A Phase I dose-escalation study of the safety, pharmacokinetics (PK) and pharmacodynamics of XL880, a VEGFR and MET kinase inhibitor, administered daily to patients (pts) with advanced malignancies

B248 Background: XL880 is a potent orally available small molecule inhibitor of MET and VEGFR2/KDR, that also inhibits PDGFR, KIT, FLT3, and Tie-2. Significant tumor growth inhibition was observed preclinically following XL880 treatment in multiple tumor models. In a previous phase 1 study (XL880 dosed on days 1-5 every 14 days) anti-tumor activity was observed. This study evaluates daily oral administration of XL880, with results reported for a range of mechanism-related biomarkers. Methods: This is a Phase 1 cohort dose escalation study. Pts with advanced malignancies are administered XL880 daily. Safety, tolerability, pharmacodynamics and pharmacokinetics are evaluated. Dose limiting toxicities (DLTs) occurring in the first 28 days of treatment are used to determine the maximum tolerated dose (MTD). Response is assessed every 8 weeks by RECIST criteria. Plasma samples were analyzed for XL880 and for pharmacodynamic biomarkers that have been shown in clinical and/or pre-clinical studies to be modulated in response to treatment with anti-angiogenic agents. Results: A total of 24 pts have been treated across 4 dose levels (60-120 mg/day) in the following order: 60 (6 pts), 80 (3 pts), 120 (3 pts), 100 (3 pts) and 80 (9 pts) mg/day. Reported DLTs were hypertension and dehydration at 120mg/day, diarrhea at 100 mg/day, and fatigue at 80 mg/day. The MTD was considered to be 80 mg/day though some pts treated more than 28 days required either dose reduction or delay. Ten pts have had stable disease, 9 for ≥3 months and 1 for ≥ 8 months. The safety profile is consistent with that seen in the prior phase 1: the AEs (≥ 10%) considered related to XL880 were hypertension, fatigue, gastrointestinal events (diarrhea, nausea, and vomiting), anorexia, and laboratory abnormalities (ALT, LDH increased, and blood in urine). All these events were of CTCAE Grade 1-2. A preliminary PK analysis indicates a mean Cmax of 26.7 ng/ml and mean AUC of 362 hr*ng/ml for the 80 mg/day cohort on Day 1. AUC generally increased with increasing dose, although high interpatient variability was observed. XL880 accumulated approximately 3- to 5-fold with repeated daily dosing across all cohorts (60 - 120 mg/day). Preliminary pharmacodynamic analysis of plasma samples demonstrated a statistically significant increase in levels of PlGF, as well as increased levels of VEGF-A after administration of XL880. A statistically significant reduction in sVEGFR2, and reduced levels of Ang2 were also observed. In addition, a trend toward increased levels of the potential mechanism-of-action-related biomarker sMET was detected. Conclusions: XL880 was generally well tolerated at 80 mg/day dosed for 28 days (protocol-defined MTD). The safety profile observed is similar to that seen with intermittent dosing. Exposure to XL880 generally increased with increasing dose, and XL880 accumulated in plasma with repeated daily dosing. Changes in anti-angiogenic pharmacodynamic markers, in addition to the observed hypertension, indicate anti-VEGFR activity of XL880 in patients. Increased plasma levels of sMET suggest that XL880 is also inhibiting MET in patients. The observed tumor shrinkage or prolonged SD (> 3months) in patients with various cancers indicate that XL880 may have antitumor activity.