P2.06-026 A Phase II Trial of the Oral FGF Receptor Inhibitor AZD4547 as 2nd or 3rd Line Therapy in Malignant Pleural Mesothelioma - Trial in Progress: Topic: Mesothelioma and SCLC

Abstract

Dysregulation of the fibroblast growth factor (FGF) pathway is observed in a variety of cancers, including mesothelioma. FGF-9 is significantly over-expressed in mesothelioma and our pre-clinical data demonstrates that inhibition of FGF receptor (FGFR)-mediated signalling in vitro results in anti-proliferative and pro-apoptic activity. FGFR-targeted tyrosine kinase inhibitors strikingly reduce tumor burden in three separate murine models of mesothelioma. AZD4547 is a potent and selective oral FGFR-1,2, and 3 tyrosine kinase inhibitor that inhibits FGFR-related signal transduction pathways which makes AZD4547 appropriate to test in MPM in the context of strong preclinical rationale.Common side effects include dry mouth, mucositis and dermatological toxicity. Serious side effects include ophthalmological toxicity, such as Retinal Pigmented Epithelium Detachment (RPED), conjunctivitis and corneal atrophy, hyperphosphatemia leading to cardiac mineralisation and renal failure. The study is an open-label single centre phase II trial of single-agent oral AZD4547 in patients with confirmed, measurable MPM who have progressed after 1st or 2nd line chemotherapy. Key inclusion/exclusion criteria include ECOG performance status 0-1; adequate organ function; and drug-specific ophthalmological and cardiac exclusion criteria. The primary endpoint is 6 month progression-free survival (PFS-6), with secondary end points of objective tumor response (modified RECIST), PFS, overall survival, toxicity and treatment duration. We will enrol 26 patients in the first of 2 stages (Simon 2-stage design). If more than 7 of the first 26 have PFS >6 months, we will continue to a total of 55 patients. Observing a total of 50 progression events will provide 90% power to identify a 6 month PFS of >45%. Correlative biomarkers including immunological biomarkers from blood and pleural fluid will also be collected. These will be correlated with disease activity, effects of study drug and clinical outcomes to detect any biomarkers and potential predictive biomarkers. As of 1st July 2016, 7 patients have been enrolled and recruitment is ongoing. There have been no grade 3 or 4 toxicities and no cardiac or ophthalmological toxicities. Main toxicities are grade 1 mucositis and dry mouth. 1 patient had hyperphosphatemia which resolved with dietary modification. AZD4547 is well tolerated with no grade 3 or 4 toxicities shown at this stage in a small number of patients. Recruitment commenced in April 2016 and stage 1 is projected to be completed by April 2017.