Intrahepatic Cholangiocarcinoma (Icc)Phase 2NCT06739252
Perioperative Treatment of High-risk Resectable CCA With HAIC Plus A+T: Neobrave CCA
A Phase 2 study testing Gemcitabine Oxaliplatin and 5FU in people with Intrahepatic Cholangiocarcinoma (Icc) and Perihilar Cholangiocarcinoma, run by Peking University at 1 site in China.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Intrahepatic Cholangiocarcinoma (Icc), Perihilar Cholangiocarcinoma
- What is being tested?
- Gemcitabine Oxaliplatin and 5FU
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1 participants
- Where
- 1 siteChina
- Study dates
- 31 Dec 2024to 22 Dec 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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:
- Blood routine examination:
- Hb≥90 g/L; B. ANC≥1.5×10^9/L; C. PLT≥75×10^9/L;
- Biochemical examination:
- 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.
Who cannot join
- Regional multiple lymph node metastases or fusion, retroperitoneal lymph node metastases;
- Peritoneal metastasis, distant metastasis;
- Previous systemic treatment, including but not limited to chemotherapy, targeted therapy, immunotherapy;
- Previous local treatment, including but not limited to HAIC, TACE, TARE, ablation, radiotherapy, etc.;
- Severe hepatic artery variation;
- Allergy to contrast agents;
Show all 19Show fewer
- Allergy to oxaliplatin;
- Vaccination with live attenuated vaccine within 4 weeks prior to first administration or planned during the study period;
- Presence of > grade 1 peripheral neuropathy;
- Presence of any active autoimmune disease or history of autoimmune disease;
- Complication of other malignancies (except for basal cell or squamous cell skin cancer or cervical carcinoma in situ that was treated curatively);
- Human immunodeficiency virus (HIV) infection or known acquired immune deficiency syndrome (AIDS);
- 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;
- Hypertension that cannot be well controlled with antihypertensive medications (systolic blood pressure ≥140 mmHg or diastolic pressure ≥90 mmHg);
- Abnormal coagulation function (INR>1.5 or APTT>1.5×ULN), with bleeding tendency or currently undergoing thrombolytic therapy, anticoagulant therapy, or antiplatelet therapy;
- Known hereditary or acquired bleeding and thrombosis tendencies, such as hemophilia, coagulation function disorders, thrombocytopenia, splenomegaly, etc.;
- Significant hemoptysis occurring within 2 months before entering the study, or daily sputum blood volume reaching half a teaspoon (2.5 ml) or more;
- Patients at risk of gastrointestinal bleeding, including:
- 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.
Trial locations and contacts
1 site in 1 country.
China1 site
Peing University Cancer Hospital
Beijing, Beijing Municipality, 100142
About this study
Official title: 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.
Read more
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.
Read the 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.
- Being tested
- Gemcitabine Oxaliplatin and 5FU
- Medical subject headings
- Cholangiocarcinoma, Cirrhosis, Familial, with Pulmonary Hypertension, Klatskin Tumor
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gemcitabine Oxaliplatin and 5FUCombination product
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.
| Study group | Role | What they receive |
|---|---|---|
| Neobrave | Experimental | Perioperative treatment Receives: Combination Product: Gemcitabine Oxaliplatin and 5FU |
What is being measured
The primary outcome is the main question the study is designed to answer.
MPR
the proportion of residual active tumor cells ≤50%
Measured: 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 outcomes (8)
pCR
pathological complete response
Measured: 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
objective response rate
Measured: Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
DCR
disease control rate
Measured: Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
R0 resection rate
Measured: 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
recurrence-free survival
Measured: From date of treatment beginning until the date of first documented recurrence, assessed up to 100 months
1-year RFS rate
Measured: From enrollment to the date after 1 year of the surgery
OS
overall survival
Measured: From date of treatment beginning until the date of death from any cause, assessed up to 100 months
Number of patients with treatment-related adverse events
Number of patients with AE, treatment-related AE (TRAE), serious adverse event (SAE) assessed by CTCAE v5.0.
Measured: Through study completion, an average of once per 1 month.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Dec 2024
- Study start31 Dec 2024
- Primary completion22 Dec 2025
- Study completion22 Dec 2025
Why it stopped: Difficulty of participants enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (30)Papers the sponsor has linked to this study.
- Other trials for Intrahepatic Cholangiocarcinoma (Icc)Studies of the same condition, open and under way.
