFR antibodies (cetuximab, ABX-EGF and EMD72000) (Busam et al, 2001;Hidalgo et al, 2001;Shin et al, 2001;Fukuoka et al, 2003;Kris et al, 2003;Burris, 2004;Rowinsky et al, 2004;Vanhoefer et al, 2004).…”

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confidence: 99%

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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Skin toxicity, a common drug-related adverse event observed in cancer patients treated with epidermal growth factor receptor (EGFR)-directed therapies is rarely seen with therapies targeting HER2. This study reports the significance of the EGFR and HER2 dimerization status in skin with regard to these dermatologic side effects. We demonstrate the differential effect of HER-directed therapies on the ligand driven activation status of EGFR, HER2 and MAPK in normal human epidermal keratinocytes. EGFR-directed therapies, such as gefitinib and cetuximab, inhibited ligand-induced activation of EGFR and MAPK in human keratinocytes. Pertuzumab, an antibody interfering with functional HER2 heterodimerization, failed to block ligand-induced HER signaling in primary keratinocytes. Using a novel proximity-based dimerization assay (eTagt) we show that EGFR homodimers are the predominant HER dimer pair in normal primary kertinocytes and in normal skin tissue from 16 patients with solid malignancies. The presence of [p]EGFR and [p]MAPK, but the absence of [p]HER2, demonstrates productive signaling via EGFR but not HER2 in human skin. These data illustrate the importance of the EGFR dimerization partner in human skin and suggests that inhibition of EGFR homodimer signaling rather than EGFR/HER2 heterodimer signaling maybe the key molecular event determining dermatologic toxicity discrepancies observed between EGFR-targeted versus HER2-targeted therapies.

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confidence: 99%

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Laux

Jain

Singh³

et al. 2005

Br J Cancer

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“…Matuzumab was administered to three patients in each dose group in an escalating, sequential manner in combination with a fixed dose of gemcitabine (1000 mg m -2 once weekly for 3 weeks, followed by a 1-week rest). Three matuzumab dose levels were planned on the basis of the prior studies (Vanhoefer et al, 2004): group I, 400 mg once weekly; group II, 800 mg every 2 weeks; and group III, 800 mg once weekly. If a DLT was observed in one of the three patients at one dose level, an additional three patients were enrolled at this dose level.…”

Section: Study Design and Treatmentmentioning

confidence: 99%

“…A phase I clinical trial with matuzumab demonstrated that it is well tolerated as a single agent at doses between 400 and 1600 mg administered weekly, biweekly, or every 3 weeks (Vanhoefer et al, 2004). Dose-limiting toxicities (DLTs) occurred at 2000 mg on a weekly schedule and consisted of grade 3 headache and fever.…”

mentioning

confidence: 99%

“…Dose-limiting toxicities (DLTs) occurred at 2000 mg on a weekly schedule and consisted of grade 3 headache and fever. Skin reactions, common with anti-EGFR agents (Thomas and Grandis, 2004), did occur with matuzumab, but results to date suggest that they are less severe than with other anti-EGFR agents and are restricted to grade 1 and 2 severity (Kollmannsberger et al, 2003;Salazar et al, 2004;Vanhoefer et al, 2004). Pharmacokinetic (PK) and pharmacodynamic (PD) results of the phase I study showed that matuzumab has predictable PKs at clinically relevant doses and that treatment with matuzumab blocks growth factor signalling through EGFR with a weekly dose of 800 mg as effectively as with doses of 1200 or 1600 mg.…”

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confidence: 99%

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Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer

et al. 2006

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The humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody matuzumab (formerly EMD 72000) is active against pancreatic cancer in preclinical studies. This phase I study assessed the safety and potential benefit of combined treatment with matuzumab and standard-dose gemcitabine. Three groups of chemotherapy-naive advanced pancreatic adenocarcinoma patients (n ¼ 17) received escalating doses of matuzumab (400 mg weekly, 800 mg biweekly, or 800 mg weekly) and gemcitabine (1000 mg m -2 weekly in weeks 1 -3 of each 4-week cycle). Toxicity, antitumour activity, pharmacokinetic (PK) parameters, and pharmacodynamic (PD) markers in skin biopsies were evaluated. Severe treatment-related toxicities were limited to grade 3 neutropenia (n ¼ 3), leucopenia (n ¼ 1), and decreased white blood cell count (n ¼ 1). Common study drug-related adverse events were skin toxicities (grade 2 ¼ 6, grade 1 ¼ 7) and fever (grade 1 ¼ 4). Matuzumab inhibited phosphorylated EGFR and affected receptor-dependent signalling and transduction; effects were seen even in the lowest-dose group. Pharmacokinetic data were consistent with results of matuzumab monotherapy. Partial response (PR) or stable disease occurred in eight of 12 evaluated patients (66.7%), with three PRs among six evaluated patients in the group receiving 800 mg weekly. Matuzumab in biologically effective doses with standard gemcitabine therapy appears well tolerated. The combination is feasible and may have enhanced activity.

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“…Normal tissue-based PD approaches have already been used with success during the clinical development of anticancer drugs acting on biomarkers present within peripheral blood mononuclear cells (Cohen et al, 2003;Peralba et al, 2003), exfoliated buccal squames (van de Vaart et al, 2000;Adjei et al, 2003) and punch biopsies of the skin (Albanell et al, 2002;Malik et al, 2003;Vanhoefer et al, 2004). The choice of normal tissue for a given drug study is likely to depend on a number of different factors, including the level and variability of expression of the biomarker of interest.…”

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confidence: 99%

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

et al. 2005

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Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n ¼ 10) and multiple (n ¼ 12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter-and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways.

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Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor

Abstract: Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.

Cited by 243 publications

References 31 publications

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development

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