Phase II Study of Trastuzumab Rezetecan Combined With Adebrelimab and Lenvatinib in Advanced HER2-Positive/Low-Expression Biliary Tract Cancer

A Prospective, Open-Label, Multicenter Phase II Study of Trastuzumab Rezetecan Combined With Adebrelimab and Lenvatinib for HER2-Positive or Low-Expression Locally Advanced or Metastatic Biliary Tract Cancer in the Second-Line or Later Setting

An investigation into the survival outcomes, progression-free survival, and safety of triple therapy with Trastuzumab Rezetecan, Adebrelimab, and Lenvatinib in patients with advanced HER2-positive/low-expressing biliary tract cancer after the failure of at least two prior systemic therapies.

Study Overview

• Status: Recruiting
• Conditions: Biliary Tract Neoplasms Immunotherapy
• Intervention / Treatment: Drug: Trastuzumab Rezetecan; Drug: Adebrelimab; Drug: Lenvatinib

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shuman Kuang; Phone Number: +86-10-69156042; Email: kuangshuman@163.com

Study Locations

• China
  • Beijing Municipality
    • Beijing, Beijing Municipality, China, 100730
      • Recruiting
      • Chinese Academy of Medical Sciences & Peking Union Medical College Hospital (CAMS&PUMCH)
      • Contact: Haitao Zhao, Professor; Phone Number: +861069156042; Email: zhaoht@pumch.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. The subjects voluntarily participated in the study and agreed to sign the written informed consent form, and they had good compliance.
2. Age: 18 years or above, Gender: Open to al
3. Locally advanced or metastatic cholangiocarcinoma confirmed by pathological histology or cytology, including cholangiocarcinoma (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma) and gallbladder cancer
4. Having progressed or experienced intolerance after at least one systemic treatment regimen in the past
5. HER2 positive (IHC 3+ or IHC 2+ and FISH detects HER2/CEP17 ≥ 2.0), HER2 low expression (IHC 2+/FISH- or IHC 1+)
6. There is at least one measurable lesion that meets the requirements of RECIST v1.1.
7. The ECOG score is between 0 and 1.
8. Expected survival period ≥ 12 weeks
9. The organs and bone marrow have sufficient functions and meet the following requirements: (within 14 days before starting the treatment): 1) Blood routine examination: (within 14 days before the screening, no blood transfusion, no use of granulocyte colony-stimulating factor [G-CSF], no use of drugs to correct): A. Hemoglobin (Hb) ≥ 90 g/L; B. Neutrophil count (ANC) ≥ 1.5 × 109/L; C. Platelet count (PLT) ≥ 75 × 109/L; 2) Blood biochemical examination should meet the following standards (within 14 days before the screening, no albumin transfusion): A. Serum total bilirubin [BIL] ≤ 2xULN (for Gibert syndrome patients, ≤ 3xULN); B. Alanine aminotransferase [ALT] and aspartate aminotransferase [AST] ≤ 3.0xULN; C. For patients with liver metastasis, ALT and AST should be ≤ 5xULN; Serum creatinine (Cr) ≤ 1.5xULN or endogenous creatinine clearance rate ≥ 50 ml/min (Cockcroft-Gault formula): Male: Cr clearance rate = ((140 - age) x weight) / (72 x blood Cr); Female: Cr clearance rate = ((140 - age) x weight) / (72 x blood Cr) x 0.85 (weight unit: kg; blood Cr unit: mg/mL)
10. For both male participants with fertile female partners and female participants with fertile partners, they must take effective contraceptive measures from the moment they sign the informed consent form until 7 months after the last administration of the test drug. During the same period, male participants must agree not to donate sperm, and female participants must agree not to donate eggs. For female participants with fertility, the serum HCG test must be negative within 7 days before the first administration of the drug, and they must be in the non-lactation period.

Exclusion Criteria:

