Perioperative Treatment of High-risk Resectable CCA With HAIC Plus A+T: Neobrave CCA

January 26, 2026 updated by: Peking University

Perioperative Treatment of High-risk Resectable Cholangiocarcinoma With Hepatic Arterial Infusion Chemotherapy (HAIC) Combined With Atezo/Bevacizumab: a Multicenter Phase II Study (NeoBrave CCA)

Among resectable biliary tract cancers (BTC) patients, surgery has historically been the standard treatment, but even with curative surgery, the cure rates remain relatively low, with most patients relapsing in the short term and a 5-year survival rate of approximately 50% or lower.

In BTC, numerous exploratory studies on neoadjuvant treatment have been conducted, yielding varying results, but overall indicating that neoadjuvant therapy can enhance R0 resection rates and prolong survival in certain patients, particularly those with borderline resectable and locally advanced BTC.

Currently, there remains a lack of large prospective randomized controlled phase III clinical trials confirming the exact benefits of neoadjuvant and adjuvant therapies for BTC. The SWOG 1815 study is a randomized, open-label phase III trial comparing GAP with Gemcitabine/Cisplatin (GC) in patients with advanced BTC. In exploratory subgroup analyses, GAP improved mOS compared to GC in patients with locally advanced disease (19.2 vs. 13.7 months; HR 0.67, 95% CI 0.42-1.06, p = 0.09). Thus, patients with locally advanced disease may benefit more from GAP treatment. In another multi-institutional, single-arm, phase II trial, patients received a total of 4 cycles of preoperative GAP (Gemcitabine 800 mg/m2, Cisplatin 25 mg/m2, nab-Paclitaxel 100 mg/m2, administered on days 1 and 8 of a 21-day cycle) before attempting radical surgical resection. The median follow-up time for all patients was 17 months; the disease control rate was 90%. Therefore, the preoperative neoadjuvant therapy of Gemcitabine, Cisplatin, and nab-Paclitaxel for iCCA is feasible and safe, with no adverse effects on perioperative outcomes. More recently, neoadjuvant D + GemCis was confirmed to result in a higher surgical resection rate among patients with locally advanced BTC, and surgical resection was associated with higher survival rates.

The investigators previously explored a prospective phase II study and showed promising results of HAIC using oxaliplatin and 5-fluorouracil for perihilar cholangiocarcinoma (pCCA), with an objective response rate (ORR) of 67.6%, a mPFS of 12.2 months, and a mOS of 20.5 months. Another phase II prospective study enrolled 32 untreated BTC patients and used HAIC combined with anti-PD-1 monoclonal antibody and bevacizumab as a first-line treatment regimen, the ORR was 84.3%, and the disease control rate (DCR) was 96.9%, with one-year PFS and OS rates of 53.8% and 80.4%, respectively.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

Biliary tract cancers (BTC), mainly including cholangiocarcinoma and gallbladder cancer, are highly heterogeneous, aggressive malignant tumors with poor prognoses, exhibiting a 5-year survival rate of less than 5%.

About 70% of patients are diagnosed at an advanced localized stage or have distant metastases, losing the chance for surgical cure; among resectable BTC patients, surgery alone has historically been the standard treatment, but even with curative surgery, the cure rates remain relatively low, with most patients relapsing in the short term and a 5-year survival rate of approximately 50% or lower.

The efficacy of neoadjuvant and adjuvant therapies has been validated in other types of cancers and is recommended as standard treatment in various guidelines. In BTC, numerous exploratory studies on neoadjuvant treatment have been conducted, yielding varying results, but overall indicating that neoadjuvant therapy can enhance R0 resection rates and prolong survival in certain patients, particularly those with borderline resectable and locally advanced BTC. With advances in drug research and improvements in treatment protocols, a series of emerging treatment options like combination therapy, targeted therapy, and immunotherapy have significantly improved treatment outcomes, providing favorable conditions for perioperative treatment of BTC.

Currently, there remains a lack of large prospective randomized controlled phase III clinical trials confirming the exact benefits of neoadjuvant and adjuvant therapies for BTC. The SWOG 1815 study is a randomized, open-label phase III trial comparing GAP with Gemcitabine/Cisplatin (GC) in patients with advanced BTC. In exploratory subgroup analyses, GAP improved mOS compared to GC in patients with locally advanced disease (19.2 vs. 13.7 months; HR 0.67, 95% CI 0.42-1.06, p = 0.09); the objective response rate (ORR) for locally advanced disease was 28% vs. 21% (p = 0.74). Thus, patients with locally advanced disease may benefit more from GAP treatment. In another multi-institutional, single-arm, phase II trial including 30 resectable, high-risk iCCA patients (tumor size >5 cm, multiple tumors, major vascular invasion or lymph node involvement seen on imaging), patients received a total of 4 cycles of preoperative GAP (Gemcitabine 800 mg/m2, Cisplatin 25 mg/m2, nab-Paclitaxel 100 mg/m2, administered on days 1 and 8 of a 21-day cycle) before attempting radical surgical resection. The median follow-up time for all patients was 17 months; the disease control rate was 90% (disease progression: 10%, partial response: 23%, stable disease: 67%). Therefore, the preoperative neoadjuvant therapy of Gemcitabine, Cisplatin, and nab-Paclitaxel for iCCA is feasible and safe, with no adverse effects on perioperative outcomes.

