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• W4254238051 abstract "2002 Background: EMD 72000, an IgG1 humanized anti-EGFR MAb, has a prolonged half life and we showed that 1200q3w has favorable PK profile when compared to more frequent schedules (Tabernero et al, Proc ASCO 2003, abst 770). To define the OBD of q3w EMD 72000, we have now studied additional dose levels: 400, 800 and 1600 mg. Methods: Skin and tumor biopsies were performed at - 24 hrs and + 43 days of treatment. pEGFR, pMAPK, Ki67 and p27 were done by immunohistochemistry. Results: 51 patients (p) with EGFR+ tumors were treated, including the 1200 mg cohorts (also q1w and q2w). Patient characteristics, median (range): Karnofsky 90% (80%–100%), age 59 (43–79), and prior chemotherapy 3 (1–11). To date, 22 paired skin samples have been analyzed. Data on 1600 mg are not yet available. EMD 72000 induced decreases in Ki67, pMAPK, pEGFR and an increase in p27. The two best discriminating markers were pEGFR and pMAPK with a dose-dependent incremental inhibition and near complete signaling suppression at the 1200 mg dose level (Table). Data is reported as mean inhibition from baseline and as number of p with complete inhibition (<5% residual positivity). Grade 1 and 2 skin toxicity was observed in 43% and 35% of p, respectively. Skin toxicity was lower in the 400 mg. Drug troughs at 800-1200 mg q3w were 4–10 times higher than preclinical active levels. Activity: 3 PRs, 4 prolonged SD out of 39 evaluable p with colon cancer. Conclusions: This PD skin study with EMD 72000 shows a dose response effect on EGFR pathway inhibition. The dose level with suboptimal receptor inhibition also resulted in lower skin rash. Our findings suggest that the OBD will be close to 1200 mg q3w and supports a surrogate marker approach to OBD identification with anti-EGFR agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck Merck KGaA" @default.
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• W4254238051 date "2004-07-15" @default.
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• W4254238051 title "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)" @default.
• W4254238051 doi "https://doi.org/10.1200/jco.2004.22.90140.2002" @default.
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