Our lead VDA product is OXi4503, which is in a Phase 1b clinical trial in relapsed/refractory acute myeloid leukemia. OXi4503 has a unique dual mechanism of action that disrupts the shape of tumor bone marrow endothelial cells (BMECs) through reversible binding to tubulin at the colchicine binding site, downregulating intercellular adhesion molecules. This causes alterations to the endothelial cell shape, releasing quiescent adherent tumor cells from BMECs and activating the cell cycle, making the tumor cells vulnerable to chemotherapy. OXi4503 also directly kills tumor cells via myeloperoxidase activation of a fluorquinone cytotoxic mediator.
The following select publications are from the peer-reviewed literature and discuss the scientific data surrounding the use of OXi4503.
OXi4503 (Combretastatin A1-Phosphate/CA1P)
Clinical—Phase 1 Studies:
Bosse RC, Wasserstrom B, Wise E, Meacham A, Cogle CR. Chemosensitizing leukemia by targeting the leukemia microenvironment with vascular disrupting combretastatins [abstract]. Blood. 2014;124(21):2315.
Cummings J, Zweifel M, Smith N, Ross P, Peters J, Rustin G, et al. Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial. Br J Cancer. 2012;106(11):1766-1771.
Patterson DM, Zweifel M, Middleton MR, Price PM, Folkes LK, Stratford MR, et al. Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors. Clin Cancer Res. 2012;18(5):1415-1425.
Turner D, Gonzalez A, Pettiford L, Meacham A, Wise E, Bosse RC, et al. A phase I study of the vascular disrupting combretastatin, OXi4503, in patients with relapsed and refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) [abstract]. Blood. 2013;122(21):1463.
Benezra M, Phillips E, Tilki D, Ding BS, Butler J, Dobrenkov K, et al. Serial monitoring of human systemic and xenograft models of leukemia using a novel vascular disrupting agent. Leukemia. 2012;26(8):1771-1778.
Hua J, Sheng Y, Pinney KG, Garner CM, Kane RR, Prezioso JA, et al. Oxi4503, a novel vascular targeting agent: effects on blood flow and antitumor activity in comparison to combretastatin A-4 phosphate. Anticancer Res. 2003;23(2B):1433-1440.