Exploration of Sintilimab + Bevacizumab + AG Chemotherapy as First-Line Treatment for Unresectable Advanced/Metastatic Cholangiocarcinoma

Official title

Clinical Study Protocol for a Single-Center, Prospective, Single-Arm Trial Assessing Icaritin Soft Capsules as Postoperative Adjuvant Therapy in Hepatocellular Carcinoma Patients With High-Risk Factors for Recurrence

Overview

Evaluation of Efficacy and Safety of Sintilimab Plus Bevacizumab and AG Regimen as First-Line Therapy in Patients with Surgically Ineligible Locally Advanced or Metastatic Cholangiocarcinoma Objectives: Primary Objective: To assess the objective response rate (ORR) as per RECIST v1.1. Secondary Objectives: 1. To evaluate the disease control rate (DCR) per RECIST v1.1. 2. To determine the duration of response (DOR) per RECIST v1.1. 3. To measure progression-free survival (PFS) per RECIST v1.1. 4. To characterize the safety profile. 5. To determine overall survival (OS) . Exploratory Objectives: To investigate potential predictive biomarkers (e.g., PD-L1 expression, tumor mutational burden \[TMB\]) and their correlation with treatment efficacy (non-mandatory).

Detailed description

This study is a single-arm, Phase II clinical trial evaluating the efficacy and safety of Sintilimab plus Bevacizumab and the AG regimen as first-line therapy in patients with surgically ineligible locally advanced or metastatic cholangiocarcinoma.

After providing informed consent, patients receive:

Sintilimab: 200 mg IV Q3W Bevacizumab: 15 mg/kg IV Q3W AG Chemotherapy: Nab-paclitaxel + Gemcitabine for 8 cycles.

Post-chemotherapy, patients continue Sintilimab + Bevacizumab maintenance until:

Disease progression Death Intolerable toxicity Withdrawal of consent Initiation of new antitumor therapy Other protocol-specified reasons (Maximum treatment duration: 24 months)

Interventions

• Drug Sintilimab combined with bevacizumab and albumin-bound paclitaxel plus gemcitabine
  Patients receive sintilimab (200mg IV Q3W) combined with bevacizumab (15mg/kg IV Q3W) and the AG regimen (albumin-bound paclitaxel + gemcitabine). AG chemotherapy is administered for a total of 8 cycles. After completion of chemotherapy, patients continue sintilimab plus bevacizumab maintenance therapy until disease progression, death, intolerable toxicity, withdrawal of informed consent, initiation of new antitumor therapy, or other protocol-specified reasons for treatment discontinuation, with

Primary outcome measures

• Objective Response Rate (ORR) [Time frame: From baseline (within 28 days prior to enrollment) through disease progression or study completion, up to approximately 2 years.]

Eligibility criteria

Inclusion criteria

• Signed written informed consent prior to any trial-related procedures.
• Male or female aged \*\*≥18 years and ≤75 years\*\*.
• Histologically or cytologically confirmed, surgically unresectable locally advanced or metastatic cholangiocarcinoma.
• No prior systemic therapy; subjects who completed postoperative adjuvant therapy \*\*>6 months ago\*\* are eligible.
• Life expectancy >3 months.
• At least one measurable lesion per RECIST 1.1 criteria.
• ECOG PS score 0 or 1.
• Adequate organ function (all laboratory criteria below must be met):

（1）Absolute neutrophil count (ANC) \*\*≥1.5×10⁹/L\*\* without granulocyte colony-stimulating factor within 14 days; （2）Platelets \*\*≥90×10⁹/L\*\* without transfusion within 14 days; （3）Hemoglobin \*\*>9 g/dL\*\* without transfusion/recombinant erythropoietin within 14 days; （4）Total bilirubin ≤1.5×ULN; （5）AST/ALT ≤2.5×ULN (≤5×ULN allowed if liver metastases present); （6）Serum creatinine ≤1.5×ULN AND creatinine clearance (Cockcroft-Gault formula) \*\*≥60 mL/min\*\*; （7）INR or PT ≤1.5×ULN; （8）TSH within normal range; OR if abnormal, total T3 (or FT3) AND FT4 within normal limits; （9）Cardiac enzymes within normal limits (isolated abnormalities deemed clinically insignificant by investigator are allowed).

9\. For women of childbearing potential:

（1）Negative urine/serum pregnancy test within 3 days before Cycle 1 Day 1 (confirm equivocal urine tests with serum testing).