- More trials run by Peking UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 1 participants (actual)
Sponsor and investigators
- Lead sponsor
- Peking University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Xiaodong Wang, M.D., Study director, Peking University Cancer Hospital & Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06739252
- Sponsor's protocol ID
- Neobrave-CCA
- Status last verified
- Jan 2026
- First submitted
- 1 Dec 2024
- Last updated
- 28 Jan 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Wang X, Hu J, Cao G, Zhu X, Cui Y, Ji X, Li X, Yang R, Chen H, Xu H, Liu P, Li J, Li J, Hao C, Xing B, Shen L. Phase II Study of Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Perihilar Cholangiocarcinoma. Radiology. 2017 May;283(2):580-589. doi: 10.1148/radiol.2016160572. Epub 2016 Nov 7.
PubMed 27820684Franssen S, Holster JJ, Jolissaint JS, Nooijen LE, Cercek A, D'Angelica MI, Homs MYV, Wei AC, Balachandran VP, Drebin JA, Harding JJ, Kemeny NE, Kingham TP, Klumpen HJ, Mostert B, Swijnenburg RJ, Soares KC, Jarnagin WR, Groot Koerkamp B. Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2024 Jan;31(1):115-124. doi: 10.1245/s10434-023-14409-z. Epub 2023 Oct 9.
PubMed 37814188Franssen S, Soares KC, Jolissaint JS, Tsilimigras DI, Buettner S, Alexandrescu S, Marques H, Lamelas J, Aldrighetti L, Gamblin TC, Maithel SK, Pulitano C, Margonis GA, Weiss MJ, Bauer TW, Shen F, Poultsides GA, Marsh JW, Cercek A, Kemeny N, Kingham TP, D'Angelica M, Pawlik TM, Jarnagin WR, Koerkamp BG. Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma. JAMA Surg. 2022 Jul 1;157(7):590-596. doi: 10.1001/jamasurg.2022.1298.
PubMed 35544131Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
PubMed 32402160Hack SP, Verret W, Mulla S, Liu B, Wang Y, Macarulla T, Ren Z, El-Khoueiry AB, Zhu AX. IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer. Ther Adv Med Oncol. 2021 Jul 31;13:17588359211036544. doi: 10.1177/17588359211036544. eCollection 2021.
PubMed 34377158Hack SP, Zhu AX, Wang Y. Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities. Front Immunol. 2020 Nov 5;11:598877. doi: 10.3389/fimmu.2020.598877. eCollection 2020.
PubMed 33250900Maithel SK, Keilson JM, Cao HST, Rupji M, Mahipal A, Lin BS, Javle MM, Cleary SP, Akce M, Switchenko JM, Rocha FG. NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2023 Oct;30(11):6558-6566. doi: 10.1245/s10434-023-13809-5. Epub 2023 Jun 27.
PubMed 37368098Utuama O, Permuth JB, Dagne G, Sanchez-Anguiano A, Alman A, Kumar A, Denbo J, Kim R, Fleming JB, Anaya DA. Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Propensity Score Survival Analysis Supporting Use in Patients with High-Risk Disease. Ann Surg Oncol. 2021 Apr;28(4):1939-1949. doi: 10.1245/s10434-020-09478-3. Epub 2021 Jan 7.
PubMed 33415559Fruscione M, Pickens RC, Baker EH, Martinie JB, Iannitti DA, Hwang JJ, Vrochides D. Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review. Curr Probl Cancer. 2021 Feb;45(1):100614. doi: 10.1016/j.currproblcancer.2020.100614. Epub 2020 Jun 20.
PubMed 32622478Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437.
PubMed 36856617Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J; KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022 Feb 10;386(6):556-567. doi: 10.1056/NEJMoa2112651.
PubMed 35139274Janssen QP, O'Reilly EM, van Eijck CHJ, Groot Koerkamp B. Neoadjuvant Treatment in Patients With Resectable and Borderline Resectable Pancreatic Cancer. Front Oncol. 2020 Jan 31;10:41. doi: 10.3389/fonc.2020.00041. eCollection 2020.
PubMed 32083002Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr. Total Neoadjuvant Therapy: A Shifting Paradigm in Locally Advanced Rectal Cancer Management. Clin Colorectal Cancer. 2018 Mar;17(1):1-12. doi: 10.1016/j.clcc.2017.06.008. Epub 2017 Jun 27.
PubMed 28803718Charfare H, Limongelli S, Purushotham AD. Neoadjuvant chemotherapy in breast cancer. Br J Surg. 2005 Jan;92(1):14-23. doi: 10.1002/bjs.4840.
