Anthony S. Drager

Abstract B177: RXDX-107, a dodecanol alkyl ester of bendamustine, demonstrates improved pharmacokinetic properties and significant anti-tumor efficacy in preclinical models of solid tumors

Bendamustine is an alkylating agent that can form interstrand DNA crosslinks (ICLs) and cause cell death via several pathways, including intrinsic apoptosis. Bendamustine has proven to be a potent and effective treatment for patients with chronic lymphocytic leukemia (CLL) and rituximab-refractory indolent non-Hodgkin9s lymphoma (NHL), with additional clinical activity seen in other B-cell malignancies and in multiple myeloma (MM). However, the activity of bendamustine in the treatment of solid tumor malignancies has been less impressive, possibly due to the pharmacokinetic and biodistribution properties of bendamustine. RXDX-107 is a dodecanol alkyl ester of bendamustine, and the clinical drug product is encapsulated in human serum albumin (HSA) to form nanoparticles. RXDX-107 was designed to improve tissue biodistribution over bendamustine, which may result in superior efficacy and tolerability in patients with solid tumors. In in vitro anti-proliferative studies, RXDX-107 displayed dose-dependent cytotoxicity against multiple solid tumor cell lines, including non-small lung cancer (NSCLC), breast and ovarian cancer. While the IC50s of RXDX-107 were comparable to those of bendamustine, RXDX-107 displayed stronger induction of pH2AX (a biomarker for DNA damage) and more complete cell killing than bendamustine in multiple cell lines. Furthermore, RXDX-107 potently inhibited subcutaneous tumor growth in cell line-derived xenograft (CDX) models of human NSCLC and breast cancer. Importantly, RXDX-107 also showed single agent anti-tumor activities, including tumor regression in multiple patient-derived xenograft (PDX) models of advanced solid tumors, such as breast, lung, and ovarian cancer. In conclusion, 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. Citation Format: Leenus Martin, Roopal Patel, Anthony Drager, Renee Roemmele, Bradley McIntyre, Robert McKean, Piyush Patel, Peter Chua, Jerry Cao, Robert Shoemaker, Peter Brown, Pratik Multani, Robert Wild, Ralph Lin, Gang Li. RXDX-107, a dodecanol alkyl ester of bendamustine, demonstrates improved pharmacokinetic properties and significant anti-tumor efficacy in preclinical models of solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B177.