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.

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.