Phase 2 Trial of Adjuvant Adebrelimab Combined With Capecitabine in High-Risk Resected Cholangiocarcinoma: ACHIEVE

Postoperative adjuvant therapy for biliary system tumors has long lacked a universally recognized standard regimen. The BILCAP trial results showed a survival benefit with adjuvant therapy. The BILCAP study filled the gap in the field of postoperative adjuvant therapy for biliary system tumors. In the study, the median overall survival (OS) in the capecitabine group was 51.1 months, compared to 36.4 months in the observation group. The median recurrence-free survival (RFS) in the capecitabine group was 24.4 months, compared to 17.5 months in the observation group. Compared to the observation group, adjuvant therapy with capecitabine significantly prolonged both OS and RFS, and the capecitabine group had good tolerability with no chemotherapy-related deaths. In addition, the ASCOT study reported that adjuvant therapy with tegafur after surgery could prolong the RFS rate in patients. Therefore, in the NCCN and CSCO guidelines, capecitabine is listed as a category I recommendation for adjuvant therapy of biliary tract malignancies (BTC). However, it is regrettable that the latest reports show that in the intention-to-treat (ITT) population, the BILCAP trial failed to reach its primary endpoint of OS, with the median OS in the study group and the control group being 51.1 months and 36.4 months, respectively [HR=0.81, 95% CI(0.63,1.04), P=0.097]. Furthermore, in clinical practice, the use of capecitabine or tegafur after surgery in patients with cholangiocarcinoma at high risk of recurrence still has a high recurrence rate. Therefore, there is still a significant unmet need in the clinical postoperative adjuvant therapy for biliary tract malignancies.Based on the above background, we plan to carry out a randomized, open, and comparative study to observe the efficacy and safety of Adebrelimab combined with capecitabine for adjuvant treatment in patients with biliary tract malignancies after surgery, and to explore treatment methods to improve the efficacy of postoperative adjuvant treatment for cholangiocarcinoma.

Inclusion criteria

• Patients must sign an informed consent form;
• Ages 18-75, both genders eligible;
• ECOG performance status score (PS score) of 0 or 1;
• Patients with histologically confirmed cholangiocarcinoma (including intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma), who have undergone R0 resection and have high-risk factors for recurrence;

High-risk factors are defined as follows:

Intrahepatic cholangiocarcinoma ( Single tumor > 5 cm, multiple tumors, liver capsule breach, vascular invasion, regional lymph node metastasis) Hilar cholangiocarcinoma (Tumor invasion into surrounding tissues, vascular invasion, regional lymph node metastasis)

• No evidence of recurrence or metastatic lesions on imaging within 28 days prior to randomization;
• No prior systemic anti-cancer therapy (including radiotherapy, chemotherapy, targeted therapy, immunotherapy) before curative resection;
• Laboratory test values within 7 days prior to the first dose of study medication meet the following criteria:

Complete blood count: (except for hemoglobin, no blood transfusion or use of granulocyte colony-stimulating factor [G-CSF], no medication correction within 2 weeks prior to screening):

Absolute neutrophil count ≥1.5×109/L; Platelets ≥75×109/L; Hemoglobin ≥90 g/L;

Biochemical tests:

Serum albumin ≥30g/L; Serum total bilirubin ≤1.5×ULN; ALT and AST ≤3×ULN; Serum creatinine ≤1.5×ULN; or Cr clearance rate >50 mL/min International normalized ratio (INR) ≤1.2 or prothrombin time (PT) exceeding the normal control range by ≤2 seconds; Urine protein <2+ (if urine protein ≥2+, a 24-hour (h) urine protein quantification can be performed, and a 24h urine protein quantification of <1.0g is eligible for enrollment);

• Life expectancy of more than 6 months.

Exclusion criteria

• Pathological diagnosis of mixed hepatocellular carcinoma and other non-hepatic extra-bile duct cholangiocarcinoma or ampulla of Vater malignant tumor components;
• History of prior systemic treatment;
• History of or concurrent other malignancies, excluding non-melanoma skin cancer, cervical carcinoma in situ, and papillary thyroid carcinoma that have been adequately treated;
• Active tuberculosis infection. Patients with active tuberculosis infection within 1 year prior to enrollment; history of active tuberculosis infection more than 1 year prior to enrollment without proper anti-tuberculosis treatment or tuberculosis is still active;
• History of autoimmune diseases or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis;
• Requirement for long-term systemic corticosteroids (dosage equivalent to >10mg prednisone/day) or any other form of immunosuppressive treatment. Subjects using inhaled or topical corticosteroids may be included;
• Severe cardiopulmonary or renal dysfunction;
• Inadequately controlled arterial hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) (based on the average of ≥2 blood pressure readings), allowing the achievement of the above parameters through the use of antihypertensive treatment; history of hypertensive crisis or hypertensive encephalopathy;
• Within 3 months prior to enrollment, significant clinical bleeding symptoms or a clear tendency to bleed; abnormal coagulation function (PT >14s), tendency to bleed, or undergoing thrombolytic or anticoagulant therapy;
• HBV DNA >2000 IU/ml, active HCV infection (positive HCV antibody and HCV-RNA level above the lower limit of detection);
• Active infection requiring systemic treatment;
• Human immunodeficiency virus (HIV, HIV1/2 antibody) positive;
• History of psychiatric medication abuse, alcoholism, or drug addiction;
• History of allergy to study medication;
• Other factors deemed by the investigator to potentially affect subject safety or trial compliance. Such as severe diseases requiring concurrent treatment (including psychiatric diseases), severe laboratory test abnormalities, or other family or social factors.