Sacituzumab Tirumotecan in Previously Treated TROP2-Positive Advanced Biliary Tract Cancer

A Single-Arm, Phase II, Multicenter Study to Evaluate the Efficacy and Safety of Sacituzumab Tirumotecan as Second-Line or Later Therapy in Patients With TROP2-Positive Advanced Biliary Tract Cancer

This is a single-arm, Phase II, multicenter clinical trial evaluating sacituzumab tirumotecan in patients with TROP2-positive advanced biliary tract cancer who have experienced disease progression after, or intolerance to, at least one prior line of systemic therapy.

Eligible participants will receive sacituzumab tirumotecan monotherapy. The primary objective is to evaluate objective response rate as assessed by the investigator according to RECIST version 1.1. Secondary objectives include evaluation of progression-free survival, overall survival, and safety. Exploratory analyses will assess the association between TROP2 protein expression and clinical efficacy, as well as potential mechanisms of resistance.

Biliary tract cancer is an aggressive malignancy with limited treatment options after failure of first-line systemic therapy. Standard second-line chemotherapy has shown limited antitumor activity, and there remains a substantial unmet need for more effective therapeutic strategies in patients with previously treated advanced biliary tract cancer.

TROP2 is a transmembrane glycoprotein expressed in multiple epithelial tumors and has been reported to be frequently expressed in biliary tract cancer. Sacituzumab tirumotecan is a TROP2-directed antibody-drug conjugate designed to selectively deliver a cytotoxic payload to TROP2-expressing tumor cells. Based on the biological rationale of TROP2 expression in biliary tract cancer and the clinical activity of TROP2-directed antibody-drug conjugates in other solid tumors, this study is designed to evaluate sacituzumab tirumotecan in this molecularly selected patient population.

This study will enroll patients with TROP2-positive advanced biliary tract cancer who have progressed after, or were intolerant to, at least one prior line of systemic therapy. All enrolled participants will receive sacituzumab tirumotecan monotherapy until radiographic disease progression, unacceptable toxicity, withdrawal of consent, investigator decision, or other protocol-defined discontinuation criteria.

Tumor response will be assessed by investigators according to RECIST version 1.1. The primary efficacy endpoint is objective response rate. Additional assessments include progression-free survival, overall survival, safety, and exploratory biomarker analyses. The study uses a Simon two-stage design to allow early termination for insufficient antitumor activity while permitting continued enrollment if prespecified response criteria are met.

Inclusion Criteria:

Participants must meet all of the following criteria to be eligible for enrollment:

1. Age ≥18 years, male or female.

2. Histologically or cytologically confirmed locally advanced, recurrent, or metastatic biliary tract cancer, with disease progression after, or intolerance to, at least one prior line of systemic therapy.

3. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

4. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.

5. TROP2 expression by immunohistochemistry (IHC) ≥1+.

6. Life expectancy of at least 3 months.

7. Adequate organ and bone marrow function, without transfusion, recombinant human thrombopoietin, or colony-stimulating factor treatment within 2 weeks before the first dose of study treatment, defined as follows:

   1. Hematology: absolute neutrophil count ≥1.5 × 10^9/L; platelet count ≥80 × 10^9/L; hemoglobin ≥90 g/L.
   2. Liver function: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤2.5 × upper limit of normal (ULN); total bilirubin ≤1.5 × ULN; albumin ≥30 g/L. For participants with liver metastases at baseline, ALT and AST must be ≤5 × ULN and total bilirubin must be ≤3 × ULN.
   3. Renal function: serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min as calculated using the standard Cockcroft-Gault formula.
   4. Coagulation function: international normalized ratio (INR), activated partial thromboplastin time (APTT), and prothrombin time (PT) ≤1.5 × ULN.

8. Female participants of childbearing potential and male participants with partners of childbearing potential must agree to use effective medically accepted contraception from the time of signing the informed consent form until 6 months after the last dose of study treatment.

9. Voluntarily agrees to participate in the study, provides written informed consent, has good compliance, and is willing to cooperate with study follow-up.

Exclusion Criteria:

Participants who meet any of the following criteria will be excluded:

1. Prior treatment with any TROP2-directed therapy or any topoisomerase I inhibitor-containing therapy, including antibody-drug conjugate (ADC) therapy, whether administered in the adjuvant, neoadjuvant, or advanced disease setting.

2. Ongoing or active infection.

3. Participation in another clinical trial of an antitumor drug within 4 weeks before screening.

4. History of another uncured malignancy within 5 years, except cured basal cell carcinoma of the skin or carcinoma in situ of the cervix.

