Dose-dependent inhibition of the EGFR and signalling pathways with the anti-EGFR monoclonal antibody (MAb) EMD 72000 administered every three weeks (q3w). A phase I pharmacokinetic/pharmacodynamic (PK/PD) study to define the optimal biological dose (OBD)

Salazar, R.; Tabernero, J.; Rojo, Federico; Jiménez, E.; Montaner, I.; Casado, Esther; Sala, Gianluca; Tillner, J.; Malik, Rajesh; Baselga, José

doi:10.1200/jco.2004.22.90140.2002

Cited by 14 publications

(6 citation statements)

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“…In phase I testing it was well tolerated with grade 1 or 2 skin toxicity reported in two thirds of the patients [ 42 , 43 ]. It has a half-life of approximately 10 days permitting effective administration once every two or three weeks [ 44 ]. Matuzumab is currently undergoing phase II evaluation in NSCLC [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

Recent advances of novel targeted therapy in non-small cell lung cancer

Katzel

Fanucchi

2009

J Hematol Oncol

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Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced nonsmall cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.

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Section: Introductionmentioning

confidence: 99%

Recent advances of novel targeted therapy in non-small cell lung cancer

Katzel

Fanucchi

2009

J Hematol Oncol

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“…Phase I studies reported that matuzumab was well tolerated at doses between 400 and 1600 mg and demonstrated antitumour activity in oesophagus, ovary, lung and colorectal carcinoma [37]. PD assays in tumour and skin biopsies showed a superior biological effect at doses over 1000 mg, with similar activity comparing different administration schedules [38,39]. Matuzumab PD studies in skin and tumour samples proved a greater biological effect at doses higher than 1000 mg, with similar results in different administration schedules.…”

Section: Monoclonal Antibodies Against Egfr: Cetuximab and Other Antimentioning

confidence: 68%

Pharmacodynamics: biological activity of targeted therapies in clinical trials

et al. 2007

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Anticancer drug discovery and development in cancer are currently undergoing of fast transformation. The selection of a therapeutic and effective dose using conventional cytotoxic agents has been based on the consecution of the maximally tolerated dose. However, this principle does not apply for new targeted therapies, where the definition of the optimal biologic dose (OBD) should be preferred. The definition of OBD might be established based on pharmacokinetic endpoints and, ideally, on pharmacodynamic assays by demonstrating directly the biological effect on the target and its downstream molecules in normal or tumor tissues. Normal tissues, such as peripheral blood mononuclear cells, skin or mucosa, may be excellent surrogates for explore the exposure of a drug and the dynamic target inhibition in vivo. In addition, tumor pharmacodynamic assays may determine the biologic effects of a therapy because tumor cells respond in a different way to targeted drugs than normal tissues, and to identify biomarkers that would permit to predict the individual response. In conclusion, these studies provide demonstration of proof of concept for biological and molecular mechanisms of selected drug, to select the appropriate population to be treated, to help the interpretation of clinical data, to inform the identification of optimal dose and schedule, to evaluate the clinical response and to contribute to take decisions for final approval by authorities.

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“…This study included pharmacodynamic assessment and correlative studies, evidencing that EMD72000 induced a complete inhibition of pEGFR and pMAPK with an increase in p27 in skin biopsies in all patients, whereas pAkt was only inhibited in responding patients. An expanded phase of the prior study has shown dose-dependent inhibition of downstream pathways in surrogate tissues, supporting an optimal biologic dose-seeking approach [57]. A weekly schedule in patients with EGFRexpressing solid tumors has been recently reported, evidencing that headache and fever were dose-limiting, and documenting a RR of 23%, including patients with head and neck, colorectal, and esophageal cancers [58].…”

Section: Emd72000mentioning

confidence: 96%