Oncolytic Virotherapy Combined With Tislelizumab Plus Lenvatinib in Patients With Advanced Biliary Tract Cancer (OPTIONS-05)

Inclusion Criteria:

• Written informed consent obtained.
• Age ≥ 18 years at time of study entry.
• Participants must have unresectable or metastatic histologically or cytologicallyconfirmed biliary tract cancer (BTC)
• Participants must have failed 1 line of systemic regimens for advanced BTC due todisease progression or toxicity.
• At least one measurable site of disease as defined by RECIST criteria with spiral CTscan or MRI.
• Performance status (PS) ≤ 2 (ECOG scale).
• Life expectancy of at least 12 weeks.
• Adequate blood count, liver-enzymes, and renal function: absolute neutrophil count ≥ 1,500/L, platelets ≥75 x103/L; Total bilirubin ≤ 3x upper normal limit; AspartateAminotransferase (SGOT), Alanine aminotransferase (SGPT) ≤ 5 x upper normal limit (ULN); International normalized ratio (INR) ≤1.25; Albumin ≥ 31 g/dL; Serum Creatinine ≤ 1.5 x institutional ULN or creatinine clearance (CrCl) ≥ 30 mL/min (if using theCockcroft-Gault formula )
• Female patients with reproductive potential must have a negative urine or serumpregnancy test within 7 days prior to start of trial.
• Subject is willing and able to comply with the protocol for the duration of the studyincluding undergoing treatment, adherence to contraceptive measures, scheduled visitsand examinations including follow up.

Exclusion Criteria:

• History of cardiac disease, including clinically significant gastrointestinal bleedingwithin 4 weeks prior to start of study treatment
• Thrombotic or embolic events such as cerebrovascular accident (including transientischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 monthsPrior to the first dose of study drug with the exception of thrombosis of a segmentalportal vein.
• Prior treatment with oncolytic virotherapy.
• Radiotherapy administered less than 4 weeks prior to study treatment start.
• Major surgery within 4 weeks of starting the study treatment OR subjects who have notrecovered from effects of major surgery.
• Patients with second primary cancer, except adequately treated basal skin cancer orcarcinoma in-situ of the cervix.
• Immunocompromised patients, e.g. patients who are known to be serologically positivefor human immunodeficiency virus (HIV).
• Participation in another clinical study with an investigational product during thelast 30 days before inclusion or 7 half-lifes of previously used trial medication,whichever is longer.
• Any condition or comorbidity that, in the opinion of the investigator, would interferewith evaluation of study Treatment or interpretation of patient safety or studyresults, including but not limited to:

1. history of interstitial lung disease
2. Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) coinfection (i.e doubleinfection)
3. known acute or chronic pancreatitis
4. active tuberculosis
5. any other active infection (viral, fungal or bacterial) requiring systemictherapy
6. history of allogeneic tissue/solid organ transplant
7. diagnosis of immunodeficiency or patient is receiving chronic systemic steroidtherapy or any other form of immunosuppressive therapy within 7 days prior to thefirst dose of Tislelizumab treatment.
8. Has an active autoimmune disease requiring systemic treatment within the past 3months or a documented history of clinically severe autoimmune disease, or asyndrome that requires systemic steroids or immunosuppressive agents. Exceptions:Subjects with vitiligo, hypothyroidism, diabetes mellitus type I or resolvedchildhood asthma/atopy are an exception to this rule. Subjects that requireintermittent use of bronchodilators or local steroid injections would not beexcluded from the study. Subjects with Hashimoto thyroiditis, hypothyroidismstable on hormone replacement or psoriasis not requiring treatment are notexcluded from the study.
9. Live vaccine within 30 days prior to the first dose of Tislelizumab treatment orduring study treatment.
10. History or clinical evidence of Central Nervous System (CNS) metastasesExceptions are: Subjects who have completed local therapy and who meet both ofthe following criteria: I. are asymptomatic and II. have no requirement forsteroids 6 weeks prior to start of Tislelizumab treatment. Screening with CNSimaging (CT or MRI) is required only if clinically indicated or if the subjecthas a history of CNS

• Medication that is known to interfere with any of the agents applied in the trial.
• Any other efficacious cancer treatment except protocol specified treatment at studystart.
• Patient has received any other investigational product within 28 days of study entry.
• Female subjects who are pregnant, breast-feeding or male/female patients ofreproductive potential who are not employing an effective method of birth control (failure rate of less than 1% per year). [Acceptable methods of contraception are:implants, injectable contraceptives, combined oral contraceptives, intrauterinepessars (only hormonal devices), sexual abstinence or vasectomy of the partner]. Womenof childbearing potential must have a negative pregnancy test (serum β-HCG) atscreening.
• Patient with any significant history of non-compliance to medical regimens or withinability to grant reliable informed consent.