A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases
| Autor: | Jordi Andreu, Shefali Agarwal, Maria Herranz, May Han, Marc Credi, Wei Yin, Maria Elena Elez, James Gifford, Philip Komarnitsky, Isabel Rico, Jose Mateos, Josep Tabernero, Ludmila Prudkin, José Baselga, M. J. Carreras |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Liver tumor Metabolic Clearance Rate Peripheral edema Pain Pharmacology Gastroenterology Drug Administration Schedule Pharmacokinetics Internal medicine Pancreatic cancer Ficlatuzumab Neoplasms medicine Edema Humans Aged Dose-Response Relationship Drug business.industry Hepatocyte Growth Factor Liver Diseases Liver Neoplasms Cancer Antibodies Monoclonal Middle Aged Proto-Oncogene Proteins c-met medicine.disease Treatment Outcome Oncology Tolerability Cough Pharmacodynamics Area Under Curve Asthenia Female medicine.symptom business Signal Transduction |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 20(10) |
| ISSN: | 1557-3265 |
| Popis: | Purpose: This study evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of ficlatuzumab, a humanized hepatocyte growth factor (HGF) inhibitory monoclonal antibody, as monotherapy in patients with advanced solid tumors and liver metastases. Patients and Methods: Patients with p-Met (phosphorylated c-Met)–positive tumors enrolled in three dose-escalation cohorts, receiving ficlatuzumab 2, 10, or 20 mg/kg once per 14-day cycle. Pharmacodynamic changes in liver tumor biopsies and serum, pharmacokinetics, safety, and clinical activity were assessed. Results: No dose-limiting toxicities occurred in the 19 patients enrolled (n = 6, 2 mg/kg; n = 7, 10 mg/kg; n = 6, 20 mg/kg). The most frequent diagnosis was colorectal cancer (n = 15; 79%). The most common treatment-emergent adverse events were asthenia, peripheral edema, hepatic pain (32% each), and cough (26%). Laboratory abnormalities of decreased serum albumin were present in all patients. Ficlatuzumab at 20 mg/kg lowered median levels of tumor p-Met (−53%), p-ERK (−43%), p-Akt (−2%), and increased median HGF levels (+33%), at the last on-study time point relative to baseline. Mean serum HGF levels increased with ficlatuzumab dose and number of treatment cycles. Ficlatuzumab exhibited linear pharmacokinetics and long terminal half-life (7.4–10 days). Best overall response was stable disease in 28% of patients, including 1 patient with pancreatic cancer with stable disease >1 year. Conclusions: Ficlatuzumab exhibited good safety/tolerability and demonstrated ability to modulate the HGF/c-Met pathway and downstream signaling in the tumor in patients with advanced solid tumors. Safety, pharmacodynamic, and pharmacokinetic data for ficlatuzumab confirmed the recommended phase II dose of 20 mg/kg once per 14-day cycle. Clin Cancer Res; 20(10); 2793–804. ©2014 AACR. |
| Databáze: | OpenAIRE |
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