Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating Proof of Mechanism Pharmacodynamic Studies
In: Journal of clinical oncology, Jg. 29 (2011), Heft 10, S. 1271-1279
Online
academicJournal
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Zugriff:
Purpose The hepatocyte growth factor/c-MET axis is implicated in tumor cell proliferation, survival, and angiogenesis. ARQ 197 is an oral, selective, non―adenosine triphosphate competitive c-MET inhibitor. A phase I trial of ARQ 197 was conducted to assess safety, tolerability, and target inhibition, including intratumoral c-MET signaling, apoptosis, and angiogenesis. Patients and Methods Patients with solid tumors amenable to pharmacokinetic and pharmacodynamic studies using serial biopsies, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and circulating endothelial cell (CEC) and circulating tumor cell (CTC) enumeration were enrolled. Results Fifty-one patients received ARQ 197 at 100 to 400 mg twice per day. ARQ 197 was well tolerated, with the most common toxicities being grade 1 to 2 fatigue, nausea, and vomiting. Dose-limiting toxicities included grade 3 fatigue (200 mg twice per day; n = 1); grade 3 mucositis, palmar-plantar erythrodysesthesia, and hypokalemia (400 mg twice per day; n = 1); and grade 3 to 4 febrile neutropenia (400 mg twice per day, n = 2; 360 mg twice per day, n = 1). The recommended phase II dose was 360 mg twice per day. ARQ 197 systemic exposure was dose dependent and supported twice per day oral dosing. ARQ 197 decreased phosphorylated c-MET, total c-MET, and phosphorylated focal adhesion kinase and increased terminal deoxynucleotidyl transferase―mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) staining in tumor biopsies (n = 15). CECs decreased in 25 (58.1 %) of 43 patients, but no significant changes in DCE-MRI parameters were observed after ARQ 197 treatment. Of 15 patients with detectable CTCs, eight (53.3%) had ≥ 30% decline in CTCs after treatment. Stable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), ≥ 4 months was observed in 14 patients, with minor regressions in gastric and Merkel cell cancers. Conclusion ARQ 197 safely inhibited intratumoral c-MET signaling. Further clinical evaluation focusing on combination approaches, including an erlotinib combination in non―small-cell lung cancer, is ongoing.
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Phase I Trial of a Selective c-MET Inhibitor ARQ 197 Incorporating Proof of Mechanism Pharmacodynamic Studies
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Autor/in / Beteiligte Person: | YAP, Timothy A ; OLMOS, David ; COLLINS, David ; DESOUZA, Nandita M ; LEACH, Martin O ; SAVAGE, Ronald E ; WAGHORNE, Carol ; FENG, CHAI ; GARMEY, Edward ; SCHWARTZ, Brian ; KAYE, Stan B ; DE BONO, Johann S ; BRUNETTO, Andre T ; TUNARIU, Nina ; BARRIUSO, Jorge ; RIISNAES, Ruth ; POPE, Lorna ; CLARK, Jeremy ; FUTREAL, Andrew ; GERMUSKA, Michael |
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Zeitschrift: | Journal of clinical oncology, Jg. 29 (2011), Heft 10, S. 1271-1279 |
Veröffentlichung: | Alexandria, VA: American Society of Clinical Oncology, 2011 |
Medientyp: | academicJournal |
Umfang: | print, 40 ref |
ISSN: | 0732-183X (print) |
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