Pharmacokinetic and pharmacodynamic phase I trial of ARQ197 incorporating dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies investigating the antiangiogenic activity of selective c-Met inhibition


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Shahneen Sandhu1, Tim Yap1, Nina Tunariu1, Martyn Lolkema1, Daniel Tan1, Andre Brunetto1, Rebecca Kristeleit1, Salma Alam1, L. Rhoda Molife1, Joyce Kapawa1, Michael Germuska2, Edward Garmey3, Feng Chai3, James Li3, Stan B. Kaye1, Nandita deSouza1, Johann S. de Bono1

1 Royal Marsden NHS Foundation Trust, Sutton, UK, 2The Institute of Cancer Research, Drug Development Unit, Sutton, UK, 3ArQule Inc, Woburn, Massachusetts, USA

Abstract

Background

ARQ 197 is a selective non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumour cell proliferation, invasion and angiogenesis. Preclinical data and declines in circulating endothelial cells (CEC) in patients receiving ARQ197 suggest antiangiogenic potential of c-Met inhibition.

Method

ARQ197 was administered orally twice daily (bd) to patients with advanced solid tumours. Pre and post-therapy tumour biopsies were preformed for c-Met and FAK immunohistochemistry (n=16). CEC enumeration was evaluated in all patients and 12 patients in the dose expansion cohort underwent DCE and Diffusion Weighted (DW) MRI studies.

Results

29 (14 F ;15 M) patients received ARQ197 at doses of 100 (n=3), 200 (n=6), 300 (n=16) and 400 (n=4) mg bd. 3 patients experienced dose limiting toxicities of CTCAEv3 grade (G)3 fatigue (200 mg bd); G3 hand-foot syndrome, G3 mucositis and G3 febrile neutropenia (400 mg bd). The MTD /recommended phase 2 dose (RP2D) of ARQ197 was established at 300mg bd. Other toxicities were G1-2 fatigue (n=5) and gastrointestinal symptoms (n=3). Mean AUC0-12h and Cmax increased linearly through the MTD. Significant post-ARQ197 inhibition of high baseline phosphorylated c-Met and FAK expression in tumour tissue was seen in all dose cohorts confirming target inhibition. Disease stabilization was seen in 11 patients for up to 23 weeks with tumour regressions up to 12.4%. 13/20 patients had post-ARQ197 CEC declines of up to 100%. The preliminary analyses of ktrans histograms of pelvic tumours in the DCE-MRI cohort showed a ktrans median reduction of 20.1% on day 7 of ARQ197 (intrapatient baseline variability: 2.8%) which was sustained (ktrans median decline: 8.3%) on day 56 of ARQ197 suggesting antiangiogenic effects.

Conclusion

ARQ197 is well tolerated with MTD/RP2D of 300mg bd, linear PK and evidence of target inhibition. CEC and preliminary DCE-MRI data suggest antiangiogenic effects of c-Met inhibition with ARQ197.