Hepatic Arterial Infusion Chemotherapy Plus Envafolimab and Lenvatinib for First-Line Unresectable Advanced Biliary Tract Cancer

Official title

Safety and Efficacy of Hepatic Arterial Infusion Chemotherapy (GP Regimen) and Intra-arterial Infusion of Envafolimab Combined With Lenvatinib for Unresectable Advanced First-line Biliary Tract Cancer: A Multicenter, Phase Ib/II, Single-arm Clinical Study

Overview

Advanced biliary tract cancer has a poor prognosis and limited efficacy with current regimens. This multicenter single-arm phase Ib/II trial explores the efficacy and safety of HAI-GP chemotherapy combined with intraoperative arterial envafolimab and lenvatinib as first-line therapy for unresectable BTC. It conducts dose exploration to confirm the optimal dosage and evaluates clinical outcomes, aiming to establish a better comprehensive treatment strategy.

Interventions

• Drug HAIC Combined Regimen Treatment Group
  In Phase Ib, nine patients will be enrolled and allocated to three dose cohorts to receive the combination regimen of HAIC (GP) + intra-arterial infusion of envafolimab + lenvatinib. Dose-limiting toxicities (DLTs) will be monitored for 28 days following administration. If no DLTs occur, the regimen will be considered tolerable, and patients will continue follow-up until 60 days post-administration. Investigators confirm Phase II initiation and optimal dose per safety data. In Phase II, 20 subj

Primary outcome measures

• Primary endpoint for Phase Ib: Dose-Limiting Toxicity (DLT) [Time frame: Within 28 days after first dose (one safety observation cycle)]
• Primary endpoint for Phase II:Objective Response Rate (ORR) [Time frame: Every 6 weeks (every two 21-day treatment cycles), up to completion of maximum six 21-day combination treatment cycles]

Eligibility criteria

Inclusion criteria

Patients must meet all of the following inclusion criteria:

• Age between 18 years and \[missing value\] years, inclusive.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Histologically or cytologically confirmed biliary tract carcinoma, deemed unsuitable for radical surgical resection.
• At least one measurable lesion as determined by the investigator in accordance with mRECIST or RECIST version 1.1.
• Estimated life expectancy greater than 3 months.
• No prior systemic therapy or local anti-tumor treatment, except for surgery (biliary drainage is permitted).
• Patients who experience relapse more than 6 months after completion of postoperative adjuvant therapy may be enrolled.
• Child-Pugh score of \[missing value\] points.
• Adequate organ function to meet the criteria for chemotherapy:

• Bone marrow function: absolute neutrophil count ≥ \[missing value\]/L; platelet count ≥ \[missing value\]; hemoglobin ≥ \[missing value\];
• Hepatic function: total bilirubin ≤ \[missing value\] × upper limit of normal (ULN); for patients without liver metastases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ \[missing value\] × ULN; for patients with confirmed liver metastases, AST and ALT ≤ \[missing value\] × ULN;
• Renal function: serum creatinine ≤ \[missing value\] × ULN; routine urinalysis showing urinary protein < \[missing value\]; if baseline urinary protein is \[missing value\], a 24-hour urine collection must confirm total protein ≤ 1 g/24 h;
• Coagulation function: international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN; for patients receiving anticoagulant therapy, PT must be within the therapeutic range intended for the anticoagulant used.
• Female patients must be postmenopausal or, if premenopausal, have a negative urine or serum pregnancy test; male patients must agree to use effective contraception or have undergone surgical sterilization during the trial and for 8 weeks following the final dose of the study drug.

Exclusion criteria

Patients meeting any of the following criteria will be excluded:

• Known hypersensitivity to the investigational drug(s).
• Current participation in another interventional clinical trial, or receipt of any investigational drug or use of investigational device within 4 weeks prior to first dosing.
• History of malignancy outside the biliary tract within 5 years prior to first dosing, except for adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or carcinoma in situ that has been completely resected.
• Previous treatment with immune checkpoint inhibitors including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or drugs targeting other stimulatory or co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137).
• History of solid organ or hematopoietic stem cell transplantation.
• Any condition requiring systemic corticosteroids (equivalent to prednisone or above) or other immunosuppressive therapy within 14 days prior to randomization.
• Active autoimmune disease or history of autoimmune disease with potential for recurrence.
• Radiographic evidence of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), or prior noninfectious pneumonitis identified on screening chest computed tomography (CT).
• Severe infection within 4 weeks prior to randomization, including but not limited to hospitalization due to infectious complications, bacteremia, or severe pneumonia.
• Severe chronic or active infection (including tuberculosis) requiring systemic (oral or intravenous) antibiotic therapy within 14 days prior to randomization.
• Known history of Human Immunodeficiency Virus (HIV) infection (i.e., HIV-1/2 antibody positive); untreated active Hepatitis B. \*Note: Subjects with Hepatitis B meeting the following criteria are eligible: HBV viral load < 2000 copies/mL (200 IU/mL) prior to the first dose, with anti-HBV therapy administered throughout the chemotherapy period to prevent viral reactivation. For subjects who are anti-HBc (+), HBsAg (-), anti-HBs (-), and HBV viral load (-), prophylactic anti-HBV therapy is not required, but close monitoring for viral reactivation is necessary.\* Patients with active Hepatitis C infection (HCV antibody positive and HCV-RNA above the lower limit of detection) are excluded.
• Concurrent participation in another therapeutic clinical trial.
• Presence of obstructive jaundice (enrollment permitted following active intervention such as biliary drainage or stenting and subsequent normalization of liver function).
• Meeting any of the following cardiovascular criteria:

