Short-Course Radiotherapy Combined With mFOLFOX6, PD-1 Antibody and Cetuximab (for RAS/BRAF Wild-Type)/Bevacizumab (for RAS/BRAF Mutant) in High-Risk pMMR/MSS Rectal Adenocarcinoma: a Phase III Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 204
- 试验地点
- 1
- 主要终点
- 3 years DFS Rate
研究概览
简要总结
To explore the efficacy and safety of an intensified treatment regimen consisting of short-course radiotherapy followed by mFOLFOX6 chemotherapy combined with precise targeted therapy (based on RAS/BRAF status: cetuximab for wild-type, bevacizumab for mutant) and a PD-1 monoclonal antibody, compared with short-course radiotherapy followed by mFOLFOX6 chemotherapy alone, in high-risk locally advanced pMMR/MSS rectal adenocarcinoma through a prospective, randomized controlled phase III clinical study, providing high-level evidence-based medical evidence to establish a superior neoadjuvant treatment strategy for this population.
详细描述
Patients with locally advanced rectal cancer (LARC) who have high-risk factors, such as low rectal cancer, clinical stage T4b, positive mesorectal fascia (MRF), and positive extramural vascular invasion (EMVI), are at extremely high risk of distant metastasis. For these LARC patients with high-risk factors, the pathological complete response (PCR) rate with neoadjuvant chemotherapy alone is relatively low, ranging from 4.3% to 13.3%. Therefore, the use of a more potent comprehensive neoadjuvant treatment regimen, including concurrent chemoradiotherapy combined with targeted therapy and immunotherapy, may offer greater benefits to these patients. For patients with high-risk LARC, this study aims to explore whether the combination of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) can improve the pathological responce rate, and achieve better long-term survival benefits. The study will investigate the efficacy and safety of short-course radiotherapy, mFOLFOX6, PD-1 monoclonal antibody and cetuximab (for RAS/BRAF Wild-Type)/bevacizumab (for RAS/BRAF Mutant) for high-risk LARC.
Based on the above theoretical and clinical needs, we conducted a preliminary phase II exploratory study (the CRIT study). This study preliminarily validated the safety and excellent preliminary efficacy of the strategy of "short-course radiotherapy (SCRT) followed by mFOLFOX6 chemotherapy combined with RAS-guided targeted therapy and a PD-1 monoclonal antibody," achieving a pathological complete response (pCR) rate of 62.1% (66.7% in the RAS/BRAF wild-type subgroup and 57.1% in the RAS/BRAF mutant subgroup), which is much higher than historical controls, suggesting that this regimen has great clinical application value. Therefore, a phase III randomized controlled trial is being conducted.
Enrolled patients will be randomized into 2 groups with different treatment regimen. The control group will receive neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen. The experimental group will receive neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy (combined with targeted and immune therapy in the experimental group), patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy (combined with PD-1 monoclonal antibody and targeted drugs in the experimental group). Bevacizumab is not used in the last cycle with RAS/BRAF mutations. Surgery is performed 8-10 weeks after the completion of SCRT. If pelvic MRI indicates clinical complete response (CCR) and N0, or T1N0M0, local excision (LE) will be performed. Otherwise, total mesorectal excision (TME) will be performed. The decision regarding adjuvant chemotherapy after surgery will be made by the attending physician.
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
- None
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
- •Before conducting procedures related to the research protocol but not part of routine care, written informed consent, voluntarily signed and dated by the subject, must be obtained in accordance with regulations and institutional guidelines.
- •Age 18-75 years.
- •Histologically or cytologically confirmed pMMR/MSS rectal adenocarcinoma; all other histological types are excluded.
- •Distance from the lower margin of the rectal tumor to the anal verge ≤10 cm.
- •Clinical staging with high-risk factors, including cT3Nx, EMVI(+), or cT4, ±MRF(+), ±EMVI(+).
- •No evidence of distant metastasis before treatment.
- •No prior anti-cancer treatment (radiotherapy, chemotherapy, targeted therapy, or immunotherapy).
- •ECOG performance status of 0-
- •Peripheral blood counts and liver and kidney function within the following allowable ranges (tested within 15 days before the start of treatment):
- •White blood cells (WBC) ≥3.0×10^9/L or absolute neutrophil count (ANC) ≥1.5×10^9/L;
- •Hemoglobin (HGB) ≥80 g/L; ③Platelets (PLT) ≥100×10^9/L; ④Liver transaminases (AST/ALT) <3.0 times the upper limit of the normal range; ⑤Total bilirubin (TBIL) <1.5 times the upper limit of the normal range; ⑥Creatinine (CREAT) <1.5 times the upper limit of the normal range.
