Abstract
14044 Background: XL647 is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases involved in tumorigenesis, angiogenesis, and metastasis, including EGFR/ErbB1, ErbB2/HER2, VEGFR2/KDR, and EphB4. In a previous Phase I study, the MTD was 350 mg when XL647 was dosed orally for 5 consecutive days every 14 days. Of 41 pts treated, one pt with NSCLC achieved a PR and 14 pts had prolonged stable disease (3.5–14+ months). The purpose of the present study is to determine the MTD of XL647 administered orally on a continuous daily schedule. Methods: Pts are enrolled in successive cohorts to receive XL647 daily for repeated 28 day cycles. PK sampling is performed to determine Cmax, and AUC at each dose level. Plasma samples are analyzed by ELISA for mechanism-of-action related molecules. Eyebrow hair bulbs are being evaluated by IHC to monitor effects of XL647 on signal transduction pathways downstream of EGFR. Tumor response is assessed every 8 weeks by RECIST. Pts remain on study until PD or unacceptable AEs. Results: Twelve pts have been enrolled. The starting dose was 75 mg (n=3) and has been escalated to150 mg (n=3), 200 mg (n=3) and 300 mg (n=3). To date, dose escalation continues as no DLTs have occurred and the MTD has not been determined. Ten pts remain on study, including 4 with stable disease for at least 3 months. In cohort 2, eyebrow samples from 3 pts were analyzed. XL647 caused a significant reduction in the phosphorylation of the EGFR downstream signaling kinases AKT (up to 73%) and ERK (up to 78%) in 2/3 and 3/3 pts, respectively. Preliminary analysis of potential plasma protein biomarkers from pts in cohorts 1 and 2 showed a trend towards upregulation of PlGF plasma levels in 4/6 pts during XL647 treatment. Conclusions: XL647 is well-tolerated when administered daily at doses tested to date. Dose escalation will continue until the MTD is defined. Analysis of eyebrow samples demonstrated its feasibility as a potential surrogate epidermal tissue for assessing inhibition of EGFR downstream targets by XL647. Updated safety, PK and pharmacodynamic results will be presented. [Table: see text]
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