1. Histopathological examination confirmed that the bile duct tumors were of non-adenocarcinoma pathological types such as ampullary carcinoma, small cell carcinoma, neuroendocrine tumor, sarcoma, mucinous cystic tumor, etc
2. Having another active malignant tumor within 5 years or simultaneously, excluding cervical carcinoma in situ that has been fully treated, as well as skin basal cell or squamous cell carcinoma
3. The adverse reactions from previous anti-tumor treatments have not yet recovered to a NCI-CTCAE v5.0 rating of ≤ 1 (excluding cases of hair loss, meeting the numerical requirements of the inclusion criteria, or other situations judged by the investigator not to affect the treatment with the study drug)
4. Any disease evidence determined by the researchers (such as severe or uncontrolled systemic diseases, including uncontrolled hypertension, moderate or severe ascites with clinical symptoms; uncontrollable or moderate to large amounts of pleural effusion, pericardial effusion, accompanied by acute or chronic uncontrolled pancreatitis, active bleeding disorders, active infections, active ILD/interstitial lung disease, severe chronic gastrointestinal diseases related to diarrhea, mental disorders/socioeconomic conditions) or the history of allogeneic organ or syngeneic bone marrow transplantation that the researchers consider makes the subject unsuitable for participation in the study or affects the compliance with the study protocol
5. History of severe cardiovascular and cerebrovascular diseases: Within 12 months prior to randomization, there were manifestations of NYHA "grade 3 or above" congestive heart failure, unstable angina pectoris, myocardial infarction, poorly controlled arrhythmia or cerebral hemorrhage; cardiac echocardiography showed left ventricular ejection fraction (LVEF) < 50%; corrected QT interval (QTe) > 480ms (calculated using the Fredericia method; if QTc is abnormal, it can be continuously detected for 3 times at intervals of 2 minutes, and the average value is taken); poorly controlled hypertension (systolic blood pressure ≥ 150 mmHg and/or diastolic blood pressure ≥ 100 mmHg, based on the average value obtained from ≥ 2 measurements); previous occurrence of hypertensive crisis or hypertensive encephalopathy
6. The subjects have congenital or acquired immune system deficiencies (such as HIV-infected individuals); or have a history of organ transplantation.
7. Those who had active tuberculosis within 1 year prior to enrollment, or those who had a history of active tuberculosis infection more than 1 year ago but did not receive proper treatment.
8. The study excluded patients who had a history of gastrointestinal bleeding within 6 months prior to treatment or who had a clear tendency towards gastrointestinal bleeding; patients with known hereditary or acquired bleeding disorders (such as coagulation dysfunction) or thrombosis tendencies were also excluded.
9. Within 4 weeks prior to the start of the treatment, had undergone major surgical procedures (except for biopsy procedures); the surgical incision had not yet fully healed; was expected to undergo major surgical treatment during the study period; minor traumatic surgeries (such as biopsy procedures) that were performed within 7 days prior to the start of the treatment
10. Severe, non-healed or open wounds, active ulcers or untreated fractures
11. Previous or current presence of central nervous system metastasis
12. The first study: Using attenuated live vaccines within 28 days before the start of the treatment, or it is expected that attenuated live vaccines will be needed during the study treatment period or within 60 days after the last administration of the study drug.
13. Patients with active autoimmune diseases, or those who have a history of autoimmune diseases and require long-term use of systemic glucocorticoids (equivalent dose of prednisone ≥ 10 mg/day, for more than 2 weeks) or immunosuppressants for treatment
14. Based on the researchers' assessment, there are other factors that might have affected the research results or led to the premature termination of this study, such as alcohol abuse, drug addiction, having other serious diseases (including mental illnesses) that require combined treatment, severely abnormal laboratory test values, family or social factors, and other circumstances that might have affected the safety of the subjects or the collection of trial data.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HER2-positive; Triplet therapy of Rekon Trastuzumab, Adebelimab, and Lenvatinib	Drug: Trastuzumab Rezetecan; The recommended dosage is 4.8 mg/kg. A fixed dose of 408 mg is administered for patients weighing ≥85 kg. It is given via intravenous infusion every 3 weeks (Q3W). The first infusion should be administered over 90 minutes. If the prior infusion was well-tolerated, subsequent infusions may be shortened to 30 minutes.; Drug: Adebrelimab; A fixed dose of 1200 mg is administered via intravenous infusion every 3 weeks (±3 days). The infusion duration should be controlled between 30 and 60 minutes and must not exceed 2 hours.; Drug: Lenvatinib; Administered orally once daily with food (preferably at the same time each day). The dose is 12 mg/day for patients weighing ≥60 kg and 8 mg/day for those <60 kg. The dose can be de-escalated based on toxicity according to the following scheme: 12 mg/day → 8 mg/day → 4 mg/day → discontinuation. If the investigator deems the patient intolerant, dose reduction across levels may be considered if deemed necessary.
Experimental: HER2-low expression; Triplet therapy of Rekon Trastuzumab, Adebelimab, and Lenvatinib	Drug: Trastuzumab Rezetecan; The recommended dosage is 4.8 mg/kg. A fixed dose of 408 mg is administered for patients weighing ≥85 kg. It is given via intravenous infusion every 3 weeks (Q3W). The first infusion should be administered over 90 minutes. If the prior infusion was well-tolerated, subsequent infusions may be shortened to 30 minutes.; Drug: Adebrelimab; A fixed dose of 1200 mg is administered via intravenous infusion every 3 weeks (±3 days). The infusion duration should be controlled between 30 and 60 minutes and must not exceed 2 hours.; Drug: Lenvatinib; Administered orally once daily with food (preferably at the same time each day). The dose is 12 mg/day for patients weighing ≥60 kg and 8 mg/day for those <60 kg. The dose can be de-escalated based on toxicity according to the following scheme: 12 mg/day → 8 mg/day → 4 mg/day → discontinuation. If the investigator deems the patient intolerant, dose reduction across levels may be considered if deemed necessary.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate	Using imaging for assessment	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
disease control rate	DCR was assessed per RECIST 1.1 and refers to the proportion of patients whose tumor shrinkage or control met the predefined criteria and was maintained for a minimum specified duration, encompassing CR, PR, and SD.	through study completion, an average of 1 year
progression-free survival	Progression-Free Survival (PFS) was defined as the time from treatment initiation to the first occurrence of disease progression or death from any cause.	through study completion, an average of 1 year
Serious adverse events	SAEs were prospectively collected through electronic medical records.	through study completion, an average of 1 year
Adverse reaction event	Blood test，Outpatient follow-up and telephone follow-up	through study completion, an average of 1 year
Overall Survival	Overall Survival (OS) was defined as the time from randomization (or treatment initiation) to death from any cause.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
duration of response	DoR was measured from the date of the first documented objective tumor response (per RECIST 1.1 criteria) to the date of the first documented progression or death from any cause.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Collaborators and Investigators

• Sponsor: Peking Union Medical College Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2026
• Primary Completion (Estimated): April 15, 2027
• Study Completion (Estimated): April 15, 2028

Study Registration Dates

• First Submitted: June 25, 2026
• First Submitted That Met QC Criteria: July 14, 2026
• First Posted (Actual): July 15, 2026

Study Record Updates

• Last Update Posted (Actual): July 15, 2026
• Last Update Submitted That Met QC Criteria: July 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Lenvatinib; Immune Checkpoint Inhibitors; Biliary Tract Cancer; Adebrelimab; Trastuzumab Rezetecan; HER2-Positive/Low-Expression
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Biliary Tract Diseases; Biliary Tract Neoplasms; lenvatinib
• Other Study ID Numbers: 1811-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No