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

Official title

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

Overview

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.

Detailed description

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).

Interventions

• Drug Albumin-bound Paclitaxel + Tegafur Gimeracil Oteracil (S-1) + Anlotinib
  Albumin-bound Paclitaxel, 125mg/m2,iv.drip,d1,d8,Q3W +Tegafur Gimeracil Oteracil (S-1) 40-60mg,p.o,bid,d1-d14,Q3W+Anlotinib 10mg,p.o,d1-d14,Q3W
• Drug Oxaliplatin + Leucovorin + Fluorouracil (FOLFOX regimen)
  Oxaliplatin 85 mg/m2,d1,iv.drip,Q2W + Leucovorin 400mg/m2,d1,iv.drip,Q2W+ Fluorouracil 2400 mg/m2 civ46h, Q2W

Primary outcome measures

• Overall Survival [Time frame: From randomisation to death, up to 5 years]
• Progression-Free Survival [Time frame: From randomisation to disease progression or death, up to 5 years]

Secondary outcome measures (2)

• Objective Response Rate [Time frame: From randomisation, up to 5 years]
• Disease control rate [Time frame: From randomisation, up to 5 years]

Eligibility criteria

Inclusion criteria

• Signed a written informed consent form before enrollment;
• Age >18 years, both male and female are eligible;
• Patients with pathologically confirmed advanced biliary tract that has progressed after first-line gemcitabine-based therapy;
• 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);
• ECOG Performance Status (PS) score: 0-1;
• Expected survival time longer than 12 weeks;
• 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;
• 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;
• The subject voluntarily participates in this study, has good compliance, and is willing to cooperate with safety and survival follow-ups.

Exclusion criteria

• Subjects with a history of or concurrent malignancies, except for cured basal cell carcinoma of the skin or carcinoma in situ of the cervix;
• Known allergy to macromolecular protein preparations or known hypersensitivity to the components of the administered drugs;
• Subjects with existing thyroid dysfunction that cannot be maintained within the normal range by medication;
• Uncontrolled hypertension despite optimal treatment, defined as systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg;
• 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;
• Subjects with any active autoimmune disease or a history of autoimmune disease;
• 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;
• Subjects with central nervous system metastases;
• 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);
• Subjects with significant hemoptysis (fresh blood) within 2 months before enrollment or daily hemoptysis volume ≥2.5 ml;
• 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;
• Subjects with a history or current evidence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severely impaired lung function;
• 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;
• 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);
• Subjects who have received or may receive a live vaccine within 4 weeks before or during the study;
• Subjects with a known history of psychiatric drug abuse, alcoholism, or drug addiction;
• Pregnant or breastfeeding women or those planning to conceive during the study period;
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• The First Affiliated Hospital of Sun Yat-sen University — Guangzhou

Publications

• Zhang W, Sun Y, Jiang Z, Qu W, Gong C, Zhou A. Nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) as first-line treatment for advanced biliary tract adenocarcinoma: a phase 2 clinical trial. Hepatobiliary Surg Nutr. 2023 Feb 28;12(1):37-44. doi: 10.21037/hbsn-21-172. Epub 2021 Oct 18. PMID 36860259
• Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, Zhao F, Ahmad R, Zhao J. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. 2018 Sep 19;11(1):120. doi: 10.1186/s13045-018-0664-7. PMID 30231931
• Klein O, Kee D, Nagrial A, Markman B, Underhill C, Michael M, Jackett L, Lum C, Behren A, Palmer J, Tebbutt NC, Carlino MS, Cebon J. Evaluation of Combination Nivolumab and Ipilimumab Immunotherapy in Patients With Advanced Biliary Tract Cancers: Subgroup Analysis of a Phase 2 Nonrandomized Clinical Trial. JAMA Oncol. 2020 Sep 1;6(9):1405-1409. doi: 10.1001/jamaoncol.2020.2814. PMID 32729929
• Li X, Zhou N, Yang Y, Lu Z, Gou H. Efficacy and biomarker analysis of second-line nab-paclitaxel plus sintilimab in patients with advanced biliary tract cancer. Cancer Sci. 2024 Jul;115(7):2371-2383. doi: 10.1111/cas.16179. Epub 2024 Apr 18. PMID 38638055
• Lim SH, Hong JY, Park JO, Park YS, Kim ST. Pemetrexed and Erlotinib as a Salvage Treatment in Patients With Metastatic Biliary Tract Cancer Who Failed Gemcitabine-containing Chemotherapy: A Phase II Single-arm Prospective Study. Anticancer Res. 2023 Sep;43(9):4161-4167. doi: 10.21873/anticanres.16607. PMID 37648323
• Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DV, Borad MJ, Bridgewater J, Harris WP, Murphy AG, Oh DY, Whisenant J, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Fan B, Wu B, Chamberlain CX, Jiang L, Gliser C, Pandya SS, Valle JW, Zhu AX. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double- PMID 32416072
• Merters J, Lamarca A. Integrating cytotoxic, targeted and immune therapies for cholangiocarcinoma. J Hepatol. 2023 Mar;78(3):652-657. doi: 10.1016/j.jhep.2022.11.005. Epub 2022 Nov 15. PMID 36400328
• Yoo C, Kim KP, Jeong JH, Kim I, Kang MJ, Cheon J, Kang BW, Ryu H, Lee JS, Kim KW, Abou-Alfa GK, Ryoo BY. Liposomal irinotecan plus fluorouracil and leucovorin versus fluorouracil and leucovorin for metastatic biliary tract cancer after progression on gemcitabine plus cisplatin (NIFTY): a multicentre, open-label, randomised, phase 2b study. Lancet Oncol. 2021 Nov;22(11):1560-1572. doi: 10.1016/S147 PMID 34656226

Identifiers

NCT: NCT06662877 · IIT-2024-658

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