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

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.

Inclusion Criteria:

1. Subjects voluntarily agree to participate in the study, sign the informed-consent form, demonstrate good compliance, and are willing to attend follow-up visits.
2. Histologically or cytologically confirmed unresectable locally advanced or metastatic biliary-tract cancer (gallbladder carcinoma, cholangiocarcinoma, or ampullary carcinoma of pancreaticobiliary type).
3. Age 18-70 years (inclusive) at the time of informed consent, either male or female.
4. ECOG performance status 0-1 and life expectancy ≥ 12 weeks.
5. Received one prior line of systemic therapy containing a platinum agent, gemcitabine, or fluoropyrimidine (non-taxane), with or without PD-1/PD-L1 antibody.
6. 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.
7. At least one measurable lesion according to RECIST v1.1:

1. .Lesion diameter ≥ 10 mm on contrast-enhanced MRI or CT.
2. .Lesions treated with prior local therapy may be considered measurable if they have progressed and meet RECIST v1.1 criteria.
3. .Lesions previously treated with radioactive seed implantation cannot be used as target lesions.

8.No clinically significant cardiovascular, pulmonary, cerebral, or other major organ dysfunction.

9.Adequate Major Organ and Bone-Marrow Function Criteria

1. 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

2. Coagulation

   • International Normalized Ratio (INR) ≤ 1.5 × upper limit of normal (ULN)
   • Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN

3. 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

4. Renal Function

   • Serum creatinine ≤ 2 × ULN
   • Calculated creatinine clearance (CCr) ≥ 40 mL/min (Cockcroft-Gault or equivalent)

5. 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

6. 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

7. Cardiac Function

   • Left ventricular ejection fraction (LVEF) ≥ 60 % as determined by two-dimensional echocardiography.

     10.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.

   Exclusion Criteria:

   1. Known hypersensitivity to any component of the study drugs (QL1706, albumin-bound paclitaxel, or lenvatinib).

   2. Prior anti-cancer therapy within specified wash-out periods before the first dose of study treatment:

      • Fluoropyrimidines (e.g., S-1, capecitabine): ≤ 2 weeks

      • Other cytotoxic chemotherapy: ≤ 3 weeks
      • Small-molecule targeted therapy: ≤ 2 weeks
      • Biologic therapy, large-molecule targeted therapy, or immunotherapy: ≤ 4 weeks

   3. Histologic diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or undifferentiated carcinoma of the biliary tract.

   4. Obstructive jaundice that has not been adequately relieved (bilirubin not reduced to protocol-specified limits).

   5. Other malignancies within the past 5 years, except adequately treated basal-cell or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix.

   6. Any history or current evidence of brain metastases.

   7. Hepatic tumor burden ≥ 70 % of total liver volume, as determined by the investigator.

   8. Major surgery or invasive procedure within 4 weeks prior to enrollment, unless wound healing is complete (exceptions: venous catheterization, percutaneous drainage, or biliary drainage for obstructive jaundice).

   9. Loco-regional anti-tumor therapy within 4 weeks, including trans-arterial chemoembolization (TACE), cryoablation, or radiofrequency ablation of liver metastases.

   10. Clinically significant electrolyte disturbances, as judged by the investigator.

   11. Uncontrolled hypertension (systolic ≥ 140 mmHg and/or diastolic ≥ 90 mmHg) despite optimal medical management.

   12. High risk of fatal vascular invasion/bleeding in the opinion of the investigator (e.g., tumor likely to erode a major vessel during the study).

   13. Bleeding diathesis or significant bleeding history within 3 months, including:

       • > 30 mL bleeding, hematemesis, melena, or hematochezia

       • Hemoptysis (> 5 mL fresh blood within 4 weeks)

       • Congenital or acquired coagulopathy
       • Clinically relevant hemorrhagic events (e.g., gastrointestinal bleeding, hemorrhagic gastric ulcer).

   14. Clinically significant cardiovascular disease, including:

       • Acute myocardial infarction, severe/unstable angina, or coronary artery bypass graft surgery within 6 months

       • New York Heart Association (NYHA) class > II congestive heart failure

       • Symptomatic ventricular arrhythmias requiring medication

       • QTc interval ≥ 480 ms on ECG.

   15. Active or uncontrolled severe infection ≥ CTCAE grade 2.

   16. Persistent toxicity > CTCAE grade 2 from prior anti-cancer therapy (except alopecia, lymphopenia, or ≤ grade 2 oxaliplatin-related neuropathy). Patients with prior immune-related adverse events that have resolved to baseline or are stable on replacement therapy may be enrolled after specialist consultation.

   17. Pregnancy (positive pregnancy test) or lactation.

   18. Any condition that, in the investigator's opinion, would compromise patient safety or data integrity, including:

       • Seizure disorder requiring treatment

       • Clinically significant metabolic, physical, or laboratory abnormalities

       • Any disease state that could interfere with study participation or result in undue risk.

   19. Known HIV infection or clinically significant chronic liver disease, including:

       • Active hepatitis B virus (HBV) infection (HBV DNA > 1 × 10⁴ copies/mL or > 2000 IU/mL)
       • Hepatitis C virus (HCV) infection with detectable HCV RNA (> 1 × 10³ copies/mL)
       • Other hepatitis, cirrhosis.

   20. Active or suspected autoimmune disease (e.g., myasthenia gravis, myositis, autoimmune hepatitis, SLE, RA, inflammatory bowel disease, MS, vasculitis, glomerulonephritis, uveitis, hypophysitis). Exceptions may apply for vitiligo, psoriasis, or thyroiditis that is controlled with replacement therapy.

   21. Any social or medical condition (e.g., alcohol or drug abuse, severe psychiatric illness) that, in the investigator's judgment, could interfere with adherence to study procedures, compromise safety, or lead to premature study discontinuation.