A phase II study of two dosing regimens of GSK 1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in patients (pts) with papillar...

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Author(s): R. Srinivasan, W. M. Linehan, U. Vaishampayan, T. Logan, S. M. Shankar, L. J. Sherman, Y. Liu, T. K. Choueiri; National Cancer Institute, Bethesda, MD; Karmanos Cancer Institute, Wayne State University, Detroit, MI; Indiana University School of Medicine, Indianapolis, IN; GlaxoSmithKline, Collegeville, PA; Dana-Farber Cancer Institute, Boston, MA
Background: GSK089 is a potent, orally available small molecule inhibitor of MET and VEGFR2. Activating mutations and/or amplifications in MET have been described in pts with PRC. Two of 4 PRC pts treated with intermittent dosing of GSK089 on a Phase I study sustained partial responses (PR) for 1 and > 3 years respectively. The aim of the current study is to evaluate the efficacy, safety and tolerability of 2 dosing regimens of GSK089 as a single agent in pts with advanced sporadic PRC (SPRC) or hereditary PRC (HPRC).
Methods: Adults with advanced PRC are enrolled in 2 cohorts with different dosing schedules of GSK089: cohort 1) 240 mg/day on days 1-5 of every 14 days (5-on/9-off); cohort 2) 80 mg daily. Pts are stratified based on status of MET-pathway activation (activating MET mutation, MET [7q31] amplification, or trisomy 7). The primary endpoint is RECIST response rate, assessed every 8 weeks. Plasma markers reflecting potential effects of MET inhibition and anti-VEGF therapy are analyzed.
Results: As of December 15, 2008, 37 pts were enrolled in the 5-on/9-off cohort (19 with MET activation including 5 HPRC, 18 SPRC without MET activation or unknown MET status), and 16 pts in the daily dosing cohort (2 with HPRC, 14 SPRC with unknown MET status). Enrollment is ongoing in cohort 2. In cohort 1, of the 35 evaluable pts, 4 pts (2 HPRC and 2 SPRC) had confirmed PRs and 27 had stable disease (SD) as best response with 6 ?12mo, 3 ? 9mo and 3 ? 6mo. Four of 5 HPRC pts (1 not evaluated) had shrinkage (15-53%) in all measurable tumors. Twenty-three SPRC pts had shrinkage (2-58%) in the sum of measurable tumors. In cohort 2, of the 9 evaluable pts, 2 (both SPRC) had confirmed PRs, and 7 had SD. The most frequent adverse events (AEs) associated with GSK089 were fatigue, hypertension, nausea, vomiting, diarrhea, and increased ALT/AST, primarily grades 1 and 2. Preliminary results from cohort 1 indicated that plasma shed Met (sMET) and VEGF increased and sVEGFR2 decreased after 2 cycles with changes maintained after 4 cycles.
Conclusions: GSK089 is well tolerated and demonstrates anti-tumor activity in pts with PRC with both 5-on/9-off and daily dosing. VEGF, sVEGFR2, and sMET are promising pharmacodynamic markers for biological activity of GSK089.