QL1706（Iparomlimab/Tuvonralimab) Combined With Gemcitabine and Cisplatin as First-Line Treatment for PD-L1-Positive Biliary Tract Cancer

Prior treatment

• Prior treatment with anti-PD-1/PD-L1 agents, anti-CTLA-4 agents, or other antitumor immunotherapies.
• Presence of unresolved Grade \>1 toxicities related to any previous antitumor therapy (persistent Grade 2 alopecia, fatigue, or endocrine disorders well-controlled with hormone replacement therapy are excluded).
• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first drug administration. Replacement therapies (e.g., levothyroxine, insulin, physiological corticosteroids for adrenal or pituitary insufficiency) are not regarded as systemic treatment. Known primary immunodeficiency. Patients with positive autoantibodies only should be assessed by the investigator for the presence of autoimmune disease.
• Systemic corticosteroid therapy (excluding nasal, inhaled, or other topical corticosteroids) or any other form of immunosuppressive therapy within 4 weeks prior to first dose. Note: Physiologic doses of corticosteroids (≤ 10 mg/day of prednisone or equivalent) are permitted.
• Known allogeneic organ transplant (except corneal transplant) or allogeneic hematopoietic stem cell transplant.
• Presence of clinically significant cardiovascular and cerebrovascular diseases, including:
  • Electrocardiogram abnormalities (e.g., complete left bundle branch block, second-degree or higher heart block, ventricular arrhythmias, or atrial fibrillation) that are symptomatic and difficult to control.
  • Unstable angina, congestive heart failure, or chronic heart failure of New York Heart Association (NYHA) Class ≥ 2.
  • Any arterial thrombotic, embolic, or ischemic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack) within 6 months prior to enrollment.
  • Uncontrolled hypertension (systolic blood pressure \> 140 mmHg, diastolic blood pressure \> 90 mmHg).
• Major surgical procedure (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to first dose, or non-healing wounds, ulcers, or fractures.
• Active tuberculosis; patients currently receiving anti-tuberculosis treatment or those who received anti-tuberculosis therapy within 1 year before the first drug administration.
• Vaccination with live attenuated vaccine within 4 weeks prior to first dose.
• Pregnant or breastfeeding females, or females planning to become pregnant before drug administration, during treatment or within 6 months after the last dose of study drug.

Other illness

• History of other malignancies within 5 years prior to enrollment, except for radically cured basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma in situ with no evidence of recurrence, or other malignancies with complete remission and no active disease for at least 2 years prior to enrollment.
• Known allergy to any active ingredient or excipient of the study drugs.
• Active or uncontrolled infection requiring systemic treatment.
• Confirmed HIV positivity or history of acquired immunodeficiency syndrome (AIDS).
• Untreated active hepatitis B (defined as HBsAg positive with HBV-DNA copy number \> 2000 IU/mL); patients with HBV-DNA positive may be enrolled if levels show a declining trend.
• Active HCV infection (HCV antibody positive and HCV-RNA above the lower limit of detection).
• Psychiatric disorders preventing treatment compliance.

Lab values

• Poorly controlled diabetes (fasting blood glucose \> 10 mmol/L).
• Any concomitant disease, prior treatment, abnormal laboratory findings, history of substance abuse or current substance use, which in the investigator's judgment may compromise patient safety, hinder informed consent acquisition, affect treatment compliance or interfere with the safety assessment of the study drug.

Other

• Histologically or cytologically confirmed diagnosis of tumors containing components other than biliary adenocarcinoma (e.g., neuroendocrine carcinoma, squamous cell carcinoma, or mixed histologies).
• Clinically uncontrolled pleural effusion or ascites (patients who do not require drainage or have no significant increase in fluid for 3 days after drainage cessation may be enrolled).
• Clinically active diverticulitis, abdominal abscess, or gastrointestinal obstruction.
• Urinalysis showing protein ≥ 2+ with 24-hour urine protein \> 1.0 g.

• Have signed the written informed consent form and be able to comply with all scheduled visits and study procedures specified in the protocol.
• Aged between 18 and 75 years old (inclusive), with no restriction on gender.
• Histologically confirmed unresectable or metastatic advanced biliary tract adenocarcinoma, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer.
• PD-L1-positive tumor (Combined Positive Score \[CPS\] ≥ 1).
• Have at least one measurable lesion per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
• No prior systemic therapy (chemotherapy, targeted therapy, or immunotherapy). Patients who relapse more than 6 months after curative surgery, and if they have received adjuvant therapy (chemotherapy and/or radiotherapy), relapse more than 6 months after completion of adjuvant therapy, are eligible.
• Life expectancy of at least 12 weeks.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1.
• Have adequate organ and bone marrow function. Laboratory test results obtained within 7 days prior to enrollment shall meet the following requirements. No blood products, erythropoietin, colony-stimulating factors, thrombopoietin, albumin or other parenteral corrective medications are allowed within 14 days before laboratory testing:
  • Hematology: Absolute Neutrophil Count (ANC) ≥ 1.5×10⁹/L; Platelet (PLT) count ≥ 100×10⁹/L; Hemoglobin (HGB) \> 9 g/dL.
  • Liver function: Total Bilirubin (TBIL) ≤ 1.5 × Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 × ULN.
  • Renal function: Creatinine clearance (calculated by the Cockcroft-Gault formula) ≥ 60 mL/min.
  • Thyroid function: Thyroid-stimulating hormone (TSH) within normal range. If baseline TSH is outside normal range, patients are eligible if total T3 (or FT3) and FT4 are within normal limits.
  • Cardiac enzymes: Within normal limits (isolated laboratory abnormalities deemed clinically insignificant by the investigator are allowed).
• Female participants of childbearing potential and male participants whose partners are of childbearing potential must agree to use effective contraception throughout the treatment period and for 6 months after the last study drug administration.