With the in-depth research on immune checkpoint inhibitors, during the pre-planned interim analysis of TOPAZ-1 (NCT03875235) (data cutoff date August 11, 2021), the addition of Durvalumab significantly improved OS in patients with advanced BTC compared to the control group receiving GC chemotherapy (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66-0.97; p = 0.021). Meanwhile, neoadjuvant D + GemCis was confirmed to result in a higher surgical resection rate among patients with locally advanced BTC, and surgical resection was associated with higher survival rates.

The investigators previously explored a prospective phase II study and showed promising results of HAIC using oxaliplatin and 5-fluorouracil for perihilar cholangiocarcinoma (pCCA), with an objective response rate (ORR) of 67.6%, a mPFS of 12.2 months, and a mOS of 20.5 months. Another phase II single-arm, single-center, prospective study enrolled 32 untreated BTC patients, among which iCCA accounted for 34.4% (11/32), pCCA for 53.1% (17/32), and gallbladder cancer for 12.5% (4/32). Using HAIC combined with anti-PD-1 monoclonal antibody and bevacizumab as a first-line treatment regimen, the ORR was 84.3%, and the disease control rate (DCR) was 96.9%, with one-year PFS and OS rates of 53.8% and 80.4%, respectively.

Based on this study, the investigators plan to conduct a prospective single-arm phase II clinical study to further explore the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with atezolizumab and bevacizumab (Atezo/Bev) foras perioperative treatment of resectable cholangiocarcinoma with high-risk recurrence factors, while also investigating prognostic and predictive biomarkers related to efficacy to provide new evidence for the perioperative treatment of initially resectable but high-risk recurrence factor intrahepatic and perihilar cholangiocarcinoma.

Study Type

Interventional

Enrollment (Actual)

1

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Beijing Municipality
      • Beijing, Beijing Municipality, China, 100142
        • Peing University Cancer Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

1. Age: 18-80 years, regardless of gender; 2. Diagnosis of intrahepatic cholangiocarcinoma or perihilar cholangiocarcinoma confirmed by pathological tissue/cytological diagnosis; 3. Meeting the criteria for surgical resection; 4. Presence of high-risk recurrence factors: iCCA (single mass >5cm, or multiple lesions, or accompanied by satellite lesions, or accompanied by portal vein/hepatic vein invasion, or CA199 >200U/ml); pCCA (invasion of secondary branches of the bile duct, or invasion of portal vein/hepatic artery, or accompanied by intrahepatic metastasis); 5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1; 6. Child-Pugh class A; 7. Normal major organ function, meeting the following standards:

  1. Blood routine examination:

    A. Hb≥90 g/L; B. ANC≥1.5×10^9/L; C. PLT≥75×10^9/L;

  2. Biochemical examination:

A. ALB ≥30g/L; B. ALT and AST<5×ULN; C. TBiL ≤2×ULN; D. Creatinine ≤1.5×ULN; (3) Coagulation function: A. International normalized ratio (INR) ≤1.5×ULN; B. Activated partial thromboplastin time (APTT) ≤1.5×ULN. 8. Subjects voluntarily join this study, sign informed consent, have good compliance, and cooperate with follow-up.

Exclusion Criteria:

  1. Regional multiple lymph node metastases or fusion, retroperitoneal lymph node metastases;
  2. Peritoneal metastasis, distant metastasis;
  3. Previous systemic treatment, including but not limited to chemotherapy, targeted therapy, immunotherapy;
  4. Previous local treatment, including but not limited to HAIC, TACE, TARE, ablation, radiotherapy, etc.;
  5. Severe hepatic artery variation;
  6. Allergy to contrast agents;
  7. Allergy to oxaliplatin;
  8. Vaccination with live attenuated vaccine within 4 weeks prior to first administration or planned during the study period;
  9. Presence of > grade 1 peripheral neuropathy;
  10. Presence of any active autoimmune disease or history of autoimmune disease;
  11. Complication of other malignancies (except for basal cell or squamous cell skin cancer or cervical carcinoma in situ that was treated curatively);
  12. Human immunodeficiency virus (HIV) infection or known acquired immune deficiency syndrome (AIDS);
  13. Within 6 months prior to entering the study, occurrences of the following: myocardial infarction, severe/unstable angina, NYHA class II heart failure or above, poorly controlled arrhythmias (including QTcF interval male >450 ms, female >470 ms, QTcF interval calculated using the Fridericia formula), symptomatic congestive heart failure;
  14. Hypertension that cannot be well controlled with antihypertensive medications (systolic blood pressure ≥140 mmHg or diastolic pressure ≥90 mmHg);
  15. Abnormal coagulation function (INR>1.5 or APTT>1.5×ULN), with bleeding tendency or currently undergoing thrombolytic therapy, anticoagulant therapy, or antiplatelet therapy;
  16. Known hereditary or acquired bleeding and thrombosis tendencies, such as hemophilia, coagulation function disorders, thrombocytopenia, splenomegaly, etc.;
  17. Significant hemoptysis occurring within 2 months before entering the study, or daily sputum blood volume reaching half a teaspoon (2.5 ml) or more;
  18. Patients at risk of gastrointestinal bleeding, including:

