Anlotinib in Combination With PD1 With Gemcitabine Plus(+)Cisplatin for Unresectable or Metastatic Biliary Tract Cancer

Exclusion Criteria

• •Patients who meet any of the following conditions will be excluded from the trial:
• •1. Patients who previously received systemic treatment for advanced unresectable or metastatic cholangiocarcinoma will be excluded. Neoadjuvant or adjuvant therapy is acceptable if treatment is completed at least 6 months prior to randomization and shows no progression.
• •2. Patients suffering from other active malignancies within 5 years or coexisting with cholangiocarcinoma, except adequately treated localized neoplasms including, but not limited to: basal cell or squamous cell skin cancer, superficial bladder cancer, in situ prostate cancer, in situ cervical cancer, and in situ breast cancer.
• •3. Patients who are preparing for or have previously undergone organ or allogenic bone marrow transplantation.
• •4. Patients with symptomatic moderate or severe ascites requiring paracentesis and drainage (except patients with imaging showing mild ascites but no clinical symptoms); or patients with uncontrolled or moderate and severe pleural or pericardial effusion.
• •5. Patients who have a history of gastrointestinal hemorrhage within preceding 6 months or gastrointestinal hemorrhagic tendency, e.g., esophagogastric varices with a risk of hemorrhage, active peptic ulcer, fecal occult blood being continuously positive (if fecal occult blood is positive at baseline, reexamination can be considered; if reexamination is still positive, esophagogastroduodenoscopy (EGD) should be considered; if EGD indicates esophagogastric varices with a risk of hemorrhage, then the patient will be excluded).
• •6. Patients with hereditary or acquired bleeding tendency (e.g., coagulation dysfunction) or thrombophilia, e.g., hemophilia patients; or patients who are currently receiving or recently received (within preceding 10 days) full-dose anticoagulant or thrombolytic agents orally or by injection for therapeutic purposes (prophylactic usage of low-dose aspirin or low molecular heparin is acceptable).
• •7. Patients who are receiving or recently received (within preceding 10days) aspirin (\>325 mg/d (maximum antiplatelet dose)) or dipyridamole, ticlopidine, clopidogrel and cilostazol.
• •8. Patients who have a history of thrombosis or embolism within preceding 6 months, including cerebrovascular events (transient ischemic attack, cerebral hemorrhage and cerebral infraction) and pulmonary embolism.
• •9. Patients with uncontrolled heart disease or relevant symptoms, e.g., (1) heart failure with NYHA \> 2 (Appendix 5) or UCG showing LVEF \<50%; (2) unstable angina; (3) a history of myocardial infraction within preceding 1 year; (4) supraventricular or ventricular arrhythmia with clinical significance indicating treatment or intervention; (5) QTc \> 450ms (male); QTc \> 470ms(female) (QTc is calculated by Fridericia law; if QTc is abnormal, it can be continuously measured 3 times with an interval of 2 minutes, taking the average).
• •10. Patients with hypertension uncontrolled by drug or treatment (SBP≥140 mmHg or DBP≥90 mmHg) (based on≥2 measurements and taking average); or patients with a history of hypertensive emergency or hypertensive encephalopathy.
• •11. Patients who have severe vascular diseases (e.g., aortic aneurysm requiring surgical repair or with recent peripheral arterial thrombosis) within preceding 6 months.
• •12. Patients with severe, unhealed or open wounds, and active ulcers or untreated fractures.
• •13. Patients who received major operation (except diagnosis) within preceding 4 weeks, or who are expected to receive major operation during the trial period.
• •14. Patients who are unable to swallow tablets, or with malabsorption syndrome or any condition that may affect gastrointestinal absorption.
• •15. Patients with aeroperitoneum that cannot be explained by puncture or recent surgery.
• •16. Patients with brain metastases before or at present
• •17. Patients suffering from uncontrolled systemic diseases including, but not limited to: diabetes, hypertension, pulmonary fibrosis, acute pulmonary disease, interstitial lung disease, cirrhosis, angina and severe arrhythmia.
• •18. Patients suffering from interstitial pneumonia or ILD, or with a history of interstitial pneumonia or ILD requiring hormone therapy, or with other pulmonary fibrosis，organic pneumonia(e.g., obliterative bronchiolitis), pneumoconiosis, drug-induced pneumonia and idiopathic pneumonia that may interfere with the diagnosis and management of immune-related pulmonary toxicity; or patients with CT image indicating active pneumonia or severely impaired pulmonary function during screening. Radiation pneumonia is acceptable in the radiation field. Patients with active tuberculosis will be excluded.
• •19. Patients suffering from active autoimmune disease or with a history of autoimmune disease that may recur (including, but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis, hyperthyroidism and hypothyroidism \[patients controlled only by hormone replacement therapy are acceptable\]) will be excluded; patients with dermatosis requiring no systemic treatment, including vitiligo, psoriasis and alopecia, are acceptable; patients win T1DM controlled by insulin therapy, or patients with completely-relieved childhood asthma requiring no intervention in adulthood are acceptable; patients with asthma requiring bronchodilator intervention will be excluded.
• •20. Patients who received immunosuppressive drug or systemic hormone therapy to achieve immunosuppression (prednisone\>10mg/d or hormones of equivalent effects) within preceding 14 days.
• •21. Patients who received strong CYP3A4/CYP2C19 inducer including rifampin (and its analogs) and hypericum perforatum or strong CYP3A4/CYP2C19 inhibitor within preceding 14 days.
• •22. Patients who have a history of severe allergies to any monoclonal antibody or anti-angiogenic targeted drugs.
• •23. Patients who had severe infection within preceding 4 weeks including, but not limited to: infection, bacteremia and complications of severe pneumonia resulting in hospitalization; or patients who received therapeutic antibiotics orally or intravenously within preceding 2 weeks (prophylactic usage of antibiotics \[e.g., prevention of urinary tract infection or exacerbation of COPD\] is acceptable).
• •24. Patients with innate or acquired immunodeficiency (e.g., patients infected with HIV)
• •25. Patients who previously received anti-PD-1 therapy or other immunotherapies targeting PD-1/PD-L1, or tyrosine kinase inhibitor therapy.
• •26. Palliative radiotherapy for non-target lesions to control symptoms is acceptable, but should be completed at least 2 weeks prior with adverse events not recovering to ≤CTCAE grade 1
• •27. Patients who received attenuated live vaccine within preceding 28 day, or who are expected to receive the vaccine during sintilimab treatment or within 60 days after the last dose of sintilimab.
• •28. Patients who received anti-tumor cytotoxic chemotherapy, biotherapy (e.g., monoclonal antibody), immunotherapy (e.g., IL-2 or interferon) or other investigational drugs within 4 weeks prior to registration.
• •29. Patients with other factors that may affect the outcomes or lead to withdrawal (judged by the researcher), including alcohol abuse, drug abuse, other serious disease (including mental illness) requiring combined treatment, significantly abnormal laboratory test index, and family or society factors that may affect patient safety.
• •30. Patients who previously received antitumor therapy and prior toxicity has not recovered to CTCAE grade 0-1, aside from the following conditions:
• •1. alopecia;
• •2. hyperpigmentation;
• •3. peripheral neurotoxicity recovered to \< CTCAE grade 2;
• •4. long-term toxicity caused by radiotherapy cannot recover (judged by the researcher).
• •31. Patients who have active tuberculosis(TB) and are receiving anti-TB therapy, or who received anti-TB therapy within 1 year prior to screening.
• •32. Patients who are pregnant or lactating. -