METRO-BIBF Phase II, randomised, placebo controlled, multicentre, feasibility study of low dose (metronomic) cyclophosphamide (MCy) with and without nintedanib in advanced ovarian cancer (AOC)

AOC patients have generally been heavily pretreated with intravenous (IV) chemotherapy (CT) and their prospects are limited – median overall survival (OS) - 9 mo. MCy is an oral option which is well tolerated, does not require IV access or numerous hospital visits and has clinical benefit lasting >4 months for 19-25% (Kummar 2015, Hall 2010). MCy has anti-angiogenic properties; it has been shown to inhibit endothelial cells in tumour and host vasculature. Augmenting this mechanism has been explored in AOC by the addition of bevacizumab to MCy where ORR of ∼30% have been reported for high grade serous AOC (PFS-6.2mo and median OS 16.9 mo) (Chura 2007, Garcia 2008). Nintedanib (N) is an oral tyrosine kinase inhibitor (TKI) which inhibits VEGFR, PDGFR and FGFR. Combining MCy with N offers an oral option to control symptoms in patients with AOC maintaining QoL with minimal toxicity. This trial of MCy +/- N will explore the activity of MCy alone and the potential benefits of adding N. Trial design: A placebo controlled, randomised phase II design, with direct comparison of OS, aiming to detect an increase of 2 mo, i.e. median OS in the combination arm of 7 mo (HR 0.71). Patients with AOC who have received 2 or more lines of chemotherapy for AOC, are platinum resistant / intolerant and/or not suitable for any further IV CT, with ECOG PS 0-2 and life expectancy of >6 weeks will be recruited. All receive MCy 100mg/day continuously with N/placebo at 200mg bd until progression. The starting dose was later reduced to nintedanib / placebo 150mg bd due to a perceived excess of TKI related toxicity (abdominal cramps and diarrhoea). Patients will be stratified for prior treatment with bevacizumab but previous antiangiogenic TKI is NOT permissible. Primary outcome is OS. Secondary outcomes include safety, ORR only for patients with evaluable disease at trial entry, PFS and QoL. 89 of 124 patients have been recruited to date. Clinical trial identification: NCT01610869 References: Kummar S et al. Clin Cancer Res. 2015 Apr 1;21(7):1574-82. Hall M et al. (2010). IJGC abstract no. 467 Chura JC et al (2007). Gyn Onc. 107(2):326-30 Garcia AA et al (2008). J Clin. Onc. 26:76-82 Legal entity responsible for the study: University College London Boerhinger Ingelheim