| Eligibility |
Inclusion Criteria:
- 1. Written informed consent and any locally-required authorization obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations 2. Age= 20 years at time of study entry 3. Eastern Cooperative Oncology
Group (ECOG) performance status of 0 or 1 4. Life expectancy of = 16weeks 5.
Histologically proven BTC, including intrahepatic cholangiocarcinoma, extrahepatic
bile duct cancer, gallbladder cancer, ampulla of vater cancer 6. Unresectable or
recurrent 7. Failed to 1st-line chemotherapy for their advanced BTC, but no more than
2 lines of prior chemotherapy regimen 8. At least one measurable lesion that can be
accurately assessed at baseline by computed tomography (CT) (magnetic resonance
imaging [MRI] where CT is contraindicated) and is suitable for repeated assessment as
per RECIST 1.1.
9. Body weight >30kg 10. Adequate normal organ and marrow function measured within 28
days prior to administration of study treatment as defined below:
• Haemoglobin =9.0 g/dL
• Absolute neutrophil count (ANC) = 1.5 x 10 9/L
- Platelet count = 75 x 10 9/L
- Serum creatinine = 1.5 x upper limit of normal (ULN), or estimated glomerular
filtration rate = 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology
Collaboration equation
- AST and ALT = 3.0 x ULN, or AST and ALT = 5.0 x ULN for patients with documented
liver metastases
- Serum total bilirubin = 1.5 x ULN (total bilirubin must be < 3 x ULN for patients
with Gilberts syndrome)
- International normalized ratio (INR) = 1.5 or prothrombin time = 1.5 x ULN
- Activated partial thromboplastin time (aPTT) = 1.5 x ULN
11. Patients with inactive/asymptomatic carrier, chronic, or active hepatitis B
virus (HBV) must have HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500
copies/mL) at Screening 12. Females of childbearing potential must be willing to
use a highly effective method of birth control for the duration of the study, and
= 120 days after the last dose of study drugs and have a negative serum pregnancy
test = 7 days of first dose of study drugs 13. Non-sterile males must be willing
to use a highly effective method of birth control for the duration of the study
and for = 120 days after the last dose of study drugs
Exclusion Criteria:
- 1. Unacceptable toxicity on prior anti-PD-1/PD-L1 treatment, defined as follows:
1. = Grade 3 AE related to anti-PD-1/PD-L1 treatment that did not respond to
standard therapy and warranted treatment discontinuation.
2. = Grade 2 irAE(immune-related adverse event) associated with anti-PD-1/PD-L1
unless the AE(adverse event) resolved or was well controlled by withholding the
anti-PD-1/PD-L1 and/or treatment with steroids, with the exception of prior
colitis, encephalitis, myocarditis, hepatitis, uveitis and pneumonitis, which are
exclusionary.
3. Central nervous system or ocular AE of any grade related to anti-PD-1/PD-L1 Note:
Patients with a prior endocrine AE are permitted to enroll if they are stably
maintained on appropriate replacement therapy and are asymptomatic.
2. Active leptomeningeal disease or uncontrolled, untreated brain metastasis
• Patients with a history of treated and, at the time of screening, asymptomatic
CNS metastases are eligible, provided they meet all the following:
1. Brain imaging at screening shows no evidence of interim progression
2. All brain metastases with supratentorial location
3. No ongoing requirement for corticosteroids as therapy for CNS disease;
anticonvulsants at a stable dose allowed
4. No stereotactic radiation or whole-brain radiation within 14 days prior to first
dose of study drug(s)
- Patients with new asymptomatic central nervous system metastases detected at
the screening scan must receive radiation therapy and/or surgery for central
nervous system metastases.
5. Following treatment, these patients may then be eligible, provided all other
criteria, including those for patients with a history of brain metastases, are
met.
3. Active autoimmune diseases or history of autoimmune diseases that may relapse
Note: Patients with the following diseases are not excluded and may proceed to
further screening:
6. Controlled Type I diabetes
7. Hypothyroidism (provided it is managed with hormone replacement therapy only)
8. Controlled celiac disease
9. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis,
alopecia)
10. Any other disease that is not expected to recur in the absence of external
triggering factors 4. Any active malignancy = 2 years before first dose of study
drugs except for the specific cancer under investigation in this study and any
locally recurring cancer that has been treated curatively (eg, resected basal or
squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the
cervix or breast) 5. Any condition that required systemic treatment with either
corticosteroids (> 10 mg daily of prednisone or equivalent) or other
immunosuppressive medication = 14 days before first dose of study drugs
Note: Patients who are currently or have previously been on any of the following
steroid regimens are not excluded:
1. Adrenal replacement steroid (dose = 10 mg daily of prednisone or equivalent)
2. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with
minimal systemic absorption
3. Short course (= 7 days) of corticosteroid prescribed prophylactically (eg, for
contrast dye allergy) or for the treatment of a non-autoimmune condition (eg,
delayed-type hypersensitivity reaction caused by contact allergen) 6.
Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium,
sodium, or corrected calcium despite standard medical management or = Grade 3
hypoalbuminemia = 14 days before first dose of study drugs 7. History of
interstitial lung disease, noninfectious pneumonitis or uncontrolled diseases,
including pulmonary fibrosis, acute lung diseases, etc.
8. Severe chronic or active infections (including tuberculosis infection, etc.)
requiring systemic antibacterial, antifungal or antiviral therapy, within 14 days
prior to first dose of study drugs 9. Known history of HIV infection 10. Active
hepatitis C infection (defined by a detectable HCV RNA). 11. Any major surgical
procedure requiring general anesthesia = 28 days before first dose of study drugs
12. Prior allogeneic stem cell transplantation or organ transplantation 13. Any
of the following cardiovascular risk criteria:
1. Cardiac chest pain, defined as moderate pain that limits instrumental activities
of daily living, = 28 days before first dose of study drugs
2. Symptomatic pulmonary embolism = 28 days before first dose of study drugs
3. Any history of acute myocardial infarction = 6 months before first dose of study
drugs
4. Any history of heart failure meeting New York Heart Association Classification
III or IV = 6 months before first dose of study drugs
5. Any event of ventricular arrhythmia = Grade 2 in severity = 6 months before first
dose of study drugs
6. Any history of cerebrovascular accident = 6 months before first dose of study
drugs
7. QTc interval (corrected by Fridericia's method) > 450 msec Note: If QTc interval
is > 450 msec on initial electrocardiogram (ECG), a follow up ECG will be
performed to confirm result
8. Cardiac left ventricular ejection fraction = 40% or lower limit of normal as
assessed by echocardiography. The same modality used at baseline must be applied
for subsequent evaluations.
9. Any episode of syncope or seizure = 28 days before first dose of study drugs 14.
Inadequately controlled hypertension (defined as systolic blood pressure > 150
mmHg and/or diastolic blood pressure > 100 mmHg) 15. Hypersensitivity to
tislelizumab or sitravatinib, to any ingredient in the formulation, or to any
component of the container 16. Bleeding or thrombotic disorders or use of
anticoagulants such as warfarin or similar agents requiring therapeutic INR
monitoring within 6 months before first dose of study drugs 17. Any systemic
chemotherapy within 28 days of the first dose of study drugs or immunotherapy
(eg, interleukin, interferon, thymoxin, etc.), hormone therapy, targeted therapy,
or any investigational therapies within 14 days or 5 half-lives (whichever is
shorter) of first dose of study drugs 18. Any herbal medicine used to control
cancer within 14 days of first dose of study drugs 19. Toxicities (as a result of
prior anticancer therapy) that have not improved to baseline or stabilized,
except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and
specific laboratory abnormalities) 20. Administration of live vaccine = 4 weeks
prior to first dose of study drugs Note: Seasonal vaccines for influenza are
generally inactivated vaccines and are allowed. Intranasal vaccines are live
vaccines and are not allowed.
21. Underlying medical conditions or alcohol or drug abuse or dependence that
will be unfavorable for the administration of study drugs or affect the
explanation of drug toxicity or AEs; or expected insufficient compliance during
the study according to investigator's judgement 22. Participation in another
clinical study, unless it is an observational (non interventional) clinical study
or during the follow-up period of an interventional study 23. Inability to
swallow capsules or disease significantly affecting gastrointestinal function
such as malabsorption syndrome, resection of the stomach or small bowel,
bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial
or complete bowel obstruction 24. Spinal cord compression in one or more of the
following criteria
1. Not definitively treated with surgery and/or radiation
2. Treated but without evidence that disease has been clinically stable for > 2
weeks prior to first dose of study drugs 25. Pregnant or breastfeeding woman 26.
Regardless of the severity, patients with any signs or medical history of
bleeding; within 4 weeks prior to allocation, patients with any bleeding events =
CTCAE level 3, unhealed wounds, ulcers or fractures 27. Patients with
artery/venous thrombotic occurred within 6 months before allocation, such as
cerebrovascular accident (including temporary ischemic attack), deep vein
thrombosis and pulmonary embolism
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