Overview

Patients with advanced biliary tract malignant tumors who had not received systematic treatment before and could not be cured were selected as the subjects of the study. The primary endpoint of the study was investigator-assessed 6-month progression-free survival (6-month PFS%) based on the RECIST v1.1 criteria, and 43 subjects were planned to be enrolled. Patients eligible for enrollment will receive Adebrelimab and a tyrosine kinase inhibitor (TKI) in combination with gemcitabine and oxaliplatin (GEMOX).

Eligibility

Inclusion Criteria:

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1. The patient voluntarily participated in the study and signed the informed consent;

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       2) ≥ 18 years old (calculated on the day of signing the informed consent), male or
          female;

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       3) Patients with advanced biliary tract malignant tumors confirmed by
          histopathology or cytology;

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       4) Subjects must be able to provide fresh or archived tumor tissue
          (formalin-fixed, paraffin-embedded [FFPE] blocks or at least 5 unstained FFPE
          slides) and their pathology reports. If less than 5 unstained slides are
          available from the subject or tumor tissue is not available (e.g., because of
          exhaustion of previous diagnostic tests), enrollment may be allowed on a
          case-by-case basis after discussion;

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       5) The subject is not suitable for surgery, or has progressed after surgery and/or
          local treatment;

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       6) Patients with progression after local therapy, where local therapy (including
          but not limited to surgery, radiotherapy, arterial embolization, arterial
          infusion, radiofrequency ablation, cryoablation, or percutaneous ethanol
          injection) has been completed at least 4 weeks prior to the baseline imaging
          scan, Toxicity (except alopecia) caused by topical treatment must be restored
          to the National Cancer Institute-Common Terminology Criteria for Adverse
          Events, Version 5.0 (NCI-CTCAE v5.0) rating ≤ 1;

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7) No previous systemic therapy for BTC

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       8) At least one measurable lesion (according to the requirements of RECIST v1.1,
          the long diameter of the measurable lesion on spiral CT scan is ≥ 10 mm or the
          short diameter of the enlarged lymph node is ≥ 15 mm; the lesion that has
          received local treatment in the past can be used as the target lesion after the
          progress is confirmed according to the criteria of RECIST v1.1)

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       9) The physical condition score of the Eastern Cooperative Oncology Group (ECOG)
          was 0 ~ 2 (see Attachment 1 for the ECOG score standard);

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10) Expected survival ≥ 12 weeks;

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      11) The functions of main organs are basically normal, and there are serious
          abnormalities of blood, heart, lung, liver, kidney, bone marrow and other
          functions and immunodeficiency diseases, which meet the requirements of the
          protocol: A) Blood routine examination: (except for hemoglobin, no blood
          transfusion within 14 days before screening, no use of granulocyte
          colony-stimulating factor [G-CSF], and no use of corrective therapy within 7
          days) I. Hemoglobin ≥ 90 G/L; II. Neutrophil count ≥ 1.5 × 109/L; III. Platelet
          count ≥ 50 × 109/L; B) Biochemical examination: (no albumin transfusion within
          14 days) I. Serum albumin ≥ 29 G/L; II. Alanine aminotransferase (ALT) and
          aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN); III.
          Total bilirubin (TBIL) ≤ 1.5 times ULN;

IV. Creatinine Cr ≤ 1.5 X ULN or Cr clearance > 50 mL/min (Cockcroft-Gault formula below):

Male: Cr clearance = ( (140-age) × body weight)/ (72 × blood Cr) Female: Cr clearance = ( (140-age) × body weight)/ (72 × blood Cr) × 0.85 Weight unit: kg; Blood Cr unit: mg/mL; V. Urine protein < 2 + (if urine protein ≥ 2 +, 24-hour (H) urine protein can be quantified, and 24-hour urine protein < 1.0 G can be included in the group); C) Coagulation function: activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN (can be screened for the use of stable dose of anticoagulant therapy such as low molecular weight heparin or warfarin and INR is within the expected therapeutic range of anticoagulant); D) Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be examined, and if T3 and T4 levels are normal, they can be included; Color Doppler echocardiography: left ventricular ejection fraction (LVEF) was greater than or equal to 60%.

