A National Multicenter, Randomized, Placebo-Controlled Phase III Clinical Trial Comparing Long-Course Versus Short-Course Radiotherapy Followed by Immunotherapy Combined With Total Neoadjuvant Therapy (TNT) to Long-Course Radiotherapy Followed by TNT in Locally Advanced Rectal Cancer
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 444
- 试验地点
- 1
- 主要终点
- complete response (CR) rate
研究概览
简要总结
This study is a national multicenter, prospective randomized, placebo- controlled Phase III clinical trial designed to investigate the potential therapeutic benefit of immunotherapy combined with total neoadjuvant therapy (TNT) and to compare the efficacy of different radiotherapy modalities followed by immunotherapy.
详细描述
This study is a national multicenter, prospective randomized, placebo- controlled phase III clinical trial, with the following objectives: 1. For patients with LARC, to determine whether the efficacy of TNT combined with immunotherapy is superior to that of the treatment mode of LCRT followed by TNT; 2. To compare the differences in efficacy and toxicity between long-course radiotherapy and short-course radiotherapy under the mode of TNT combined with immunotherapy.
For precision management of patients with cCR post-neoadjuvant therapy, dynamic MRD monitoring was implemented, including baseline and follow-up testing for patients having tumors ≤5 cm from the anal verge.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients or their family members agree to participate in the study and sign the informed consent form;
- •Age 18-75 years, male or female;
- •Histologically confirmed Locally Advanced rectal adenocarcinoma;
- •Immunohistochemistry and/or genetic testing confirmed pMMR/MSS;
- •inferior margin ≤ 10 cm from the anal verge;
- •ECOG performance status score is 0-1;
- •Untreated with anti-tumor therapy for rectal cancer, including radiotherapy, chemotherapy, surgery, etc;
- •There was no operative contraindication;
- •Laboratory tests were required to meet the following requirements: white blood cell (WBC) ≥ 4×109/L; Absolute neutrophil count (ANC) ≥ 1.5×109/L; Platelet count ≥ 100×109/L; Hemoglobin ≥90 g/L; Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN); Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; Serum creatinine ≤1.5 times the upper limit of normal value or creatinine clearance rate ≥50 mL/min; International normalized ratio (INR) ≤ 1.5 × ULN; Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;
- •Urinary protein < 2+ or 24-hour urinary protein excretion < 1 g at baseline.
排除标准
- •Patients with MSI-H/dMMR LARC；
- •Subjects who have previously received any form of immunotherapy, including but not limited to immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, or any other treatment targeting tumor immunomodulatory mechanisms;
- •Presence of any concurrent disease, condition (including laboratory abnormality), history of substance abuse, or current evidence thereof, which, in the judgment of the Investigator, may compromise subject safety, interfere with the process of obtaining informed consent, affect subject compliance, or confound the safety assessment of the investigational product(s).
研究组 & 干预措施
Group A: SCRT + iTNT
Group A: SCRT + iTNT
Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days).
Immunotherapy (HLX10): 300 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Short-course radiotherapy (Radiation)
Group B: LCRT + iTNT
Group B: LCRT + iTNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
Immunotherapy (HLX10): 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Capecitabine (Drug)
Group C: LCRT + TNT
Group C: LCRT + TNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
TNT Chemotherapy (CAPEOX regimen) with immunotherapy placebo:
HLX10 placebo: 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: TME surgery (Procedure)
Group C: LCRT + TNT
Group C: LCRT + TNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
TNT Chemotherapy (CAPEOX regimen) with immunotherapy placebo:
HLX10 placebo: 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Capecitabine (Drug)
Group A: SCRT + iTNT
Group A: SCRT + iTNT
Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days).
Immunotherapy (HLX10): 300 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Oxaliplatin (Drug)
Group C: LCRT + TNT
Group C: LCRT + TNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
TNT Chemotherapy (CAPEOX regimen) with immunotherapy placebo:
HLX10 placebo: 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: HLX10 placebo (Drug)
Group A: SCRT + iTNT
Group A: SCRT + iTNT
Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days).
Immunotherapy (HLX10): 300 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: TME surgery (Procedure)
Group B: LCRT + iTNT
Group B: LCRT + iTNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
Immunotherapy (HLX10): 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Long-course radiotherapy (Radiation)
Group A: SCRT + iTNT
Group A: SCRT + iTNT
Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days).
Immunotherapy (HLX10): 300 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Capecitabine (Drug)
Group B: LCRT + iTNT
Group B: LCRT + iTNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
Immunotherapy (HLX10): 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: TME surgery (Procedure)
Group C: LCRT + TNT
Group C: LCRT + TNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
TNT Chemotherapy (CAPEOX regimen) with immunotherapy placebo:
HLX10 placebo: 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Long-course radiotherapy (Radiation)
Group B: LCRT + iTNT
Group B: LCRT + iTNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
Immunotherapy (HLX10): 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Oxaliplatin (Drug)
Group C: LCRT + TNT
Group C: LCRT + TNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
TNT Chemotherapy (CAPEOX regimen) with immunotherapy placebo:
HLX10 placebo: 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: Oxaliplatin (Drug)
Group A: SCRT + iTNT
Group A: SCRT + iTNT
Radiotherapy (SCRT): Total dose 25 Gy delivered in 5 fractions (5 Gy per fraction, once daily over 5 consecutive days).
Immunotherapy (HLX10): 300 mg via intravenous infusion every 3 weeks (q3w) for 6 cycles, initiated 1 week after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: HLX10 (Drug)
Group B: LCRT + iTNT
Group B: LCRT + iTNT
Radiotherapy with Concurrent Chemotherapy (LCRT):
Total dose 50.4 Gy delivered in 28 fractions (1.8 Gy per fraction, once daily, 5 days per week).
Concurrent Capecitabine: 825 mg/m² orally twice daily, 5 days per week (administered on radiotherapy days).
Immunotherapy (HLX10): 300 mg IV infusion q3w for 6 cycles, initiated 2 weeks after radiotherapy completion.
Chemotherapy (CAPEOX regimen):
Oxaliplatin: 130 mg/m² IV infusion over 120 minutes on Day 1.
Capecitabine: 1000 mg/m² orally twice daily (morning and evening, 30 minutes after meals) on Days 1-14.
Cycle duration: 3 weeks per cycle; initiated 2 weeks post-radiotherapy; total of 6 cycles during the neoadjuvant phase.
Then followed by a total mesorectal excision(TME) or Watch & Wait strategy for clinical complete remission voluntary patients.
干预措施: HLX10 (Drug)
结局指标
主要结局
complete response (CR) rate
时间窗: an expected average of 12 months
Defined as pathological complete response (pCR) + Clinical complete response (cCR)
次要结局
- Overall Survival(an expected average of 5 years)
- Adverse events (AEs) were graded according to the NCI CTCAE version 5·0(an expected average of 1.5 years)
- 3-year event-Free Survival(an expected average of 3 years)
研究者
Tao Zhang
MD
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology