14073 Background: E7080 is a potent inhibitor of the split-kinase family of transmembrane growth factor receptors including Flt-1 and KDR. In addition, E7080 also potently inhibits FGFR1 and PDGFRβ tyrosine kinase activities. In an in vitro angiogenic model, E7080 inhibited VEGF-driven umbilical vein endothelial cell (HUVEC) proliferation and tube formation. Using H460 and Colo205 mouse xenograft models, E7080 significantly inhibited tumor growth at doses from 1 to 100 mg/kg. Methods: A Phase I and pharmacologic study was conducted to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of E7080 in pts with advanced malignancies. Eligible pts with adequate hematologic, renal and hepatic function, and with tumors refractory to standard therapies, were treated with E7080 administered orally on a once daily continuous dose schedule in cycles of 4 weeks. Dose escalation was performed according to an accelerated design of 100% dose increases in subsequent cohorts until the first patient experienced ≥ CTC grade 2 toxicity. Results: As of November 17th, 2006, 37 pts with documented progressive disease (PD) have been treated at the following dose levels: 0.2 mg/d, 0.4 mg/d, 0.8 mg/d, 1.6 mg/d, 3.2 mg/d, 6.4 mg/d, 12.5 mg/d and 16 mg/d. Median number of cycles was 1 (0–11). Median age = 60 years (25–84), 20 pts were male, 17 were female. 37 pts were evaluable for toxicity. 1 patient experienced grade 3 hypertension (DLT) in the 16 mg/d cohort, other related toxicities ≥ grade 2 include hemorrhage and thrombosis (n=1), tachycardia (n=1), febrile neutropenia (n=1), proteinuria (n=1), thrombocytopenia (n=1) and hypertension (n=1). MTD has not been reached and this study is continuing to recruit. 24 pts were evaluable for efficacy, 3 are too early to evaluate. 1 patient had a partial response (high grade sarcoma) after 2 cycles, and 15 pts experienced stable disease from 2+ to 11 months, and 11 pts continue on therapy. Pharmacokinetic (PK) studies: preliminary data suggest that the PK is linear over the range 0.2 mg/d to 12.5 mg/d. Conclusions: E7080 is safe and well tolerated at doses acheived so far and has shown promising first signs of anti-cancer activity associated with potent activity in pre-clinical models. Clinical and PK data from subsequent doses and follow- up will be presented. No significant financial relationships to disclose.
42P Using patient-reported outcomes (PROs) in phase I/II dose-finding oncology trials (DPOT): A global survey