- •No history of other malignancies; not pregnant or breastfeeding, and effective contraception must be used during the study period and for 6 months after the last dose.
排除标准
- •Patients with a history of severe drug allergies (including allergies to platinum agents, 5-FU, LV, and 5-HT3 receptor antagonists);
- •Patients who have participated in or are currently participating in other clinical trials within 4 weeks prior to enrollment;
- •A history of having received anti-PD-1, PD-L1, PD-L2, CTLA-4, or any other specific T-cell costimulatory or checkpoint pathway-targeted therapy;
- •Severe electrolyte abnormalities;
- •Presence of gastrointestinal diseases, such as active ulcers in the stomach or duodenum, ulcerative colitis, or tumors with active bleeding that have not been resected; or other conditions that may lead to gastrointestinal bleeding or perforation; or gastrointestinal perforation that has not healed after surgical treatment;
- •History of arterial thrombosis or deep vein thrombosis within 6 months; history of bleeding or evidence of bleeding tendency within 2 months; or patients receiving high-dose anticoagulation therapy;
- •Pregnant or breastfeeding women, or women of childbearing potential with a positive pregnancy test before the first dose; or female participants and their partners who are unwilling to strictly practice contraception during the study period;
- •Presence of other active malignancies (except for malignancies that have been treated with curative intent and have been disease-free for more than 3 years, or in situ cancers that can be cured with adequate treatment);
- •Presence of severe ECG abnormalities or active coronary artery disease, severe/unstable angina, newly diagnosed angina or myocardial infarction within 12 months prior to study entry, or New York Heart Association (NYHA) Class II or higher congestive heart failure;
- •Patients with active infections (infections causing fever above 38°C);
- •Patients with uncontrolled hypercalcemia, hypertension, or diabetes;
- •Patients with severe pulmonary diseases (interstitial pneumonia, pulmonary fibrosis, severe emphysema, etc.);
- •Patients with psychiatric disorders that may affect clinical treatment or a history of central nervous system diseases;
- •Patients with severe complications (bowel obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders, etc.);
- •Presence of any CTCAE Grade 2 or higher toxicity caused by previous treatments that has not resolved (excluding anemia, alopecia, and skin pigmentation);
- •Any unstable medical condition that may affect patient safety and compliance with the study;
- •Patients deemed by the investigator as unsuitable for participation in this clinical trial.
研究组 & 干预措施
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: PD-1 monoclonal antibody (Drug)
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: mFOLFOX6 regimen (Drug)
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Surgical resection (Procedure)
SCRT + mFOLFOX6
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen. After completing the first cycle of mFOLFOX6 chemotherapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy. Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Short-Course Radiotherapy (Radiation)
SCRT + mFOLFOX6
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen. After completing the first cycle of mFOLFOX6 chemotherapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy. Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: mFOLFOX6 regimen (Drug)
SCRT + mFOLFOX6
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen. After completing the first cycle of mFOLFOX6 chemotherapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy. Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Surgical resection (Procedure)
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Short-Course Radiotherapy (Radiation)
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Cetuximab (Drug)
SCRT + mFOLFOX6 + PD-1 Antibody + Targeted Therapy
The neoadjuvant treatment phase includes short-course radiotherapy (SCRT) combined with four cycles of the mFOLFOX6 regimen, PD-1 monoclonal antibody, and molecularly targeted drugs (selected based on RAS status; patients with RAS/BRAF wild-type receive cetuximab, while those with RAS/BRAF mutations receive bevacizumab). After completing the first cycle of mFOLFOX6 chemotherapy combined with targeted and immune therapy, patients undergo SCRT at a dose of 5Gy × 5 fractions. At least 7 days after the completion of radiotherapy, patients continue with three additional cycles of mFOLFOX6 chemotherapy combined with PD-1 monoclonal antibody and targeted drugs (bevacizumab is not used in the last cycle of the bevacizumab group). Surgery is performed 8-10 weeks after the completion of SCRT.
干预措施: Bevacizumab (Drug)
结局指标
主要结局
3 years DFS Rate
时间窗: 3 years
3 years Disease Free Survival Rate
次要结局
- pCR rate(1 year)
- 3 years OS rate(3 years)
- 3 years DMFS Rate(3 years)
- 3 years RFS Rate(3 years)
- R0 resection rate(1 year)
- CR rate(1 year)
- Toxicities Associated with Neoadjuvant Therapy(1 year)
研究者
Jun Huang
Professor
Sixth Affiliated Hospital, Sun Yat-sen University