A phase I study of MK-0646, a humanized monoclonal antibody against the insulin-like growth factor receptor type 1 (IGF1R) in advanced solid tumor patients in a q2 wk schedule

Hidalgo, María Jesús Cancelo; Gómez, Miquel; Lewis, Nancy; Vuky, Jacqueline; Taylor, Grant; Hayburn, J. L.; Hsu, Karl; Kosh, Michele; Picozzi, Vincent J.

doi:10.1200/jco.2008.26.15_suppl.3520

Cited by 44 publications

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“…When it occurred in the present study, it was adequately controlled by oral antihyperglycemic agents and did not interfere with dalotuzumab dosing. Thrombocytopenia has also been reported (as a DLT) in a prior study of dalotuzumab (28) and also in a study of the anti-IGF-1R antibody AMG-479 (16). None was observed in the present study.…”

Section: Discussionsupporting

confidence: 83%

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

Atzori

Tabernero

Cervantes

et al. 2011

Clinical Cancer Research

110

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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 mg/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.

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Section: Discussionsupporting

confidence: 83%

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

Atzori

Tabernero

Cervantes

et al. 2011

Clinical Cancer Research

110

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“…In the case of the IgG1 antibody MK-0646 (Merck), pre-and post-tumor biopsies were collected and used to show tumor downregulation of key pathway components such as IGF-1R, pAKT, pERK, and pS6 (45). One notable clinical differentiation point among the molecules is that antibodies with the IgG1 backbone have been reported to have potentially greater severity of hematological toxicities than IgG2 antibodies, because dose limiting toxicities (DLT) of grade 3 and 4 thrombocytopenia have been described for AMG-479 and MK-0646 in several studies (42,45,46). An alternate explanation is that these antibodies may bind to different epitopes, thus contributing to different potency and toxicity.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Targeting the Insulin-like Growth Factor Receptor-1R Pathway for Cancer Therapy

Zha¹,

Lackner²

2010

Clinical Cancer Research

128

111

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Signaling through the insulin-like growth factor receptor (IGF-1R) is required for neoplastic transformation by a number of oncogenes, and preclinical validation studies have suggested IGF-1R is an attractive target for anticancer therapy. A number of small molecules and antibodies targeting IGF-1R have entered clinical development, and early results have suggested that these agents have generally acceptable safety profiles as single agents. Some evidence of antitumor activity has also been reported. This review highlights key aspects of the IGF-1R signaling pathway that implicate it as an attractive therapeutic target in the management of cancer, as well as some key lessons that have emerged from early clinical development of anti-IGF-1R targeting agents. In addition, we consider the importance of selecting indications characterized by pathological alterations in the signaling pathway, rational selection of combinations based on signaling pathway interactions, and strategies for patient selection based on analysis of predictive biomarkers. Clin Cancer Res; 16(9); 2512-7. ©2010 AACR.

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“…En cuanto a la toxicidad, se pudieron analizar en ese momento los datos de 178 pacientes, comunicándose una toxicidad grado 3-4 de hiperglucemia (11% vs 4%), astenia (9% vs 7%) y neutropenia (14% vs 14%) como toxicidades más reseñables 32 . Otros anticuerpos de distintas compañías farmacéuticas que están siendo estudiados actúan contra el IGFR1 con un perfil de tolerancia similar al CP-751871 [33][34][35][36][37] . Se ha detectado en estos estudios clínicos la presencia de un aumento de IGF1 y hormona del crecimiento circulante que era previsible, así como una hiperglicemia 31,38,39 .…”

Section: Bloquear Al Receptor Extracelularmenteunclassified

Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology

Bosch-Barrera

Hernández

Abella

2010

An Sist Sanit Navar

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revisiones0La vía de la insulina y el factor de crecimiento similar a la insulina, una nueva diana terapéutica en oncología Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology J. Bosch-Barrera, A. Hernández, L.e. Abella resUMen La biología molecular del cáncer ha permitido identificar nuevas dianas para atacar las células tumorales. Recientemente se ha propuesto la vía de señalización de la insulina y el factor de crecimiento similar a la insulina como una de estas dianas. En esta revisión se describe su función biológica, los datos de laboratorio y estudios poblacionales que alertan de su papel en el cáncer y se describen los elementos claves de esta vía de señalización: los ligandos (insulina, IGF1, IGF2), sus receptores y la cascada de señales intracelular que desencadena su activación. Así mismo se revisan las distintas estrategias que se están investigando para bloquearla, algunas de las cuales ya se encuentran en estudios avanzados fase III. Los datos preliminares indican que los fármacos diseñados para bloquear esta vía pueden ser una nueva arma terapéutica para los pacientes oncológicos en un futuro próximo.Palabras clave. Factor de crecimiento similar a la insulina I. Factor de crecimiento similar a la insulina II. Receptor de la insulina. Receptores relacionados con el receptor de la insulina. ABsTrACTThe molecular biology of cancer has made it possible to identify new targets for attacking tumourous cells. One of these recently proposed targets is the insulin and insulin-like growth factor signaling pathway. This review describes its biological function, laboratory data, population studies that warn of its role in cancer, and the key elements of this signaling pathway: the ligands (insulin, IGF1, IGF2), its receptors and the cascade of intracellular signals that trigger its activation. Also reviewed are the different strategies under investigation for blocking it, some of which are already in phase III advanced studies. The preliminary data indicate that the medicines designed for blocking this pathway might be a new therapeutic weapon for oncology patients in the near future.

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A phase I study of MK-0646, a humanized monoclonal antibody against the insulin-like growth factor receptor type 1 (IGF1R) in advanced solid tumor patients in a q2 wk schedule

Cited by 44 publications

References 0 publications

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

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

Targeting the Insulin-like Growth Factor Receptor-1R Pathway for Cancer Therapy

Insulin and insulin-like growth factor pathway, a new targeted therapy in oncology

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