(1) Presence of active peptic ulcer lesions; (2) History of melena or hematemesis within the past 3 months; (3) For stool occult blood (+) or (+/-), need to retest stool routine within 1 week; if still (+) or (+/-), esophagogastroduodenoscopy is needed; if ulcers or bleeding diseases are present and considered to have potential bleeding risks by the treating physician; 19. Thrombotic events occurring within 6 months prior to entering the study, such as cerebrovascular accidents (including transient ischemic attacks, intracerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism; 20. Infections requiring drug intervention occurring within 4 weeks prior to first medication (such as requiring intravenous antibiotics, antifungal or antiviral medications), or fever of unknown origin >38.5°C during screening/ prior to first medication; 21. Participation in any other drug clinical trials within 4 weeks prior to first administration; 22. Known history of substance abuse or drug addiction; 23. Presence of other serious physical or mental diseases or abnormal laboratory tests that may increase the risk of participation in the study or interfere with study results, and patients deemed unsuitable for participation in this study by the investigator.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Neobrave
Perioperative treatment
Combination product: Gemcitabine Oxaliplatin and 5FU
The perioperative treatment plan includes neoadjuvant therapy and adjuvant therapy. Neoadjuvant therapy consists of three cycles of HAIC combined with atezolizumab and bevacizumab (atezo/bev), while adjuvant therapy includes two cycles of HAIC combined with atezolizumab and bevacizumab (atezo/bev), along with additional capecitabine or tegafur as auxiliary maintenance treatment for three cycles. The total treatment duration for the perioperative period is six months. HAIC regimen: gemcitabine (1,000 mg/m2, 2h, d1) + oxaliplatin (35 mg/m2, 2h, d1-2) + 5-FU (0.75g/m2, 22h, d1-2); atezolizumab (PD-L1 inhibitor): 1200 mg, intravenous infusion, administered within 24 hours before HAIC treatment; bevacizumab: 7.5 mg/kg, intravenously infused before HAIC treatment (bevacizumab use is paused during the third neoadjuvant treatment). Each cycle lasts for three weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MPR
Time Frame: From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning
the proportion of residual active tumor cells ≤50%
From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with treatment-related adverse events
Time Frame: Through study completion, an average of once per 1 month.
Number of patients with AE, treatment-related AE (TRAE), serious adverse event (SAE) assessed by CTCAE v5.0.
Through study completion, an average of once per 1 month.
pCR
Time Frame: From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning
pathological complete response
From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning
ORR
Time Frame: Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
objective response rate
Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
DCR
Time Frame: Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
disease control rate
Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
R0 resection rate
Time Frame: From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning
From the date of treatment beginning to the date of pathological results after the surgery, assessed up to 6 months since the date of treatment beginning
RFS
Time Frame: From date of treatment beginning until the date of first documented recurrence, assessed up to 100 months
recurrence-free survival
From date of treatment beginning until the date of first documented recurrence, assessed up to 100 months
1-year RFS rate
Time Frame: From enrollment to the date after 1 year of the surgery
From enrollment to the date after 1 year of the surgery
OS
Time Frame: From date of treatment beginning until the date of death from any cause, assessed up to 100 months
overall survival
From date of treatment beginning until the date of death from any cause, assessed up to 100 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking University

Investigators

  • Study Director: Xiaodong Wang, M.D., Peking University Cancer Hospital & Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 31, 2024

Primary Completion (Actual)

December 22, 2025

Study Completion (Actual)

December 22, 2025

Study Registration Dates

First Submitted

December 1, 2024

First Submitted That Met QC Criteria

December 16, 2024

First Posted (Actual)

December 18, 2024

Study Record Updates

Last Update Posted (Actual)

January 28, 2026

Last Update Submitted That Met QC Criteria

January 26, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Neobrave-CCA

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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