Anlotinib Plus Nab-Paclitaxels and S-1 for Patients with Advanced Biliary Tract Cancer As Second-Line Treatment

Anlotinib Plus Nab-Paclitaxels and S-1 Versus FOLFOX for Patients with Advanced Biliary Tract Cancer As Second-Line Treatment: a Phase 2/3, Multi-centric Double-stage Randomized Controlled Trial

Biliary tract cancer (BTC) presents with a 5-year survival rate less than 5%. The goal of this clinical trial is to evaluate if Anlotinib plus Nab-Paclitaxels and S-1 as second-line regimen can improve the treatment efficacy in advanced biliary tract cancer (BTC) after progression upon first-line standard treatment, in comparison with standard second-line FOLFOX regimen.

Biliary tract cancer (BTC) mainly includes intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma, and the 5-year survival rate is less than 5%. Most patients were diagnosed as advanced stage, and missed the opportunity of radical surgery. ABC-02 study established gemcitabine combined with platinum drugs as the first-line standard treatment for unresectable BTC. However, after the disease progresses, the second-line treatment options and efficacies are limited. In recent years, BTC second-line treatment has made some breakthroughs in the field of chemotherapy and targeted therapy. However, the benefits of chemotherapy, immunotherapy and targeted drugs alone in the second line treatment of BTC is unsatisfactory. The combined scheme of two or three drugs sees the possibility of patients benefiting, but it still needs better scheme design and larger sample size for further verification. A phase II single-arm small-sample clinical trial exploring albumin-bound paclitaxel combined with S-1 capsule in the first-line treatment of advanced biliary adenocarcinoma initially showed the efficacy and safety of AS regimen in cholangiocarcinoma, and the efficacy and safety of Anlotinib in BTC were also confirmed in the small-sample study. Therefore, this study intends to explore the efficacy and safety of the second-line treatment of advanced BTC with Anlotinib combined with AS chemotherapy in comparison with the establised standard second-line regimen (FOLFOX).

Inclusion Criteria:

1. Signed a written informed consent form before enrollment;
2. Age >18 years, both male and female are eligible;
3. Patients with pathologically confirmed advanced biliary tract that has progressed after first-line gemcitabine-based therapy;
4. Have measurable lesions (according to RECIST 1.1 criteria, non-lymph node lesions with a long diameter ≥10 mm on CT scan, or lymph node lesions with a short diameter ≥15 mm on CT scan);
5. ECOG Performance Status (PS) score: 0-1;
6. Expected survival time longer than 12 weeks;
7. Key organ functions meet the following criteria (without the use of any blood components or growth factors within 14 days): Hematology: Neutrophils ≥1.5×10⁹/L; Platelet count ≥100×10⁹/L; Hemoglobin ≥ 90 g/L; Liver and kidney function: Serum creatinine (SCr) ≤ 1.5 times the upper limit of normal (ULN) or creatinine clearance rate ≥50 ml/min (Cockcroft-Gault formula); Total bilirubin (TBIL) ≤ 1.5 times the ULN; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ≤ 2.5 times the ULN (if abnormal liver function is due to liver metastasis, then ≤ 5 times the ULN); urine protein < 2+; if urine protein ≥ 2+, 24-hour urine protein quantification must show protein ≤1g;
8. Normal coagulation function, no active bleeding or thrombotic diseases: International Normalized Ratio (INR) ≤ 1.5 × ULN; Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN; Prothrombin Time (PT) ≤ 1.5 × ULN;
9. The subject voluntarily participates in this study, has good compliance, and is willing to cooperate with safety and survival follow-ups.

Exclusion Criteria:

1. Subjects with a history of or concurrent malignancies, except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix;
2. Known allergy to macromolecular protein preparations or known hypersensitivity to the components of the administered drugs;
3. Subjects with existing thyroid dysfunction that cannot be maintained within the normal range by medication;
4. Uncontrolled hypertension despite optimal treatment, defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg;
5. Subjects with uncontrolled cardiac clinical symptoms or diseases, such as: (1) heart failure above NYHA class II, (2) unstable angina, (3) myocardial infarction within the past year, (4) clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention;
6. Subjects with any active autoimmune disease or a history of autoimmune disease;
7. Subjects using immunosuppressive agents or systemic or absorbable local corticosteroids for immunosuppressive purposes (prednisone dose >10 mg/day or equivalent efficacy corticosteroids) who continue to use them within 2 weeks before enrollment;
8. Subjects with central nervous system metastases;
9. Subjects with active infections or unexplained fever >38.5°C during screening or before the first dose (subjects with tumor-related fever, as judged by the investigator, may be enrolled);
10. Subjects with significant hemoptysis (fresh blood) within 2 months before enrollment or daily hemoptysis volume ≥2.5 ml;
11. Subjects with any condition that may increase the risk of gastrointestinal bleeding or perforation, such as active peptic ulcers, known intraluminal metastatic lesions, inflammatory bowel disease, history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days before the start of the study;
12. Subjects with a history or current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired lung function;
13. Subjects with a history or current evidence of bronchiectasis, cavitary pulmonary tuberculosis, lung abscess, rheumatic heart disease with mitral valve stenosis, or cardiogenic pulmonary edema, which could cause hemoptysis;
14. Subjects with congenital or acquired immune deficiencies, such as those infected with HIV or with active hepatitis (transaminase levels not meeting inclusion criteria, hepatitis B reference: HBV DNA ≥1000 IU/ml; hepatitis C reference: HCV RNA ≥1000 IU/ml);
15. Subjects who have received or may receive a live vaccine within 4 weeks before or during the study;
16. Subjects with a known history of psychiatric drug abuse, alcoholism, or drug addiction;
17. Pregnant or breastfeeding women or those planning to conceive during the study period;
18. Subjects whom the investigator deems should be excluded from the study, such as those with factors that may lead to early termination of the study.