A Single-Center, Single-Arm, Open-Label Phase II Study of Iparomlimab and Tuvonralimab (QL1706) in Combination With Albumin-Bound Paclitaxel and Lenvatinib as Second-Line Therapy for Unresectable or Metastatic Biliary Tract Cancer
Biliary tract carcinoma (BTC) is a highly aggressive malignancy with rising incidence worldwide. Most patients present at an advanced stage and have a dismal prognosis. First-line gemcitabine-platinum plus PD-1/PD-L1 blockade has become the new standard, yet no established second-line therapy exists after progression on this regimen. Combining dual checkpoint inhibition (PD-1/CTLA-4) with anti-angiogenic therapy and chemotherapy may overcome primary resistance.Although several studies have evaluated immune-checkpoint inhibitors (ICIs) alone or combined with anti-angiogenic agents in advanced BTC, overall survival improvements remain modest, and enrolled patients have typically progressed after chemotherapy only. Thus, the optimal second-line regimen in the immunotherapy era-especially the efficacy and safety of combining ICIs with chemotherapy-warrants further investigation.Dual PD-1/PD-L1 plus CTLA-4 blockade can comprehensively reactivate anti-tumor immunity by relieving T-cell suppression and enhancing cytotoxic function. QL1706, developed by Qilu Pharmaceutical using the proprietary MabPair™ platform, is the first bispecific antibody simultaneously targeting PD-1 and CTLA-4, showing synergistic anti-tumor activity and favorable tolerability. Lenvatinib is a multi-target tyrosine-kinase inhibitor with anti-angiogenic and immunomodulatory properties.For patients progressing after first-line therapy, preliminary data indicate that combining ICIs with anti-angiogenic agents (VEGFR2 antibodies or TKIs) yields modest efficacy; however, prospective evidence-especially for those refractory to chemotherapy plus PD-1/PD-L1 inhibitors-is lacking. Therefore, we designed an exploratory clinical trial evaluating QL1706 combined with albumin-bound paclitaxel and lenvatinib as second-line treatment for unresectable or metastatic BTC, aiming to provide a safe and effective option, particularly for patients previously exposed to PD-1/PD-L1 inhibitors, to prolong survival and improve quality of life.
⁃ Subjects voluntarily agree to participate in the study, sign the informed-consent form, demonstrate good compliance, and are willing to attend follow-up visits.
⁃ Histologically or cytologically confirmed unresectable locally advanced or metastatic biliary-tract cancer (gallbladder carcinoma, cholangiocarcinoma, or ampullary carcinoma of pancreaticobiliary type).
⁃ Age 18-70 years (inclusive) at the time of informed consent, either male or female.
⁃ ECOG performance status 0-1 and life expectancy ≥ 12 weeks.
⁃ Received one prior line of systemic therapy containing a platinum agent, gemcitabine, or fluoropyrimidine (non-taxane), with or without PD-1/PD-L1 antibody.
⁃ Patients who develop distant metastasis after curative-intent surgery are eligible if they received adjuvant chemotherapy without a taxane and relapse \< 6 months after completion of adjuvant therapy.
⁃ At least one measurable lesion according to RECIST v1.1:
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⁃ .Lesion diameter ≥ 10 mm on contrast-enhanced MRI or CT.
⁃ .Lesions treated with prior local therapy may be considered measurable if they have progressed and meet RECIST v1.1 criteria.
⁃ .Lesions previously treated with radioactive seed implantation cannot be used as target lesions.
• No clinically significant cardiovascular, pulmonary, cerebral, or other major organ dysfunction.
• Adequate Major Organ and Bone-Marrow Function Criteria
⁃ Hematology • White blood cell (WBC) count ≥ 4.0 × 10⁹/L
∙ Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
‣ Platelet count ≥ 75 × 10⁹/L
‣ Hemoglobin ≥ 80 g/L
⁃ Coagulation
∙ International Normalized Ratio (INR) ≤ 1.5 × upper limit of normal (ULN)
‣ Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN
⁃ Liver Function
∙ Total serum bilirubin ≤ 1.5 × ULN
‣ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN - Patients with concurrent liver metastases may be enrolled if ALT/AST ≤ 5 × ULN
‣ For obstructive jaundice: serum total bilirubin must be ≤ 1.5 × ULN after adequate internal or external biliary drainage
‣ Serum albumin ≥ 30 g/L
⁃ Renal Function
∙ Serum creatinine ≤ 2 × ULN
‣ Calculated creatinine clearance (CCr) ≥ 40 mL/min (Cockcroft-Gault or equivalent)
⁃ Urinalysis
⁃ • Urine protein \< 2+ on dipstick
⁃ \- If urine protein ≥ 2+, a 24-hour urine collection is required and must show total protein \< 1.0 g to permit enrollment
⁃ Thyroid Function
⁃ • Thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) all within ±10 % of the institutional normal range
‣ Patients with non-autoimmune hypothyroidism whose FT3/FT4 levels are maintained within the normal range on stable replacement therapy are eligible
‣ If TSH falls outside the above range, FT3, FT4, and clinical status must be assessed; subjects may be enrolled if findings indicate a non-acute, stable condition
⁃ Cardiac Function
∙ Left ventricular ejection fraction (LVEF) ≥ 60 % as determined by two-dimensional echocardiography.
• Contraception requirements
‣ Women of child-bearing potential must use a medically acceptable contraceptive method (e.g., IUD, oral contraceptive, condom) from screening through 6 months after the last dose of study drug; must have a negative serum or urine β-hCG test within 7 days before enrollment and must not be breastfeeding.
‣ Men with partners of child-bearing potential must use effective contraception during the study and for 6 months after the last dose.