Another cancer target receiving plenty of interest is the tumour vasculature. While antiangiogenic agents prevent blood vessels from forming, vascular disrupting agents attack them once they have formed. Blood vessels within tumours have extremely permeable thin walls, and have increased rates of endothelial cell proliferation. Vascular disrupting agents act selectively on these cells, by affecting the tubulin cyto-skeleton. Ultimately, the vessels start to leak plasma, blood viscosity increases and the vessels decrease in thickness, slowing blood flow down. Nutrients no longer reach the tumour, leading to cell death.
One such agent is plinabulin, which is being developed by US company Nereus. In a Phase I study, 13 patients with advanced cancer – 10 of whom had non-small cell lung cancer – were given 30mg/m2 of the new drug in combination with docetaxel on days 1 and 8 of 21-day cycles.1 Two of the NSCLC patients experienced a partial response, and four a lesser response, which is better than the normal response rate in similar patients with NSCLC.
A Phase II trial is also being carried out in a total of 167 patients with advanced NSCLC who had previously received chemotherapy, with subjects randomised to receive docetaxel alone or in combination with plinabulin.2 Docetaxel was given in 75mg/m2 doses on day 1, and plinabulin given to the combination arm on days 1 and 8 in 30 or 20mg/m2 doses.
At the time of reporting, 110 patients had been dosed in the 30mg/m2 group, and the lower dose was starting. Of the 64 patients evaluable
at that time, six out of 27 in the combination arm had achieved a partial response, compared with two of the 37 in the docetaxel only group. It was well tolerated, and the trial continued with 20mg/m2 doses to determine the best dose for Phase III trials.
references
1. M. Millward et al. J. Clin. Oncol. 2009, 27 (15), Abst 3571
2. A.C. Mita et al. J. Clin. Oncol. 2010, 28 (15), Abst 7592