Phase II Study of Trastuzumab Rezetecan Combined With Adebrelimab and Lenvatinib as First-Line Therapy for Advanced HER2-Positive/HER2-Low Biliary Tract Cancer

A Prospective, Open-label, Multicenter Phase II Clinical Study of Rikang Trastuzumab in Combination With Adebrelimab and Lenvatinib for First-line Treatment of HER2-positive or Low-expressing Locally Advanced or Metastatic Biliary Tract Cancer

This phase II study evaluates the efficacy and safety of Trastuzumab Rezetecan in combination with Adebrelimab and Lenvatinib as first-line therapy for patients with locally advanced or metastatic HER2-positive or HER2-low biliary tract cancer. The primary objective is the objective response rate (ORR). Key secondary objectives include efficacy endpoints-progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and duration of response (DoR)-and safety assessments comprising adverse events (AEs), serious adverse events (SAEs), vital signs, and laboratory findings.

Inclusion Criteria:

1. The HER2-positive subjects voluntarily participated in the study and agreed to sign the written informed consent form, and they had good compliance.
2. Age ≥ 18 years old, gender not limited;
3. Locally advanced or metastatic cholangiocarcinoma, including cholangiocarcinoma (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma) and gallbladder cancer, which has been confirmed by pathological histology or cytology;
4. Not suitable for radical surgical resection or local treatment. Subjects who have not received any systemic anti-tumor therapy in the past; allowed to have received radical treatment previously (including surgical treatment and postoperative adjuvant chemotherapy and/or radiotherapy), and the interval from the last administration of radical treatment to disease recurrence is at least 6 months, and no systemic anti-tumor treatment was received during the recurrence or metastasis stage.
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 (no albumin transfusion within 14 days before the screening): 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) × weight) / (72 × blood Cr); Female: Cr clearance rate = ((140 - age) × weight) / (72 × blood Cr) × 0.85 (weight unit: kg; blood Cr unit: mg/mL)
10. For both male subjects with fertile partners and female subjects 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 subjects must agree not to donate sperm, and female subjects must agree not to donate eggs. For female subjects 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-breastfeeding period.

Exclusion Criteria:

1. Histological or cytological pathology 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 basal cell or squamous cell carcinomas of the skin.
3. Participants who have previously received immunotherapy, HER2-targeted, or ADC drug treatment, including immune checkpoint inhibitors (such as anti-PD-1/L1 antibodies, anti-CTLA-4 antibodies, anti-TIGIT antibodies, anti-LAG3 antibodies, etc.), immune checkpoint agonists (such as CD40, CD137, OX40 antibodies, etc.), and any other treatments targeting the immune mechanism of tumor treatment;
4. 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 determined by the investigator not to affect the treatment with the study drug).
5. 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;
6. 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.
7. The subjects have congenital or acquired immune system deficiencies (such as HIV-infected individuals); or have a history of organ transplantation;
8. Those who had active tuberculosis within one year prior to enrollment, or those who had a history of active tuberculosis infection more than one year ago but did not receive proper treatment.
9. The study excluded those who had a history of gastrointestinal bleeding within 6 months prior to treatment or who had a clear tendency towards gastrointestinal bleeding; those with known hereditary or acquired bleeding disorders (such as coagulation dysfunction) or thrombosis tendencies;
10. Within 4 weeks prior to the start of the treatment, if one has undergone major surgical procedures (except for biopsy procedures); if the surgical incision has not fully healed; if major surgical treatment is expected to be required during the study period; if a minor traumatic surgical procedure (such as biopsy procedures) was performed within 7 days prior to the start of the treatment.
11. Severe, non-healed or open wounds, active ulcers or untreated fractures;
12. Previous or current presence of central nervous system metastasis;
13. The first study requires that the subjects use attenuated live vaccines within 28 days before the start of the treatment, or that they are expected to use attenuated live vaccines during the study treatment period or within 60 days after the last administration of the study drug.
14. Patients with active autoimmune diseases, or those with a history of autoimmune diseases and who require long-term use of systemic glucocorticoids (equivalent dose of prednisone ≥ 10 mg/day, for more than 2 weeks) or immunosuppressants.
15. 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 abuse, having other serious diseases (including mental illnesses) that require combined treatment, severely abnormal laboratory test values, family or social factors, and other situations that might have affected the safety of the subjects or the collection of trial data.