Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors
| Autor: | Anthony Polverino, Chaan Ng, Marilyn Mulay, Michael Bass, Robert S. Benjamin, Razelle Kurzrock, Roy S. Herbst, Andy Van Vugt, Michelle Purdom, Antonis Koutsoukos, Jeffrey M. Silverman, Lee S. Rosen, Jeffrey S. Wiezorek, Ren Y. Xu, David D. Chang, Yu Nien Sun |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male Niacinamide Vascular Endothelial Growth Factor A Cancer Research Indoles Maximum Tolerated Dose Nausea Oligonucleotides Antineoplastic Agents Pharmacology chemistry.chemical_compound Growth factor receptor Pharmacokinetics Neoplasms Motesanib Humans Medicine Adverse effect Protein Kinase Inhibitors Aged Aged 80 and over business.industry Middle Aged Bioavailability Vascular endothelial growth factor Treatment Outcome Oncology chemistry Area Under Curve Pharmacodynamics Hypertension Female medicine.symptom business |
| Zdroj: | Journal of Clinical Oncology. 25:2369-2376 |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.2006.07.8170 |
| Popis: | Purpose AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. Patients and Methods AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined. Results Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001). Conclusion In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing. |
| Databáze: | OpenAIRE |
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