Varlitinib in Combination With Capecitabine for Advanced or Metastatic Biliary Tract Cancer (TreeTopp)

Inclusion Criteria:

Subjects will be eligible for the study if they:

1. Are of or older than the legal age in the respective countries at the time when written informed consent is obtained
2. Have histologically or cytologically confirmed advanced (unresectable) or metastatic biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma (CCA), gallbladder cancer and carcinoma of Ampulla of Vater. This includes clinical diagnosis of biliary tract cancer with histological confirmation of adenocarcinoma.
3. Have received and failed one and only one prior line of systemic treatment for advanced or metastatic disease with radiologic evidence of disease progression. This prior line of systemic treatment must also contain gemcitabine
4. Have received at least 6 doses of gemcitabine containing treatment in first line (Adjuvant therapy is not regarded as 1st line therapy)
5. Have radiographically measurable disease based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as assessed by Independent Central Review (ICR) (For Part 1)
6. Have no evidence of biliary duct obstruction, unless obstruction is controlled by local treatment or, in whom the biliary tree can be decompressed by endoscopic or percutaneous stenting with subsequent reduction in bilirubin to below or equal to 1.5 × upper level of normal (ULN)
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Are able to understand and willing to sign the informed consent form

9. Have adequate organ and hematological function:

   1. Hematological function, as follows:

      • Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
      • Platelet count ≥ 100 × 109/L

   2. Renal functions, as follows:

      • Estimated glomerular filtration rate or creatinine clearance > 50 mL/min/1.73m2

   3. Hepatic function, as follows:

      • Albumin ≥ 3 g/dL
      • Total bilirubin ≤ 1.5 × ULN
      • Aspartate aminotransferase and alanine aminotransferase ≤ 5 × ULN

Exclusion Criteria:

Subjects will be ineligible for the study if they:

1. Are currently on or have received anti-cancer therapy within the past 3 weeks before receiving the first dose of study medication
2. Are currently on or have received radiation or local treatment within the past 3 weeks for the target lesion(s) before receiving the first dose of study medication
3. Have evidence of multiple (≥ 2) peritoneal metastases or ascites at baseline as assessed by ICR (For Part 1). (Ascites which can be attributed by non-malignant causes is not excluded. Minimal ascites, which does not require paracentesis is permitted.)
4. Have had major surgical procedures within 14 days prior to first dose of study medication
5. Have a known metastatic brain lesion(s), including asymptomatic and well controlled lesion(s)
6. Have malabsorption syndrome, diseases significantly affecting gastrointestinal function, resection of the stomach or small bowel, or difficulty in swallowing and retaining oral medications which in the opinion of the Investigator could jeopardize the validity of the study results
7. Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, unstable angina pectoris, cardiac arrhythmia, diabetes, hypertension, or psychiatric illness/social situations that would limit compliance with study requirements
8. Have any history of other malignancy unless in remission for more than 1 year (non-melanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary)
9. Are female patients who are pregnant or breast feeding
10. Have been previously treated with varlitinib or have been previously treated with capecitabine as first line therapy for advanced or metastatic disease. For patients who have previously received capecitabine as a radiosensitizer or as part of their adjuvant therapy and their disease has relapsed for more than 6 months after their last dose of capecitabine adjuvant therapy, their capecitabine therapy will not be considered as a line of systemic chemotherapy for metastatic/advanced disease, and thus they can participate in the study
11. Have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication
12. Have unresolved or unstable serious toxicity (≥ common terminology criteria for adverse events [CTCAE] 4.03 Grade 2), with the exception of anemia, asthenia, and alopecia, from prior administration of another investigational drug and/or prior cancer treatment
13. Have a known positive test for human immunodeficiency virus, hepatitis C (treatment naïve or after treatment without sustained virologic response), or hepatitis B infection with hepatitis B virus deoxyribonucleic acid exceeding 2000 IU/mL
14. Have a known history of drug addiction within last 1 year which, in the opinion of the Investigator, could increase the risk of non-compliance to investigational product
15. Need continuous treatment with proton pump inhibitors during the study period
16. Have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or have a history of interstitial lung disease or current interstitial lung disease
17. Have any history or presence of clinically significant cardiovascular, respiratory, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic or psychiatric disease or any other condition which in the opinion of the Investigator could jeopardize the safety of the patient or the validity of the study results
18. Have a baseline corrected QT interval (Fridericia's formula) (QTcF) > 450 ms or patients with known long QT syndrome; torsade de pointes; symptomatic ventricular tachycardia; an unstable cardiac syndrome in the past 3 months before screening visit; > class 2 New York Heart Association heart failure; or > class 2 angina pectoris; or receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic, dofetilide, sotalol, or methadone. Please also see prohibited medication/therapy (Section 5.4.10.1)