A pharmacodynamic/pharmacokinetic study of ficlatuzumab in patients with advanced solid tumors and liver metastases.

Autor:	Tabernero J; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York jtabernero@vhio.net., Elez ME; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Herranz M; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Rico I; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Prudkin L; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Andreu J; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Mateos J; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Carreras MJ; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Han M; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Gifford J; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Credi M; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Yin W; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Agarwal S; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Komarnitsky P; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York., Baselga J; Authors' Affiliations: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona; CRC Hospital Quirón de Barcelona, Barcelona, Spain; AVEO Oncology, Cambridge, Massachusetts; and Memorial Sloan-Kettering Cancer Center, New York, New York.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2014 May 15; Vol. 20 (10), pp. 2793-804. Date of Electronic Publication: 2014 Mar 14.
DOI:	10.1158/1078-0432.CCR-13-1837
Abstrakt:	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. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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