A Phase 2 interventional study of Gemcitabine Oxaliplatin and 5FU in Intrahepatic Cholangiocarcinoma (Icc) and Perihilar Cholangiocarcinoma, sponsored by Peking University. Terminated at 1 site in China. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-01-28.
Sponsored by Peking University · Phase 2, Interventional, and Treatment
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.
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.
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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:
A. Hb≥90 g/L; B. ANC≥1.5×10\^9/L; C. PLT≥75×10\^9/L;
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) 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.
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.
MPR
the proportion of residual active tumor cells ≤50%
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
pCR
pathological complete response
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
objective response rate
Time frame: Evaluation of tumor burden based on RECIST 1.1 criteria through study completion, an average of once per 3 months.
DCR
disease control rate
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
recurrence-free survival
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
overall survival
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
Number of patients with AE, treatment-related AE (TRAE), serious adverse event (SAE) assessed by CTCAE v5.0.
Time frame: Through study completion, an average of once per 1 month.
Plan to share: No
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