BISCAY, a phase Ib, biomarker-directed multidrug umbrella study in patients with metastatic bladder cancer.

TPS4577 Background: Despite progress with immunotherapy (IO), there remains a significant unmet medical need for patients with metastatic urothelial bladder cancer (UBC). A patient’s molecular tumour profile enables a targeted small molecule (SM) + IO approach to treatment, particularly in PD-L1 -ve patients. Tumour biomarker profiling to enrol for trials assessing a single targeted agent leads to high screen failure rates and disappointment for patients who are biomarker-negative. BISCAYavoids these issues through centralised screening aligned to a portfolio of targeted SM+IO treatments, such that all patients are allocated to a treatment group determined by their tumour biomarker profile. Methods: Patients with metastatic UBC who have failed at least one prior platinum regimen are eligible. The primary objective is safety and tolerability of new combinations of SM and IO durvalumab (D) PD-L1 antibody treatment. Secondary objectives include overall response rate (ORR), and evaluating markers of response to combination treatment. Tumour samples are evaluated centrally utilising next generation sequencing and biomarker results are used to allocate patients to treatment (Table 1). The study will explore whether adding a SM to IO therapy in patients with specific biomarker expression may trigger increased neoantigen release and improve immunosensitisation. Biomarker prevalence and overlap, mechanism of action and preclinical data enabled a treatment allocation algorithm to be developed with the following adjusted prevalences: AZD4547 alone or in combination with D (~11%), D+O (~19%), D+AZD1775 (~46%) and D alone (~22%). 20 patients in each cohort will detect a 20% improvement over D ORR (80% probability). Additional combinations are being considered for inclusion as faster recruiting cohorts complete. Clinical trial information: NCT02546661.Biomarkers and treatment allocation. Treatment Group Target Tumour Biomarkers Prevalence (%) AZD4547 monotherapy FGFRi FGFR3 mut/fusions 11 D + AZD4547 FGFRi FGFR3 mut/fusions 11 D + olaparib (O) PARPi HRR gene panel 28 D + AZD1775 Wee1i CDKN2A homozygous loss/inactivation mut 35 RB1 homozygous loss/inactivatuion mut 24 CCNE1 amp 11 MYC, MYCL, MYCN amp 17 D monotherapy unselected 22