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Final results of a pharmacokinetic (PK) and pharmacodynamic (PD) phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition

Yap, T. A., Frentzas, S., Tunariu, N., Barriuso, J., Harris, D., Germuska, Michael, Waghorne, C., Li, J., deSouza, N. and de Bono, J. S. 2009. Final results of a pharmacokinetic (PK) and pharmacodynamic (PD) phase I trial of ARQ 197 incorporating dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition. Journal of Clinical Oncology 27 (15) , abstr 3523.

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Abstract

ARQ 197 (ARQ) is a selective non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell proliferation, invasion and angiogenesis. Preclinical data and declines in circulating endothelial cell (CEC) levels in patients (pts) receiving ARQ suggest antiangiogenic potential of c-Met inhibition. Methods: ARQ was administered orally twice daily (bid) to pts with advanced solid tumors. Pre and post-therapy tumor biopsies were mandated for c-Met and FAK immunohistochemical studies during dose escalation (n = 16). CEC enumeration was evaluated. 12 pts are being investigated in the maximum tolerated dose (MTD) expansion cohort with DCE and Diffusion Weighted (DW) MRI. Results: 29 pts (14 F/15 M; mean 54.4 yrs) received ARQ at doses of 100 (n = 3), 200 (n = 6), 300 (n = 16), and 400 (n = 4) mg bid. 3 pts experienced dose limiting toxicities of CTCAEv3 grade (G)3 fatigue (200 mg bid); G3 hand-foot syndrome, G3 mucositis and G3 febrile neutropenia (400 mg bid). This established the ARQ MTD/recommended phase II dose (RP2D) at 300 mg bid. Other toxicities were G1-2, such as fatigue (n = 5); diarrhea, nausea and vomiting (n = 3). Mean AUC0-12h and Cmax increased linearly through the MTD. Statistically significant post-ARQ inhibition of high baseline phosphorylated c-Met and FAK expression in tumor tissue was seen in all dose cohorts confirming target inhibition. Disease stabilization (SD) was seen in 11 pts for up to 23 weeks with tumor regressions up to 12.4%. 13 of 20 pts had post-ARQ CEC declines of up to 100%. In the DCE-MRI cohort to date, preliminary analyses of ktrans histograms from pelvic lesions were consistent with antiangiogenic effects, with a ktrans median reduction of 20.1% on day 7 of ARQ (intrapatient baseline variability: 2.8%). This effect was still present (ktrans median decline: 8.3%) on day 56 of ARQ. Conclusions: ARQ is well tolerated with MTD/RP2D of 300mg bid, linear PK and evidence of phosphorylated c-Met and FAK inhibition. CEC and preliminary DCE-MRI data support the antiangiogenic effects of c-Met inhibition with ARQ. Correlation with other DCE parameters and DW changes will be presented.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Psychology
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher: American Society of Clinical Oncology
Last Modified: 04 Jun 2017 06:51
URI: http://orca-mwe.cf.ac.uk/id/eprint/65395

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