P0125 A phase 1/2 trial of BNC105P with everolimus in metastatic renal cell carcinoma.

Background In patients with metastatic renal cell carcinoma (mRCC), everolimus represents a standard of care option for patients who have had prior vascular endothelial growth factor (VEGF)-directed therapy. BNC105P is an inhibitor of tubulin polymerisation and preclinical studies suggest possible synergy with everolimus. In this phase 1/2 study, the efficacy and safety of the combination was explored. Methods A phase 1 study in patients with clear-cell mRCC and any number of different prior treatments was done using a classical 3+3 design to evaluate standard doses of everolimus with increasing doses of BNC105P (4.2, 8.4, 12.6, and 16 mg/m 2 ). At the recommended phase 2 dose, patients with clear-cell mRCC and one to two prior treatments (including ⩾1 VEGF-TKI) were randomised to BNC105P with everolimus (group A) or everolimus alone (group B). Patients were stratified by MSKCC risk factors and number of prior VEGF-TKIs. The primary endpoint of the study was 6-month progression-free survival. Findings 15 patients were included in the phase 1 component, and a dose of BNC105P at 16 mg/m 2 with everolimus at 10 mg daily was identified as the recommended phase 2 dose. In the phase 2 study, 139 patients were randomised across 77 treatment centres (United States of America (USA): 63; non-USA: 14), with 69 and 67 evaluable patients in groups A and B, respectively. Six-month progression-free survival was similar in the treatment groups (group A: 33.82% versus group B: 30.30%, p = 0.66) and no difference in median progression-free survival was observed (group A: 4.7 months versus group B: 4.1 months; p = 0.49). Most adverse events were consistent with everolimus-related toxic effects. Changes in several biomarkers (matrix metalloproteinase-9, stem-cell factor, sex hormone binding globulin, and serum amyloid A protein) were associated with clinical outcome with BNC105P. Conclusions Although the primary endpoint was not met in an unselected population, intriguing correlative studies suggest several potentially predictive biomarkers. Further prospective assessment of BNC105P in relevant biomarker-based subsets is warranted. [ABSTRACT FROM AUTHOR]