A phase II study of selective HDAC6 inhibition with KA2507 for second-line treatment of advanced biliary tract cancer (ABC-11).

Abstract

TPS4652 Background: The ABC-02 trial provided Level A evidence supporting the use of cisplatin plus gemcitabine as first-line chemotherapy for advanced biliary tract cancer (ABC) [Valle, 2010]. In second line therapy oxaliplatin and 5FU and ivosedinib for IDH1 mutated cancers are options [Lamarca, 2019; Abou-Alfa, 2019] however there remains significant unmet need for patients without actionable alterations. Histone deacetylase 6 (HDAC6) is over-expressed in cholangiocarcinoma, reducing primary cilia. This is mediated through increased resorption in normal human cholangiocytes via tubulin deacetylation in the ciliary axoneme. Inhibition of HDAC6 elicits both cell intrinsic and extrinsic anti-cancer activity. HDAC6 inhibition reversed oncogenic loss of ciliation and demonstrated preclinical efficacy in a syngeneic rat orthotopic biliary cancer model [Gradilone, 2013]. KA2507 is a potent and selective small molecule inhibitor of HDAC6. Phase I dose escalation study identified an oral dose of 800mg bid for further development, being well tolerated and showing evidence of selective target engagement. Methods: ABC-11 is a Phase II multi-centre, open-label study of KA2507 in 40 evaluable patients with advanced biliary tract cancer previously treated with standard of care chemotherapy. The study follows a single-arm single-stage design using A’Hern’s methodology. Eligible patients receive continuous 28-day cycles of fixed daily oral dose of KA2507 until death, disease progression or other pre-defined reason for study drug discontinuation. Tumour assessment is made at baseline and at 8-weekly intervals using RECIST 1.1 criteria until disease progression; primary endpoint is PFS at 4 months. Independent Data Monitoring Committee will review 4 month PFS and other data after first six patients, after a total of 17 patients (futility analysis, corresponding to cut-off of the Simon’s minimax 2-stage design; 33% was set as the target 4-month PFS rate expected with KA2507) and at least annually thereafter. Subject to availability of adequate tissue, mandatory pre-treatment and on-study tumour biopsy samples will undergo multiparameter flow cytometry of immune cell subsets, immunofluorescence analysis of immune cell subsets (activation status and topology) and T cell repertoire studies. The study received regulatory and ethical approval to proceed in January 2020 and enrolment is in progress. Clinical trial information: NCT04186156 .