CRUK/21/015: SAFIR-ABC10: molecular screening for precision medicine in advanced biliary cancers

Background Despite the description of accepted treatment standards of care (SoC) in the last 10-years, survival for advanced biliary tract cancer (ABC) remains poor and is an area of significant unmet need.

Genomic profiling has demonstrated actionable molecular alterations (AMA) in 40-60% of ABC and preliminary data have been promising. This study proposal was suggested following an MRC stratified medicine proposal 3-years ago.

Aims We propose a study of maintenance therapy in ABC following 1st line SoC treatment (currently Cisplatin and Gemcitabine described in the ABC-02 study) directed by molecular profiling to determine the benefit of precision medicine in ABC. Methods Patients with ABC will be profiled whilst on 1st line SoC chemotherapy.

If the patient has stable or responding disease and (1) has an AMA, they will be randomised to targeted therapy or to continue on SoC, (2) has a putative AMA, to targeted therapy only (3) has no AMA, to Regorafenib-Durvulumab vs SoC. If the patient progresses on SoC they will proceed to either AMA or Regorafenib-Durvulumab.

The primary outcome will be progression free survival (PFS) in arm (1) and secondary endpoints include PFS in arm (3) and OS for the whole cohort. Cross over will be permitted in randomised sub-studies.

Where infrastructure permits, patients will have pre and 8 week ABC-10 therapy biopsies for multiparameter flow cytometry of immune cell subsets, multiparameter immunofluorescence of immune cell subsets, whole genome and T cell repertoire studies. Additionally, peripheral blood will be taken for circulating tumour DNA as well as germline DNA analysis.

The study has been developed and will be be run in collaboration with the sponsors, UNICANCER who aim to recruit 400 of 800 patients.

A key collaborations is the Glasgow Precision Oncology Laboratories (GPOL) who will run the initial profiling using an Agilent SureSelect platform in addition to multiple collaborations that have been established with Pharma to provide drug and financial support.

How the results of this research will be used The data, if positive, will be used to establish targeted therapies as SoC for ABC.

There are multiple secondary outputs including the development of putative drug-target combinations (cohort 2) and the value of Regorafenib-Durvulumab and further translational outputs (cohort 3).

ABC-10 will represent the single largest cohort of ABC patients molecularly profiled and prospectively treated with clinical trial quality data permitting multiple further outputs and collaborations.