التفاصيل البيبلوغرافية
العنوان:
Data from A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors
المؤلفون:
José Baselga , Ronald B. Langdon , Susana Roselló , Emiliano Calvo , Karl Hsu , William D. Hanley , Robert A. Beckman , James S. Hardwick , Jason Clark , Holly Brown , Serena Di Cosimo , Jordi Rodon , Cristina Gamez , Jorge Guijarro , Amparo Domingo , Edith Rodríguez-Braun , Jordi Andreu , Ludmila Prudkin , Andrés Cervantes , Josep Tabernero , Francesco Atzori
بيانات النشر:
American Association for Cancer Research (AACR), 2023.
سنة النشر:
2023
الوصف:
Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose.Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses.Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively.Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.
URL الوصول:
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::03a62cead42815eb5e608a90e67e3afb https://doi.org/10.1158/1078-0432.c.6520260
حقوق:
OPEN
رقم الأكسشن:
edsair.doi.dedup.....03a62cead42815eb5e608a90e67e3afb
قاعدة البيانات:
OpenAIRE