PubMed 15635596Burotto M, Wilkerson J, Stein WD, Bates SE, Fojo T. Adjuvant and neoadjuvant cancer therapies: A historical review and a rational approach to understand outcomes. Semin Oncol. 2019 Feb;46(1):83-99. doi: 10.1053/j.seminoncol.2019.01.002. Epub 2019 Jan 26.
PubMed 30738604
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Perioperative Treatment of High-risk Resectable Cholangiocarcinoma With Hepatic Arterial Infusion Chemotherapy (HAIC) Combined With Atezo/Bevacizumab: a Multicenter Phase II Study (NeoBrave CCA)
- ClinicalTrials.gov ID
- NCT06739252
- Acronym / sponsor ID
- Neobrave-CCA
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Difficulty of participants enrollment
- Enrolment
- 1 participants (actual)
- Lead sponsor
- Peking UniversityUniversity, hospital or other
- Study start
- 31 Dec 2024 (actual)
- Primary completion
- 22 Dec 2025 (actual)
- Study completion
- 22 Dec 2025 (actual)
- First posted
- 18 Dec 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Neobrave | Experimental | Combination Product: Gemcitabine Oxaliplatin and 5FUPerioperative treatment |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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:
- Blood routine examination:
- Biochemical examination:
- 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.
Key exclusion criteria (19 listed)
- Regional multiple lymph node metastases or fusion, retroperitoneal lymph node metastases;
- Peritoneal metastasis, distant metastasis;
- Previous systemic treatment, including but not limited to chemotherapy, targeted therapy, immunotherapy;
- Previous local treatment, including but not limited to HAIC, TACE, TARE, ablation, radiotherapy, etc.;
- Severe hepatic artery variation;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gemcitabine Oxaliplatin and 5FUThe 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. | Combination product | Neobrave |
Primary outcome
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%
8 secondary outcomes
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
ORR
Time frame: 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.
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
RFS
Time frame: 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
OS
Time frame: From date of treatment beginning until the date of death from any cause, assessed up to 100 months
Number of patients with treatment-related adverse events
Time frame: Through study completion, an average of once per 1 month.
Results and safety
The study was stopped early (reason given: Difficulty of participants enrollment). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2026.
- Background: PubMed 27820684Wang X, Hu J, Cao G, Zhu X, Cui Y, Ji X, Li X, Yang R, Chen H, Xu H, Liu P, Li J, Li J, Hao C, Xing B, Shen L. Phase II Study of Hepatic Arterial Infusion Chemotherapy with Oxaliplatin and 5-Fluorouracil for Advanced Perihilar Cholangiocarcinoma. Radiology. 2017 May;283(2):580-589. doi: 10.1148/radiol.2016160572. Epub 2016 Nov 7.
- Background: PubMed 37814188Franssen S, Holster JJ, Jolissaint JS, Nooijen LE, Cercek A, D'Angelica MI, Homs MYV, Wei AC, Balachandran VP, Drebin JA, Harding JJ, Kemeny NE, Kingham TP, Klumpen HJ, Mostert B, Swijnenburg RJ, Soares KC, Jarnagin WR, Groot Koerkamp B. Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2024 Jan;31(1):115-124. doi: 10.1245/s10434-023-14409-z. Epub 2023 Oct 9.
- Background: PubMed 35544131Franssen S, Soares KC, Jolissaint JS, Tsilimigras DI, Buettner S, Alexandrescu S, Marques H, Lamelas J, Aldrighetti L, Gamblin TC, Maithel SK, Pulitano C, Margonis GA, Weiss MJ, Bauer TW, Shen F, Poultsides GA, Marsh JW, Cercek A, Kemeny N, Kingham TP, D'Angelica M, Pawlik TM, Jarnagin WR, Koerkamp BG. Comparison of Hepatic Arterial Infusion Pump Chemotherapy vs Resection for Patients With Multifocal Intrahepatic Cholangiocarcinoma. JAMA Surg. 2022 Jul 1;157(7):590-596. doi: 10.1001/jamasurg.2022.1298.
- Background: PubMed 32402160Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, Li D, Verret W, Xu DZ, Hernandez S, Liu J, Huang C, Mulla S, Wang Y, Lim HY, Zhu AX, Cheng AL; IMbrave150 Investigators. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020 May 14;382(20):1894-1905. doi: 10.1056/NEJMoa1915745.
