Abstract
14680 Background: TKI258 (dovitinib lactate), is a multi-tyrosine kinase inhibitor of VEGF receptors-1,2,3, FGF receptors-1, 2, 3, PDGFR-β, c-KIT and FLT3. To evaluate the pharmacodynamic effect of TKI258 in patients, a panel of plasma angiogenesis biomarkers were evaluated in two Phase I clinical trials - acute myeloid leukemia (AML) and locally advanced or metastatic melanoma. Methods: Plasma samples were analyzed from selected dosing groups of patients during the dose escalation stages of the two Phase I trials. 19 AML patients received TKI258 at doses ranging 200 - 600 mg/day, with an initial 14 day cycle (7 days on/7 days off), followed by a continuous daily dosing schedule (28 day cycle). 16 melanoma patients received 200 - 500 mg/day on once daily dosing (28 day cycle). Plasma VEGF, placental growth factor (PLGF), basic FGF (bFGF), and soluble VEGFR1 and VEGFR2 (sVEGFR1 and 2) were measured by multiplex assays using Meso-Scale Discovery platform. Plasma levels of each marker were frequently monitored during the course of treatment. Results: Average baseline VEGF levels were higher in the melanoma patients (234 pg/ml, n=16) than in the AML patients (68 pg/ml, n=19). In AML patients, dose- dependent inductions of VEGF (3–11 fold) and PLGF (3–8 fold) at 400 and 600 mg dosing were observed at Cycle 1 Days 3 and 7, and returned to near-baseline levels at the end of Cycle 1 at Day 14 after 1 week off drug treatment 1. In melanoma patients, inductions of VEGF (∼3 fold) and PLGF (2–9 fold) as well as decrease of sVEGFR2 (30–50%) in patients treated with 400 and 500 mg TKI258 were observed at the end of Cycle 1. Significant induction of bFGF (6-fold) was observed at 500 mg TKI258 treatment group in melanoma patients at the end of Cycle 1, but not at other doses or in the AML patients. Conclusions: PlasmaVEGF and PLGF induction and sVEGFR2 decrease could serve as pharmacodynamic biomarkers of VEGFR inhibition by TKI258. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
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