sponsor decision

The purpose of the study is to assess the efficacy of varlitinib in combination with capecitabine as measured by objective response rate (ORR) assessed by independent central review (ICR), based on RECIST v1.1 criteria.

Also to explore the role of biomarkers as predictors of response and clinical benefit with varlitinib

Inclusion Criteria:

1. Are of or older than the legal age in the respective countries at the time when written informed consent is obtained.

2. Are able to understand and willing to sign the informed consent form.

3. Have histologically confirmed diagnoses of relapsed, locally advanced (unresectable) or metastatic biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer and carcinoma of Ampulla of Vater.

4. Have eligible tumor tissue (archival or fresh) for the evaluation of relevant primary endpoints.

   (Note: For patients without eligible tumor tissue, a discussion with the sponsor is mandatory).

5. Have radiographically measurable disease as determined by the investigator based on the RECIST v1.1 criteria.

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 1.5 x upper level of normal (ULN).

7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

8. Have an estimated life expectancy of more than 3 months, at the time of screening.

9. Have adequate organ and hematological function:

   1. Hematological function, as follows:

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

   2. Renal functions, as follows:

      • estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) > 50 mL/min/1.73m2

   3. Hepatic function, as follows:

      • Total bilirubin ≤ 1.5 x ULN
      • aspartate aminotransferase and alanine aminotransferase ≤ 5 x ULN

Exclusion Criteria:

1. Have received systemic anti-cancer treatment except (neo-) adjuvant therapy for early stage disease.
2. Are currently on or have received radiation or local treatment within the past 4 weeks for the target lesion(s), prior to screening.
3. Had undergone major surgical procedures within 28 days prior to study cycle 1 day 1.
4. Have a metastatic brain lesion(s), including asymptomatic and well controlled lesion(s).
5. Have malabsorption syndrome, diseases significantly affecting gastrointestinal function, or difficulty in swallowing and retaining oral medications.
6. Have any history of other malignancy unless in remission for more than 1 year (skin carcinoma and carcinoma-in-site of uterine cervix treated with curative intent is not exclusionary).
7. Are female patients who are pregnant or breast feeding.
8. Have been previously treated with varlitinib or capecitabine.
9. Have received any investigational drug (or have used an investigational device) within the last 14 days before receiving the first dose of study medication.
10. Have unresolved or unstable serious toxicity (≥ CTCAE 4.03 Grade 2), with the exception of anemia, asthenia, and alopecia, from prior administration of another investigational drug and/or prior anti-cancer treatment.
11. Have a known positive test for human immunodeficiency virus, active viral hepatitis C, viral hepatitis B infection with hepatitis B virus DNA exceeding 2000 IU/mL.
12. Have a known history of drug addiction within last 1 year, on the basis of which there could be a higher risk of non-compliance to study treatment.
13. Need continuous treatment with proton pump inhibitors during the study period.
14. Have a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, or with a history of interstitial lung disease or current interstitial lung disease.
15. Have any history or presence of clinically significant condition which in the opinion of the investigator could jeopardize the safety of the patient or the validity of the study results.
16. Have a baseline corrected QT interval > 450 ms or patients with known long QT syndrome, torsade de pointes, symptomatic ventricular tachycardia, unstable cardiac syndrome in the past 3 months before screening visit, > class 2 NYHA (The New York Heart Association Functional Classification heart failure), > grade 2 CCS (the Canadian Cardiovascular Society Guidelines) angina pectoris, or receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic, dofetilide, or sotalol methadone.

Are of or older than the legal age in the respective countries at the time when written informed consent is obtained.