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.
References 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.