• New York Heart Association (NYHA) Class II or higher heart failure within 3 months prior to initiation of study treatment;
• Major cardiovascular events including myocarditis, myocardial infarction, cerebrovascular events, unstable arrhythmia, or unstable angina within 6 months prior to initiation of study treatment;
• Symptomatic pulmonary embolism within \[missing value\] months prior to randomization;
• Known artery disease or left ventricular ejection fraction (LVEF) < 40%.
• Lactating women.
• Women of childbearing potential unwilling to use contraception.
• Vulnerable populations other than elderly or illiterate individuals, including those with mental illness, cognitive impairment, or critical illness.
• Any other reason deemed by the investigator to render the subject unsuitable for study participation.

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

China · 1 center

• Study Chair Liu Chang , West China Hospital, Chengdu, Sichuan 610041 — Chengdu

Publications

• Jian Zhou FJ, Shi Guo-Ming, et al. . Gemox chemotherapy in combination with anti-PD1 antibody toripalimab and lenvatinib as first-line treatment for advanced intrahepatic cholangiocarcinoma: A phase 2 clinical trial. JOURNAL OF CLINICAL ONCOLOGY, 2021, 39(15_suppl):4094-4094 doi:10.1200/JCO.2021.39.15
• Victoria Ruiz I, Uboha NV, Jamal R, Mejia FC, Ahumada M, Im SA, Gomez-Roca C, Shapira-Frommer R, Perets R, Yanez E, Dutcus C, Okpara CE, Ghori R, Jin F, Groisberg R, Castanon E. Lenvatinib Plus Pembrolizumab for Patients With Previously Treated Advanced Colorectal Cancer: Results From the Phase II LEAP-005 Study. Clin Colorectal Cancer. 2026 Jun;25(2):225-238.e2. doi: 10.1016/j.clcc.2026.01.003. E PMID 41763955
• Li J, Deng Y, Zhang W, Zhou AP, Guo W, Yang J, Yuan Y, Zhu L, Qin S, Xiang S, Lu H, Gong J, Xu T, Liu D, Shen L. Subcutaneous envafolimab monotherapy in patients with advanced defective mismatch repair/microsatellite instability high solid tumors. J Hematol Oncol. 2021 Jun 21;14(1):95. doi: 10.1186/s13045-021-01095-1. PMID 34154614
• Macarulla T, Ren Z, Chon HJ, Park JO, Kim JW, Pressiani T, Li D, Zhukova L, Zhu AX, Chen MH, Hack SP, Wu S, Liu B, Guan X, Lu S, Wang Y, El-Khoueiry AB. Atezolizumab Plus Chemotherapy With or Without Bevacizumab in Advanced Biliary Tract Cancer: Clinical and Biomarker Data From the Randomized Phase II IMbrave151 Trial. J Clin Oncol. 2025 Feb 10;43(5):545-557. doi: 10.1200/JCO.24.00337. Epub 2024 O PMID 39423355
• Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klumpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a PMID 37075781
• Valle JW, Lamarca A, Goyal L, Barriuso J, Zhu AX. New Horizons for Precision Medicine in Biliary Tract Cancers. Cancer Discov. 2017 Sep;7(9):943-962. doi: 10.1158/2159-8290.CD-17-0245. Epub 2017 Aug 17. PMID 28818953
• Chai Y. Immunotherapy of biliary tract cancer. Tumour Biol. 2016 Mar;37(3):2817-21. doi: 10.1007/s13277-015-4743-x. Epub 2016 Jan 4. PMID 26729196
• Mu MY, Chen ZX, Cao YZ, Fu XB, Qiu LJ, Qi H, Gao F. Transarterial chemoembolization combined with intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: a phase 2 study. Cancer Lett. 2025 Sep 28;628:217851. doi: 10.1016/j.canlet.2025.217851. Epub 2025 Jun 3. PMID 40472923

Identifiers

NCT: NCT07636798 · 20261377

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