Phase I trial to determine the dose range for the c-Met inhibitor ARQ 197 that inhibits c-Met and FAK phosphorylation, when administered by an oral twice-a-day schedule

Yap, Tami; Harris, David C.H.; Barriuso, Jorge; Wright, M.; Riisnaes, Ruth; Clark, Jonathan; Ledaki, Ioanna; Savage, Ronald E.; Chen, T.; Bono, Johann S. de

doi:10.1200/jco.2008.26.15_suppl.3584

Cited by 21 publications

(10 citation statements)

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“…Two phase I trials of ARQ197 have been performed. One trial showed disease stabilization in 7 of 11 patients, with prolonged stabilization for [32 weeks in 5 tumor types, including gastric cancer [91]. Another trial of 36 patients reported that 5.5% achieved a PR, and 53% had SD [92].…”

Section: C-met Tyrosine Kinase Inhibitorsmentioning

confidence: 98%

Molecular targeted agents for gastric and gastroesophageal junction cancer

Oshima

Masuda

2011

Surg Today

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Despite recent improvements in surgical techniques and chemotherapy, advanced cancers of the stomach and gastroesophageal junction (GEJ) continue to have poor clinical outcomes. However, molecules intimately related to cancer cell proliferation, invasion, and metastasis have been studied as candidates for molecular targeted agents. Target molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways are considered to be promising candidates for molecular targeted therapy for gastric and GEJ cancer. In this review we focus on the recent developments in targeting relevant pathways in these types of cancer.

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Section: C-met Tyrosine Kinase Inhibitorsmentioning

confidence: 98%

Molecular targeted agents for gastric and gastroesophageal junction cancer

Oshima

Masuda

2011

Surg Today

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“…For example, in phase I and II studies, administration of XL880, an orally available small-molecule inhibitor of c-Met and vascular endothelial growth factor receptor 2, has been associated with mild to moderate hypertension, nausea, anorexia, vomiting, fatigue, and liver function abnormalities (27)(28)(29)(30). Treatment with ARQ 197, a selective, non-ATP-competitive smallmolecule inhibitor of c-Met, has been associated with fatigue, nausea, vomiting, diarrhea, and anorexia (30,31), and treatment with XL184, a small-molecule inhibitor of c-Met, vascular endothelial growth factor receptor 2, Kit, Ret, Flt3, and Tie-2, has been associated with palmar/plantar erythema, mucositis, elevations of alanine aminotransferase and lipase, diarrhea, and hypopigmentation of the hair (32). Fatigue, nausea, vomiting, and anorexia were also observed during AMG 102 administration; however, hypertension and significant liver enzyme abnormalities were not observed.…”

Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, and Pharmacodynamics of AMG 102, a Fully Human Hepatocyte Growth Factor–Neutralizing Monoclonal Antibody, in a First-in-Human Study of Patients with Advanced Solid Tumors

Gordon

Sweeney

Mendelson

et al. 2010

Clinical Cancer Research

150

137

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Purpose: The aims were to assess the safety, pharmacokinetics, maximum tolerated dose, and antitumor activity of AMG 102, a fully human hepatocyte growth factor/scatter factor (HGF/SF)-neutralizing monoclonal antibody, in patients with solid tumors.Experimental Design: Patients (N = 40) with refractory advanced solid tumors were enrolled into six sequential dose-escalation cohorts (0.5, 1, 3, 5, 10, or 20 mg/kg AMG 102 i.v. every 2 weeks) and a doseexpansion cohort (20 mg/kg AMG 102 every 2 weeks). Safety, anti-AMG 102 antibody formation, pharmacokinetics, tumor response, and exploratory biomarkers were assessed.Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia (5%), myalgia (5%), and hypertension (5%). Two patients experienced dose-limiting toxicities: one patient (0.5 mg/kg cohort) experienced grade 3 hypoxia and grade 3 dyspnea and one patient (1 mg/kg cohort) experienced grade 3 upper gastrointestinal hemorrhage. No anti-AMG 102 antibodies were detected, and AMG 102 had linear pharmacokinetics within the dose range investigated. Sixteen of 23 (70%) evaluable patients had a best response of stable disease with progression-free survival ranging from 7.9 to 40 weeks. Circulating levels of the biomarker HGF/SF (bound and unbound) increased in a dose-dependent manner, whereas soluble c-Met concentrations were generally similar across doses.Conclusions: AMG 102 is safe and well tolerated, has a favorable pharmacokinetic profile, and will be further investigated as a monotherapy and in combination with other agents.

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“…Of 33 evaluable patients, 2 achieved a partial response and 19 reported stable disease. Another Phase I trial examining the pharmacodynamics of ARQ197 in patients with advanced, safely biopsiable, solid tumors reported 1 DLT (grade 3 fatigue) in 14 patients treated to date (60). Inhibition of c-Met phosphorylation was observed.…”

Section: Small-moleculetyrosine Kinase Inhibitorsmentioning

confidence: 99%

Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer

Eder

Woude

Boerner

et al. 2009

Clinical Cancer Research

477

410

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A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas of the breast, liver, lung, ovary, kidney, and thyroid. Notably, activating mutations in c-Met have been positively identified in patients with a particular hereditary form of papillary renal cancer, directly implicating c-Met in human tumorigenesis. Aberrant signaling of the c-Met signaling pathway due to dysregulation of the c-Met receptor or overexpression of its ligand, hepatocyte growth factor (HGF), has been associated with an aggressive phenotype. Extensive evidence that c-Met signaling is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated considerable interest in c-Met and HGF as major targets in cancer drug development.This has led to the development of a variety of c-Met pathway antagonists with potential clinical applications. The three main approaches of pathway-selective anticancer drug development have included antagonism of ligand/receptor interaction, inhibition of the tyrosine kinase catalytic activity, and blockade of the receptor/effector interaction. Several c-Met antagonists are now under clinical investigation. Preliminary clinical results of several of these agents, including both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have been encouraging. Several multitargeted therapies have also been under investigation in the clinic and have demonstrated promise, particularly with regard to tyrosine kinase inhibition.

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Phase I trial to determine the dose range for the c-Met inhibitor ARQ 197 that inhibits c-Met and FAK phosphorylation, when administered by an oral twice-a-day schedule

Cited by 21 publications

References 0 publications

Molecular targeted agents for gastric and gastroesophageal junction cancer

Molecular targeted agents for gastric and gastroesophageal junction cancer

Safety, Pharmacokinetics, and Pharmacodynamics of AMG 102, a Fully Human Hepatocyte Growth Factor–Neutralizing Monoclonal Antibody, in a First-in-Human Study of Patients with Advanced Solid Tumors

Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer

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