（2）Non-childbearing potential defined as:

• Postmenopausal (≥1 year amenorrhea), OR
• Surgically sterilized/hysterectomy. 10. All subjects (regardless of gender) at conception risk must use contraception with <1% annual failure rate during treatment and for 120 days after last dose.

Exclusion criteria

• Other malignancies within 5 years prior to first dose (excluding radically cured basal cell carcinoma, squamous cell carcinoma of skin, or carcinoma in situ).
• Current participation in interventional clinical trials or receipt of other investigational drugs/devices within 4 weeks before first dose.
• Prior therapy with:

<!-- -->

• Anti-PD-1/PD-L1/PD-L2 agents;
• Drugs targeting stimulatory/co-inhibitory T-cell receptors (e.g., CTLA-4, OX-40, CD137).

4\. Systemic administration of antitumor Chinese herbal medicines or immunomodulators (e.g., thymosin, interferon, interleukin) within 2 weeks (except localized use for pleural effusion).

5\. Active autoimmune disease requiring systemic treatment within 2 years (e.g., disease-modifying drugs, corticosteroids ≥10 mg/day prednisone equivalent, immunosuppressants).

• Exclusions: Hormone replacement (thyroxine/insulin/physiologic steroids);
• Known primary immunodeficiency;
• Isolated autoantibody positivity requires investigator confirmation of no autoimmune disease.

6\. Systemic glucocorticoids (excluding topical/inhaled) or immunosuppressive therapy within 4 weeks.Note: Physiologic-dose steroids (≤10 mg/day prednisone equivalent) permitted.

7\. Prior anti-angiogenic therapy (e.g., bevacizumab). 8. Active bleeding within 3 months prior to first dose:

• Hemoptysis (≥2.5 mL/fresh blood episode);
• Gastrointestinal bleeding. 9. High bleeding risk: Tumor invasion of major vessels or radiologist/investigator-assessed bleeding tendency.

10\. Major surgery within 4 weeks (excluding biopsy). 11. Severe unhealed wounds/ulcers/fractures. 12. Aspirin (>325 mg/day) or platelet-inhibiting NSAIDs for >10 consecutive days within 10 days prior to first dose.

13\. Full-dose anticoagulants/thrombolytics for >10 consecutive days within 10 days prior to first dose.Note: Prophylactic low-dose anticoagulants allowed:

（1）Warfarin ≤1 mg/day (INR ≤1.5); （2）Heparin ≤12,000 U/day; （3）Aspirin ≤100 mg/day. 14. Hereditary bleeding disorders, coagulopathy, or thrombotic history. 15. Clinically uncontrolled pleural effusion/ascites (asymptomatic/minimal fluid without drainage allowed).

16\. Allogeneic organ transplant (excluding corneas) or hematopoietic stem cell transplant.

17\. Hypersensitivity to sintilimab/bevacizumab or excipients. 18. Inadequate recovery from prior intervention toxicities (i.e., >Grade 1 or not returned to baseline, excluding alopecia/fatigue).

19\. HIV infection (HIV 1/2 antibody-positive). 20. Untreated active HBV:

• HBsAg-positive AND HBV-DNA > local ULN;
• Exceptions:

a. HBV-DNA <500 IU/mL with ongoing antiviral therapy; b. Anti-HBc (+) only with HBV-DNA monitoring. 21. Active HCV infection (HCV antibody-positive AND detectable HCV-RNA). 22. Live attenuated vaccines within 4 weeks prior to first dose. 23. Pregnancy or breastfeeding. 24. Uncontrolled systemic diseases, including:

• Severe uncontrolled cardiac arrhythmias (e.g., complete LBBB, ≥Grade II AV block, VT/AF);
• Unstable angina, CHF, NYHA Class ≥II heart failure;
• Arterial thromboembolism within 6 months (e.g., MI, stroke, TIA);
• Major surgery/unhealed wounds within 4 weeks; biopsy within 7 days (except IV catheterization);
• Uncontrolled hypertension (>140/90 mmHg);
• Active tuberculosis;
• Uncontrolled systemic infection;
• Clinical diverticulitis, intra-abdominal abscess, GI obstruction;
• Decompensated liver disease/active hepatitis;
• Uncontrolled diabetes (fasting glucose >10 mmol/L);
• Urine protein ≥++ AND 24-hr urine protein >1.0 g. 25. Psychiatric disorders impairing treatment compliance. 26. Any condition that may:

（1）Interfere with trial results; （2）Prevent full study participation; （3）Pose additional risks (per investigator judgment).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• the Second Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou

Identifiers

NCT: NCT07328802 · CHOL-Sintilimab-Bevacizumab-AG

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