- Background: PubMed 34377158Hack SP, Verret W, Mulla S, Liu B, Wang Y, Macarulla T, Ren Z, El-Khoueiry AB, Zhu AX. IMbrave 151: a randomized phase II trial of atezolizumab combined with bevacizumab and chemotherapy in patients with advanced biliary tract cancer. Ther Adv Med Oncol. 2021 Jul 31;13:17588359211036544. doi: 10.1177/17588359211036544. eCollection 2021.
- Background: PubMed 33250900Hack SP, Zhu AX, Wang Y. Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities. Front Immunol. 2020 Nov 5;11:598877. doi: 10.3389/fimmu.2020.598877. eCollection 2020.
- Background: PubMed 37368098Maithel SK, Keilson JM, Cao HST, Rupji M, Mahipal A, Lin BS, Javle MM, Cleary SP, Akce M, Switchenko JM, Rocha FG. NEO-GAP: A Single-Arm, Phase II Feasibility Trial of Neoadjuvant Gemcitabine, Cisplatin, and Nab-Paclitaxel for Resectable, High-Risk Intrahepatic Cholangiocarcinoma. Ann Surg Oncol. 2023 Oct;30(11):6558-6566. doi: 10.1245/s10434-023-13809-5. Epub 2023 Jun 27.
- Background: PubMed 33415559Utuama O, Permuth JB, Dagne G, Sanchez-Anguiano A, Alman A, Kumar A, Denbo J, Kim R, Fleming JB, Anaya DA. Neoadjuvant Chemotherapy for Intrahepatic Cholangiocarcinoma: A Propensity Score Survival Analysis Supporting Use in Patients with High-Risk Disease. Ann Surg Oncol. 2021 Apr;28(4):1939-1949. doi: 10.1245/s10434-020-09478-3. Epub 2021 Jan 7.
- Background: PubMed 32622478Fruscione M, Pickens RC, Baker EH, Martinie JB, Iannitti DA, Hwang JJ, Vrochides D. Conversion therapy for intrahepatic cholangiocarcinoma and tumor downsizing to increase resection rates: A systematic review. Curr Probl Cancer. 2021 Feb;45(1):100614. doi: 10.1016/j.currproblcancer.2020.100614. Epub 2020 Jun 20.
- Background: PubMed 36856617Patel SP, Othus M, Chen Y, Wright GP Jr, Yost KJ, Hyngstrom JR, Hu-Lieskovan S, Lao CD, Fecher LA, Truong TG, Eisenstein JL, Chandra S, Sosman JA, Kendra KL, Wu RC, Devoe CE, Deutsch GB, Hegde A, Khalil M, Mangla A, Reese AM, Ross MI, Poklepovic AS, Phan GQ, Onitilo AA, Yasar DG, Powers BC, Doolittle GC, In GK, Kokot N, Gibney GT, Atkins MB, Shaheen M, Warneke JA, Ikeguchi A, Najera JE, Chmielowski B, Crompton JG, Floyd JD, Hsueh E, Margolin KA, Chow WA, Grossmann KF, Dietrich E, Prieto VG, Lowe MC, Buchbinder EI, Kirkwood JM, Korde L, Moon J, Sharon E, Sondak VK, Ribas A. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023 Mar 2;388(9):813-823. doi: 10.1056/NEJMoa2211437.
- Background: PubMed 35139274Schmid P, Cortes J, Dent R, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Untch M, Fasching PA, Cardoso F, Andersen J, Patt D, Danso M, Ferreira M, Mouret-Reynier MA, Im SA, Ahn JH, Gion M, Baron-Hay S, Boileau JF, Ding Y, Tryfonidis K, Aktan G, Karantza V, O'Shaughnessy J; KEYNOTE-522 Investigators. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N Engl J Med. 2022 Feb 10;386(6):556-567. doi: 10.1056/NEJMoa2112651.
- Background: PubMed 32083002Janssen QP, O'Reilly EM, van Eijck CHJ, Groot Koerkamp B. Neoadjuvant Treatment in Patients With Resectable and Borderline Resectable Pancreatic Cancer. Front Oncol. 2020 Jan 31;10:41. doi: 10.3389/fonc.2020.00041. eCollection 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Xiaodong Wang, M.D. study director
Peking University Cancer Hospital & Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Gemcitabine Oxaliplatin and 5FU in people with Intrahepatic Cholangiocarcinoma (Icc) and Perihilar Cholangiocarcinoma, run by Peking University at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Difficulty of participants enrollment). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06739252, which also lists 30 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2026.