For tumours to grow larger than a few millimetres in size, it is necessary for them to develop their own blood supply. There are two fundamentally different approaches to targeting blood vessels that supply tumours. The approach that is most developed is aimed at preventing new tumour blood vessels from growing and is called anti-angiogenesis. Several drugs such as bevacizumab and sunitinib and pazopanib are already licensed for use in different tumours. The other approach uses drugs, called vascular disruptive agents, to selectively damage the blood vessels already supplying cancers so that the blood flow to cancer can be stopped and the cancers rapidly die.
This is an area of research where 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 confirmed the laboratory findings that it is the most potent vascular disruptive agent (VDA) yet 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 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. The CTRT funded staff involved in the trials combining fosbretabulin with paclitaxel, with carboplatin and with the VEGF inhibitor bevacizumab, in the hope that these drugs would attack the viable rim thus improving activity of the combination therapy.
These single-arm combination trials produced positive results that required confirmation in randomised trials. Professor Rustin designed a trial comparing bevacizumab alone versus bevacizumab plus fosbretabulin in patients with relapsed ovarian cancer. Although he could not obtain funding for the cost of bevacizumab for the trial to be performed in the UK, the GOG group with help from the NCI and Genentech were able to perform the trial in the USA. Preliminary results suggest the 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 plus bevacizumab, the fosbretabulin was given once every 3 weeks and there were no translational studies. A trial was therefore designed where fosbretabulin was given weekly and blood biomarkers were measured to determine not only whether the combination is better than single-agent VEGF inhibitor alone but also hopefully provide us with a signature of which tumours are most likely to benefit. Pazopanib an oral anti-angiogenic tyrosine kinase inhibitor was combined with fosbretabulin in this trial. The CTRT funded the biomarker work which is unfortunately unlikely to show any meaningful results due to small numbers.
The trial was run by the Clinical Trials Unit in Manchester with GSK, 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 looked at the best dose of the combination. The phase II, randomised part of the study involved more centres aiming to recruit 110 patients and started in July 2016. Despite some dramatic responses being seen in the combination arm Novartis stopped the trial following four reversible cardiac events. Despite only 21 patients being randomised in the trial before it was stopped, the median progression-free survival was 7.6 months in the fosbretabulin plus 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 have recently been published. ( Morgan RD, Banerjee S, Hall M, Clamp AR, Zhou C, Hasan J, Orbegoso C, Taylor S, Tugwood J, Lyon AR, Dive C, Rustin GJS, Jayson GC. Pazopanib and Fosbretabulin in recurrent ovarian cancer (PAZOFOS): A multi-centre, phase 1b and open-label, randomised phase 2 trial. Gynecol Oncol. 2020 Mar;156(3):545-551).
Further research is needed to develop VDAs with less cardiac toxicity or better ways to prevent it.