Gemcitabine-Cisplatin Plus Envafolimab in Resectable Biliary Tract Malignancies

Official title

The Efficacy and Safety of Gemcitabine-Cisplatin Plus Envafolimab as Neoadjuvant Therapy in Resectable Biliary Tract Malignancies at High Risk of Recurrence

Overview

This trial is to evaluate the efficacy of Gemcitabine-Cisplatin (GC) plus Envafolimab neoadjuvant therapy in the patients at high risk of recurrence. Primary endpoint: Major Pathologic Response (MPR). It will also learn about the safety of drug including Gemcitabine-Cisplatin (GC) plus Envafolimab as a neoadjuvant therapy in this trial.

Detailed description

This trial is a single-arm interventional clinical study to evaluate the efficacy and safety of neoadjuvant gemcitabine-cisplatin plus Envafolimab in resectable biliary tract malignancies patients with high-risk of recurrence. Patients with high-risk factors for recurrence. The criteria were defined as meeting at least one of the following: a. Preoperative CA19-9 ≥ 200 U/mL; b. Tumor diameter ≥5 cm or multiple tumor nodules on imaging; c. Regional lymph node metastasis with a short-axis diameter ≥ 1.0 cm on imaging; d. Vascular invasion (portal vein or hepatic artery) on imaging; e. Low or undifferentiated histologic grade. The primary endpoint: Major Pathologic Response (MPR). Secondary endpoints: Overall Survival (OS), Disease-free survival (DFS), Objective Response Rate (ORR) per the Response Evaluation Criteria In Solid Tumors (RECIST v1.1), Pathologic Response Rate (PCR), and R0 resection rate. The incidence and severity of adverse events (AEs), serious adverse events (SAEs), and laboratory test abnormalities judged as per the CTCAE v5.0 criteria. Exploratory endpoint: Relationship between carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 125 (CA125), Pathological biomarker expression, spatial transcriptome (if samples are sufficient), gut microbiome metagenome sequencing, and treatment response.

Interventions

• Drug Neoadjuvant therapy followed by surgery
  First: Envafolimab: 400 mg on Day 1, repeated every 3 weeks (Q3W). GC chemotherapy: Gemcitabine: 1000 mg/m2 in 100 mL of 0.9% sodium chloride injection, administered intravenously over 30 minutes on Days 1 and 8, repeated Q3W. Cisplatin: 25 mg/m2 in 500 mL of 5% glucose injection, administered intravenously over 2 hours on Day 1 and 8, repeated Q3W. Of note, no target drugs is involved. Second: Radical resection eligibility will be assessed by the investigator; those with indeterminate resec

Primary outcome measures

• Major Pathologic Response (MPR) [Time frame: From enrollment to 2-4 weeks after completion of thrid cycle (each cycle is 21 days) of neoadjuvant therapy, surgical pathological findings will be obtained, or patients will be assessed as unresectable.]

Secondary outcome measures (6)

• Residual viable tumor cell ratio [Time frame: From enrollment to 2-4 weeks after completion of thrid cycle (each cycle is 21 days) of neoadjuvant therapy, surgical pathological findings will be obtained, or patients will be assessed as unresectable.]
• Objective Response Rate (ORR) [Time frame: From enrollment until 2-4 weeks after completion of neoadjuvant therapy (three cycles, each cycle is 21 days)]
• Pathologic Response Rate (PCR) [Time frame: From enrollment to 2-4 weeks after completion of thrid cycle (each cycle is 21 days) of neoadjuvant therapy, surgical pathological findings will be obtained, or patients will be assessed as unresectable.]
• R0 resection [Time frame: From enrollment to 2-4 weeks after completion of thrid cycles (each cycle is 21 days) of neoadjuvant therapy, surgical pathological findings will be obtained, or patients will be assessed as unresectable.]
• Overall Survival (OS) [Time frame: From enrollment up to 2 years following treatment initiation]
• Disease-free survival (DFS) [Time frame: From enrollment up to 2 years following treatment initiation]

