Gem+Nab-P+LEN+TIS for Advanced Unresectable BTC (GALENT-BT)

• Study Background Biliary tract malignancies (BTCs), including gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC), are aggressive cancers with a 5-year survival rate <5%. Current first-line systemic therapies (e.g., gemcitabine/cisplatin) yield limited efficacy (ORR <30%, median OS ~11.7 months). Preclinical and clinical evidence suggests synergistic effects of combining chemotherapy, anti-angiogenic agents, and immune checkpoint inhibitors. The GALENT-BT trial evaluates a novel quadruplet regimen-Gemcitabine + nab-Paclitaxel + Lenvatinib + Tislelizumab-to improve outcomes in advanced unresectable BTCs.
• Study Objectives

Primary Objective: Assess the safety and tolerability of the quadruplet regimen over 8 treatment cycles.

Secondary Objectives:

Evaluate objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and surgical conversion rate.

Monitor adverse events (AEs), serious adverse events (SAEs), and quality of life (QoL).

Exploratory Objectives: Investigate biomarkers (e.g., PD-L1 expression, genetic mutations) and radiomic/pathologic features associated with treatment response.

• Study Design

Design: Prospective, single-arm, open-label, single-center, phase II trial.

Sample Size: Two-stage enrollment:

Stage 1 (Lead-in): 9 participants for initial safety evaluation. If ≤3/9 experience grade ≥3 AEs, proceed to Stage 2.

Stage 2 (Expansion): 20 additional participants (total 29 evaluable patients).

Duration: 36 months (June 2024-June 2027).

• Study Population

Inclusion criteria

Adults aged 18-75 years with histologically confirmed, untreated, advanced unresectable BTC (GBC/ICC/ECC) or recurrent BTC (≥3 months post-adjuvant therapy).

ECOG PS 0-1, measurable disease per RECIST 1.1, adequate organ function.

Exclusion criteria

Prior systemic therapy for advanced BTC, severe comorbidities, pregnancy, or intolerance to study drugs.

• Intervention

Regimen:

Gemcitabine: 1000 mg/m² IV on Days 1 and 8 of each 21-day cycle.

nab-Paclitaxel: 125 mg/m² IV on Days 1 and 8.

Lenvatinib: 4-8 mg orally daily (weight-based dosing) on Days 1-21.

Tislelizumab: 200 mg IV on Day 1.

Treatment Duration: 6-8 cycles (adjustable for tolerability), followed by 3-year survival follow-up.

• Assessments

Efficacy:

Tumor response evaluated by CT/MRI every 6 weeks using RECIST 1.1.

ORR, DCR, PFS, OS, and surgical conversion rate calculated.

Safety:

AEs/SAEs graded per CTCAE v5.0.

Laboratory monitoring (hematology, liver/renal function, thyroid panels).

QoL: Assessed via EORTC QLQ-HCC18 questionnaire at baseline, treatment cycles, and follow-up.

Inclusion criteria

• Aged 18-75 years, regardless of gender.
• Histologically or cytologically confirmed, untreated primary advanced unresectable biliary tract malignancies (BTC), including intrahepatic cholangiocarcinoma (ICC), extrahepatic chololiocarcinoma (ECC), and gallbladder cancer (GBC); or untreated recurrent BTC (prior adjuvant/neoadjuvant chemotherapy allowed if completed ≥3 months before recurrence, excluding regimens containing PD-1/L1 inhibitors, gemcitabine, nab-paclitaxel, or lenvatinib).
• ECOG performance status score 0-1.
• Expected survival ≥3 months.
• At least one measurable target lesion per RECIST v1.1 criteria.
• Adequate organ function:

Hematologic: Hemoglobin ≥90 g/L; WBC ≥lower limit of normal (LLN); ANC ≥1.5×10⁹/L; platelets ≥100×10⁹/L.

Renal: Serum creatinine ≤1.5×ULN; endogenous creatinine clearance rate ≥55 mL/min.

Hepatic: Total bilirubin ≤1.5×ULN; ALT/AST ≤2.5×ULN (≤3×ULN for intrahepatic BTC or liver metastases; ALT/AST ≤5×ULN for liver metastases).

Coagulation: INR ≤1.5×ULN; APTT within normal range.

• No prior systemic therapy for advanced BTC (chemotherapy, radiotherapy, targeted therapy, immunotherapy, or hormonal therapy). Patients with post-R2 resection are eligible.
• Negative serum/urine pregnancy test (for women of childbearing potential) and agreement to use contraception during the study and for 6 months post-treatment.
• Willing and able to provide written informed consent.

Exclusion criteria

• Severe systemic infection or uncontrolled comorbidities (e.g., heart failure, thyroid disorders, psychiatric conditions).
• Known hypersensitivity or intolerance to study drugs or their excipients.
• Pregnancy, lactation, or refusal to use effective contraception.
• Participation in other clinical trials within 30 days prior to enrollment.
• Inability to understand or unwillingness to sign informed consent.
• Any condition that, in the investigator's judgment, may compromise patient safety or compliance (e.g., severe concurrent illness, abnormal lab results, psychosocial factors).
• Prior use of PD-1/L1 inhibitors, gemcitabine, nab-paclitaxel, or lenvatinib in adjuvant/neoadjuvant settings.