RXDX-107, A Dodecanol Alkyl Ester of Bendamustine, Demonstrates Greater Stability and Broad Antitumor Activity in Multiple Pre-Clinical Models of Solid Tumor

Abstract

Purpose: RXDX-107 is a dodecanol alkyl ester of bendamustine encapsulated in human serum albumin (HSA) to form nanoparticles. The anti-tumor activity of bendamustine in solid tumor malignancies has been less impressive, partially due to short half-life. RXDX-107 was designed to extend the half-life and improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. Experimental Design:The anti-tumor activity of RXDX-107 was measured in cellular anti-proliferation assay, cell-line derived xenograft (CDX) models and patient-derived xenograft (PDX) models. The mechanism of action and pharmacodynamics properties were measured by comet assay. The tumor accumulation was measured by a novel LC-MS/MS method. Results:In in vitro anti-proliferative studies, RXDX-107 displayed dose-dependent cytotoxicity against multiple solid tumor cell lines. While the IC50 of RXDX-107 were comparable to those of bendamustine, RXDX-107 displayed more complete cell killing. RXDX-107 exhibited enhanced pharmacodynamics properties, including stronger induction of pH2AX (a biomarker for DNA damage) and higher interstrand crosslinks (ICLs) formation. RXDX-107 significantly reduces tumor growth in human NSCLC xenograft models. RXDX-107 also showed single agent anti-tumor activities, including tumor regression in multiple PDX models of solid tumors including breast, lung, and ovarian cancer. Furthermore, the mode of action data exhibit slow and sustained release of bendamustine from RXDX-107, and high intratumoral accumulation of RXDX-107. Conclusions:Our preclinical data demonstrate potent and broad anti-tumor activity of RXDX-107 across a variety of solid tumor types, and support further clinical development of this novel drug candidate for the treatment of solid tumors.