Angiogenesis is the process by which a tumour grows new blood vessels and embeds itself in the circulation to gain the nutrients it needs to survive and thrive, and stopping this process stops the tumour from growing. Numerous drugs have been developed with this aim, and a new potential treatment being developed by Boehringer Ingelheim, BIBF 1120, acts on receptors for three different angiokinase that are involved in the angiogenesis process: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and platelet derived growth factor (PDGF).1 It was shown to inhibit cell proliferation and induce apoptosis in a variety of preclinical models, and is now in clinical trials for several different solid tumours.
In one Phase I dose escalation trial, for example, 61 patients with advanced solid tumours were given the drug in doses of 50–450mg once a day or 150–300mg twice a day in four week treatment courses, interspersed by a one-week washout period.2 MRI assessment indicated that 42 patients experienced an antiangiogenic effect. Most drug-related adverse events were mild to moderate, and a dose of 200mg twice a day was recommended for Phase II monotherapy studies.
Several such trials have taken place. In a double blind, two arm randomised study in patients with locally advanced or metastatic relapsed NSCLC, 73 patients were given 150 or 250mg of the drug twice a day.3 One patient experienced a confirmed partial response, five tumour shrinkage close to partial response, and a further 20 tumour shrinkage. In another, 84 patients with ovarian cancer that had previously responded to chemotherapy but had relapsed were given the drug or placebo.4 Five of those given the drug completed nine months of treatment, compared with none of the placebo group.
Phase I combination studies have also been carried out, including one with paclitaxel and carboplatin in advanced gynaecological malignancies,5 and with pemetrexed in pretreated non-small cell lung cancer.6 In both cases, efficacy looked promising. Phase III trials are now under way in both NSCLC and ovarian cancer.
References
1. G.J. Roth et al. J. Med. Chem. 2009, 52, 4466
2. K. Mross et al. Clin. Cancer Res. 2010, 16, 311
3. J. von Pawel et al. J. Thoracic Oncol. 2008, 3 (4, Suppl. 1) Abst 1630
4. J.A. Ledermann et al. J. Clin. Oncol. 2009, 27 (15, Suppl.) Abst 5501
5. A. du Bois et al. Ann. Oncol. 2010, 21, 370
6. P.M. Ellis et al. Clin. Cancer Res. 2010, 16, 2881