A Phase 2 study of the dual MET/VEGFR2 inhibitor XL880 in patients (pts) with papillary renal carcinoma (PRC).

B249 Background: XL880 is a potent, orally available small molecule inhibitor of MET and VEGFR2/KDR. Activating mutations or amplifications in MET have been described in pts with PRC. In a phase 1 study, XL880 dosed intermittently was generally well tolerated and resulted in partial responses (PR) in 3 of 4 PRC pts enrolled, of which two are durable after 25 and 12+ months respectively. Methods: This is a Phase 2 study enrolling pts diagnosed with PRC with MET status (presence or absence of activating mutation) characterized in the germ line (all) and tumor (where possible). Pts with PRC, adequate organ function and ECOG 0-2, receive XL880 at 240 mg/day on Days 1-5 of 14 day treatment cycles. Response is assessed every 8 weeks by RECIST criteria. Optional tumor biopsies are analyzed by immunohistochemistry (IHC) for XL880 effects on drug targets and downstream readouts. Plasma markers reflecting effects of anti-angiogenic therapy such as VEGF-A, sVEGFR2 and Ang2 are analyzed. Results: Preliminary data are reviewed for 19 pts (17 germ line MET wildtype, 2 with a germ line MET mutation). Of 18 evaluable pts, 14 had decreases in tumor size at the first 8-week evaluation (range 1-25%). Fifteen pts (12 still active) have had stable disease (11 for ≥ 3 months, 3 for ≥ 6 months and 1 still active at 12 months). As of 8-August-07, 1 pt showed uPR (unconfirmed PR). Safety data (cut-off 1-June-07) show the following AEs considered related to XL880, and reported in at least 2 pts: hypertension (6 pts, 38%) and diarrhea, dizziness, fatigue, and headache (each in 2 pts, 13%). There were no related AEs of CTCAE Grade 4 and 5. A preliminary pharmacokinetic analysis indicated that mean pre-dose (ie, approximate trough) concentrations of XL880 relative to the 5th day of the first 14 day cycle (ie, 105 ng/mL) were generally consistent with values seen in at the MTD in Phase 1 (ie, 132 ng/mL), and Day 5 pre-dose concentrations appeared generally unchanged from cycle to cycle. IHC analysis comparing baseline and post-dose biopsies demonstrated a marked increase in apoptosis and a decrease in proliferation in lymph node metastases from a pt with sporadic PRC with wildtype MET. In the majority of pts analyzed, administration of XL880 resulted in statistically significant changes in plasma levels of PlGF, VEGF-A, sVEGFR2, and EPO: pharmacodynamic biomarkers which have been shown to be modulated in response to treatment with anti-angiogenic agents. A trend toward reduced Ang2 levels after XL880 treatment was also observed. These findings indicate potential pharmacodynamic inhibition of VEGF signaling by XL880, and are consistent with the observation of hypertension in some patients. In addition, the potential mechanism-of-action-related biomarker sMET was increased in a statistically significant manner. Conclusions: In pts with PRC, XL880 demonstrated antitumor activity. The majority of the pts experienced prolonged stable disease (including tumor shrinkage). One pt had SD for 5 months and showed uPR at Week-23 CT evaluation. XL880 was generally well tolerated in this pt population. PlGF, VEGF-A, sVEGFR2, EPO, Ang2, and sMET may be promising pharmacodynamic markers to monitor the biological activity of XL880.