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
| Autor: | E. Rodríguez-Braun, Karl Hsu, James S. Hardwick, Jordi Andreu, Jordi Rodon, Ludmila Prudkin, José Baselga, Josep Tabernero, Francesco Atzori, Amparo Soler Domingo, Jorge Guijarro, Robert A. Beckman, Jason Clark, Susana Roselló, Emiliano Calvo, William D. Hanley, Andrés Cervantes, Ronald B. Langdon, Cristina Gamez, Serena Di Cosimo, Holly Brown |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Cancer Research Maximum Tolerated Dose medicine.medical_treatment Antineoplastic Agents Pharmacology Antibodies Monoclonal Humanized Drug Administration Schedule Receptor IGF Type 1 Insulin-like growth factor Pharmacokinetics Neoplasms medicine Humans Aged Aged 80 and over Dose-Response Relationship Drug Dalotuzumab business.industry Cancer Antibodies Monoclonal Middle Aged medicine.disease Oncology Tolerability Pharmacodynamics Monoclonal Toxicity Female business |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(19) |
| ISSN: | 1557-3265 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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