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

To evaluate the preliminary efficacy of KA2507 (an orally active potent and selective HDAC6 inhibitor) in patients with advanced biliary tract cancer (BTC) previously treated with standard of care chemotherapy.

To evaluate the efficacy of KA2507 (an orally active potent and selective HDAC6 inhibitor) in patients with advanced biliary tract cancer (BTC) previously treated with standard of care chemotherapy.

ABC-11 is an open-label, multi-centre study of HDAC6 inhibition using KA2507 in patients with advanced biliary tract cancer previously treated with standard of care chemotherapy.

This is a single-arm single-stage phase II study designed using A'Hern's methodology.

The primary objective of this study is to assess the preliminary efficacy of KA2507 in patients with advanced BTC previously treated with standard of care chemotherapy

A fixed daily dose of KA2507 (800mg BID) will be administered to all patients based on a phase I study, KTP-003.

Eligibility Criteria:
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