5. Known hypersensitivity to the study drug or any of its components.

6. Any of the following cardiovascular or cerebrovascular diseases or risk factors:

   1. Myocardial infarction, unstable angina, acute or persistent myocardial ischemia, New York Heart Association (NYHA) class III or IV heart failure, symptomatic or poorly controlled severe arrhythmia, cerebrovascular accident, transient ischemic attack, or other severe cardiovascular or cerebrovascular disease within 6 months before the first dose of study treatment.
   2. History of myocarditis, primary cardiomyopathy, specific cardiomyopathy, or other myocardial disease.
   3. Deep vein thrombosis within 3 months before the first dose of study treatment, unless stable for ≥2 weeks after treatment with low-molecular-weight heparin or a drug with similar efficacy; peripheral arterial thromboembolic event, pulmonary embolism, or other severe thromboembolic event within 3 months before the first dose of study treatment.
   4. Life-threatening major vascular disease, such as aortic aneurysm or aortic dissecting aneurysm, or major vascular disease requiring surgery within 6 months before the first dose of study treatment.

7. Uncontrolled systemic disease as judged by the investigator, including:

   1. Poorly controlled diabetes mellitus, defined as fasting blood glucose ≥10 mmol/L on two consecutive tests.
   2. Poorly controlled hypertension, defined as systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg.
   3. Symptomatic pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once per week.

8. History of noninfectious interstitial pulmonary fibrosis or noninfectious pneumonitis requiring steroid treatment; current interstitial pulmonary fibrosis or noninfectious pneumonitis; or suspected interstitial pulmonary fibrosis or noninfectious pneumonitis that cannot be ruled out by imaging during screening.

9. Documented severe dry eye syndrome, severe meibomian gland disease and/or blepharitis, or history of severe corneal disease that may impair or delay corneal healing.

10. Clinically significant pulmonary impairment due to pulmonary comorbidities, including but not limited to severe asthma within 3 months before the first dose of study treatment, severe chronic obstructive pulmonary disease, restrictive lung disease, autoimmune, connective tissue, or inflammatory disease that may involve the lungs, such as rheumatoid arthritis, Sjögren syndrome, or sarcoidosis, or prior total pneumonectomy.

11. Active chronic inflammatory bowel disease, gastrointestinal obstruction, severe ulcer, gastrointestinal perforation, intra-abdominal abscess, or acute gastrointestinal bleeding.

12. Active gastrointestinal disease or other condition that may significantly affect the absorption, distribution, metabolism, or excretion of study treatment, such as refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow medication, or prior major bowel resection.

13. Risk of esophagotracheal fistula or esophagopleural fistula, or tumor invasion or compression of surrounding vital organs or blood vessels, such as the heart, esophagus, or superior vena cava, accompanied by related symptoms, such as superior vena cava syndrome.

14. Toxicities from prior antitumor therapy that have not recovered to Grade ≤1 according to NCI CTCAE version 5.0 or to the level specified in the eligibility criteria, except for toxicities considered by the investigator to pose low safety risk, such as alopecia or fatigue.

15. Active autoimmune disease requiring systemic treatment within the past 2 years, including disease-modifying agents, immunosuppressive drugs, or systemic corticosteroids at a dose of >10 mg/day prednisone or equivalent. Hormone replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency, is not considered systemic treatment. Participants who have received systemic corticosteroids at >10 mg/day prednisone or equivalent or other immunosuppressive drugs within 2 weeks before the first dose of study treatment will also be excluded.

16. Severe infection within 4 weeks before the first dose of study treatment, including but not limited to infection with complications requiring hospitalization, sepsis, or severe pneumonia; or active infection requiring systemic anti-infective therapy within 2 weeks before the first dose of study treatment.

17. Known active tuberculosis. Participants suspected of having active tuberculosis must undergo clinical evaluation to rule out active tuberculosis.

18. Hepatitis B virus (HBV) infection with detectable HBV DNA, defined according to local laboratory requirements as ≥10 IU/mL or above the lower limit of detection, unless antiviral therapy is initiated before treatment according to institutional practice to ensure adequate viral suppression and is maintained during the study and for 6 months after the last dose of study treatment. Participants who are anti-HBc positive but have undetectable HBV DNA do not require antiviral therapy unless HBV DNA becomes >10 IU/mL or reaches the lower limit of detection according to local laboratory requirements during treatment.

19. Positive human immunodeficiency virus (HIV) test or history of acquired immunodeficiency syndrome (AIDS); known active syphilis infection.

20. History of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

21. Major surgery within 4 weeks before the first dose of study treatment, or anticipated need for major surgery during the study.

22. Known hypersensitivity to the study drug or any of its components, including polysorbate 20, or history of severe hypersensitivity reaction to other biologic agents.

23. Receipt of nonspecific immunomodulatory therapy within 2 weeks before the first dose of study treatment, including but not limited to interferon or interleukin-2, or Chinese patent medicines approved for antitumor indications.

24. Receipt of strong cytochrome P450 3A4 (CYP3A4) inhibitors or strong CYP3A4 inducers within 7 days before the first dose of study treatment, or need to continue such medications during the study.

25. Receipt of a live vaccine within 30 days before the first dose of study treatment, or planned receipt of a live vaccine during the study.

26. Rapid disease deterioration during screening before study drug administration, such as a significant change in performance status.

27. Pregnant or breastfeeding women.

28. Any condition that, in the investigator's judgment, may interfere with evaluation of the study drug, compromise participant safety, affect interpretation of study results, or otherwise make the participant unsuitable for participation in this study.