Developing drugs that target tumour blood vessels

Professor Gordon Rustin

Vascular disruptive agents therapy

For tumours to grow larger than a few millimetres in size, they must develop their own blood supply. There are two fundamentally different approaches to targeting blood vessels that supply tumours. Anti-angiogenesis is the most developed approach at aimed preventing new tumour blood vessels from growing. Several drugs such as bevacizumab, sunitinib and pazopanib are already licensed for use in different tumours. The other approach uses drugs, called vascular disruptive agents, (VDAs) these selectively damage the blood vessels already supplying cancers so that the blood flow to cancer can be stopped and the cancers rapidly die.

In this area of research, the team at Mount Vernon have led the world in initiating and running clinical trials of these novel agents. The CTRT has been crucial in providing additional support, to make these trials possible. We completed a phase 1 trial of OXI4503 in 2010 and the laboratory findings confirmed that it is the most potent vascular disruptive agent that has yet been tested in man. This drug is currently showing promise in the treatment of myeloid leukaemia, but for commercial reasons is no longer being developed for solid tumours. The CTRT has helped to fund staff involved in the initial phase 1 trial of combretastatin; (A4 phosphate also known as CA4P or fosbretabulin.) Laboratory studies have shown that although the centre of the tumour is killed by VDAs, through the selective shut down of blood supply to the cancer; there is a viable rim remaining that causes the tumour to re-grow. Therefore, the CTRT funded the staff and trials combining fosbretabulin, paclitaxel, carboplatin and the VEGF inhibitor; bevacizumab. With this combination, the intention is that these drugs would attack the viable rim thus improving the activity of the combination therapy.

Clinical trials

These single-arm combination trials produced positive results that required confirmation in randomised trials. Professor Rustin designed a trial comparing bevacizumab alone versus bevacizumab with fosbretabulin in patients with relapsed ovarian cancer. However, he could not obtain funding for the cost of bevacizumab and for the trial to be performed in the United Kingdom; therefore the Gynecologic Oncology Group (GOG), Genentech and the National Cancer Institute (NCI) stepped in and were able to perform the trial in the United States. The preliminary results suggest the drug combination has achieved its objective in improving progression-free survival. This is the first randomised trial to prove the benefit of VDAs.

In the GOG trial of fosbretabulin with bevacizumab; the fosbretabulin was given once every 3 weeks and there were no translational studies. Therefore another trial was designed where fosbretabulin was given weekly and the blood biomarkers were measured to determine whether the combination is better than single-agent VEGF inhibitor alone. Pazopanib is an oral anti-angiogenic tyrosine kinase inhibitor, was combined with fosbretabulin in this trial. These results would have hopefully provided us with a signature of which tumours are most likely to benefit. The CTRT funded the biomarker work however it is unlikely to show any meaningful results due to small numbers. (1)

The trial was run by the ‘Clinical Trials Unit in Manchester’ with GlaxoSmithKline, Novartis and Oxigene providing some funding and free drugs. The CTRT supported the salary of a data manager and research nurse, who spent a third of their time on this trial. The first part of this trial was completed in February 2016 and studied the best dosage for the combination. Then in July 2016 phase II commenced, as the randomised part of the study more centres were involved; aiming to recruit 110 patients. Despite some dramatic responses being seen in the combination, Novartis stopped the trial following four reversible cardiac events. Only 21 patients were a part of randomisation in the trial before it was stopped completely. Their participation showed the median progression-free survival was 7.6 months in the fosbretabulin and pazopanib group vs. 3.7 months in the single-agent pazopanib group (Hazard Ratio=0.30, 95%CI 0.08-1.03, P=0.06). These results were published in March 2020. (1) Further research is needed to develop VDAs with less cardiac toxicity or better ways to prevent it.

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[1] Morgan, R., Banerjee, S., Hall, M., Clamp, A., Zhou, C., Hasan, J., Orbegoso, C., Taylor, S., Tugwood, J., Lyon, A., Dive, C., Rustin, G. and Jayson, G., 2020. Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. Gynecologic Oncology, 156(3), pp.545-551.