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      12) Fertile women: must agree to abstain from sex (abstain from heterosexual
          intercourse) or use a reliable, effective method of contraception for at least
          120 days from the signing of the informed consent until the final
          administration of the study drug. Serum HCG test must be negative within 7 days
          before the start of study treatment; And must be non-lactating. A woman is
          considered fertile if she has menstruated, has not yet reached postmenopausal
          status (no continuous periods for ≥12 months, no cause other than menopause is
          found), and has not undergone sterilization (such as hysterectomy, bilateral
          tubal ligation, or bilateral oophorectomy).

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      13) For male patients whose partner is a woman of reproductive age, they must agree
          to abstain from sex for at least 120 days from the signing of the informed
          consent until the final administration of the study drug, or to use a reliable
          and effective method of contraception. Male subjects also had to agree not to
          donate sperm during the same time period. Male subjects with a pregnant partner
          are required to use condoms and do not need to use other methods of
          contraception.

Exclusion Criteria:

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1. Active malignancies other than BTC within 5 years or at the same time. Cured localized tumors, such as skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder carcinoma, prostate carcinoma in situ, cervical carcinoma in situ, breast carcinoma in situ, etc., could be included in the group.

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       2) Patients who are preparing for or have previously received organ or allogeneic
          bone marrow transplantation;

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       3) Other investigational drug treatment received within 28 days prior to the start
          of study treatment;

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       4) Moderate and severe ascites with clinical symptoms, i.e. requiring therapeutic
          puncture, drainage or Child-Pugh score > 2 (except for those with only a small
          amount of ascites on imaging but without clinical symptoms); uncontrolled or
          moderate or more pleural effusion and pericardial effusion;

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       5) If there is a history of gastrointestinal bleeding or a definite tendency of
          gastrointestinal bleeding within 6 months before the start of study treatment,
          such as bleeding risk or severe esophageal and gastric varices, local active
          gastrointestinal ulcer lesions, and persistent positive fecal occult blood,
          they should not be included in the group (if the fecal occult blood is positive
          at baseline, it can be reexamined, and if it is still positive after
          reexamination, Gastroduodenal endoscopy (EGD) is required, and esophagogastric
          varices with EGD suggesting a risk of bleeding are not eligible);

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       6) Abdominal fistula, gastrointestinal perforation, or abdominal abscess within 6
          months prior to the start of study treatment;

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       7) Known presence of inherited or acquired bleeding (e.g., coagulopathy) or
          thrombophilia, e.g., in patients with hemophilia; current or recent (within 10
          days prior to the start of study treatment) use of full-dose oral or injectable
          anticoagulants or thrombolytics for therapeutic purposes (low-dose aspirin,
          low-molecular-weight heparin, prophylactic use permitted);

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       8) current or recent use (within 10 days prior to study treatment) of aspirin (>
          325 mg/day (maximum antiplatelet dose) or dipyridamole, ticlopidine,
          clopidogrel, and cilostazol;

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       9) Thrombotic or embolic events, such as cerebrovascular accident (including
          transient ischemic attack, cerebral hemorrhage, cerebral infarction), pulmonary
          embolism, etc., occurred within 6 months before the start of study treatment;

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      10) Clinical symptoms or diseases of the heart that are not well controlled, such
          as:
       1. LVEF (left ventricular ejection fraction) < 50% according to New York Heart
          Association (NYHA) standard II or above cardiac dysfunction or cardiac color
          Doppler ultrasound examination;
       2. unstable angina pectoris;
       3. Myocardial infarction within 1 year prior to the start of study treatment;
       4. Supraventricular or ventricular arrhythmias of clinical significance require
          treatment or intervention;
       5. QTc > 450ms (male); QTc > 470ms (female) (QTc interval is calculated by
          Fridericia formula; if QTc is abnormal, it can be detected three times at an
          interval of 2 minutes, and the average value is taken);

