1.A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma.
Pal S1, Azad A2, Bhatia S3, Drabkin H4, Costello B5, Sarantopoulos J6, Kanesvaran R7, Lauer R8, Starodub A9, Hauke R10, Sweeney CJ11, Hahn NM12, Sonpavde G13, Richey S14, Breen T15, Kremmidiotis G16, Leske A16, Doolin E16, Bibby DC16, Simpson J16, Iglesia Clin Cancer Res. 2015 Aug 1;21(15):3420-7. doi: 10.1158/1078-0432.CCR-14-3370. Epub 2015 Mar 18.
PURPOSE: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).
2.Clinical, pharmacodynamic, and pharmacokinetic evaluation of BNC105P: a phase I trial of a novel vascular disrupting agent and inhibitor of cancer cell proliferation.
Rischin D1, Bibby DC, Chong G, Kremmidiotis G, Leske AF, Matthews CA, Wong SS, Rosen MA, Desai J. Clin Cancer Res. 2011 Aug 1;17(15):5152-60. doi: 10.1158/1078-0432.CCR-11-0937. Epub 2011 Jun 20.
PURPOSE: To determine the recommended phase II dose and evaluate the safety and toxicity profile and pharmacokinetic (PK) and pharmacodynamic (PD) effects of BNC105P, an inhibitor of tubulin polymerization that has vascular disrupting and antiproliferative effects.
3.A phase II clinical trial of the vascular disrupting agent BNC105P as second line chemotherapy for advanced Malignant Pleural Mesothelioma.
Nowak AK1, Brown C, Millward MJ, Creaney J, Byrne MJ, Hughes B, Kremmidiotis G, Bibby DC, Leske AF, Mitchell PL, Pavlakis N, Boyer M, Stockler MR. Lung Cancer. 2013 Sep;81(3):422-7. doi: 10.1016/j.lungcan.2013.05.006. Epub 2013 Jun 17.
BNC105P is a tubulin polymerisation inhibitor that selectively disrupts tumour vasculature and suppresses cancer cell proliferation. This agent has exhibited preclinical and phase I activity in Malignant Pleural Mesothelioma (MPM). This phase II, single arm trial investigated the efficacy and safety of BNC105P as second line therapy in MPM. Participants had progressive MPM after first line pemetrexed/platinum chemotherapy, ECOG PS 0-1, adequate organ function, and measurable disease. BNC105P 16 mg/m(2) was administered intravenously on day 1 and 8 every 21 days until progression or undue toxicity. The primary endpoint was centrally reviewed objective response rate (RR). Tumour response was assessed every two cycles using modified RECIST. 30 patients were enrolled in 10 months, predominantly male (90%), ECOG PS 1 (77%), epithelioid histology (67%), and non-metastatic disease (67%). All patients received at least one dose of study drug, with a median of 2 cycles.
4.Tubulin colchicine binding site inhibitors as vascular disrupting agents in clinical developments.
Ji YT, Liu YN, Liu ZP1. Curr Med Chem. 2015;22(11):1348-60.
Tumor vasculature is an important target in cancer treatment. Two distinct vasculartargeting therapeutic strategies are applied to attack cancer cells indirectly. The antiangiogenic approach intervenes in the neovascularization processes and blocks the formation of new blood vessels, while th e antivascular approach targets the established tumor blood vessels, making vascular shutdown and resulting in rapid haemorrhagic necrosis and tumor cell death. A number of compounds with diverse structural scaffolds have been designed to target tumor vasculature and they are called vascular disrupting agents (VDAs). The biological or ligand-directed VDAs utilize antibodies, peptides or growth factors to deliver toxins or pro-coagulants or proapoptotic affectors to tumor-related blood vessels, while the small-molecule VDAs selectively target tumor blood vessels and have little effects on the normal endothelium. Among the small-molecule VDAs, the tubulin colchicine binding site inhibitors have been extensively studied and many of them have entered the clinical trials, including CA-4P, CA-1P, AVE8062, OXi4503, CKD-516, BNC105P, ABT-751, CYT- 997, ZD6126, NPI-2358, MN-029 and EPC2407.