Eligibility criteria

Inclusion criteria

• Participants who have signed a written Informed Consent Form (ICF);
• Male or female participants aged 18-80 years;
• Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0/1;
• Biliary Tract Cancer (BTC) diagnosed by puncture pathology prior to enrollment;
• Participants must meet the following requirements for major vital organ function: a. Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L; platelet count ≥ 90×10⁹/L; hemoglobin ≥ 9 g/dL; b. Coagulation function: international normalized ratio (INR) ≤ 1.2; c. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3 times the upper limit of normal (ULN); d. Serum albumin ≥ 3.5 g/dL; total bilirubin ≤ 1.5 times the ULN. Patients with obstructive jaundice who meet the eligibility criteria after percutaneous transhepatic cholangial drainage or endoscopic retrograde cholangiopancreatography treatment are also eligible for enrollment; e. Child-Pugh class A or B; f. Serum creatinine ≤ 1.5 times the ULN;
• Patients with high-risk factors for recurrence. The criteria are defined as meeting at least one of the following: a. Preoperative CA19-9 ≥ 200 U/mL; b. Tumor diameter ≥ 5 cm or multiple tumor nodules on imaging; c. Regional lymph node metastasis with a short-axis diameter ≥ 1.0 cm on imaging; d. Vascular invasion (portal vein or hepatic artery) on imaging; e. Low or undifferentiated histologic grade;
• Participants who have at least 1 measurable lesion (RECIST v1.1);
• Be able to provide fresh stool samples and liver samples if undergoing surgery.

Exclusion criteria

• Pathological diagnosis of hepatocellular carcinoma, mixed hepatocellular carcinoma, and other non-cholangiocarcinoma malignant tumor components;
• Prior systemic therapy for BTC, including immunotherapy, targeted therapy, or chemotherapy;
• History of other prior or concurrent malignancies, except those with complete treatment and disease-free survival for more than 5 years;
• Presence of an active, known or suspected autoimmune disease, or requirement for long-term systemic corticosteroid therapy (equivalent to ≥ 10 mg prednisone daily) or other immunosuppressive agents. Participants using inhaled or topical corticosteroids will not be excluded;
• Presence of ascites, hepatic encephalopathy, sclerosing cholangitis, or other concurrent organ dysfunctions that would preclude tolerance of general anesthesia or hepatectomy;
• Women who are breastfeeding or pregnant;
• Any other factors that, in the investigator's judgment, may compromise participant safety or trial compliance, including serious comorbidities requiring ongoing treatment, clinically significant laboratory abnormalities, or relevant social or family-related issues.

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

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Valle JW, Kelley RK, Nervi B, Oh DY, Zhu AX. Biliary tract cancer. Lancet. 2021 Jan 30;397(10272):428-444. doi: 10.1016/S0140-6736(21)00153-7. PMID 33516341
• Zhao Z, Wu H, Han J, Jiang K. Global trends and disparities in gallbladder and biliary tract cancers: insights from the global burden of disease study 2021. Eur J Gastroenterol Hepatol. 2025 May 1;37(5):573-584. doi: 10.1097/MEG.0000000000002947. Epub 2025 Feb 14. PMID 39975993
• Wang Y, Xun Z, Yang X, Wang Y, Wang S, Xue J, Zhang N, Yang X, Lu Z, Zhou J, Zhou K, Sang X, Zhao H. Local-regional therapy combined with toripalimab and lenvatinib in patients with advanced biliary tract cancer. Am J Cancer Res. 2023 Mar 15;13(3):1026-1037. eCollection 2023. PMID 37034211
• von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wulfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invas PMID 30516102
• Le Roy B, Gelli M, Pittau G, Allard MA, Pereira B, Serji B, Vibert E, Castaing D, Adam R, Cherqui D, Sa Cunha A. Neoadjuvant chemotherapy for initially unresectable intrahepatic cholangiocarcinoma. Br J Surg. 2018 Jun;105(7):839-847. doi: 10.1002/bjs.10641. Epub 2017 Aug 31. PMID 28858392
• Oh DY, Ruth He A, Qin S, Chen LT, Okusaka T, Vogel A, Kim JW, Suksombooncharoen T, Ah Lee M, Kitano M, Burris H, Bouattour M, Tanasanvimon S, McNamara MG, Zaucha R, Avallone A, Tan B, Cundom J, Lee CK, Takahashi H, Ikeda M, Chen JS, Wang J, Makowsky M, Rokutanda N, He P, Kurland JF, Cohen G, Valle JW. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evid. 2022 Aug;1 PMID 38319896
• Pereira RA, Barcellos G, Lenz G, Pereira AAL, Biachi de Castria T. Neoadjuvant Chemotherapy in Resectable Biliary Tract Cancer: A Systematic Review and Metanalysis. J Surg Oncol. 2026 Mar;133(3):313-325. doi: 10.1002/jso.70169. Epub 2025 Dec 22. PMID 41424434
• Chen F, Sheng J, Li X, Gao Z, Hu L, Chen M, Fei J, Song Z. Tumor-associated macrophages: orchestrators of cholangiocarcinoma progression. Front Immunol. 2024 Sep 3;15:1451474. doi: 10.3389/fimmu.2024.1451474. eCollection 2024. PMID 39290697

Identifiers

NCT: NCT07599995 · SRRSH

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