NCT06739252

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

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

• Status: Terminated
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 1 (actual)
• Sponsor: Peking University · Academic / Other
• Sex: All
• Age: 18 Years – 80 Years
• Healthy volunteers: Not accepted

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. 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.

Conditions

• Intrahepatic Cholangiocarcinoma (Icc)
• Perihilar Cholangiocarcinoma

Interventions

Type	Name	Description
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.

Timeline

• Start date: 2024-12-31
• Primary completion: 2025-12-22
• Completion: 2025-12-22
• First posted: 2024-12-18
• Last updated: 2026-01-28

Locations

1 site across 1 country: China