Abstract 5463: Development of a pharmacokinetic (PK)-pharmacodynamic (PD) model to guide combination-dosing strategies of aflibercept (VEGF Trap) and doxorubicin chemotherapy in a systemic preclinical model of human acute myeloid leukemia

Combination therapy utilizing an anti-angiogenic agent and cytotoxic chemotherapy represents a standard therapeutic approach in solid tumors; however the efficacy of this approach in hematological malignancies has not been established. In order to maximize anti-tumor effects, the in vivo mechanism of action as well as timing of administration of the anti-angiogenic agent with respect to the cytotoxic agent in such “liquid tumors” may be crucial. We performed detailed pharmacodynamic modeling to study the effects of the sequential combination of an anti-angiogenic (aflibercept) agent with doxorubicin (DOX) chemotherapy on tumor growth in a systemic model of human acute myeloid leukemia. Disease in sublethally irradiated SCID mice was established in marrow and other sites (e.g. central nervous system) by intraveneous injection of stable luciferase-transfected human AML (HEL) cells. Animals were then treated with aflibercept (25 mg/kg) or PBS (vehicle) i.p., on days 0, 4, and 7 (n=5 per group). On day 7, one dose of DOX 3mg/kg was also administered. In vivo leukemia disease burden was quantified on days 0, 5, 7, 14, 21 and 28 days by bioluminescent imaging. The total tumor load was calculated as the area under the curve of bioluminescence (photons/second/cm2/steradian) versus time using the trapezoidal rule (units: photons/second/cm2/steradian*days) for days 0-21 (AUC0-21) and days 0-28 (AUC0-21) in those animals surviving to day 28 (n=2 in PBS + DOX, n=3 in aflibercept + DOX). We found that the mean (AUC0-21) ± SE value was lower in animals treated with aflibercept+DOX (6.86e-08±3.2e-08) than in PBS + DOX (1.63e-09±7.9e-08) treated mice. Additionally, the fold change from baseline bioluminescence (ratio of day 21 to day 0) was higher in PBS + DOX treated animals (4.379 ± 0.5101) than aflibercept+DOX treated animals (3.077 ± 0.2037), although this difference was not statistically significant (p=0.05). In the animals that survived till day 28, the mean (AUC0-28) ± SE values were similar: PBS + DOX = 2.44e-09 ± 2.17e-09 and aflibercept + DOX = 7.21e-08 ± 3.39e-08. Conclusions: We conclude that there was a trend for improved inhibition of leukemia growth when aflibercept was combined with DOX over DOX treatment alone in SCID mice engrafted with systemic human AML disease. Although changes were noted over a 28 day period, this change was most remarkable at day 21. Integration of this PD data with drug PK in the same model system is ongoing. This PKPD modeling approach will enable us to predict the effects of different dosing frequency and schedules of anti-VEGF therapy in combination with cytotoxic agents in acute leukemia and will provide new insight into the development of rational dosing regimens of these agents in future clinical trials of patients with aggressive hematological cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5463. doi:10.1158/1538-7445.AM2011-5463