Francesco Atzori 1 , Josep Tabernero , Andrés Cervantes , Ludmila Prudkin , Jordi Andreu , Edith Rodríguez-Braun , Amparo Domingo , Jorge Guijarro , Cristina Gamez , Jordi Rodon , Serena Di Cosimo , Holly Brown , Jason Clark , James S Hardwick , Robert A Beckman , William D Hanley , Karl Hsu , Emiliano Calvo , Susana Roselló , Ronald B Langdon , José Baselga Show Affiliations »
Abstract
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 C(min) 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. (18)F-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. ©2011 AACR
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 C(min) 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. (18)F-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. ©2011 AACR
Entities: Chemical
Disease
Gene
Species
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Year: 2011
PMID： 21810918 DOI： 10.1158/1078-0432.CCR-10-3336
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531