• 11)Hypertension that is not well controlled by antihypertensive medication (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg) (based on the average of BP readings obtained from ≥ 2 measurements) allows the use of antihypertensive therapy to achieve the above parameters; previous hypertensive crisis or hypertensive encephalopathy;

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      12) Major vascular disease (e.g., aortic aneurysm requiring surgical repair or with
          recent peripheral arterial thrombosis) within 6 months prior to the start of
          study treatment; severe, unhealed or dehiscent wounds, and active ulcers or
          untreated fractures; Major surgery has been performed within 4 weeks prior to
          the start of study treatment (except for diagnosis) or is expected to be
          performed during the study period;

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      13) There is evidence of intra-abdominal pneumatosis that cannot be explained by
          puncture or recent surgery;

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      14) prior or present central nervous system metastasis; Metastatic disease
          involving major Airways or vessels (for example, total occlusion of the main
          portal vein or vena cava due to tumor invasion, where the main portal vein is
          the confluence of the splenic vein and the superior mesenteric vein and where
          the hepatic portal vein divides into left and right branches) or a large
          mediastinal tumor mass located in the center (< 30 mm from the carina) should
          be excluded from the group;

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      15) Patients with history of hepatic encephalopathy; Current interstitial pneumonia
          or interstitial lung disease, or a previous history of interstitial pneumonia
          or interstitial lung disease requiring hormone therapy, or other pulmonary
          fibrosis, organizing pneumonia that may interfere with the judgment and
          management of immune-related pulmonary toxicity (e. Bronchiolitis obliterans),
          pneumoconiosis, drug-associated pneumonia, idiopathic pneumonia, or evidence of
          active pneumonia on computed tomography (CT) images of the chest during the
          screening period, or subjects with severely impaired lung function, with a
          history of radiation pneumonitis in the permissive field; active tuberculosis;

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      16) Active autoimmune disease or history of autoimmune disease with potential for
          recurrence (including but not limited to: autoimmune hepatitis, interstitial
          pneumonia, uveitis, enteritis, hypophysitis, vasculitis, nephritis,
          hyperthyroidism, hypothyroidism [only subjects that can be controlled by
          hormone replacement therapy may be included]); Subjects with skin diseases that
          do not require systemic treatment such as vitiligo, psoriasis, alopecia,
          controlled type I diabetes mellitus on insulin therapy, or asthma that has
          completely resolved in childhood and does not require any intervention in
          adulthood may be included; asthma patients who require medical intervention
          with bronchodilators may not be included;

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      17) use of immunosuppressant or systemic hormone therapy for immunosuppression
          (dose > 10 mg/day prednisone or other iso-effective hormone) within 14 days
          prior to initiation of study treatment;

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18) Known history of severe allergy to any monoclonal antibody drug;

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      19) Severe infection within 4 weeks prior to the start of study treatment,
          including but not limited to hospitalization for complications of infection,
          bacteremia, or severe pneumonia; therapeutic antibiotics administered orally or
          intravenously within 2 weeks prior to the start of study treatment (patients
          receiving prophylactic antibiotics (e.g., to prevent urinary tract infection or
          exacerbation of chronic obstructive pulmonary disease are eligible for the
          study);

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20) patients with congenital or acquired immune deficiency (such as HIV infection);

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21) co-infection with hepatitis B and hepatitis C;

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      22) Have received live attenuated vaccine within 28 days prior to the start of
          study treatment or are expected to require such vaccine during treatment with
          or within 60 days of the last dose of Aderbelizumab In the judgment of the
          investigator, the patient has other factors that may affect the results of the
          study or lead to the forced termination of the study, such as alcoholism, drug
          abuse, other serious diseases (including mental illness) requiring combined
          treatment, serious laboratory abnormalities, accompanied by family or social
          factors, which will affect the safety of the patient.