A Study of Selective HDAC6 Inhibition With KA2507 in Advanced Biliary Tract Cancer

Inclusion Criteria:

* Age ≥18 years
* Signed informed consent
* Histological or cytological diagnosis of advanced (i.e. metastatic disease, or irresectable locally advanced, or recurrent) biliary tract cancer (to include intra or extra hepatic and gall bladder; ampullary cancer will not be included).
* Patient must have disease amenable to biopsy at baseline and consent to pre-treatment biopsy
* Clear evidence of disease progression following standard of care first line therapy with at least 1 measurable lesion using CT/MRI as defined by RECIST 1.1, OR clear evidence of disease progression based on the emergence of non-measurable disease (e.g. new cytologically confirmed ascites, pleural or pericardial effusion)
* Previous treatment with any line of chemotherapy for advanced disease (e.g. currently gemcitabine/cisplatin) OR radiotherapy
* ECOG performance status grade 0-1
* Adequate biliary drainage, with no evidence of ongoing infection
* Estimated life expectancy \> 3 months
* Patients intolerant of first-line standard of care chemotherapy will also be eligible provided there is evidence of disease progression

Exclusion Criteria:

* Unresolved or unstable serious toxic side-effects of prior chemotherapy or radiotherapy, i.e. ≥ grade 2 per CTCAE (common terminology criteria for adverse events, v5.0) except fatigue, alopecia and infertility
* Clinical evidence of cerebral metastases
* History of previous malignancy that could interfere with response evaluation
* Concurrent treatment with other investigational drugs within 4 weeks of initiating treatment
* Inadequate renal, liver, or haematological function defined as any of:

  * eGFR \< 45 ml/min/1.73 m2 using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula
  * ALT and/or AST \> 5 x ULN
  * Neutropenia (absolute neutrophil count \< 1.5 x 109/L)
  * Platelets \<100 x 109/L
  * Haemoglobin ≤ 9 g/dL). NB the use of transfusion to achieve desired Hb is acceptable
  * Total bilirubin ≥ 1.5 x ULN (except for patients with known Gilbert's syndrome)
* Known haemoglobinopathy due to HbS or HbC disease, α or β thalassemia, or Glucose-6-phosphate dehydrogenase (G6PD) deficiency
* Concomitant use of dapsone
* Untreated severe hypothyroidism
* Significant heart disease defined as any of the following:

  * NYHA grade 3 or 4 symptomatic heart failure
  * Unstable angina or acute myocardial infarction within 3 months
  * cardiac ventricular arrhythmia within 3 months that is not controlled by drug therapy and/or by cardiac ablation
  * QTcF \> 470 ms on screening ECG or history of Torsades de pointes
* Any other concurrent severe and/or uncontrolled medical or surgical condition which, in the view of the investigator, could compromise the patient's participation in the study
* Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen \[anti-HBc\] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
* Active infection requiring antibiotics within two weeks prior to treatment
* Males who are unable to or refuse to use barrier contraception during treatment and for 3 months after
* Women who are pregnant, breast-feeding or either unable to or refuse to use effective means of contraception during treatment
* Patients who are unable to swallow capsules and/or have a surgical or anatomical condition that precludes swallowing and absorbing oral medication on an ongoing basis
* Any other condition that would, in the investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures